Main Topic:
In this episode of Oncology Unscripted, Dr John Marshall reflects on a practice-changing cholangiocarcinoma study from China and what it reveals about the rapid evolution of cancer research worldwide. As novel therapies transform care and China expands its investment in science while the US devests, he asks whether we can keep pace and the impacts of the global evolution of in oncology.

Interview:  
Watch now as Dr John Marshall sits down with Dr Louis Weiner, director of Georgetown University’s Lombardi Cancer Center, for a candid conversation about leadership, scientific change, and the future of oncology. Reflecting on innovation, institutional transition, and the pressures reshaping cancer research, they explore what it means to evolve as a leader and honoring the work and the people.

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John Marshall, MD:
Hello, everybody, from San Francisco, California. My name is Dr. John Marshall, and you are on—maybe unwisely—Oncology Unscripted. But thanks for joining me. I love this meeting, but let's first talk about the news of 2026.

Top of the line is: we're out to get new countries. Now, I'm sort of running for mayor of Havana. I don't know if it's important that I, in fact, speak Spanish—because I don't. I speak a little bit of French. My Spanish is terrible. But maybe it won't matter, because I am who I am, and they're looking for just my kind of person to go be mayor of Havana. So, if you see that and you get a chance to vote, vote me in. I love the whole country of Cuba—it's beautiful.

Second, in today's newspaper—I couldn't believe it—this guy named Dr. Oz, you know him, he's an actual cardiologist, believe it or not. Then he became the talk show host. And then, for some reason, he's the head of CMS at this point—one of the head overseers of healthcare here in the country. And he said his position was that alcohol is good. This couldn’t have made me happier. This couldn’t have been a better holiday present, because I'm a big alcohol fan myself, and now I can feel less guilty about it. His rationale is that if you drink more, you'll be with people more, you'll be more relaxed, and the camaraderie will pay off in terms of lessening your anxiety and stress—and the world will be a happier place.

So, don’t be smart. We don't want people in our country to be intelligent or educated. Drink more. Be less educated. You'll be happier in the long run. That's the official position of our government today.

Probably the most important new news from a healthcare perspective is that the House approved an extension on the Affordable Care Act. This has been an incredible threat and uncertainty for so many of our patients. The people who depend on that health insurance could never afford cancer care without it. Having the extension of the Affordable Care Act—for them—talk about lowering your stress. Maybe better than alcohol is actually being insured.

I don’t know if you go to many meetings out there, but this one is called GI ASCO. It's always in San Francisco. It's always in this building that I'm standing in now. I have perfect attendance. I’ve been to every one since they started. You should get a special ribbon for that. I think there’s probably one down there for that.

They are a little bit more environmentally conscious—no plastic covering to this. Just a piece of paper. Totally recyclable old name badge. Way to go, ASCO, on that.

Do you go to meetings or don’t you? I come to this one for a very, very important reason. I come to this one for the people. It’s a small meeting. It’s just the GI gang, both from the industry side and the academic side. It’s a very heavy global presence that comes. I know almost everybody here, and there are only like 3,000 people here. There’s time to stop and say hello to almost everybody you know—give them a hug, share a little COVID, maybe flu, with each other—but then know that you are connected again. And this is something Zoom doesn’t do. This is something you can’t check on—somebody’s kids—over a meeting. But that’s one of the main reasons I come.

I love these people. These are people that share in our values and our motivation to try and cure cancer. We all take care of the group of cancers—GI cancers—which are the most common, most fatal cancers on our planet. We are inspired to do this. We know it’s a steep climb, and we do it together. I’m so very pleased to be a part of this community, and it’s the main reason I come.

Main reason—people. Second reason—pipelines. There’s a lot of data out there, and there are a lot of companies here that finally have new products for GI cancers. We’ll talk a little bit about that in more specific detail, but if you just look at the number of groups that are here—the number of people who’ve got innovative, new approaches—whether it’s novel immunotherapy, targeted agents, combinations of those, targeted antibodies that are delivering toxic payloads—we’re seeing waterfall plots that we haven’t seen in decades.

So, response rates, survivals, progression-free survivals that really compare favorably to our traditional chemotherapy approaches. We are on the cusp of a true revolution in the world of GI cancer.

And, surprisingly, one more—led by the world of pancreatic cancer. So, let’s talk a little bit about precision in GI oncology. The biggest breakthroughs that we are seeing at this meeting have to do with RAS targeting.

There are a bunch of RAS drugs out there now. There are some that are more out in front than others. There are some that are degraders that break down the RAS. There are some that block pan-RAS, so they hit a bunch of RAS targets. There are some that are very specific for one particular kind of RAS mutation—and they’re working.

Now, they’re not curing everybody. But we’re seeing great waterfall plots, even with single agents, in a disease that we haven’t cracked in a long, long time—and that is pancreatic cancer.

So, we are all incredibly optimistic about what we are seeing. We are anticipating approvals this year for some—maybe one or more—of these agents. We’re excited about the possibility of combining these RAS-targeted agents with things like immunotherapy or others. We are already starting to try and think about: is the pan-RAS better than an isolated targeted RAS? What are the toxicities? How are we going to manage it? Because we’re fully expecting these drugs to get approval and to get rapidly incorporated into our day-to-day management.

First, pancreas cancer. We’re seeing it in biliary cancers. We’re seeing it in stomach cancers. Where we’re not seeing it just yet is in colorectal cancer. And I would’ve predicted a long time ago that colon was going to be the easiest nut to crack. And yet, we’ve made progress. But in fact, what we’re going to see now—biliary, hepatocellular, pancreas cancer, stomach cancers—we’re going to see a lot of evolution over the next several years.

A good friend, and really a fabulous speaker, Dr. Andrew Ko from here in San Francisco—UCSF—was the discussant just an hour ago in this building, where he did a great job of setting the stage of both the excitement for the future, but also a healthy respect for what we are going to need to understand to march forward quickly but effectively for all of those patients we’re sitting across the exam room from—that need our help.

So, precision medicine is finally making its way to GI cancers—led by the RAS wave that we are seeing. So, stay tuned. You’re going to have new drugs out there. There’s going to be competition. A lot of people talking about it.

As we talked a lot about pipelines and the new drugs that were coming out, one of the common questions we get is: what's missing? What have we not been studying well enough? And I have a pretty consistent answer—and that is the microbiome.

We don’t understand the impact of those bacteria on us, on our health, on the effectiveness of drugs, etc. And until we really start digging into that science, I don’t think we’ll see that next wave of innovation. So, the answer is microbiome.

So, why do I come to GI ASCO every year? Well, you already know the number one reason—that’s people. I love them. They’re my family, and I love to catch up with them just like you do with your family around the holidays. This is my family visit for the holidays.

Second—pipelines. Understanding what’s out there today, what’s coming, and how we are going to cure patients with GI cancer. It’s going to be through these pipelines.

And then last—the latest data. And that’s around precision medicine. We are about to embark on a wave of therapies that target RAS, and you’re going to start to see cancer shrink as these new drugs come into play.

Our job, then, over the next couple of years, is to take this new understanding, this new ability to control precision medicine, and apply it to our patients—to cure more patients with GI cancers.

Thanks for joining me from San Francisco. Totally unscripted. John Marshall, Oncology Unscripted.

Microbes, Mutagens, and Mortality: CRC in a Younger Generation

John Marshall, MD: John Marshall Oncology Unscripted. A lot of good data coming out on all sorts of things. You know, I'm a colon cancer guy, so I really want to talk about two clinical trials in the colon cancer space.

One was a paper in Nature—it's actually a few months old—but, you know, I keep seeing all these young people with colon cancer, and I keep thinking: it's the microbiome. It's gotta be. And this paper actually found a version of E. coli that produces a toxin that, if you're exposed to it at a young age—say 10, 11, 12 years old—it dramatically increases your risk of getting colon cancer later.

Now, I sort of didn’t think of it as one bacterium causing one toxin causing a toxicity. I always thought it was more of a gamish—what swamp do you have? What's the nature of your rainforest, your bacteria in the colon, that's causing it? But what I'm excited about is that we're continuing to see, week after week, month after month, new data that supports a better understanding of the microbiome—one that we hope will translate into not just identifying people who are at risk for early-onset colon cancer, but, as you know, other diseases as well.

And as a related story—this comes out of Cancer Investigation—patients who are taking GLP-1 drugs had lower colon cancer death rates. So basically, they looked at colon cancer patients, and the strongest signal was in those who were obese. But if you were on a GLP-1 versus not on a GLP-1, your survival was much better on one.

So, again, how do GLP-1 drugs work? Uh, we don’t really know. But I think probably our interface with our microbiome is one of the ways they have an effect. And so it kind of feeds back to this: the healthier we can get our innards, our inner colony of bacteria—I really think it's where our soul resides—the healthier we can get that, the better our outcomes will be. Again, not just for colon cancer, but for other diseases as well.

Just some high-level stuff that you probably didn’t see in your scanning of the week’s journals. 

John Marshall, Oncology Unscripted.

Rewriting the Gut Story: Diet, Microbes, and Modern Disease—Interview with Dr Robynne Chutkan

John Marshall, MD: Hey, everybody out there? John Marshall for Oncology Unscripted. I promised you my new office. It's not that great, is it? When you get old, they take you from the big office down to the small one, but I do have a view. You see, I've got the view out there—a rooftop. I can see all the air conditioners and whether they're working or not. The helipad’s just right over there. So that's gonna get exciting sometimes. I got a halo. You see my little halo in the window there? But I am sort of angelic, as you know. 

But really the reason we are gathered here today is to talk about maybe my favorite topic—so much my favorite topic that my family is tired of hearing about it—and that is our microbiome. And I honestly feel like it is where our heart and our soul reside. And I, as a good Presbyterian, I actually think this is where the soul must live.

And so I am lucky enough to have, as a friend and a colleague, Dr. Robynne Chutkan, who is joining us today. She is really an expert in the microbiome, as much as any of us is an expert right now. She's leading the way in understanding this companion that we have through life, of these bacteria and other organisms that we grow and live with all our lives. And so she's nice enough to join us today to help us oncology people get a better understanding of the microbiome and its impact on our health.

So, Robynne, we have spent decades as partners in crime, and I'm so grateful to get reconnected to you. So, give the crowd a little bit of your background, and how the heck did you get interested in the microbiome?

Robynne Chutkan, MD: Well, first of all, I couldn't ask for a more wonderful kindred spirit in my obsession with the microbiome and stool and all of it. So, I knew that we were connected through more than just Georgetown and Lombardi, so thank you for that.

I am a butt doctor amongst all these very distinguished oncologists. And thank you so much for the invitation to speak at the Ruesch Symposium a few weeks ago. One of the things I really saw there was how siloed we are. I was sitting there through the talks thinking, "I went to medical school, I was chief resident—I had no idea what you guys were talking about with the pharmaceuticals." And I think some of the oncologists felt similarly when I was talking about fecal Faecalibacterium prausnitzii and short-chain fatty acids and butyric acid.

So, we're very siloed. But one thing for sure—and I appreciate your comments about the soul and so on—because when you look down at where your GI tract is located, it is smack dab in the center of your body. So there's really no question: it’s sort of the engine for everything, and all the organs—your brain, your heart, your lungs, your immune system—rely on the nutrients extracted there and the processes to function properly.

John Marshall, MD: Yeah. But you're like this highly trained gastroenterologist, and you decided—I can't remember how long ago—to sort of say, you know, this isn't really the way I think people get better. So maybe talk a little bit about that.

Robynne Chutkan, MD: Sure. Yeah. Because it was very personal. I came to Georgetown in 1997, joined the faculty as an IBD gastroenterologist, primarily focusing on IBD, which had been the focus of my fellowship at Mount Sinai. And very quickly, I realized that nobody was talking about food—including me.

Patients would come in and tell me about their diet, and I was like, “Okay, that all sounds great. What are you taking?” And this was pre-biologics—this was the late ’90s. I remember actually going to that meeting in Amsterdam for the International Organization for IBD when they were presenting the data on cA2, which became infliximab. It didn’t even have a name at the time. And so I was as skeptical as the next about the role of diet. But something happened that really stopped me in my tracks. 

This was a patient—she actually worked at the hospital, a young woman—and she had relocated to New Jersey and came back after a couple of years. She worked in the radiology department, and I saw her, and I said to her, “So, what are you on? You look great.” And she said, “I’m on nothing.” And I gave my usual spiel of, “Oh, that’s like driving a car with no insurance. That’s dangerous, you know, if you have a flare-up.” And so I thought, okay, she’s feeling right, sure. Well, let me take a look at her colon.

I did her colonoscopy, and all—she had Crohn’s colitis—all the previous cobblestoning and ulceration—gone. And I was like, “You—I cannot believe this. You must be taking something. What are you doing?” And she told me about a diet she was on called the Specific Carbohydrate Diet.

John Marshall, MD: I thought it was like... because it was the Newark Costco—was just a better Costco. No, it’s a diet, actually. She was following...

Robynne Chutkan, MD: Yeah. But I'll tell you, I was really skeptical. And I wasn’t just skeptical—I was afraid for her. Because the idea that you could treat inflammatory bowel disease without medication just was so counter to what I’d been taught. I’d been taught by Dr. Janowitz, who was taught by Dr. Crohn, and came from this sort of IBD world. But I started really looking at this, and what I found—John, I'm sure it’s the same in the oncology world—is that patients were sort of in this “don’t ask, don’t tell.”

So we did a survey in my IBD clinic, and we found that 70% of the patients were using some sort of complementary or alternative technique. Now, this is 2025—it’s very different—but in 1997–1998, this was unusual. And a lot of those modalities were just things like massage, or some of them were doing herbal things. But patients were definitely looking for things. And so I started putting patients on these different diets and so on.

We ended up coming up with a modified version of the Specific Carbohydrate Diet, which is sort of a low-carb first cousin of Paleo, but adding more fiber because it seemed pretty clear that fiber was important for gut health. And we presented that data in 2014 at Digestive Disease Week, and we showed that we actually had a 79% remission rate using this diet. Now, this is 2014, so biologics had been around.

John Marshall, MD: Did anybody believe you?

Robynne Chutkan, MD: The craziest thing is that all my GI colleagues were in the exhibit hall looking at the scopes. A few foreigners—some Europeans, some folks from Asia—were interested. But there was zero interest. Crickets. It's so funny that you asked that. So it was a small study—it was 12 patients: 9 with ulcerative colitis and 3 with Crohn’s. But what we showed—not just that they felt better—we actually had endoscopic images of mucosal healing, which, as you know, is a gold standard for remission—not just “patients feel better.” And the vast majority of patients were able to get off medication completely or reduce it.

One of the things we found when we dug a little deeper with that data is that there was a clear correlation with the amount of fiber. So, the patients who just said, “Okay, I’m gonna stop eating the processed breads and pastries and cheese, and I’m gonna have bacon and eggs for breakfast, chicken for lunch, steak for dinner with two broccoli florets”—those patients really didn’t have the same result. So, there was a clear correlation with the amount of fiber people were consuming.

John Marshall, MD: Connect the dots for me. So, it is a diet modification that's changing health, and we're talking microbiome. So, I keep thinking about, you know, what is it that's actually—take us to pathways of what's that doing to our microbiome in order to sort of rebalance? I think of it as soil. I often use a rainforest, not just a pine forest.

Robynne Chutkan, MD: Absolutely—terrain. Love the—yes, the terrain. That’s exactly right. And so fiber really seems to be key. I always like to remind people it’s less about eliminating and it’s more about adding. You can overcome a hot dog or a piece of cake if you are eating enough fiber. And by fiber, I don’t mean—I always have this as a prop—this granola bar that’s been in my drawer for 10 years. Like, I don’t mean this. I should have my apple prop. But unprocessed plant fiber. Because what that does—it’s poorly digestible, indigestible fiber—the kind that gives you gas—because it’s supposed to, because it’s not there to feed you, it’s there to feed your gut microbes.

That fiber is fermented by gut bacteria in our colon by organisms like Faecalibacterium prausnitzii—ferment it, turn it into short-chain fatty acids. And short-chain fatty acids don’t just keep the lining of the gut healthy. They help to modulate the immune system to sort of keep it at that Goldilocks—not too high, not too low—level. And so, really critically important.

You can’t just take a short-chain fatty acid supplement. It doesn’t really work that way. These compounds are very labile. And so there is this direct line between fiber consumption, levels of short-chain fatty acids, and outcome.

And we saw the same thing during COVID. We saw this UMass study that looked at microbial analysis, and they found that the composition of the gut microbiome—specifically the levels of Faecalibacterium prausnitzii—were very positively associated with better outcomes with COVID, and very predictive—92% accuracy.

And what’s so interesting, John, is some of the same organisms that they found were inversely correlated with outcomes—so, Enterococcus faecalis. They saw high levels of Enterococcus faecalis were associated with poor outcomes. We see high levels of Enterococcus faecalis in the colon cancer microbiome. So, we're seeing that signature.

John Marshall, MD: So, okay. So, you've got diet affecting the rainforest or the terrain, as you say. You've got now a—I don’t know what the right words are—but a healthier balance or the right partners to go through life with. That then leads to health. So, in your case, IBD. In most of our audience's cases, you know, it’s immune responsiveness to immune therapies, to young people getting colon cancers, to, you know, primaries responding differently than metastases, for example.

So, can you sort of hypothesize connecting those dots?

Robynne Chutkan, MD: Absolutely. And I think one of the most profound ones is when we think about weight. So, we know that we can give two people the identical meal and they will extract a different amount of energy and calories from that, based on microbial composition.

Microbes can change a palate, they can change the metabolism of the foods, they can change the transit of the food through the gut. That can determine what’s absorbed. So, it is less about the meal in some ways—I mean, the meal is still important, don’t get me wrong—but your composition of microbes...

And again, you can’t just go borrow some Faecalibacterium prausnitzii from your plant-eating friend because they only stick around about half an hour or so.

So, one of the things that is very frustrating—and I’m sure you find the same thing, ’cause you talk about the CVS aisle that’s gonna fix all of this—is trying to explain to people: it’s not just some microbes; it’s the environment in which those microbes grow. And we all have plenty of healthy microbes in our gut—if we feed them correctly—that are gonna proliferate and really sort of take root, reproduce, and create shifts.

That’s much more effective than taking a store-bought probiotic. The analogy is: you take a cheetah from the plains—the Serengeti, wherever cheetahs live—and I put it in my backyard here near Rock Creek, and I feed the cheetah Cheetos... the cheetah is not gonna do very well. So, it’s not just the microbes—it’s really the environment. And you have to create that environment. And that environment seems to be a high-fiber environment.

We have data from the American Gut Project published in 2019—10,000 people from over 40 countries asking that question: what is the most important factor for a healthy microbiome? And the answer seemed to be the amount of plant diversity in the diet, with this magic number of 30. So again, it wasn’t being vegan or even vegetarian—it’s about eating more plant fiber.

John Marshall, MD: Since I first heard that magic number—30—from you just a couple of weeks ago, I’ve been counting through the week, and I’m actually pretty good. I was already pretty good, but I’m pretty close to that on most weeks.

Robynne Chutkan, MD: Fantastic.

John Marshall, MD: So, you gave me a target, and I’ve even started to share that...

Robynne Chutkan, MD: Oh, I love that.

John Marshall, MD: ...with other people out there. So I’m grateful.

John Marshall, MD: I scour the literature for papers on this subject, and mostly it's the cancer literature I'm looking for. And what I am seeing is increasingly the impact you and others like you are having on science. What was kind of fringy when you first started—to be fair—you've matured this into now being able to start to measure it and to start to be able to influence it for cancer prevention. I've seen literature around CNS disease and dementia, of course the connection to heart disease, in your world of IBD, etc. If you could wave a wand, what would you want to be able to do? What would you want to be able to measure or assess to say: you've got a good microbiome, and here's how you'll fix yours?

Robynne Chutkan, MD: Yeah, I mean, it sounds a little bit counterintuitive, but it's almost like we have to get away from the science a little bit. Because what I find is—the science—we're in this sort of retailization of medicine. It's about selling a product, whether that is a pharmaceutical product or a probiotic at CVS. And people have this idea that if I just buy the right product, I’m gonna be fine. So it really is this idea of: what sort of platform of health and wellness are we encouraging people to build?

John Marshall, MD: Well, I guess what I'm after is: is there a Chem 20 for the microbiome?

Robynne Chutkan, MD: Okay.

John Marshall, MD: Right? Uh, so how do I measure it?

Robynne Chutkan, MD: Right now—no. And let’s remember too, that after the billions of dollars and the decades spent on the Human Genome Project—how many genetic diseases did we cure? Right? So, just like the genes are just a suggestion, the microbiome isn’t magic—it’s important. We have large data sets now that show that early antibiotic use is a major risk factor for Crohn’s disease. So, I think it’s—yes—looking at a 30-year-old and what are they doing. But I think it’s really important to say: Was this person vaginally born or C-section? Were they breastfed? How many antibiotics did they get in early life? Because I think this stuff is developing decades back.

John Marshall, MD: I’ve observed that I think there are a lot of only children with early-onset colon cancer. I wonder if there is some sort of helicopter parent phenomenon.

Robynne Chutkan, MD: Oh no—that’s mine.

John Marshall, MD: We don’t have enough time to cover all of this, but I want you to talk a little bit about ultra-processed foods and what that means. But I also want you to prompt me, because in an hour I have a meeting with the dean of the medical school on another topic. But, you know, when we went to medical school, there was maybe two hours spent on microbiome. We learned it, we got the test right, and then we forgot it. Right? So, what should our curriculum be? 

Talk a little bit about ultra-processed food, and then sort of give us a quick version of—if you were in charge of the curriculum right over there—what you’d do with that curriculum?

Robynne Chutkan, MD: Wonderful. So, ultra-processed foods—the NOVA classification—it’s not an acronym, it’s actually Nova, developed by Dr. Monteiro and colleagues in Brazil. Four groups. One is essentially unprocessed or minimally processed foods—so fruits, vegetables, meat, eggs, etc. Two is processed ingredients—so that’s things like oils, butter, things like that. So, group three of processed foods is sort of taking processed ingredients and adding them to an unprocessed food. Okay. But ultra-processed foods are bioengineered ingredients. So, when you start to see—I mean, the good rule of thumb is: if you start to see maltodextrin...

John Marshall, MD: Don’t we need these to feed the planet? We have people dying of starvation, and I don’t think—I personally don’t think—there’s enough money or access to, you know, the Saturday farmers’ market down in Arlington. Right? So how do we balance the need to feed the planet versus this problem?

Robynne Chutkan, MD: I mean, that’s such an important point, John. But I think there’s a lot between farmers’ market food and ultra-processed food. Because, let’s be clear—these ingredients are not added just to create the food. They’re added to increase the shelf life and the palatability—to keep us eating more and to make it so this food never goes bad. That’s not necessary—that’s commerce.

And what’s really concerning is that a lot of the people eating these foods—these are health-adjacent foods. So they’re plant milks, and gluten-free, and dairy-free, and bars. And so a lot of the people eating them think they’re really healthy. They think, “Oh, this is great—I’m eating this gluten-free thing, and I’m eating this bar, and it only has these ingredients.” But these are foods that never...

John Marshall, MD: We had a guest a couple of episodes ago, and he was the one who uncovered the fact that ultramarathon runners get more colon cancer. And one of my hypotheses is that it’s because they live on those...

Robynne Chutkan, MD: ...on the go. Absolutely. The bars and the go. Absolutely.

John Marshall, MD: So what should I tell the people down the hall?

Robynne Chutkan, MD: Well, the first thing is—it’s not either/or. We cannot be in a situation where the patients know more about this stuff than the physicians. And I think part of the problem is it’s been this like, “Oh, it’s fringe,” and “That’s functional medicine.” I’m a conventionally trained doctor. I wear a white coat. I have a prescription pad. So, we have to—right—we have to bring this into how we’re approaching patients, how we’re educating patients. Because otherwise, people are getting this from a health coach who’s selling them $3,000 worth of useless supplements and telling them not to do chemo. So, it is really an imperative that we include this, and we have to teach our residents and fellows and patients about it.

John Marshall, MD: I’m gonna let that be the last word. Dr. Robynne Chutkan—just an amazing discussion. And we could go on for maybe several episodes—maybe we should. But we have to close it there.

We know this is important. We’ve got to figure this out. And I think the better we understand the topic that you are reviewing—the microbiome—the better we will be at preventing disease and treating it once it happens. So, Dr. Robynne Chutkan, thank you very much for joining us on Oncology Unscripted.

Robynne Chutkan, MD:

 Thanks for having me. Such a pleasure.

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John Marshall, MD: John Marshall for Oncology Unscripted. There's been all sorts of stuff going on out there in healthcare—in the business of healthcare—and a recent article that was just published in The New York Times told us something about the relationship between the National Health Service, how patients get access to drugs there in Great Britain, and our relationship with them and the tariffs. You're like, how could the tariffs have anything to do with the National Health Service?

Well, let me give you a very short little background, if you don't know already, on the National Health Service—Britain’s public health system. The Brits love it. It's tax-based. It's not fancy, it's not frilly. But if we're going to bring in some new medicine or some new expensive therapy—whatever it is—the budget has to be balanced.So, either they have to remove something from what the patients have access to, or they have to raise taxes. And there is a committee known as the NICE committee, the National Institute of Clinical Excellence—staffed by physicians that, in fact, governs that. 

You're thinking, where is Marshall going with this?Well, where he is going—and The New York Times presented this—is that because of the tariffs, right? Britain makes some drugs, and we import them here and use them. Well, if the tariffs are in place, those drugs will be more expensive to import. And the whole idea behind the tariffs is to make it so that more Americans are doing the manufacturing.

Well, the Trump administration and the National Health Service just made a new deal where the Brits will get access to more drugs—so they'll raise their expenses, if you will. And it's going to hit the bottom line over there...because they're going to have access to medicines that they don’t currently have access to. In exchange, the U.S. is going to say, “Well, we'll waive those tariffs on drugs you import.” So, it is access over here for an economic change—an international economic change—around the tariffs.

I have no idea how this is going to work out. I didn’t really understand all the math—were taxes going to go up in Great Britain? Were they going to call it a wash because the tariffs were not going to be in place? I don’t know.

The good thing for patients in the UK is that they're going to have more access to more medicines. What I worry about is that it'll come on the backs of either going into debt—if the National Health Service goes into more debt, sort of like our healthcare system—or, in fact, they raise taxes, or somehow they magically make the budgets balance.

So, we need to look ahead to 2026 and see just what happens with this UK National Health Service–Trump tariff deal that was just reported in The New York Times.

Stay tuned here for more updates on Oncology Unscripted.

[03:04]

Editorial/Main Topic
What I Tell Every New Patient With Cancer

John Marshall, MD: John Marshall for Oncology Unscripted.I start almost every new patient appointment by talking with the patient and saying that I—I don't really know why people get cancer. We memorize lists of what we're supposed to do and what we're not supposed to do, but, bluntly, almost everybody sitting across the room from me didn't do anything on the bad list, and yet here they are, sitting there with cancer.

It seems to me—and I think this is popular science thinking as well—that we probably all get cancer all the time. But our bodies actually have outstanding spell checkers and an outstanding functional immune system that can see early cancers and fix them before they cause any trouble. So, what that actually means, then, is that those cancers that make it—those cancers that survive through the spell checker or through the immune system—must have figured out a way to get around the spell checker, or have broken the spell checker, or maybe are hiding from the immune system.

And so, almost all of our new research going on right now in cancer medicine is either trying to fix the spell checker—and by this, I mean targeted therapies, signaling pathways, et cetera—or it's trying to turn back on, wake back up, or uncover the tumor from the immune system so the immune system can go in and do its job.

And so, I think what you see at almost any conference nowadays focuses on those two approaches. It's not some new chemotherapy, although chemo continues to be very important and has cured a whole lot of people, so don't get me wrong about that. But what we're seeing in terms of innovation has a lot to do with improving the immune system, measuring the immune system, having better immunotherapy or immunotherapy combinations, and, at the same time, uncovering the molecular abnormalities of our cancers and having targets to those—and, in some cases, combining those with novel therapies as well.

So, be on the lookout for the next innovation: either fixing your spell checker or fixing your immune system. But, in support of that, let's look at some of the coolest, latest data that's practice changing in our world today.  John Marshall for Oncology Unscripted.

[05:42]

Interview
New Hope in GI Cancer Care: A Candid Conversation with Dr Yelena Janjigian

John Marshall, MD: Hey, everybody out there in videoland or maybe you’re in podcast land walking your neighborhood. Maybe you have a pit mix dog you're walking because she hasn’t been out in a while, but wherever you are, this is for Oncology Unscripted, and I am a lucky guy because I am joined today by not only a great friend, but also someone who is really setting the standard of care for us in so many ways in GI cancers, and that's Dr. Yelena Janjigian. Yelena, how is New York City today? How is it up there?

Yelena Jangigian, MD: Thanks for having me, Donna. It's great. New York is the best place to be. It's beautiful and sunny, getting ready for holiday season. It's always good to catch up with you and talk research and talk gastric cancer and esophagus cancer outcomes.

John Marshall, MD: Do the stores already have, like, decorations ready to go up there?

Yelena Jangigian, MD: I have not been out, but I've noticed some things here and there in offices.

John Marshall, MD: What do you mean you haven't been out? You live in the hospital, in the clinic, don't you go out?

Yelena Jangigian, MD: Not out in shops, but I've noticed a few, like, you know, holidays, actually. Some of them are actually skipping Thanksgiving and going into holiday season decorations in random offices. So, but, you know, the spirit is, you know, cheerful in New York.

John Marshall, MD: It is a good time of year. I know you very well, and I know lots of our listeners know you very well. Give us a quick little bio on what you're doing right now.

Yelena Jangigian, MD: I'm a physician-scientist working at Memorial Sloan Kettering Cancer Center, focused on advancing care and helping patients with esophagus and stomach cancer live longer using both targeted and immunotherapies. Our lab is focused on trying to understand how we can overcome resistance to some of these medications using both tissue culture and other models. And, of course, I also lead a big group at Memorial Sloan Kettering Cancer Center. We have 45 oncologists all focused on one mission: to improve cancer care for worldwide options for gastric cancer, but also anywhere from esophagus down to the anal canal. So, it's a big group of very dedicated individuals. 

John Marshall, MD: So now I know why you haven't been outside. Because you haven't slept, you haven't left.

Yelena Jangigian, MD: Annual review time. A lot of paperwork. 

John Marshall, MD: Well, let's get into the weeds a little bit on how you are, in fact, helping to lead the improvement in outcomes for patients. But before we jump in, as an old guy in this space, I do have frustration that we in the GI cancer world haven't made more progress compared to our friends in some other cancers. And I know in upper GI and stomach and adenos, etc., precision medicine hasn't been consistent. Things that work in the metastatic setting haven't necessarily worked in the adjuvant setting. It's taken us a long time to get precision medicine targets that are viable for therapies, etc. What are your thoughts about that and why that might be so?

Yelena Jangigian, MD: So, yeah, I think it's important to start from basic knowledge that these diseases can be quite heterogeneous. And even in biomarkers such as HER2, cut-and-paste approaches from, for example, breast cancer into gastroesophageal cancer have not been the best way to do it. In fact, understanding the co-occurring alterations in our disease—the RAS pathway activation, the PD-L1 co-occurring with HER2—is what made the major milestone in the breakthrough in first-line setting beyond trastuzumab. So, I think understanding that this disease, in its nature, because of the nature of the GI epithelium, is more complex but also more heterogeneous than some of our other solid tumors is really critical. And also, because it's a rare disease in some countries, uniform and reflexive testing of biomarkers, where you get enough of a critical mass of data into the clinic so that you understand how each individual subset of a subset—for example, within HER2 tumors, p53-mutant tumors may do differently than p53 wild-type, RAS amplified vs RAS neutral—things like that. Until we do things in larger scale really going forward for all patients, we won't understand this nuance because in colon, breast, lung—the big three—there's more data, breadth and depth, these discoveries can be made.

John Marshall, MD: I was thinking about the idea of mostly colon cancer, and we've been seeing with IO therapy, where we're going to go in a minute, that even in MSS colon cancers, if it's primary disease, we are seeing responses when we would never see them in metastatic disease. So we're looking at microbiome interface or different biology of primaries versus mets. That's sort of what you're doing here with the Matterhorn study, is you're taking some leads from metastatic and applying them into the neoadjuvant-adjuvant setting. Does that feel right to you?

Yelena Jangigian, MD: Yeah, that's right. I think that whole paradigm of go to the late, late-stage setting, demonstrate benefit in heavily pretreated population, and only then move it to metastatic early line, and then only then move it to adjuvant or neoadjuvant space—that’s where the oncology field, I think, lacked an understanding of bigger leaps moved to perioperative settings or a minimal residual disease setting. Because you may not demonstrate a signal that you want in a fourth-line ECOG 2 patient with peritoneal carcinomatosis and ascites. By then, it may be too late. And that's what I think helped me bring, for example, agents like pembrolizumab-trastuzumab combination, Keynote 811. Because doing studies in later line, you understand that HER2 target becomes even more complicated. And again, targeting HER2 with just better HER2 inhibitors, as was working in breast, is not working in gastric. And so moving it to first line with dual immune checkpoint and anti-HER2 combination was the paradigm shift. And I think that's what we're trying to replicate in some other biologically important subset.

John Marshall, MD: I'll spare you having to do the weeds of the study. So, the Matterhorn study: neoadjuvant FLOT plus/minus durvalumab, regardless of PD-1 status, or as you measured tumor area positivity, or both, really, with pre-op/post-op kind of approach, placebo control, maintenance afterwards. Big study. Global. Josep Tabernero is always good to have as a first author. You're the senior author. How much of a pain in the neck is it to run a big clinical trial like that?

Yelena Jangigian, MD: It was fun to do, because we had to convince industry partners to do the study, because Merck had the Phase III registration perioperative pembrolizumab study. Going through to convince AstraZeneca leadership that their design was not as optimal as the modern FLOT approach—so high risk, high reward in some theory, right? But you're asking them to roll a bunch of dice—948 patients—and to be able to present that data. So, it was presented at ASCO in the plenary and then published in New England Journal of Medicine. It was definitely a high reward, and for the patient, and for the community. To be able to unify East versus West, put it all in the same trial—the trial actually recruited ahead of schedule at the time of the global pandemic—and it was always really rewarding to be able to tell patients that you had a great response, complete response, and to see the R0 resections. The dogma was that you need radiation for these patients, and we've moved away—even increasingly in the community setting. I hear from clinicians who came to me saying, “This is a perfect time for you to update us about this.” I'm taking this to the clinic, and it's part of the NCCN guidelines now. 

John Marshall, MD: So, give us the high level. I mean, you got survival benefit, you got PFS, you got response rate delta, toxicity as expected—not zero, but as expected. High level, for our clinicians out there—what are the numbers they walk into?

Yelena Jangigian, MD: The timeline of this was at ASCO we presented the pathCR and EFS data, which was also published in Nature Medicine. And in Berlin, this past ESMO, we also presented—and this was a big splash—because it's been shown with immunotherapy before that pathCR may be improved, but will it translate to eventual survival. Check. And then, for the first time ever, we were able to demonstrate that you will also see OS benefit. And that was the splash at ESMO. We will be publishing that data in a manuscript format. To show that a pathCR can be an early surrogate of survival, and I think it's all important for us as researchers because, in my program, I have three separate first-in-kind ISDs in perioperative setting building on MATTERHORN. So, to know early which of the strategies will be successful to take forward in Phase III—waiting for pathCR would be much more practical.

One common public service announcement I want to make—people are still a little confused about the number of cycles in the Matterhorn. In fact, that’s probably one of the most common emails or direct messages I get on social media: Why did you only give two cycles of FLOT? We did not. A cycle was defined as two doses of FLOT. So, it's two cycles, but four doses of FLOT, and two cycles of durvalumab. Durvalumab is given once a month; FLOT is given every two weeks. So, this was, as you said, standard approach, and we did see improvement in event-free survival.

What’s important to look at is not only the hazard ratio, but the two-year survival benefit which was meaningfully improved. And the grade 3/4 toxicities—we need to be careful about. Most of the side effects are related to chemotherapy. So, as clinicians are getting more and more comfortable using FLOT in the clinic, the dose reductions, the hydration, the prophylaxis, potentially the Neupogen if needed—all of those will be implemented. So, NCCN already adopted these regimens, and we're planning, hopefully, for the FDA approval in the near future.

John Marshall, MD: Yeah. I think about the number I go in with—oxaliplatin in the adjuvant setting in colon, which is, you know, overall maybe 3%, 5%, depending on how optimistic I am on that day. Here, what's the number I walk into the room with a patient? Is it another 5% or so cured by the addition of the IO therapy to FLOT? Is that a fair number to walk in the room with?

Yelena Jangigian, MD: I would say, well, it depends. So, if we're looking at a final OS, the difference was closer to 7%.

John Marshall, MD: So, a little higher. More than 5%, I can say, right? And that tail does exist, and you've got a follow-up.

Yelena Jangigian, MD: Right, and that's every year. And then, I think if you think about it, this is looking at a large Phase III study. These are all patients who did not have all laparoscopy. They didn't necessarily have the staging that you and I could do in our practice with specialty care. So, I suspect that number—or at least in our cancer center—is better.

John Marshall, MD: Got to hold up, okay. Tell me about PD-1 testing. I mean, I realize everybody could be in on this study.

Yelena Jangigian, MD: It was an all-comer accural. We used tumor area positivity (TAP) as opposed to combined positivity score (CPS). It's reproducible, and there's data to show the TAP and CPS are equivalent. The benefit appeared to be irrespective of PD-L1.

John Marshall, MD: So, they could come in cold for PD-L1 and they're still eligible for the therapy based on the study?

Yelena Jangigian, MD: NCCN restricted it by TAP-1. Unclear for regulatory reasons—that may be amended, because this was a restriction before the OS data came in. So, we'll have to see. The EMA appears to be interested in approving it, again just from the discussion with colleagues in Europe, irrespective of PD-L1 because that's a huge patient population. Irrespective of that, most tumors are PD-L1–positive. So, if you're seeing a negative case, I would call your pathologist and make sure the cellularity of the case is sufficient.

John Marshall, MD: Take a look again. You know, I think immunotherapy is certainly one of those classes of drugs that we have the highest patient awareness for. I mean, they're always coming in and saying, “Shouldn't I have some of that immunotherapy stuff?” And in some cancers, it can be quite dramatic, the impact. What's your thought, and what are we doing about trying to further optimize the impact of the immune system on treating our cancers? Where are we at?

Yelena Jangigian, MD: Yeah, so our large biomarker analysis of CHECKMATE 649, which was the FOLFOX–nivolumab vs FOLFOX study in stage IV patients, showed that chromosomal instability tumors—so CIN tumors the hazard ratio in metastatic setting for addition of immunotherapy—is not as good. Hazard ratio 0.9 for survival. So, we know those tumors don't do as well.

How do we improve? Because they're relatively cold or immune-excluded tumors, but we're trying to boost that. We know that combining the checkpoint blockade with CTLA-4 inhibitors may offer some benefit, especially from the data we see, as you said, in early-stage colon cancer. But it's very tricky to combine it with FLOT chemotherapy. So, combination with TIGIT may be helpful because, again, it's an immune-boosting, dual immune checkpoint blockade. That's to be determined.

There’s also now Fc silent bispecifics with PD-1, CTLA-4—drugs like cadonilimab, which are approved in China and actually are coming to the United States as well in metastatic settings. So that's what I'm interested in. I think for a subset of patients, it'll be a combination of PD-1 plus tumor targeting, for example, for HER2-positive tumors. For another subset, we’ll be doing dual immune checkpoint blockade—either PD-1–TIGIT, if that data pans out, or PD-1–CTLA-4—with the backbone of chemotherapy, of course, for all. Because it's been difficult to move away from chemotherapy unless it's an MSI tumor.

John Marshall, MD: Tell us how we move forward. What's next out there for the treatment of upper GI cancers?

Yelena Jangigian, MD: Well, you know, today we had a press release. The zanidatamab data—it appears to be a positive HERIZON-GEA-01 study, whatever that will be. So, it's a positive space that will be interesting to see at ASCO GI. And then, of course, the biggest disappointment of the year is the FGFR2b data with bemarituzumab—with FORTITUDE-101 having a huge splash with a large positive interim analysis that subsequently dissipated, and the curves came together. You probably saw ESMO. I think it shows that we're not quite done with biomarker development in gastroesophageal cancer, and the best is yet to come.

John Marshall, MD: Just to let you know, for Washington, D.C., that wasn't the biggest disappointment of the year. There’s been other stuff that beat that, but we don't have to go into that. Dr Yelena Janjigian—the world’s expert and really thought leader in the space of upper GI cancers—raising the bar, curing patients right and left, not just in New York City. Go shopping. Get out of there and enjoy a little time. You've deserved it. John Marshall, on behalf of Oncology Unscripted, thank you, Yelena, very much.

Yelena Jangigian, MD: Thank you so much, John. Be well. Take care. [22:20]

This transcript has been lightly edited for clarity.

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John Marshall, MD
Hello, everybody. John Marshall for Oncology Unscripted, coming to you from my now almost empty office. I've been in this office for, gosh, 20-plus years. It's the big office. You may or may not know I stepped down as the division chief here at Georgetown. We planned it—I wanted to do it a while ago. They said no. So, I finally got to step down because I wanted to do some other things. I get a lot of time back from meetings I really didn’t want to go to in the first place, so I’m happy about that. And it’s enabled me to get back to the world of clinical cancer research and to try and innovate in our space and do a lot less administrative things. So, I am glad for the clean-out, moving down to a smaller office in a fresh region. Probably one of the last times—maybe the last time—I film from this spot. 

But I wanted to take some time to review some high-level things that have changed in a big way just in the last week or two. The one that struck me the most is that there's been a change in black box warnings around hormones for postmenopausal women. I lived this too, where we went from hormones being a good thing—and all postmenopausal women were more or less taking them—to then it was unopposed estrogens were evil. And then the cancer lobby—and the breast cancer lobby—really was responsible for making it so women stopped taking hormones. We made it so terrifying that hormones were going to cause breast cancer that, you know, certainly oncologists weren’t prescribing it. GYNs stopped doing it. Primary care docs stopped doing it because no one was really willing to take the risk. And I think about the suffering, quite honestly, that postmenopausal women have endured since this time. It is really, really remarkable. And only now—only now—that people have gone back to actually look at the clinical trials and look at the studies, they actually pretty clearly show that hormone replacement is not bad for these people. In fact, if you look at the colon cancer literature, surprisingly, there was evidence that it decreased the risk of getting colon cancer. And even despite that, they didn’t want to change it around. So, I am excited about that black box warning change. If you’re a postmenopausal woman or you know some that are around you, make sure that if they’re interested, there are new options for those patients.

But there’s a second warning that has been installed, and this is around 5-FU and DPD testing—dihydropyrimidine dehydrogenase testing—for 5-FU clearance. Why I think it's a big deal is not only is it an updated Black Box, but NCCN has embraced it. I think it’s a big enough deal that I hope you will click in and watch my interview with Howard McLeod, who is really the world’s expert in this space, about what we should be doing, how to do it, and some of the practical aspects of that.

So, make sure and click on that interview and watch it. It’ll be worth your time. All you clinicians out there should do it. Now, whether or not it will become routine, whether or not it will become standard of care, whether or not you’ll get sued if you don’t do it—those things will evolve. But I do think it will be part of your everyday life. So, good to keep up to speed on that.

And then lastly, sort of an emotional note to make—and that is, this is the actual 25th anniversary of something I bet you remember. That’s when Katie Couric had a colonoscopy on television, and it was on a morning TV program, The Today Show. She did that because, of course, her husband had had colon cancer, and she became quite a strong advocate.

Her sister Emily later developed pancreas cancer and died of that, and she’s been very involved in Stand Up to Cancer and so many things. But I think back about that moment when Katie Couric said, “You’ve got to be getting your colonoscopy.”

And the reason it comes up is that, one, we’re giving her a 25th anniversary award here at Georgetown—one of our Luminary Awards. So, we’re very excited about that. I’m going to get to see her later this week and thank her in person. But I was also thinking about the impact that I believe she has had on the number of people who get colon cancer.

If you really do the math, the interventions that have changed with colonoscopy, etc., in the United States have probably reduced the number of people who get colon cancer every year by about 20,000. Now, 150,000 people get colon cancer every year. It would be much higher than that if we didn’t have effective screening. So, screening works—fewer people in our clinics—and we need to applaud her for all that she has done.

So, that’s all the gossip that’s fit to print for this session of Oncology Unscripted. I hope it gives you a little something to think about, look up, or consider as you move forward in your day tomorrow.

John Marshall. See you later.

Editorial: How Do We Translate MRD Innovation Into Everyday Oncology Practice?

John Marshall, MD
John Marshall, Oncology Unscripted. I've talked about this a bunch on our program, and this is the impact of blood-based genetic testing on cancer care—maybe other health care problems as well. And the couple of ways we do blood-based testing: one is to look for mutations from a patient with a known cancer. But we're also using blood testing to see whether or not there is still cancer around—so-called minimal residual disease. And they're similar in technology but different in terms of how we're using them.

A lot of us out there are not using the MRD testing, whether it's tissue-based or not, because the truth is we don't really know what to do with that result. If it's negative, do I not give adjuvant chemotherapy? If it's positive, do I give more adjuvant chemotherapy? What if it flips? What if it doesn't? Et cetera. So there's a lot of unknowns, but there is this wave of data that continues to come out. San Antonio Breast coming up has new data around this. We've seen it at ASCO. We've seen newer publications more recently that suggest dramatic differences if your test is positive after surgery versus if it is negative, with hazard ratios that exceed 20. This is prediction of cancer still being around. And yes, the negatives are not perfect, but they, too, are pretty good.

So, we talk about finding the right patient to give treatment to in the adjuvant setting.I am certain that some sort of MRD testing is going to be part of this. And I was lucky enough to hear a fabulous lecture by a very, very good friend of mine, Dr Scott Kopetz from MD Anderson, who summarized the current data set around this and says that this is not going to go away. This is the inevitable. The question is: how are we, as health care providers, going to use this data to guide our patients, to guide our therapies, to improve efficiency around all kinds of therapy—most importantly, right now, adjuvant therapy?

So, review these data. Look at those hazard ratios. Decide whether or not you want to begin incorporating MRD testing into your general day-to-day care. And let's see what 2020 says with regards to treatment opportunities, clinical trials, et cetera, moving forward.
John Marshall for Oncology Unscripted.

Interview: Can Pharmacogenomic Testing Make Oncology Safer? A Candid Conversation with Dr Howard McLeod

John Marshall, MD:
Hey, everybody out there, John Marshall for Oncology Unscripted. You might notice that my studio is a little bit more bare today. One of the reasons is that I’m moving. They’re kicking me out of this office for a smaller office. That’s what you get when you get old. It’s discrimination—age discrimination. It’s actually job-appropriate job discrimination.

But we’ve got some blank walls in here, and we’ve got a lot of bright content, and I am so excited to introduce to you all—if you don’t already know him, pretty famous guy in his own right—Dr. Howard McLeod.

Howard and I have known each other for decades. We can say that, I think, with some certainty. And I want him to introduce himself, because what we’ve got to talk about is critical to almost everybody’s practice who’s listening in.

Howard, welcome. Give us a little background on who you are and what your area is.

Howard McLeod, PharmD:
Thank you, John. It’s great to be on your program. I’m an avid listener, first-time appearer, as they say.

I got dragged into this area of pharmacogenomics the hard way. A little girl nearly died of her therapy instead of her leukemia when I was a fellow at St Jude’s. We ended up finding the gene responsible for that.

Then a similar situation when I was over in Glasgow—a man got one dose of 5-fluorouracil and nearly died. So genetics as a way of predicting toxicity has been the theme of my life going forward—lots of implementation work, lots of large clinical trials and such.

Fast forward to our work at Utah Tech University: a lot of what we’re doing now is asking, “What do we do with this? How do we make it work in the real world?” Making it work at Georgetown is one thing. Making it work at a small practice “in the wild” is a totally different thing.

So, how do we implement this in all places, as opposed to just a few big centers? And the dihydropyrimidine dehydrogenase story that we’re going to talk about today is just one example. There’s a lot of activity around supportive care—Which pain med? Which antiemetic? Which antidepressant?—but this specific example is very much a toxicity example, and I’m looking forward to discussing it with you.

John Marshall, MD:
Let’s drill into this. One of our themes for this season right now is the increased utilization of molecular profiling—identifying positive signals for therapies.

I’ve always thought that pharmacogenomics—because I work with a guy named John Deeken here, who is a you, John—yeah, and he’s been preaching your same gospel for a long time: that we need to be doing more pharmacogenomic testing on our patients to optimize dosing.

There’s another discussion going on within the cancer community that we’re probably overdosing people, even up to the target, much less to toxicity.

Having lived this and preached this a long time, give me your take: why don’t you think pharmacogenomics has had stronger uptake in the community compared to, say, tumor molecular profiling?

Howard McLeod, PharmD:
Yeah, the oncology community is influenced by a couple of key things. One is strong, large, randomized clinical trials. It’s a little more difficult to do those kinds of trials for individualizing therapy—though they have now been done—for individualizing classes of therapy, not just individual drugs, particularly in the supportive care space.

So that’s part of it. Reimbursement needs to be there. There has to be a way of getting the test with a rapid turnaround. But part of it is also just: what are you used to?

I remember when PET scans first came out, no one would order one. Finally, radiology got more comfortable calling them—it wasn’t just nuclear medicine physicians, but radiologists would now call the PET component. Suddenly, you visit a cancer patient and you get a CT/PET. Maybe not quite that much, but conceptually it’s become so normal.

I think what we’re seeing now is a bit of a tipping point where some of the experience we’ve gained with tumor genomics and with inherited cancer genomics is causing us to say, “Wait a minute. I don’t need to waste my time—or the patient’s, more importantly—giving them the wrong drug when I can weed some things out and choose a better one.”

So, I think now it’s become more of a clinical efficiency tool, and that’s where we’re seeing the uptake start to happen.

John Marshall, MD:
There have been early adopters on DPD testing and then later adopters—I think our group here has been later adopters, to be quite blunt.

I’ll share with you that in the last, I would say, almost 10 years, when I write that first script for 5-FU or capecitabine for somebody, my sphincters are a little tight for the first couple of weeks. I personally have never written a script for somebody who turned out to be completely deficient at a life-threatening level, but I’ve taken care of several patients who’ve had that diagnosed and then come to us as a tertiary care referral.

Start us off, because a lot of our audience probably is not 100% sure where we are. I’m not asking for your hour-long, grand rounds, high-level talk, but: what are we talking about here? What are we testing for in these patients?

Howard McLeod, PharmD:
Yeah. So 5-fluorouracil has been around for longer than us—it’s been around a long time. Most of it is degraded to a less active or inactive metabolite that is then eliminated from the body.

Dihydropyrimidine dehydrogenase—or DPD, or DPYD as the gene name—is responsible for that first degradation step. If that enzyme is impaired—or completely deficient—then a lot more drug gets shunted down the active pathway: incorporating into DNA, into RNA, inhibiting thymidylate synthase, all the mechanisms we talk about in terms of how this drug really works.

So you end up with this preferential shunting into the active pathways. If you can’t get rid of it, then you’re forced to “use it,” and it all goes down that path.

Initially, the cases that were found by Bob Diasio and by other groups in the Netherlands and elsewhere were really those patients who had the extreme toxicity. Death, obviously, is as extreme as it gets. Then there’s prolonged, hospitalization.

The case that I first got involved with, where we ultimately discovered the DPYD*2A variant, involved a patient who had 21 days of ICU stay before he survived. His oncologist then asked for our help to figure out what in the world went wrong.

John Marshall, MD:
How many variants are there then? Are there… innumerable?

Howard McLeod, PharmD:
There probably are a lot more variants that haven’t yet been found, but currently the Association for Molecular Pathology—AMP, as it’s called—has two tiers of variants that they consider essential.

The first tier is especially essential, and there are 7 of those. In the second tier, there’s a lot of data but not as robust, and there are 7 of those as well. So, 14 total variants.

There have been a number of case reports that have come out even in the last couple of months, finding new variants. Those need to be vetted and proven to be truly pathogenic.

But the idea is: a handful or two—well, two handfuls or maybe three handfuls—of variants seem to be the ones that cause most of the difficulty in many populations.

So, for example, Jay Patel at Atrium Health in Charlotte has found some variants—and they were an early adopter, they’ve been routinely applying this—and he found variants that were more commonly seen in African American cancer patients. There have been others found more commonly in Southwest Asian patients—Indian, Pakistani, and so on.

But in general, those 14 seem to capture the bulk of it.

John Marshall, MD:
I was thinking about the situation in Europe, where there was a case—I think in France—where a patient died from toxicity. Correct me if I’m wrong, but it’s now a law in France, not all of the EU, that you have to measure this before you give 5-FU.

Early adopters have said, “Any information is better than none.” The later adopters, to your point about us continuing to find new variants, say, “I’m not really sure what to do with the result when I get it back. Does it mean I can’t give the drug, or I need to modify it? And if so, how?”

That lack of tightness, if you will, has been one of my personal struggles. But do you think now we’ve got enough data that we should be doing this in everybody?

Howard McLeod, PharmD:
I do. I’m obviously biased toward the early-adoption end of things, but I think we now have the ability to get fairly quick turnaround testing—not same day, by any means, but within 3 to 5 days. It’s being paid for by more and more insurance companies, so that issue is improving.

What we’re seeing is that if you have two bad copies—if you’re homozygous for variants—that’s really an extreme event.

Alan Venook at a presentation to the FDA back in January, during a public forum, data from a large Mayo study were shown in which the homozygous patients were the ones who did extremely poorly. That led to the first black-box warning in January from the FDA.

The heterozygotes had a lot of toxicity—hospitalizations, etc.—but they lived.

Those of us in oncology who are my age were literally taught, “You need to nearly kill the patient in order to kill the cancer.” So it’s difficult for folks like myself to look at this and say, “How can I under-dose this? Underdosing is worse than overdosing.”

But now I think we can refine it. We see that we can dose-reduce. If it’s an adjuvant patient, the recommended range is a 25% to 50% dose reduction. If it’s adjuvant therapy, I think a 50% reduction with subsequent dose escalation as tolerated is reasonable—and that’s a key point: don’t neglect the part about escalating as tolerated. If it’s a patient receiving active therapy for metastatic disease, then maybe you do a smaller reduction. Some patients will still get toxicity, but it’s unlikely to be fatal toxicity in that setting. So I think we’re at a point now where we’re as good as we are for renal dysfunction or liver dysfunction. It’s far from a perfect world, but we know this patient needs to be handled slightly differently.

John Marshall, MD:
That’s a really good point. I’m sitting here thinking about my electronic medical record, which I love and hate. The nurse brightly calls me to say, “Do you know the creatinine is 1.6?” And I say, “So what?”

What do I do? I probably do nothing most of the time, but every now and then I do something. There is a pop-up in my EMR that flags this, though.

But there is no pop-up in my EMR asking, “Did you do this [DPYD] testing?” Even though I’ve got all these criteria built in for other drugs.

I’m assuming that’s the next evolution—we’ll begin to increasingly see that kind of analysis.

Howard McLeod, PharmD:
Yeah. Dr Max Smith and Dr Jay Patel, whom I’ve already mentioned, and a few others have been working hard on that at their own institutions.

Right now, it’s mainly places with champions who are doing the hard work of integrating this into the EMR. But now that there have been two FDA label changes in the last seven months, and now that there’s an NCCN guideline change—at least for colorectal cancer, not yet for breast—places that make more wholesale updates are going to start doing that.

So Epic and Cerner and the others will start making big changes. The lookup tables that we all use electronically have now been updated.

It’s making it so that someone who doesn’t really know how to pronounce dihydropyrimidine dehydrogenase can still benefit from this. Frankly, you don’t want to know a lot about the enzyme, you just want to know, “I ordered the test.”

There was a day before your and my time when measuring bilirubin was a big deal. It certainly hasn’t been for the last 30–40 years. I think there will be a time when measuring this stuff is just what we do.

But right now we’re in this transition phase. We don’t want to underdose patients any more than we want to harm them with toxicity. Figuring out which side we err on as we move forward is the challenge each oncologist is facing.

John Marshall, MD:
Remind me—what percent of our patients would have some abnormality in one or more of these genes?

Howard McLeod, PharmD:
It’s right around 5% that would have some abnormality. The extreme toxicity is very rare—it’s less than 1 in 1,000. You may encounter it in your lifetime. In a busy practice like yours, it might have come through, but most practices will never see that extreme, fatal toxicity.

The fatal part will be caught by the testing we’re doing now, but really most of the testing is identifying those people who are going to have grade 4 toxicity with hospitalization, and asking whether we can at least manage them.

There is an approach whereby, if you know a patient is heterozygous—they have one good copy and one bad copy—you monitor them more closely and act quickly on any toxicity. The onus is on acting on it.

There is an antidote available. It has to be administered in a narrow window, and that’s the tricky part—can we orchestrate that? Often it’s just easier, in practical application, to start with a dose reduction and then move up.

John Marshall, MD:
I’m just setting out to lead a national platform clinical trial in colorectal cancer where we have not included testing as an inclusion criterion. Should we add it?

Howard McLeod, PharmD:
I would, only because it’s now in the label.

Many studies will have done DNA collection and can test retrospectively. That’s certainly another viable option—prospectively accrue, retrospectively test. But if the trial hasn’t launched already, it would be a straightforward thing to add. There is cost and logistics, but there’s a lot of pretesting going on in a clinical trial anyway. You can send all the samples to the same place—Labcorp, Quest, the big labs all do this testing now. It’s not as hard as it was even five years ago.

John Marshall, MD:
Even the molecular profiling companies for their liquid biopsies have started to bundle this in, along with germline testing and so forth. It’s going to be in our faces whether we want it or not, if we order these other tests.

Howard McLeod, PharmD:
This is just the kind of thing we can do to learn more about the patient. We’re now at a point where therapy is so successful that we can care about toxicity, pain control, and all these other issues in a more nuanced way. We’ve always cared, but there’s always been this existential piece of “saving the patient.” Now that therapies are active enough, we can start putting more attention on this next layer.

We saw what happened in pediatric oncology a couple decades ago, where survival rates got to the point where they could worry more about cardiac toxicity and such. Breast cancer has had that privilege; colorectal cancer is now starting to have that privilege, where the therapies are active enough that we can start worrying about this next layer of issues.

So it’s an exciting time. It’s inconvenient that we now need to add more testing, but I think it’s an exciting time—and a very straightforward way to apply it.

John Marshall, MD:
And hopefully it makes us more successful. “Who needs it, what are the right doses, and how do we move forward to optimize outcomes for our patients?”—that’s what we’re all about.

Dr. Howard McLeod, thank you for jumping on and letting me borrow some of your time. I know everyone who’s listening in has learned a lot and probably tomorrow will start changing their practice.

Dr. Howard McLeod, thanks a lot.

Howard McLeod, PharmD:
Wonderful to be here.

This transcript has been edited for clarity. 

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When the Sources of Trusted Information Change—Who Do We Believe?

John Marshall, MD:
Happy whatever day it is today when you're watching this. John Marshall for Oncology Unscripted. A little bit of a rainy day here in Washington, DC. It's been a little bit of a weird time here in Washington, DC—even weirder than it normally has been.

Let's start with a little of the business of our world today—the business of oncology. You may have seen that we have a new National Cancer Institute director: Dr Anthony. Professor of medicine, he's kind of a basic science guy, but he's also a medical oncologist from Dana-Farber. Would you take that job if it was offered to you? I knew some of the candidates who were in line for it—or the finalists—and you'd really have to want that job to take it right now, because of all the unsettledness at the NIH in general, et cetera. So, I'm grateful that this very smart person has said yes to the job. Now, what he does—one of his areas of expertise—is programmed cell death, which is sort of a subtle way of getting a cancer cell to kill itself, right? So maybe, just maybe, he'll use some of that expertise to help in the shifting of government. A little programmed cell death around here might go a long way. So, fingers crossed that he succeeds in maintaining and growing the research that we are doing in cancer, much of which is sponsored through the National Cancer Institute. So, fingers crossed.

But as soon as he gets the job, what happens? Well, we shut down the government.

We've done this before. It is weird in Washington when the government shuts down. Whether it's patients who now don't have a job for the moment and who risk not having health insurance to receive their ongoing cancer care—in my case—or care in general out there.We're clearly seeing an impact on patients. We're clearly seeing an impact on government operations. I'm supposed to fly to Florida to get measles, maybe, this coming weekend, and I'm not sure we will do it because—who knows if there'll be air traffic controllers available? Would you go to work if you weren't getting paid?

I had a recent call with an NCI colleague who is going to work, who is seeing patients, and is trying to manage things—but is uncertain about whether they will be paid.

I also happened to come across recently somebody in the medical center who works up in McLean. If you know what offices are in McLean, I'll let you figure that out—sort of secret spy stuff. Normally, they're incredibly busy, but because there aren't any other government activities going on, they're kind of sitting there saying, "Well, we can't do what we normally do because we're dependent on the rest of the government to do what we do." So even those who are going to work are kind of stalled.

So, there's a whole lot going on. The one positive—and it's not really a positive to make up for the negatives—is that the traffic's a lot lighter here in Washington. But still, not enough to make up for it.

Now, I do want to talk a bit about another big topic that’s come forward. You know that RFK Jr. fired 17 members of the Advisory Committee on Immunization Practices. This is the group that gathers to make recommendations around vaccines and immunizations in general. He fired a lot of them. He put some replacements in—many of whom have been featured in other articles—I won’t drill down into the weeds on some of this, but many of them are more than just anti-vaxxers. They’re suggesting that we’ve mismanaged this as a medical community, and that we’ve not been telling the true scientific story.

The new people who’ve been put in place haven’t made any formal recommendations yet. But the most recent one that came out is that there’s even some debate about whether newborns should be given hepatitis vaccines. And that data is very, very tight about how many lives are saved because of vaccines—as they all have been shown. But we’ve forgotten data, and we’re going to have to relearn the lesson going forward.

Do you read the front page of the paper or don’t you? In my family, it’s split. My wife only reads the sports section. I read the front section—or at least read the headlines.

In the Washington Post editorial page was an article written by the last six Surgeon Generals—right and left—appointed by different presidents over time. And this was a very thoughtful piece that basically summarized that RFK Jr.—he’s perfectly entitled to have his own opinions about things—but he’s not entitled (this was their conclusion) to put other people’s health at risk.

And they collaboratively, collectively, emphatically said that that is what is going on with this new ACIP committee—with RFK Jr. at the helm. That we are putting a lot of people at risk, and it’s what’s making us all very, very anxious in the medical community today.

Now, I want to talk in closing on this about a book that I am reading. Don’t worry, it’s not too boring.

And the stuff I’ve been seeing during Jeopardy—I always measure the pulse of America by what ads run during Jeopardy every night.

Now, the book I’m reading is brilliant.

It’s called Empire of Pain. It’s written by a guy named Patrick Radden Keefe, and it’s the story of the Sacklers, Purdue Pharma, and OxyContin. I’m sure you may have seen the movie about this. It’s brilliantly written, and it starts with the first advertising that was ever done for drugs.

This was Librium and Valium—done by Pfizer at the time. And the Sacklers kind of invented this strategy where they were figuring out how to tell a story of a new medicine—in this case, anti-anxiety, kind of anti-depression medicines, Librium and Valium.

These were for patients who weren’t psychotic—so they didn’t need to be admitted for their psychiatric anxiety and problems—but there were a lot of people out there who could use a little something to help take the edge off. So, they created a market. They had drugs that would solve this problem for people. And Librium and Valium became the biggest-selling drugs at their time. This was through peer-to-peer teaching. So, start thinking about your own role in this as you listen. Physicians who were trained to teach other physicians about the new medicine. Direct-to-consumer, certainly. The Sacklers owned a medical journal where they advertised in it and could write editorials about their medicine. They also had consultants that worked for it. 

Now, as I’ve been reading this, I’ve been thinking: I play all of these roles. I’m a consultant of pharmaceutical companies. I do peer-to-peer education. I do clinical trials. I write papers for journals. I do video podcasts, for God’s sake.

And so, I’m out communicating my bias, my opinions to others—to influence their practice on some level. Not my goal, but it’s certainly a downstream product of influencing their practice.

So, this family had figured out a way to take advantage—and coach and train us all—how to use medicines. And this was in the very, very early part of my career. But then what they figured out was how to take pain medicine, believe that the pain medicine would help, make it longer-acting, get a good price for it, sell it, convince us all that we needed to be on it, and increase the utilization of long-acting pain medicines. So, when I was just a fellow and a new faculty member, we were all coached that there is no high enough dose. That all patients need to be on it. That it’s normal to be on these drugs. And in point of fact, it is the right thing for people to be doing. Only now do we recognize that this was really an over-push for these people.

I’m just reading the section of the book now where people were abusing it. That they became addicted to it. And it was not really for cancer pain or other things—they were just hooked to the drug. And it took a long time for that to get broken.

So early in my career, I was pushing huge doses of this medicine. You were, too.

And now there’s nobody I’m giving much more than about 10, 20, 30 BID of long-acting pain medicine. So, we learned our lesson about how we were kind of lied to in this setting.

More recently, we have a new point-counterpoint with the government. I’m seeing it from Pfizer. I’m seeing ads today during Jeopardy and other shows like that, where Pfizer is basically reminding us all—as an audience—that vaccines can help.

The government is telling us, RFK Jr. is telling us, that vaccines are bad. That we shouldn’t be taking them. That they cause all sorts of trouble in patients, and we shouldn’t be messing with it.

But then I’ve got Pfizer doing a very clean ad over here that says, “Don’t forget vaccines.”

Let’s look a little bit at the science that’s being referred to. The science back when we were giving long-acting pain medicines, and now when we are making new recommendations by our government.

So, back then, they actually didn’t even get formal FDA approval for MS Contin, because morphine was already approved. They just got it. They just started shipping it out. They just started making it and shipping it out.

They then got approval for OxyContin—but the guy who approved it at the FDA, believe it or not, a couple of years later, starts to go and work for them outside the FDA. So, there’s a lot of question about whether that was legitimately covered.

But the idea was that OxyContin would be less addictive—but they never really showed that, even though they marketed that. 

So, the cleaner processes that we’re used to for drug approval were not put in place. And then the claims that could be made about how well these pain medicines worked—anybody could say anything. There wasn’t a lot of supervision around that until it kind of came back to bite them and haunt them.

We are, in today’s world, hearing the government, RFK Jr.’s gang, and other people talking about immunotherapy, vaccines, et cetera—saying things that have no real foundation in science. They are based on just speculation, or something somebody put on Twitter one day. And it becomes our job, in the medical community, to judge what is the correct thing to be doing.

And I think right now, you’re seeing insurance companies and pharmaceutical companies and the medical teams really sticking with the more clean science, and applying therapies based on what they know—and sort of ignoring what they’re hearing in the public media, et cetera, based on what the government is saying.

So, this has put us in a new and awkward position, where we are on the side of business in this case, and not on the side of government.

If you haven’t read this book, Empire of Pain, I would recommend that you do—particularly if you are an older person who’s lived through some of this. But I also want you to recognize that there’s a lot of pressure—mixed pressure—out there on just providing today’s standard of care.

And so, the next time you see that Pfizer ad, remember that you’re probably now on that side of the coin—advocating for ongoing immunotherapy for our patients in the form of vaccines to prevent, but also in managing and preventing other cancers from occurring through the use of immunotherapy.

Complex times. Lots going on in the news today. Lots that’s affecting our world and the treatments that we are offering. Lots to incorporate in your recommendations.

I hope this has been helpful in summarizing that, and it’s useful for you tomorrow in your practice.

John Marshall for Oncology Unscripted.

Main Topic [0:13:12] The Molecular Space Race: Will It Bring Earlier Detection and Better Treatment?

John Marshall for Oncology Unscripted. An amazing amount of science is going on right now in the cancer world—on the molecular side of things—and I like to think of it kind of like a molecular space race. Because the technology that’s out there—of being able to measure what’s going on in a tumor, what’s going on in the blood, finding different genetic characteristics, and being able to act on those—has never grown quite as fast as what we are seeing now. Just like we were racing to get to the moon or racing to orbit around the Earth, we are now seeing companies and different groups from all over the world developing and improving technologies to try and read the tea leaves of whatever’s going on in the blood, whatever’s going on in a tumor—in what I think of as a molecular space race. And I wanted to feature a paper about this that I thought was quite interesting and will set us up for the beginnings of what will be, really, a few-month-long discussion around precision medicine—to try and understand better how it’s going to help us evolve and become more efficient in the practice of not just cancer care, but healthcare in general.

Now, the paper I want to talk about is in this journal called The Journal of Clinical Oncology. Yeah, I still do get a paper version. And this one is from China. Now, I want to start by saying that I’m a little surprised this paper made it into JCO, because it is a molecular analysis done totally in China. 

But where I wanted to start from was that the funding for this work came from a bunch of philanthropic and government-supported stuff in China. A big, long list of different resources—including the healthcare system where it was started out of.

And I keep thinking about here in the United States—where we’ve been leading in investment, where we’ve been leading in discovery—we are now finding it more and more difficult to access the kind of support that came to make this science possible. So, when we think about our individual U.S.-based impact on outcomes and research and progress—without that funding—we’re going to clearly keep falling behind.

And the two papers I want to talk about—this one in China and the other one out of the European Union group—show that all of this novel, positive work is coming from other sources, other investment. Just food for thought.

But anyway, this group took patients with the attempt to try and find a blood-based test to detect early, early-stage pancreas cancer. Because, as you know, it is very, very difficult to cure pancreas cancer if it shows up clinically. I won’t go into the weeds on this paper—it’s in JCO—but they basically took some learning sets and some training sets, et cetera, and developed a panel—a blood-based panel. And they were able to show, with very high precision, that they could distinguish who had small-volume pancreatic cancer and who didn’t. They even had a cyst sub-study subgroup in there to look at—and things like that. And I think it’s worthy of being presented in JCO, because if you think about what we’ve been doing with our blood-based testing, is people who already have cancer—who then get blood-based or tissue-based genetic testing to decide what we’re going to do to treat them or how to follow them: looking for minimal residual disease or what targeted agent might be available for that individual patient. But this is the other end of where I think this kind of technology is going to go—and that is screening. Healthy population. Blood-based testing. See if you’ve got cancer or not—and intervene. And I’m very, very interested in seeing over the next 5, 10-plus years how this kind of technology shifts from just coaching us to be more efficient in the treatment of existing disease—existing cancer—and more shifting towards early detection and prevention strategies.

So, I think there’s nothing hotter than this blood-based testing that’s going on now, which is why we’ve decided to spend a few months on it. And this paper sets the stage.

The other paper I want to contrast that with also just came out in the Annals of Oncology. So yeah, good group, good journal—but not quite JCO, right? So, a little bit off the beaten path. But to me, maybe the most important paper of the week.

And this was the group from the PRODIGE 13 adjuvant colon cancer study, where after the intervention was done, patients were randomized into four groups of follow-up. Now, I don’t know what you do. NCCN says I’m supposed to do it maybe once a year. I do it a little more often than that, if I can get away with it—although that sometimes means I’ve got to do a peer-to-peer to get a scan or other things. I’ve incorporated, more recently, doing MRD testing. But the standard right now is a CEA every now and then, and a scan every now and then, and a colonoscopy every now and then.

Well, the study actually randomized patients into more intensive follow-up versus less. Now, remember why we do this in colon cancer. The primary reason is that we feel like if we can find a met before the patient feels it, that we could remove it—and maybe cure the patient, right? And so, unexpectedly, this study basically said the opposite. It didn’t matter how intensive your follow-up was. You had the same overall survival. Well-done study. Prospectively looked at.

So, then I’m thinking, oh my gosh—if it doesn’t really matter, like should we do what the breast cancer doctors do? They don’t even do follow-up scans at all, right? They do an occasional LFT and a physical exam, and that’s it. Should we begin shifting to something like that?

Know that we are dialing up in the other direction—because we’re increasingly doing MRD testing, where we’ll have an even more sensitive measure than CEA or scan to determine if somebody’s got residual or persistent cancer.

And I am hopeful that what we will show is that by identifying patients at the molecularly positive level—like an MRD test—we can intervene.

And in fact, I’m helping to lead a study across our country to test new agents in that space. That if we intervene with those new therapies, we will, in fact, cure more people through that earlier intervention than by waiting to see what grows out there in the patient’s liver or lungs, et cetera.

Recently, I have a patient—a colon cancer patient, a young man—who had an MRD-positive blood test. And his scan—regular conventional CT scan—was negative.So, I ordered a PET. Now, you could argue maybe I shouldn’t have. But he had two in a row—blood tests, positive; CT, negative. I ordered a PET. Guess what? The insurance company said, “No, you can’t order that.” So, I ended up doing a peer-to-peer review.

Don’t you love peer-to-peer reviews? How many of you initially say, “Are you actually an oncologist?” when you talk? I wasn’t—I was polite to the doc on the other end. I told her the story. She plugged in the data that now the patient was MRD positive, and she read out the approval code to let me go ahead and get the PET scan. So, clearly, MRD testing is having an influence on decision-making and insurance coverage. But it’ll become our challenge to demonstrate that knowing MRD testing is important enough that it will influence survival—unlike that Annals of Oncology paper that showed that CTs and CEAs maybe not so much.

I think this paper puts us at a higher bar for challenge—to make sure that following patients closely makes sense, and that this MRD testing better work for us. Or else, we’ll just be pulling back in general after patients are initially treated.

So, I hope you find this next series of discussions about MRD testing, et cetera, interesting and useful to you. And I hope you find these two papers a bit challenging—one that takes us to a screening test for pancreatic cancer, the other that takes us to: should we be doing anything after we follow patients, outside of these newer tests that are coming?

So, more to come. I hope it’ll be useful to you, and I hope you’ll tune in next time for Oncology Unscripted.

Crisis, Misinformation, and the Future of Cancer Care: A Candid Conversation with Dr Eric Winer 

John Marshall, MD:
Hey, everybody out there—John Marshall for Oncology Unscripted.

And I am a lucky guy to be able to talk with such an amazing contributor to our world of cancer: Dr Eric Winer. And I’m going to embarrass him for a minute. Not only are we Dukies—by the way, go Devils—but we all know he has, as everyone on this call knows, really led so much of the innovation and progress in solid tumors—specifically breast cancer. Transformed things up at Harvard first, now back to his home base of Yale, where he oversees an incredible group of people and a program. And I am just—first—honored that he said yes when I asked him for a quick interview on the world today. So, Dr Winer—Eric—thank you for joining us.

Eric Winer, MD:
Oh, pleasure to be here—and I was honored to be asked.

John Marshall, MD:
You are so cool. Thanks a lot.

I mean, what I wanted to talk with you about is the impact—the acute impact—that we are having in general around cancer research and around cancer care, since this academic versus executive branch battle that’s been going on around grant funding, around cancer care, but now more acutely with the government shutdown, we have NCI trials. You know, patients are losing insurance and this sort of thing. And I know what it feels like here in Washington, but I thought—you, having a pretty broad vision around things in the country and maybe on a global scale—might have some reflections on this.

So, maybe just wax poetic a second about what the last several months have been like, and how the last month has made that even more.

Eric Winer, MD:
Sure. So, the last several months have not been easy, for sure. In truth, there are not that many grants that have not been refunded at our center at Yale. There are some—and there are people who lost some funding—and we’ve done our best to backfill whenever possible.

I think there’s a lot of anxiety. There’s a lot of anxiety, particularly among young people—young people trying to make careers in the lab, trying to make careers in clinical research—and that’s been pretty tough on everyone. And at Yale, we are one of those institutions—which I guess I should say we’re lucky to have such a large endowment—but we are one of the 8% endowment earnings tax institutions. So that is hundreds of millions of dollars a year to the university that we will be losing. And so, there have been many conversations about how it is that we’re going to manage to keep doing everything that we want to do. This is not just at the School of Medicine or in the cancer center—this is the university at large.

With, you know, with that kind of hit, I think the last few weeks have even been harder. Today there was, of course, supposed to be a Cancer Director’s meeting at the NCI. And the reason we are in our offices all day is because that was cancelled because of the shutdown.

John Marshall, MD:
Tell me the impact of that.

I mean, you guys get a lot done. I know when Lou Weiner goes up to those meetings, he comes back with a lot of fresh ideas, new collaborations, progress.

Tell me what a missed meeting—I mean, somebody said, “Well, we meet too often anyway.” What’s your take on that?

Eric Winer, MD:
Well, I think missing a meeting—you know, one meeting—isn’t such a big deal. I mean, in truth, was I perfectly happy to stay at home in Connecticut rather than go to Washington today? Sure. On the other hand, I think these meetings serve a real purpose.

It allows us to talk to one another. It allows us to hear what’s going on at the NCI, and how the Cancer Center Support Grants potentially are going to change. It’s a way of collaborating. So, I think it’s serious, and it’s concerning.

I guess my biggest worry with the government shutdown is all the people who aren’t getting paychecks. All the people diagnosed with cancer, who are living with cancer, who are struggling to find food to put on the table. You know, there were multiple stories this week—just watching the various news outlets—about government employees going to food banks. And some of those people have cancer. And it’s very hard.

I think that all the anxiety that we feel in academia at the moment—particularly related to medical research—I think now, suddenly, the whole country is feeling, with the government shutdown. And it’s hard to be under multiple stressors at the same time.

John Marshall, MD:
With cancer being one of them—particularly, think about our patients.

So, my wife accuses me of a lot of hyperbole—and she’s probably right—but I think we’re about one in three, one in five of my patients here in Washington, where one of the couple has either lost their job, is on furlough, or it’s questionable. And they’re often the one the insurance is with, right? And so, we’re trying to make plans for next scans or next cycles. And hospitals are on their heels a bit too about: will these be maintained? Will people keep up their premiums?

And so, I’m assuming you all are feeling it there in Connecticut as well, right?

Eric Winer, MD:
I mean, we don’t have as many government employees—federal government employees—as you do in DC. But, you know, I think it’s this pervasive sense of angst that so many people have that just makes it so much harder.

You know, my patients come in—and I see patients one day a week and totally enjoy it—but I have to say that the anxiety level is up for everybody. And I think that’s hard.

And it’s very hard when you’re going through difficult treatment and a difficult diagnosis, and you may be facing a diagnosis that is going to shorten your life expectancy—and to deal with everything else is pretty tough.

John Marshall, MD:
You’ve had a career in drug development, and I know you have a very good sense of global cancer research and global cancer care. There was just another colon cancer study that popped positive—using an IO plus an oral VEGF—that beat regorafenib by a nose. And I think about very expensive therapies—trial done all around the world—for a U.S. market, primarily.

And I sometimes wonder if our patients understand—or our federal government understands—just what a privilege it is to practice medicine here. Because we do have access to all the innovations. We’re the first to have access to them. We can provide them for our patients. Yes, it costs a lot of money—but it is a privilege. And we’re sort of the leading point on breakthroughs and applying those breakthroughs to our patients.

Do you think... you know, the administration before the Biden administration wanted this to happen. Certainly, RFK Jr. wants this to happen—some sort of leveling out of the playing field, of both the investment and the cost of cancer care.

Are you starting to see some of that?

Eric Winer, MD:
I don’t know that I’ve seen a lot of it.

I will—just to sort of shift a little bit—what I worry about is that the access that many people have to new treatments and drugs is not remotely distributed fairly or evenly in our country. And not all insurance is the same. Lots of people don’t have insurance. As there are threats to Obamacare and cutbacks in Medicaid and reductions in subsidies. You know, what the average family is going to pay in some states—where they've received subsidies—for their healthcare is huge. I mean, I think I read that a family of four living in Maine, when they lose their subsidy—a family of four making $130,000—is going to have to pay another $28,000 a year. They can’t do that.

That’s going to mean that people go without healthcare. And that’s going to lead to even greater inequities in the delivery of cancer care than we already know exist. You live in Washington, where the mortality for Black women with breast cancer is dramatically higher than for White women. And we know—if you look across the whole country—that if you’re a 20-year-old Black woman, a Black American woman, that you face twice the chance of dying from breast cancer as a 20-year-old White American woman before the age of 50. So, this is huge.

I will be the first to say: I believe in universal coverage. I think healthcare is a right, not a privilege. And it kills me that we’re getting further and further from that.

John Marshall, MD:
Further away. I couldn’t agree more about that.

And we spend—think how much we invest in our institutions, ourselves, and just the infrastructure and staff—to manage the complexity that you just described. And if we had a simpler system, we would reduce the cost of delivery just by that.

Eric Winer, MD:
Well, and it’s not even just about the dollars.

As treatments get more complicated, and they require more in the way of family involvement—if we have people who are struggling to get by, how are they going to have family members who can help them get through their cancer treatment?

You know, it’s interesting. We have a very large organization in New Haven called Sisters’ Journey, which is essentially a group of largely Black or African American women with breast cancer. And they are very effective advocates. They raise money. They try to help one another. And in talking to them, they realize that the care that many of their members have received over the years is just not the same—for a whole range of reasons—as the care that more affluent, and typically White, people receive.

John Marshall, MD:
Let me take you back and sort of—as we wrap up—to something you brought up at the beginning, and that’s younger people. You know, we are in the gray-hair part of our careers, but we’re still, you know, we’re out there doing our thing. But we’re OK. We’ll be OK individually.

But when you start thinking about somebody who’s 30, 40—early career—whether it’s medical or research or both. I think about my kids, who are in their early thirties. You know, what they’re going to have to deal with going forward about building careers—and the importance of that foundational science that really they provide us as we move the bar in research.

Maybe just share any further reflections you have. How vulnerable are these folks? Is it really angst that they should be worried about, or is it just angst because it’s unstable?

Eric Winer, MD:
Well, look. In the U.S. alone, we still have almost 2 million people diagnosed with cancer every year, and over 600,000 people who die from cancer. We need a lot of research still. We need research, and we need people who deliver the care. It’s just absolutely critical.

And you and I aren’t going to be those people with the breakthrough ideas. You need young people. And when a person who is 30 or 35 or 40—who’s finishing a PhD or an MD or an MD/PhD—looks at the likelihood that they’re going to get funded on their next R01, you know, with a chance of 4%. And maybe, if they’re a new investigator, it’ll be 7%. It’s hard to maintain enthusiasm. And yet, we desperately need those people to keep going into cancer research, or else we’re truly going to have a brain drain. Maybe not tomorrow. Maybe not next year. But in five years—we will.

And so, the damage that’s potentially done through these cuts in funding—and it’s not as if funding was so very generous ever—but at least there was a hope that people would get funded. But with the kinds of pay lines that exist at the moment, if I were a young person, it would be hard to maintain enthusiasm. And I’d be thinking about doing other things. I hope they don’t, but I fear they will.

John Marshall, MD:
Let me go one last place—and this is really what sometimes hurts me the most or makes me the most upset—and that’s the misinformation that’s being put out.

You know, as a GI oncologist, to see the word leucovorin on the front page of The Washington Post was shocking to me. Because, you know, we were going to cure a different problem with folic acid—fancy folic acid. And you see so much of it.

And so many of our patients are clearly reading this, because they’re coming into clinic and asking about it. So, I feel that I’m spending a much greater amount of my time just resetting reality—of what we know as science today and medicine today.

What’s your thoughts on that? Do you have any reaction to that?

Eric Winer, MD:
Well, I think, of course, misinformation is incredibly dangerous. And it’s hard for people who aren’t medical professionals to keep track of all the medical facts. I mean, medicine is complicated. But if at times people are hearing things that are just blatantly incorrect—and particularly when those comments come from people who they may respect—then it’s really challenging. I think we have to do our best to educate society about what we know and what we don’t know, and what steps people can take to improve their health and their family’s health. And when there are false statements made—it’s hugely damaging.

John Marshall, MD:
Thank you. Thank you for that feedback and thank you for your time.

I know it is Breast Cancer Awareness Month. You may or may not know that I’m sort of grumpy about that as a GI oncologist. So, if you want one of our stickers, here’s a “Love Your Butt” sticker—for, you know, the colon cancer people that are out there.

But let me again thank you so much, Dr Winer, for giving us your time and your knowledge and your experiences as we all navigate these challenging times.

We really, really appreciate your time.

Eric Winer, MD:
You bet. Take care.

John Marshall, MD:
John Marshall for Oncology Unscripted.

Thank you all very much.

[38:13]

This transcript has been lightly edited for clarity.

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ESMO, Efficiency, and Evidence: New Data, China’s Science Leap, and Leucovorin and Autism 

John Marshall, MD: Hey everybody, John Marshall from Oncology Unscripted. There is so much going on right now that we're gonna need a full hour-long show, but we're not gonna do that to you. We still promise short bites here and there of the stuff that's going on, just to make sure you're in the loop. I'm sure you are.

But let's start with a little science. And the science we wanna focus on is the upcoming ESMO meeting. We've looked at the leading abstracts that are gonna be presented there, and there's not gonna be a lot of surprises about the content. There's a lot of innovation in precision medicine and immunotherapy and different diseases, and positive randomized trials, and some exciting early-phase clinical trials. 

But what I think is worth noting is that a pretty high percentage of the science that's being presented at ESMO actually comes from China—Chinese pharmaceutical companies sponsoring it, China's institutions running the clinical trials. And there's been a lot of discussion about the quality of Chinese data.

Just recently, on September 23rd, Scott Gottlieb—who used to be, of course, the head of the FDA—did a very nice opinion piece in The Washington Post about the impact of Chinese drug development. The quality wasn't actually that bad—it was just less expensive. They were able to do clinical research much less expensively than we can here in Western society, if you will.

So, it's not so much intellectual innovation—it's efficiency in getting answers out. His whole editorial is about: how do we reshape and reprioritize our own clinical research infrastructure? How does the opportunity of a, I don't know, a world turned upside down in terms of regulatory oversight, et cetera, give us a chance to maybe improve the process, to lower the cost of drug development, so that our innovation—which we really still remain the hub for—can actually be brought forward and not create some sort of global intellectual property war, which he refers to, but more: how do we keep up with the pricing structure and the innovations that are out there?

So, I encourage you to not only look through the abstracts from ESMO—because there are some very important positive results from that—but also think a little bit about how we, in different parts of the world, even the playing field around the cost of new drug development. I encourage you to read that Scott Gottlieb Washington Post editorial.

One of the big abstracts that will be presented is around MRD ctDNA testing and using that technology as a way to define who should receive adjuvant therapy and who should not. Of course, we are interviewing the lead author on that paper, so stick around for that interview. But we clearly can see that genetic testing may, in fact, have a major impact on making us more efficient on who should get adjuvant therapy and who should not.

So, I do clearly think that's the evolution that's going forward. You wanna make sure to keep your finger on the pulse of MRD ctDNA testing in the decision-making process for adjuvant therapy and subsequent treatment.

I'm lucky enough to be running a protocol here in the United States looking at MRD positivity in patients with colorectal cancer, and others are doing it in other diseases.

One of the ways that could, in fact, make that much less expensive is digital pathology. Because it turns out that a digital image of an H&E slide—and there's some fascinating data around this—can actually predict risk almost as well as genetic testing. So, that's very inexpensive. It takes 20 minutes to scan it in, send it off to the computer, AI reads it back, and gives you a risk factor.

So, I do want you to also keep a nose out for digital pathology as an impact.

But maybe the most unsettled science that I saw in the last week actually was also in The Washington Post. Now, The Washington Post, in one issue, reported on vaccines killing children, our administration down the street is going to be talking about how evil vaccines are—continuing that discussion that their rising costs are gonna break us in the U.S. Our economy is so built around healthcare that the rising costs are eventually gonna break it. And the risk is that what I'm saying right now might land me in the same boat as Jimmy Kimmel—of getting fired. But you know, last night he was back on again. So maybe that will only be temporary. But the science I wanna talk about is this whole connection between, say, Tylenol—acetaminophen—and autism. And the only reason it says “Tylenol” is that Donald Trump can't say the word “acetaminophen.” And so many people out there are affected with autism over many, many decades—even well before Tylenol/acetaminophen was invented. But what really caught my eye is these smaller studies that have suggested that leucovorin—which is folinic acid, okay? It’s reduced folic acid—was helping in some clinical trials.

Now, I wanna remind us all that in the United States, in 1998, our diets began to be enriched with folic acid. They did that because there was very good evidence that if you had enough folic acid in your diet and you were pregnant, that you reduced the risk that the baby would have any neural tube defects.

So, our entire country is on folic acid supplementation so that we would have a reduced rate of neural tube defects. And for us—or the administration—to now be saying that we should be giving people leucovorin, which is simply a reduced form of folic acid, to try and treat autism is really wild. To the point where the recommendation came out—even this morning—pushing from the White House up to the FDA to relabel leucovorin.

Now, I give a lot of leucovorin. I'm a GI oncologist. So, let me just remind you that when we don’t have leucovorin—remember the plant broke, and so we, for a while, didn’t have leucovorin—if you just took folic acid, if you went down to Costco and bought yourself some folic acid and you took it, your body converts it to folinic acid using dihydrofolate reductase—an enzyme we all know and love, 'cause that’s where methotrexate works.

So, we’re on it anyway, right? We’re all supplemented through our diet, but also many people take multivitamins and others. But we’re all on folic acid—so much so to the point that side effects from 5-FU in the United States are different than 5-FU side effects in other parts of the world because we're all on low-dose leucovorin, if you will.

And so, before we all go crazy—and I know, if you are the parent of somebody with autism or you know somebody, you're tempted to say, “Well, let’s go out. Let’s take some folic acid”—I don't think there's any harm in that. But I think for our administration to change a label based on this amount of data is unprecedented. And I'm anxious about that because it meets a cause that they care about, but you know, it may be influencing how we develop drugs in the future.

So, it's science. Yes. Is it early? Yes. Would I like it to be true? Yes. I think we ought to study it further. Should we change a label? I think that’s taking the step too far.

So, a lot of science—whether it’s ESMO or in The Washington Post—a lot to learn as we go forward. Pay attention. Value the data that you see in front of you. Qualify it in a way that makes sense to you. And then make your recommendations to your patients and your friends based on that. I think we’ll be better off if we stick to traditional scientific method. Yes, accelerate it. Yes, make it more efficient. But we need traditional scientific method in order to improve outcomes for our patients around the world.

John Marshall, Oncology Unscripted.

[00:09:11] MedBuzz

How Are You Holding Up?

John Marshall, MD: Last Monday, I was walking around the hospital and I noticed a different mood. The hospital, in today’s world, has been kind of a safe haven. Whether you're reading the world that’s changing every day and all the rules are thrown out—in the hospital, we all had a common enemy. We had a common purpose.

And so, it’s not a political place at all. We were holding doors for each other, we were smiling and encouraging each other—whether you were a patient, whether you were administrative staff or medical staff, whatever—you were part of a team that was working together.

But this last Monday, I was walking around, and it really felt different. It felt like people were flat. It felt like people were withdrawn. It was no longer that safe space that we wanted it to be, and I was very anxious about the mood creeping in. The mood that's out there in the world today, about all the changes, was creeping into the hospital itself. It got a little lighter through the week, but I still think it’s a different place. I think it's because of the stuff that’s out there. 

Now recently—just last weekend—I was down giving a lecture to the International Society of GI Oncology, a group I helped found many years ago, and I was honored to be given the chance to give a talk at this group. It was an overview of where we are in GI cancers in general. I was thinking about and talking about our jobs, and the work we do, and the pressures that outside is applying, and the emotional connection we have with our patients and with each other, quite honestly, as a team. And I don't often do this, but all of a sudden, my throat got a little caught. I was… I was sad. A loss for words. Anxious for those around us. I'm an old guy—I can survive. But I was worried about the 30- and 40-year-olds that were in the room, that needed to carry the torch forward. I was worried about just all of those pressures that were around. And for the first time, maybe ever, I was struck by the emotion of the time. And it sort of went along with the mood of the hospital.

I'm hoping that we can kind of come out of it. I don’t know about you, and I’d love for you all to provide feedback. Is this something that you're feeling in your practices? In your workplace? Is it creeping into the medical community in a way that's disrupting what we do and how we feel?

Because I do think it’s really important right now. Part of my message back at us all is that we need to make sure and take care of each other. Support each other—whether you're supporting a patient, whether you're supporting your team or your colleague—we need to make sure that we're reading each other and are there for each other through these hard times.

So, what's the mood in your hospital right now? Is your throat getting caught a little bit when you read something or have to share thoughts with others? Or are you hanging in there and doing all right?

I hope it’s the latter, 'cause somebody needs to keep holding the torch for us and keeping things moving forward.

John Marshall, Oncology Unscripted.

[00:12:47] Candid Conversations with Experts

How Do We Treat Smarter? An Interview with Dr Thomas Powles

John Marshall, MD: Hey everybody, this is John Marshall here in Washington, DC, where nothing is normal lately. A little bit rainy today, but we need it, so maybe it’ll wash away some of our sins.

But Oncology Unscripted is fortunate enough today to have an amazing guest, Dr. Thomas Powles from London. So, it’s a little later in the day where he is than where I am. Tom has really led the charge in innovation in treatment with GU cancers. And I was first attracted and wanted to interview him not only because he’s a famous social media guy—he's really had a major impact on information sharing in our cancer community—but really because of the clinical trial that he oversees. But first off, Tom, welcome. I’m hoping you’re having a lovely day in London. We love it there—our kids live there. Do a quick introduction of yourself for our audience.

Professor Thomas Powles, MBBS, MRCP, MD: Well, John, firstly, I’ve followed your work for many years, and I’m incredibly honored to be here with you and the amazing things that you’ve done, and I’m very happy to join you.

I’m Tom Powles. I’m an oncologist in London. I’ve led a number of different trials—some have been successful, many have not been successful—and I also have collaborated with a huge number of people. And those trials which I have led have clearly been a huge team effort.

And we are making a, as you said, in GU cancer, a big charge towards curing patients with bladder cancer. We’ve done very well in kidney cancer, but we haven’t quite got there yet. And, of course, prostate cancer is a complex beast, but there are huge numbers of new therapies. So, really exciting times in GU cancer.

John Marshall, MD: Totally. So, in MRD testing—let’s jump right into that—I think of adjuvant therapy as one of the most inefficient things we do. On one level, some people were already cured by our surgical team members, if it truly is postoperative adjuvant. On another case, some patients are not cured despite receiving therapy; they have microscopic metastatic disease and relapse anyway. Then there’s that wedge of people who we do fix—we treat 100 people to help, I don’t know, a quarter of them, right?

And so, how do we find the right patient to be treated? This is where, at least in GI cancers, we’re increasingly looking at MRD, and it’s really quite controversial as to whether this has value or not. The study that you have presented and continue to update around this in GU cancers, to me, is a demonstration of just the value of it. So, maybe drill down a little bit on that study.

Professor Thomas Powles, MBBS, MRCP, MD: So, John, first, before I do, I’d like to agree with you. I think the next generation of oncologists will look at the way we select patients based off lumps on x-rays to define the presence or absence of disease as a long way from reality. Probably in the same way as we currently look at doing surgery without anesthetic—as a similar. You know, how could you treat 70% of patients who have no chance of relapse, giving them a 20% chance of life-changing toxicity, to try and help the 30% with disease. And of course, if you focus on those 30 with disease—if you have a 10% absolute survival benefit, but you're dragging along 70% at no risk—you can actually double or triple that benefit, from a 10% to a 30% survival benefit. So, it’s not just about sparing those patients who don’t need treatment—it’s about improving your hazard ratios, and that’s absolutely crucial. But then, of course, there’s the sensitivity and specificity of the tests you use. Radiology, obviously, are very, very good tests—because if you’ve got big lumps on an x-ray, you know you’ve got cancer there. But of course, postoperatively, treating unselected patients—we are scrambling around in the dark.

We currently hope that a pathology sample defines high- and low-risk disease—not biology. You know, “How big was it?” Which, of course, is completely, in my opinion, hopeless. So, we’re treating those patients who have bigger cancers because we feel they’re at higher risk.

What about if we can develop an MRD test—circulating tumor DNA—using an informed approach where we do whole exome sequencing on the primary tumor, identify up to 16 mutations, and then track those mutations over time? Can we identify those mutations in the blood?

And the answer is: yes, we can.

And what is the positive predictive value and the negative predictive value? It turns out they’re both pretty high in the adjuvant setting in bladder cancer.

Essentially, what I can tell you is that if you do an operation in bladder cancer, about 50% of the patients will relapse after that operation. And about the same proportion of patients are ctDNA positive after surgery. There’s a very strong correlation: if you’re ctDNA positive six weeks post-surgery, you’ve got a 95% chance of relapsing. If you’re ctDNA negative post-surgery, you’ve still got about a 25% chance of relapsing. But you can change that—because if you're negative and you track those patients and they become positive, they do poorly. But if they remain negative, they do really, really well.

So, the chances of dying of urothelial cancer—and this is data from the TOMBOLA trial, and also from other prospective series—if you track those patients who are negative and remain negative, the chance of dying at two years or three years of bladder cancer is minuscule. You know, it’s 3% or 4%. The chance of relapse is still about 5% or 6%, so it’s still there—it’s not perfect in those negative patients—but it’s very good in the positive patients.

What we showed in a study called IMvigor010 is that those patients who had had surgery—successful surgery for urothelial cancer—and there was no evidence of disease on radiology, that 50% who were ctDNA positive, if they received atezolizumab, you could reduce the risk of relapse and the risk of death by about 40%. Hazard ratios between 0.44 and 0.5. But atezolizumab in unselected patients had hazard ratios between 0.8 and 0.9.

So, it's that dilution of those negative patients. Focusing on the positive patients.

In those negative patients, atezolizumab had no benefit. Although many of those patients—30% of those patients who were negative—relapsed, atezolizumab made no difference, because the risk was low.

Now, if you track those patients—and in the upcoming study at ESMO in the near future, we are doing a repeat of the experiment prospectively—if you are negative, we’re continuing to track your negativity. And if you are negative and become positive, you can then enter into the study. We hadn’t done that before, and that’s novel. That will give us the reassurance that we’ve got those negative patients who remain negative—we do well—but those negative patients who become positive—can we salvage those patients?

Also, immune therapy in bladder cancer: there are two important components. One, we know that by the time you’ve got measurable disease, the cancer’s growing too fast. We lose many of those patients. So, we have to go earlier. That’s why we’re doing it in the adjuvant space. Two, it does appear the biology of the disease is potentially more sensitive to immune therapy the earlier you treat these cancers. Put that together, and we’re hoping for great results.

We’ve looked at other settings. We’ve looked at ctDNA in the neoadjuvant space. But that’s more complicated because you can be ctDNA positive because of your primary tumor or your metastatic disease. So, to define that better, we are now looking at urinary tumor DNA.

We’re beginning to get great results for utDNA. So, if you are utDNA positive and ctDNA negative, you might have bladder-only disease. If you're utDNA negative but remain ctDNA positive, you may have had a pathological complete response in your bladder. We know many of those patients relapse—and that means you haven’t gotten rid of that nodal disease, which is still micrometastatic.

So, it’s the first chapter of a series of chapters that I think is going to transform urothelial cancer.

The last part to it, which I think is important, is monitoring those patients. And ctDNA clearance is an early indicator of good drug activity. In the future, we’re going to be using ctDNA and not radiology to assess that clearance. There’s a study called the MODERN trial—Matt Galsky is leading that study. He’s comparing nivolumab to nivolumab plus a LAG-3 inhibitor, to see if ctDNA clearance is higher with the combination.

And I feel this is a revolution that’s going to stand the test of time.

John Marshall, MD: I want to dig down a little bit on the whole biology question, because in GI cancers, we don’t enjoy that sort of transitive result—where something that works in the refractory setting, metastatic disease, will work in the adjuvant setting. And I actually think MRD-positive is its own biology.

From a drug development perspective, one of the things that I’m leading here in the United States is a platform of MRD-positive colon cancers where we can then test for novel therapies. Because I don’t think the old FOLFOX and FOLFIRI are the right answer in that setting.

And I think you feel like—what I’m hearing you say is—that you’re sort of aligned with that. It’s its own unique biology, different from… it’s the difference between seeds and small plants, if you will. There’s a different biology there.

Professor Thomas Powles, MBBS, MRCP, MD: I feel strongly that that’s the case. When you drill down into some of the biology of the 010 paper—and we put that in Nature, not in a clinical journal—and the reason we went there is: we did whole exome sequencing, obviously, because that’s how we track the ctDNA using the informed approach. We also did RNA sequencing—looking at immune signatures—and we did immunohistochemistry. When you pull that together, there was some indication that there were distinct biological features of the ctDNA-positive patients compared to the negative patients. And as you track— which you can do with time—you can obviously see dynamic changes associated with ctDNA and the different mutations.

So, I do think there are different biological components to this disease. I think those patients who are ctDNA positive may not just represent lower or high risk, or disease that’s inevitably going to relapse and just isn’t yet radiologically visible. It may represent its own distinct biology, which I think is worthwhile exploring.

And in terms of coming to your trial—I don’t know enough about GI cancer—but I do feel that exploring beyond these chemotherapy regimens is really attractive. If you want to accurately identify early active signatures, MRD must be the best way of doing that.

I think it’s a really good way—across different tumor groups—of delivering positive trials for interventions which perhaps, by the time you’ve got advanced disease, it’s too late for some patients.

John Marshall, MD: And we are actually thinking even deeper than that—that maybe you begin to have disease-agnostic interventions at MRD. You might see some cross-reactivity there. So, fingers crossed that the setting you have shown, positively—the interventions around this—will trickle out to other diseases.

But I want to go one other place before we let you go. And that is—we come from different cultures. We work in different cultures.

In the United States, people feel like they have the right to whatever it is. So, if there’s an adjuvant therapy, we treat everybody. And we’re incentivized, right, as physicians to treat people—that’s how we make a living around here. Whereas in the rest of the world, this is very expensive therapy, and so we have to demonstrate positive impact.

So on our side, we’re having to show that it’s okay not to give it—that it won’t work. And usually that requires very large studies to show that you’re not even missing one person, right? The breast doctors do thousand-patient studies to show a 1% improvement in whatever intervention they’re doing.

Whereas in our kinds of cancers, we’re looking for anything that’ll help. And our cultures are different. So, talk a little bit—I know you know both cultures, you interact, and this trial is open across the various cultures—where do you see oncology going? The rising costs of drugs, the limited access to these drugs around the world, the role that MRD might play to improve access globally?

Professor Thomas Powles, MBBS, MRCP, MD: What a complicated question—and I’m going to do my best to answer it.

The first thing to say is: I’m a huge fan of the United States of America. I think it’s an aspirational culture. And when one looks around the world—and I travel the world all the time—you look at the ambition and the aspiration, the dynamism in the United States of America, it’s second to none. I’m a great fan, and I spend a lot of time there.

I’m also a fan of the FDA. Given a choice between the FDA and the EMA, I see advantages and differences between both. But I feel the FDA is a more pragmatic organization, and I have to say—I’m a great fan.

In terms of drug development, I think the last 10 or 15 years have been transformative in the cancers that I’ve treated. That wouldn’t have happened with the universities alone. We weren’t making amazing progress, and the incentive to develop multiple targets at the same time and do parallel trials has been successful.

Indeed, many of those trials that weren’t successful—we’ve learned from and moved forward. We wouldn’t have been able to do those thousand-patient trials with just the university structures that are in place. At the moment, you can’t do a study in Europe and the United States—it’s almost impossible together in a university structure. I’m sure you wouldn’t be able to do that in Asia Pacific, Europe…

And the final bit I want to say before I get to the second part is: in the cancers I treat, median survival in urothelial cancer—10 years ago—was one year. It’s now tripled to three years, with a 30% CR rate. That’s going to get even better next year, in my opinion. Kidney cancer—again, 15 years ago: one year. Now: five years.

And that’s not because of radiology. It’s not because of better diagnostics. It’s not because of better surgery. That’s all because of drug development. So, we have to look at that success and celebrate it and say, “Yes, it may have been expensive, and it may be difficult—but what else are we investing in?” We’re investing in—dare I say it—arms, we’re investing in banks, in all sorts. Isn’t it terrific? This is a good investment.

And going back to your former presidents—and of course I’ve studied Jimmy Carter and all the way through—that race against cancer that each of the presidents has tried to achieve: I think we are winning that race. I think that’s very positive.

On the other hand, there is a twofold concern:
The “no stone unturned” approach where I have to have received every drug, that approach is not helping many patients. Indeed, it’s probably harming quite a few. There are two reasons for that: One, there is this difficulty around families and aspirational societies saying, “If it’s there, I have to have it.” And two, my experience of third- or fourth-line bladder cancer—dare I say it, second-line bladder cancer—is that it’s a law of diminishing returns. In the end, it goes wrong for almost everyone. It’s probably doing as much harm as benefit for many of those patients.

You and I have both seen many patients suffering from toxicity toward the end of life, trying to get more and more cycles in. I do think Europe is more pragmatic about that. I do think if your median overall survival is seven months, your response rate is 10%, and it wasn’t significantly better from an OS perspective than placebo, I think Europeans—and the EMA—are much more pragmatic, saying, “We want to see more.” And I think that’s very reasonable.

One caveat: occasionally, those drugs that weren’t great in a second- or third-line setting have turned out to be quite active in combination in the frontline setting. The FDA is good at that. I have examples where we’ve had underwhelming results second or third line, and we moved it to the frontline setting in combination—and we’ve achieved those survival advantages.

So, I think that pragmatic approach is important. But I do not feel that every patient needs every therapy. I don’t think every patient benefits from every therapy.

One of the key questions—when one looks from a European, U.S., and global perspective—is how we assess PFS and OS endpoints. It’s clear to me that in the perioperative setting, we need to achieve OS. That’s my feeling on this. I don’t think disease-free survival as an endpoint is enough.

Two reasons—one, you can give salvage therapy subsequently to those patients that need it. And number two, you are overtreating all those patients who are not going to relapse. So, for me—we need that. I know many of my American colleagues feel DFS is important because that has a higher rate of not achieving advanced disease and avoiding advanced disease as a goal.

I have mixed feelings about that. I think patients want to live longer and feel better. In the perioperative setting, if you don’t have OS, you’re not achieving either of those goals.That’s relevant.

The last bit I’d like to say around that issue—which I think is important—is that MRD has a really important way of achieving OS. You enrich those patients that need therapy. You put some patients in harm’s way, but you do achieve OS. And MRD studies—of course—OS should be the endpoint.

The second part is: you’re sparing big groups of patients therapy who almost certainly don’t need it. Treatment would be overtreatment. Achieving overall survival advantages in that negative subgroup will be almost impossible. And indeed, the risk is low.

So, MRD achieves those goals that I think we are looking for. And I suspect, John, in the future, we won’t be talking about adjuvant therapy in the way we are now. I think we’re going to be talking about patients with MRD or without MRD. And I think, as you’ve said in your study, those patients with MRD—novel trial design to improve survival—in the end, is going to be a really important chapter in where we go next.

John Marshall, MD: I would bet—if I had enough money to throw on the table—that in fact MRD testing will become screening. And maybe in 10, 20 years, you don’t even get your bladder taken out or your colon taken out, but you just get systemic treatment and make the cancer go away before it’s a problem. But you and I can work toward that end and put ourselves out of a job.

Professor Dr. Thomas Powles, thank you so much for spending your valuable time with us. You’re clearly transforming cancer care through incorporation of MRD and innovative clinical trial design and teaching us all about how we’re going to go forward—including about how we’re going to do that as a unified global medical community.

Professor Thomas Powles, MBBS, MRCP, MD: Good pleasure. I really enjoyed it. Thank you very much indeed.

Hosted by Simplecast, an AdsWizz company. See pcm.adswizz.com for information about our collection and use of personal data for advertising.

John Marshall, MD: John Marshall for Oncology Unscripted, coming to you live from this big office. This is the biggest office because, you know, I've been the Chief of the Division here at Georgetown for 20 years. I didn't want the job when I was first offered it a long time ago. I ended up saying yes. Of course, that's a dramatic change in one's academic career—taking on administrative roles like this. You do get the big office, which is nice, but you also get a lot of other stuff. You know too much. You know who's mad at whom, you know who you need to recruit, and who you need to un-recruit—all of those things. You have the business side of a cancer business going on, and you're a doctor, and you're doing clinical research, and you're trying to educate everybody around you.

About a year or so ago, I decided in my own head that 20 years is enough. And so, as of this summer, I have officially stepped down as the Chief of the Division here at Georgetown. My colleague and much smarter friend, Dr. Steven Liu—lung cancer expert, world expert—is stepping in to be the Chief of our Division, and he's already hit the ground running. The fresh voice is honestly already a positive. You can just hear the freshness of his voice and his attitude and his energy. 

You know, the Mayo Clinic actually has a structure where you can only be in a leadership position for so many years, and it has to turn over. And I really like that. It's sort of like what we hope our presidential terms will be. But who knows—that may change. But there's a limit: you do the job for a certain period of time, and then someone else steps in and gives you that fresh voice and fresh perspective. But that's not the traditional way of doing it. Most of the time, people hold on to their position as long as they can hold on to it, until they can't do it anymore or they decide to go to some other institution.

But the reason I'm sharing this is that I'm now in this sort of weird new place. I'm an ordinary staff physician. All of a sudden—yep. I have my patients, I'm doing my thing, I'm putting people on clinical trials, I'm educating the brand-new fellows who just showed up here about a month ago. Great fun having brand-new fellows 'cause they don't even know how to spell 5-FU, much less how well it works, how it works, and the side effects, etc. So, I love the first few months 'cause you're teaching people a lot of new things that they need to know. But anyway, that part's very exciting. So, I'm still doing all of that.

But what I'm gonna have to get used to is not knowing everything—also not feeling responsible for everything. And that's gonna be a change for me. So, any of you out there who've either been through that transition or who maybe wanna offer me some therapy—I'm in line for some therapy as I transition, as I begin to slow down my academic career, withdrawing as the Chief of the Division, but still doing my day-to-day job and still trying to cure cancer.

Take care of each other out there. Take care of your bosses and those leaders. It's not a great, fun job. But also, remember: those of us who are now back in the trenches—we need to take care of each other as well. John Marshall for Oncology Unscripted.

[00:03:35] Editorial: Watching Vaccine Access Collapse In Real Time

John Marshall, MD: John Marshall Oncology Unscripted. First piece of advice: don’t read the newspaper. Second piece of advice: don’t watch C-SPAN, for sure. Just yesterday on C-SPAN was the big congressional hearings. I did read the summary of it in The Washington Post, where RFK Jr. was interviewed—cross-examined for three hours by both sides of the aisle—about what he has been doing with the CDC. And I think we all, as medical professionals, need to take a big step back and a pause and sort of ask: what the hell is going on?

You know, the specifics first. He fired everybody at the CDC. He has hired new people at the CDC. They have not come forward with any formal vaccine recommendations. This is all about vaccines and the like.

Yesterday in clinic, a patient of mine—who would be a candidate for both flu and COVID vaccines, who could have, a month ago, walked into CVS and gotten both of those injections—now, in the state of Virginia (and I think there are about 14 other states where this is true), has to have a prescription. This came out from CVS and Walgreens—that you have to write a prescription. Physicians have to write a prescription so that patients can take it to the CVS and Walgreens to get their vaccines. Some states are not providing them at all. Some states have gone the other way, where they’ve formed collaborations—and this is those cool West Coast states: Washington, Oregon, Hawaii, California. They’ve formed a consortium to say, “We are gonna set our own policy,” because the government’s policy right now is up in the air about whether you can get access to them, whether we should be providing them. How do you get access to them? And so we’re all up in the air about what's going to happen.

And then, of course, our brilliant RFK Jr.—who, by the way, doesn’t live very far from where I’m sitting right now. There was one day I was walking through Georgetown and crossed paths with him. I was like, “Ugh.” But anyway, he doesn’t live very far from here. But he’s saying that we should kind of get rid of vaccines in general—not just COVID vaccines, but vaccines in general.

And so there is, coming out from the ACIP, a set of recommendations. And a lot of states—and I live in one, Virginia, which is over that direction—had agreed from the beginning (and I think there are seven—I don’t know, a bunch of states) that they will follow whatever the law is, they will follow whatever the ACIP says. But that was before we got this new group of people who’ve stepped in to oversee this. And so it may be that it undoes things, and we’re gonna need to put new laws in place.

We just can’t have this discussion about CDC and vaccines without saying the word “Florida.” So, Florida has a Surgeon General named Joseph Ladapo. And Joseph Ladapo is a physician—MD, PhD, incredibly well-trained. He is a professor at the University of Florida. He trained at Harvard and other really good places, and he is all about public health. That’s his thing—more on the cardiovascular side of things. But during the pandemic, he was an anti-vaxxer then. And now, of course, you all know that Florida is trying to put forward where children no longer have a vaccine requirement to go to school, etc.—that they can undo that. And these are recommendations and laws that have been in place for over 100 years. And he says, “Nope, we’re not gonna do it anymore.”

You know, my mother had polio, for goodness’ sakes. Do we want to go back to that sort of world where children are going to be getting these infections that we had solved—pretty much solved—in the past? And so, you know, we’re joking about, you know, who’s gonna want to go to Disney World. Take your children to Disney World if everybody there is unvaccinated. Maybe it’s the alternative. Maybe that’s the place to go get exposed—like you remember when we were kids? We used to be told to go over and play with the kid who has chickenpox so that we would all get chickenpox. Well, maybe we’ll all just go to Florida so we all get measles, mumps, rubella, and polio—and other things like that.

So, who knows how this well-trained person has got it in his mind that this RFK Jr. sort of “vaccines are evil” is part of his mantra, and he’s applying this across the state of Florida.

So, I am so anxious about this because I think the next step is access to medical care in general. Right? We know that there are major cuts to Medicaid about to happen—influencing the shutting down of hospitals. Even in the state of Virginia, if we apply the current Medicaid cut recommendations that the new big bill signed, seven rural hospitals will have to close. Those people will not have access to hospitals in their area. Right? Also talking about reducing Medicare support. So, okay, fine—we're gonna reduce the amount of healthcare that’s available to people out there.

But what about medicines? What’s lifesaving, and what is a hoax that causes autism? Right now, the CDC and RFK think that vaccines are a hoax that cause autism. Okay, what about immunotherapy for MSI-high patients, right? Is that a hoax, or is that amazing, life-saving therapy? And so we’re splicing and dicing all of these things to the point where we’re not gonna have access to things that we know help broad populations avoid bad infections and death.

When is that gonna start to trickle down to other healthcare access, and who’s going to be making those decisions?

I think about the HPV vaccine. Right? This is available to both boys and girls. We think—we’re pretty sure—that if everybody were to get this, cervical cancer, head and neck cancers, and others would diminish dramatically because so many of them are caused by HPV infections. Are we gonna do away with those? That’s, in essence, a cancer vaccine—a prevention-of-cancer vaccine. Is that next on the chopping block? So that now our incredible discoveries of the linkage between HPV and cancer are undone—because we can’t prevent it anymore?

So, I am very unsettled. The people around us in healthcare are very unsettled. Pharmaceutical industry is very unsettled. Healthcare providers—small hospitals, rural hospitals—are very unsettled. Yet we are being led by people who do not represent the population, who do not represent the 80–90% majority of parents that want their children to have vaccines. What these people are representing are the 5–10% of people who are convinced that vaccines don’t do anything and are crazy to give.

And so we need to figure out how to push back, how to represent the majority against these people—to stand up against these people. Both sides of the aisle are uncomfortable about this. And my fingers are crossed that if enough of us get out and scream, if enough of us go up and hold a sign over a bridge or out on a walk somewhere, that enough people will hear—and we will rise up and take back our healthcare, take back our successes so that we can at least not step backwards. More people dying. More people suffering—when we’d already figured out how to prevent it.

I am hopeful, hopeful, hopeful that the months ahead will be better than the last eight months.

John Marshall for Oncology Unscripted.

[00:13:02] Main Topic: Running Into Risk: Colon Cancer and Marathon Runners

[00:00:05] MedBuzz: Back to Being ‘Just a Doctor’

John Marshall, MD: John Marshall for Oncology Unscripted, coming to you live from this big office. This is the biggest office because, you know, I've been the Chief of the Division here at Georgetown for 20 years. I didn't want the job when I was first offered it a long time ago. I ended up saying yes. Of course, that's a dramatic change in one's academic career—taking on administrative roles like this. You do get the big office, which is nice, but you also get a lot of other stuff. You know too much. You know who's mad at whom, you know who you need to recruit, and who you need to un-recruit—all of those things. You have the business side of a cancer business going on, and you're a doctor, and you're doing clinical research, and you're trying to educate everybody around you. 

About a year or so ago, I decided in my own head that 20 years is enough. And so, as of this summer, I have officially stepped down as the Chief of the Division here at Georgetown. My colleague and much smarter friend, Dr. Steven Liu—lung cancer expert, world expert—is stepping in to be the Chief of our Division, and he's already hit the ground running. The fresh voice is honestly already a positive. You can just hear the freshness of his voice and his attitude and his energy. 

You know, the Mayo Clinic actually has a structure where you can only be in a leadership position for so many years, and it has to turn over. And I really like that. It's sort of like what we hope our presidential terms will be. But who knows—that may change. But there's a limit: you do the job for a certain period of time, and then someone else steps in and gives you that fresh voice and fresh perspective. But that's not the traditional way of doing it. Most of the time, people hold on to their position as long as they can hold on to it, until they can't do it anymore or they decide to go to some other institution.

But the reason I'm sharing this is that I'm now in this sort of weird new place. I'm an ordinary staff physician. All of a sudden—yep. I have my patients, I'm doing my thing, I'm putting people on clinical trials, I'm educating the brand-new fellows who just showed up here about a month ago. Great fun having brand-new fellows 'cause they don't even know how to spell 5-FU, much less how well it works, how it works, and the side effects, etc. So, I love the first few months 'cause you're teaching people a lot of new things that they need to know. But anyway, that part's very exciting. So, I'm still doing all of that.

But what I'm gonna have to get used to is not knowing everything—also not feeling responsible for everything. And that's gonna be a change for me. So, any of you out there who've either been through that transition or who maybe wanna offer me some therapy—I'm in line for some therapy as I transition, as I begin to slow down my academic career, withdrawing as the Chief of the Division, but still doing my day-to-day job and still trying to cure cancer.

Take care of each other out there. Take care of your bosses and those leaders. It's not a great, fun job. But also, remember: those of us who are now back in the trenches—we need to take care of each other as well. John Marshall for Oncology Unscripted.

[00:03:35] Editorial: Watching Vaccine Access Collapse In Real Time

John Marshall, MD: John Marshall Oncology Unscripted. First piece of advice: don’t read the newspaper. Second piece of advice: don’t watch C-SPAN, for sure. Just yesterday on C-SPAN was the big congressional hearings. I did read the summary of it in The Washington Post, where RFK Jr. was interviewed—cross-examined for three hours by both sides of the aisle—about what he has been doing with the CDC. And I think we all, as medical professionals, need to take a big step back and a pause and sort of ask: what the hell is going on?

You know, the specifics first. He fired everybody at the CDC. He has hired new people at the CDC. They have not come forward with any formal vaccine recommendations. This is all about vaccines and the like. 

Yesterday in clinic, a patient of mine—who would be a candidate for both flu and COVID vaccines, who could have, a month ago, walked into CVS and gotten both of those injections—now, in the state of Virginia (and I think there are about 14 other states where this is true), has to have a prescription. This came out from CVS and Walgreens—that you have to write a prescription. Physicians have to write a prescription so that patients can take it to the CVS and Walgreens to get their vaccines. Some states are not providing them at all. Some states have gone the other way, where they’ve formed collaborations—and this is those cool West Coast states: Washington, Oregon, Hawaii, California. They’ve formed a consortium to say, “We are gonna set our own policy,” because the government’s policy right now is up in the air about whether you can get access to them, whether we should be providing them. How do you get access to them? And so we’re all up in the air about what's going to happen.

And then, of course, our brilliant RFK Jr.—who, by the way, doesn’t live very far from where I’m sitting right now. There was one day I was walking through Georgetown and crossed paths with him. I was like, “Ugh.” But anyway, he doesn’t live very far from here. But he’s saying that we should kind of get rid of vaccines in general—not just COVID vaccines, but vaccines in general.

And so there is, coming out from the ACIP, a set of recommendations. And a lot of states—and I live in one, Virginia, which is over that direction—had agreed from the beginning (and I think there are seven—I don’t know, a bunch of states) that they will follow whatever the law is, they will follow whatever the ACIP says. But that was before we got this new group of people who’ve stepped in to oversee this. And so it may be that it undoes things, and we’re gonna need to put new laws in place.

We just can’t have this discussion about CDC and vaccines without saying the word “Florida.” So, Florida has a Surgeon General named Joseph Ladapo. And Joseph Ladapo is a physician—MD, PhD, incredibly well-trained. He is a professor at the University of Florida. He trained at Harvard and other really good places, and he is all about public health. That’s his thing—more on the cardiovascular side of things. But during the pandemic, he was an anti-vaxxer then. And now, of course, you all know that Florida is trying to put forward where children no longer have a vaccine requirement to go to school, etc.—that they can undo that. And these are recommendations and laws that have been in place for over 100 years. And he says, “Nope, we’re not gonna do it anymore.”

You know, my mother had polio, for goodness’ sakes. Do we want to go back to that sort of world where children are going to be getting these infections that we had solved—pretty much solved—in the past? And so, you know, we’re joking about, you know, who’s gonna want to go to Disney World. Take your children to Disney World if everybody there is unvaccinated. Maybe it’s the alternative. Maybe that’s the place to go get exposed—like you remember when we were kids? We used to be told to go over and play with the kid who has chickenpox so that we would all get chickenpox. Well, maybe we’ll all just go to Florida so we all get measles, mumps, rubella, and polio—and other things like that.

So, who knows how this well-trained person has got it in his mind that this RFK Jr. sort of “vaccines are evil” is part of his mantra, and he’s applying this across the state of Florida.

So, I am so anxious about this because I think the next step is access to medical care in general. Right? We know that there are major cuts to Medicaid about to happen—influencing the shutting down of hospitals. Even in the state of Virginia, if we apply the current Medicaid cut recommendations that the new big bill signed, seven rural hospitals will have to close. Those people will not have access to hospitals in their area. Right? Also talking about reducing Medicare support. So, okay, fine—we're gonna reduce the amount of healthcare that’s available to people out there.

But what about medicines? What’s lifesaving, and what is a hoax that causes autism? Right now, the CDC and RFK think that vaccines are a hoax that cause autism. Okay, what about immunotherapy for MSI-high patients, right? Is that a hoax, or is that amazing, life-saving therapy? And so we’re splicing and dicing all of these things to the point where we’re not gonna have access to things that we know help broad populations avoid bad infections and death.

When is that gonna start to trickle down to other healthcare access, and who’s going to be making those decisions?

I think about the HPV vaccine. Right? This is available to both boys and girls. We think—we’re pretty sure—that if everybody were to get this, cervical cancer, head and neck cancers, and others would diminish dramatically because so many of them are caused by HPV infections. Are we gonna do away with those? That’s, in essence, a cancer vaccine—a prevention-of-cancer vaccine. Is that next on the chopping block? So that now our incredible discoveries of the linkage between HPV and cancer are undone—because we can’t prevent it anymore?

So, I am very unsettled. The people around us in healthcare are very unsettled. Pharmaceutical industry is very unsettled. Healthcare providers—small hospitals, rural hospitals—are very unsettled. Yet we are being led by people who do not represent the population, who do not represent the 80–90% majority of parents that want their children to have vaccines. What these people are representing are the 5–10% of people who are convinced that vaccines don’t do anything and are crazy to give.

And so we need to figure out how to push back, how to represent the majority against these people—to stand up against these people. Both sides of the aisle are uncomfortable about this. And my fingers are crossed that if enough of us get out and scream, if enough of us go up and hold a sign over a bridge or out on a walk somewhere, that enough people will hear—and we will rise up and take back our healthcare, take back our successes so that we can at least not step backwards. More people dying. More people suffering—when we’d already figured out how to prevent it.

I am hopeful, hopeful, hopeful that the months ahead will be better than the last eight months.

John Marshall for Oncology Unscripted.

[00:13:02] Main Topic: Running Into Risk: Colon Cancer and Marathon Runners

John Marshall, MD: We have been preaching on Oncology Unscripted about the very cool new data showing that if you had a personal trainer, you had an improvement in survival in colon cancer compared to if you were just told to go exercise. Right? What an amazing abstract that was presented at ASCO this year. And so we're all wondering whether Blue Cross Blue Shield should go out there and start covering personal trainers. And maybe the answer is yes.

But follow-up data on that says—and these are things we all knew before—is that too much of a good thing can be bad. A very good friend of mine and colleague of ours, Tim Cannon, here in the Northern Virginia area, actually has been doing a study that made the big time—New York Times published work that they had been doing—showing that marathoners and ultramarathoners actually had an increased risk of colon cancer. So yeah—personal trainer a few times a week, improving your cure rate. Whereas if you go too much, you strain the body. Maybe it’s an alteration in diet, maybe it’s microbiome—we’ll talk about it. You actually can make things worse.

So, I want you to listen in to our interview together. Dr. Tim Cannon and I discuss this way cool science, with an idea of trying to figure out what the heck’s going on.

Join us for Oncology Unscripted.

[00:14:38] Interview: Running Into Risk—My Interview with Dr Timothy Cannon

John Marshall, MD: Hey, everybody out there—John Marshall for Oncology Unscripted. You're frittering away more of your time, but we've got something that is clearly worth your effort. You know what? I have run, myself, three half marathons. I hated every one of them. I did it 'cause I thought I was supposed to. I trained up for it—it took a whole season to train up for it. I didn’t hurt anything too bad, which is good. I wasn’t fast—let’s be clear. I was always glad to not be doing the other half of the marathon.

So why do you care about this? Well, there's been new evidence—it’s been building over time—and it's been really led by and championed by a very good friend and colleague of mine, Dr. Tim Cannon, where too much exercise—or too much strain on the body, maybe we should rephrase that—might, in fact, be bad for us, specifically around colorectal cancer. We already know the data—'cause we've talked about it—around a personal trainer improving your survival if you had colon cancer. But what about joining an ultramarathon team?

Dr. Tim Cannon has something to say about that. Tim, introduce yourself and tell the gang your science.

Timothy Cannon, MD: Sure. So, I'm Tim Cannon. Thank you so much for having me, John. This is a study that you cite, that we've just done in the DC area, on ultramarathoners. And I had seen, in the course of about a year, three different ultramarathoners—actually, two were ultramarathoners, one was a triathlete. They had both done dozens of those types of races. And they had stage IV cancer in their 30s.

And I thought, you know, there may be a connection here. They were all describing bleeding after they run. I had heard a lot about runner's trots, or bleeding when you run long distances. And I can see how there could be a mechanism—that this could cause cancer if you run so much that you're having repeated insults to your colon, and bleeding.

And so, we decided to start a study. We opened our Cancer Prevention Center here, and that's what we're here to talk about today. I'm really glad that you had an interest in this.

The study was of 100 long-distance runners. I would call them all extreme. They had all run at least five 26.2-mile marathons. Most of them had run ultramarathons. Many of them had run 100-mile ultramarathons. They had to be between the ages of 35 and 50, not have a known familial syndrome, and not have inflammatory bowel disease. And we screened them to see if they had precancerous polyps.

John Marshall, MD: And, as you found—they did. And some of them had an increased risk for cancer. So, fascinating work. When people were doing what they thought was gonna keep them outta trouble, they might've been getting themselves into trouble.

And I know you, you and I and others have had discussions about the “why” of this. And you just described sort of a trauma. I was always thinking like watershed—not enough blood flow, maybe hypoxia. There's also the other side that I’m, you know, obsessed with—and that's microbiome. These ultramarathoners eat all sorts of funky stuff. They do these protein gels, and they do all sorts of things that are not your classic Mediterranean diet.

If you had to put your quarter down, what do you think's the reason for it?

Timothy Cannon, MD: Yeah, and we haven’t proven anything quite yet. But I'm believing more and more that there is a connection here. And like you, I thought the watershed idea made the most sense to me initially.

Since this came out, everyone is emailing me with their own ideas about it. And some of them are pretty compelling. Microbiome, I think, may be among the most compelling. You know, I've been reading about differences in abundance in people who do endurance sports. There’s a bacteria called prevotella, for instance, that's more abundant in runners—and it may be related.

Sure, there's so much we don't know about this, but that's what we're hoping to explore in part two—analyzing the microbiome. And then, of course, there’s the lifestyle. Things that characterize long-distance runners—the goos, the... you know, I’ve worried about everything. They drink a lot of electrolyte drinks out of bottles, and maybe they have high exposure to BPA. Or maybe it’s the high-protein diet that was highlighted this week in The New York Times. Who knows? It could be any of these exposures that could cause it. It’s hard to know, hard to study. To isolate any one of these variables is tricky. But I think it’s important to try to get to the bottom of it.

John Marshall, MD: We're into prevention, right? We tell people not to smoke. We tell people to eat right. Should there be some sort of sign at the beginning of a marathon that says, “You're running at your own risk”?

Timothy Cannon, MD: Yeah, like the Surgeon General’s warning. I'm not sure we know enough quite to recommend that yet. And of course, I want to emphasize what you did first at the beginning here: that exercise is—by and large—going to be a good thing. We’ll have much bigger problems from there not being enough exercise. And I think we know fairly definitively that exercise reduces the risk of cancer recurrence. So, I want to emphasize that from the beginning.

But the question is whether there’s a dose of exercise that is too much. I believe there is. I’d like to get more evidence before we start putting signs on marathons or discouraging people too much. But I could see a future where there is something like that out there.

John Marshall, MD: Breakthrough work, in my opinion. Dr. Tim Cannon, thank you so much for, I’m sure, taking time out—when you're in The New York Times, you're much needed on the interview circuit. So, it's a real honor that you’ve taken some time to talk with us and our audience. Dr. Tim Cannon—

Timothy Cannon, MD: No way. This one means the most to me, John. Thank you.

John Marshall, MD: I love being lied to on a Wednesday. Hang in there everybody, and we'll see you next time on Oncology Unscripted.

This transcript has been edited for clarity. We have been preaching on Oncology Unscripted about the very cool new data showing that if you had a personal trainer, you had an improvement in survival in colon cancer compared to if you were just told to go exercise. Right? What an amazing abstract that was presented at ASCO this year. And so we're all wondering whether Blue Cross Blue Shield should go out there and start covering personal trainers. And maybe the answer is yes.

But follow-up data on that says—and these are things we all knew before—is that too much of a good thing can be bad. A very good friend of mine and colleague of ours, Tim Cannon, here in the Northern Virginia area, actually has been doing a study that made the big time—New York Times published work that they had been doing—showing that marathoners and ultramarathoners actually had an increased risk of colon cancer. So yeah—personal trainer a few times a week, improving your cure rate. Whereas if you go too much, you strain the body. Maybe it’s an alteration in diet, maybe it’s microbiome—we’ll talk about it. You actually can make things worse.

So, I want you to listen in to our interview together. Dr. Tim Cannon and I discuss this way cool science, with an idea of trying to figure out what the heck’s going on.

Join us for Oncology Unscripted.

[00:14:38] Interview: Running Into Risk—My Interview with Dr Timothy Cannon

John Marshall, MD: Hey, everybody out there—John Marshall for Oncology Unscripted. You're frittering away more of your time, but we've got something that is clearly worth your effort. You know what? I have run, myself, three half marathons. I hated every one of them. I did it 'cause I thought I was supposed to. I trained up for it—it took a whole season to train up for it. I didn’t hurt anything too bad, which is good. I wasn’t fast—let’s be clear. I was always glad to not be doing the other half of the marathon.

So why do you care about this? Well, there's been new evidence—it’s been building over time—and it's been really led by and championed by a very good friend and colleague of mine, Dr. Tim Cannon, where too much exercise—or too much strain on the body, maybe we should rephrase that—might, in fact, be bad for us, specifically around colorectal cancer. We already know the data—'cause we've talked about it—around a personal trainer improving your survival if you had colon cancer. But what about joining an ultramarathon team?

Dr. Tim Cannon has something to say about that. Tim, introduce yourself and tell the gang your science.

Timothy Cannon, MD: Sure. So, I'm Tim Cannon. Thank you so much for having me, John. This is a study that you cite, that we've just done in the DC area, on ultramarathoners. And I had seen, in the course of about a year, three different ultramarathoners—actually, two were ultramarathoners, one was a triathlete. They had both done dozens of those types of races. And they had stage IV cancer in their 30s.

And I thought, you know, there may be a connection here. They were all describing bleeding after they run. I had heard a lot about runner's trots, or bleeding when you run long distances. And I can see how there could be a mechanism—that this could cause cancer if you run so much that you're having repeated insults to your colon, and bleeding.

And so, we decided to start a study. We opened our Cancer Prevention Center here, and that's what we're here to talk about today. I'm really glad that you had an interest in this.

The study was of 100 long-distance runners. I would call them all extreme. They had all run at least five 26.2-mile marathons. Most of them had run ultramarathons. Many of them had run 100-mile ultramarathons. They had to be between the ages of 35 and 50, not have a known familial syndrome, and not have inflammatory bowel disease. And we screened them to see if they had precancerous polyps.

John Marshall, MD: And, as you found—they did. And some of them had an increased risk for cancer. So, fascinating work. When people were doing what they thought was gonna keep them outta trouble, they might've been getting themselves into trouble.

And I know you, you and I and others have had discussions about the “why” of this. And you just described sort of a trauma. I was always thinking like watershed—not enough blood flow, maybe hypoxia. There's also the other side that I’m, you know, obsessed with—and that's microbiome. These ultramarathoners eat all sorts of funky stuff. They do these protein gels, and they do all sorts of things that are not your classic Mediterranean diet.

If you had to put your quarter down, what do you think's the reason for it?

Timothy Cannon, MD: Yeah, and we haven’t proven anything quite yet. But I'm believing more and more that there is a connection here. And like you, I thought the watershed idea made the most sense to me initially.

Since this came out, everyone is emailing me with their own ideas about it. And some of them are pretty compelling. Microbiome, I think, may be among the most compelling. You know, I've been reading about differences in abundance in people who do endurance sports. There’s a bacteria called prevotella, for instance, that's more abundant in runners—and it may be related.

Sure, there's so much we don't know about this, but that's what we're hoping to explore in part two—analyzing the microbiome. And then, of course, there’s the lifestyle. Things that characterize long-distance runners—the goos, the... you know, I’ve worried about everything. They drink a lot of electrolyte drinks out of bottles, and maybe they have high exposure to BPA. Or maybe it’s the high-protein diet that was highlighted this week in The New York Times. Who knows? It could be any of these exposures that could cause it. It’s hard to know, hard to study. To isolate any one of these variables is tricky. But I think it’s important to try to get to the bottom of it.

John Marshall, MD: We're into prevention, right? We tell people not to smoke. We tell people to eat right. Should there be some sort of sign at the beginning of a marathon that says, “You're running at your own risk”?

Timothy Cannon, MD: Yeah, like the Surgeon General’s warning. I'm not sure we know enough quite to recommend that yet. And of course, I want to emphasize what you did first at the beginning here: that exercise is—by and large—going to be a good thing. We’ll have much bigger problems from there not being enough exercise. And I think we know fairly definitively that exercise reduces the risk of cancer recurrence. So, I want to emphasize that from the beginning.

But the question is whether there’s a dose of exercise that is too much. I believe there is. I’d like to get more evidence before we start putting signs on marathons or discouraging people too much. But I could see a future where there is something like that out there.

John Marshall, MD: Breakthrough work, in my opinion. Dr. Tim Cannon, thank you so much for, I’m sure, taking time out—when you're in The New York Times, you're much needed on the interview circuit. So, it's a real honor that you’ve taken some time to talk with us and our audience. Dr. Tim Cannon—

Timothy Cannon, MD: No way. This one means the most to me, John. Thank you.

John Marshall, MD: I love being lied to on a Wednesday. Hang in there everybody, and we'll see you next time on Oncology Unscripted.

This transcript has been edited for clarity.[00:00:05] MedBuzz: Back to Being ‘Just a Doctor’

John Marshall, MD: John Marshall for Oncology Unscripted, coming to you live from this big office. This is the biggest office because, you know, I've been the Chief of the Division here at Georgetown for 20 years. I didn't want the job when I was first offered it a long time ago. I ended up saying yes. Of course, that's a dramatic change in one's academic career—taking on administrative roles like this. You do get the big office, which is nice, but you also get a lot of other stuff. You know too much. You know who's mad at whom, you know who you need to recruit, and who you need to un-recruit—all of those things. You have the business side of a cancer business going on, and you're a doctor, and you're doing clinical research, and you're trying to educate everybody around you.

About a year or so ago, I decided in my own head that 20 years is enough. And so, as of this summer, I have officially stepped down as the Chief of the Division here at Georgetown. My colleague and much smarter friend, Dr. Steven Liu—lung cancer expert, world expert—is stepping in to be the Chief of our Division, and he's already hit the ground running. The fresh voice is honestly already a positive. You can just hear the freshness of his voice and his attitude and his energy.

You know, the Mayo Clinic actually has a structure where you can only be in a leadership position for so many years, and it has to turn over. And I really like that. It's sort of like what we hope our presidential terms will be. But who knows—that may change. But there's a limit: you do the job for a certain period of time, and then someone else steps in and gives you that fresh voice and fresh perspective. But that's not the traditional way of doing it. Most of the time, people hold on to their position as long as they can hold on to it, until they can't do it anymore or they decide to go to some other institution.

But the reason I'm sharing this is that I'm now in this sort of weird new place. I'm an ordinary staff physician. All of a sudden—yep. I have my patients, I'm doing my thing, I'm putting people on clinical trials, I'm educating the brand-new fellows who just showed up here about a month ago. Great fun having brand-new fellows 'cause they don't even know how to spell 5-FU, much less how well it works, how it works, and the side effects, etc. So, I love the first few months 'cause you're teaching people a lot of new things that they need to know. But anyway, that part's very exciting. So, I'm still doing all of that.

But what I'm gonna have to get used to is not knowing everything—also not feeling responsible for everything. And that's gonna be a change for me. So, any of you out there who've either been through that transition or who maybe wanna offer me some therapy—I'm in line for some therapy as I transition, as I begin to slow down my academic career, withdrawing as the Chief of the Division, but still doing my day-to-day job and still trying to cure cancer.

Take care of each other out there. Take care of your bosses and those leaders. It's not a great, fun job. But also, remember: those of us who are now back in the trenches—we need to take care of each other as well. John Marshall for Oncology Unscripted.

[00:03:35] Editorial: Watching Vaccine Access Collapse In Real Time

John Marshall, MD: John Marshall Oncology Unscripted. First piece of advice: don’t read the newspaper. Second piece of advice: don’t watch C-SPAN, for sure. Just yesterday on C-SPAN was the big congressional hearings. I did read the summary of it in The Washington Post, where RFK Jr. was interviewed—cross-examined for three hours by both sides of the aisle—about what he has been doing with the CDC. And I think we all, as medical professionals, need to take a big step back and a pause and sort of ask: what the hell is going on?

You know, the specifics first. He fired everybody at the CDC. He has hired new people at the CDC. They have not come forward with any formal vaccine recommendations. This is all about vaccines and the like.

Yesterday in clinic, a patient of mine—who would be a candidate for both flu and COVID vaccines, who could have, a month ago, walked into CVS and gotten both of those injections—now, in the state of Virginia (and I think there are about 14 other states where this is true), has to have a prescription. This came out from CVS and Walgreens—that you have to write a prescription. Physicians have to write a prescription so that patients can take it to the CVS and Walgreens to get their vaccines. Some states are not providing them at all. Some states have gone the other way, where they’ve formed collaborations—and this is those cool West Coast states: Washington, Oregon, Hawaii, California. They’ve formed a consortium to say, “We are gonna set our own policy,” because the government’s policy right now is up in the air about whether you can get access to them, whether we should be providing them. How do you get access to them? And so we’re all up in the air about what's going to happen.

And then, of course, our brilliant RFK Jr.—who, by the way, doesn’t live very far from where I’m sitting right now. There was one day I was walking through Georgetown and crossed paths with him. I was like, “Ugh.” But anyway, he doesn’t live very far from here. But he’s saying that we should kind of get rid of vaccines in general—not just COVID vaccines, but vaccines in general.

And so there is, coming out from the ACIP, a set of recommendations. And a lot of states—and I live in one, Virginia, which is over that direction—had agreed from the beginning (and I think there are seven—I don’t know, a bunch of states) that they will follow whatever the law is, they will follow whatever the ACIP says. But that was before we got this new group of people who’ve stepped in to oversee this. And so it may be that it undoes things, and we’re gonna need to put new laws in place.

We just can’t have this discussion about CDC and vaccines without saying the word “Florida.” So, Florida has a Surgeon General named Joseph Ladapo. And Joseph Ladapo is a physician—MD, PhD, incredibly well-trained. He is a professor at the University of Florida. He trained at Harvard and other really good places, and he is all about public health. That’s his thing—more on the cardiovascular side of things. But during the pandemic, he was an anti-vaxxer then. And now, of course, you all know that Florida is trying to put forward where children no longer have a vaccine requirement to go to school, etc.—that they can undo that. And these are recommendations and laws that have been in place for over 100 years. And he says, “Nope, we’re not gonna do it anymore.”

You know, my mother had polio, for goodness’ sakes. Do we want to go back to that sort of world where children are going to be getting these infections that we had solved—pretty much solved—in the past? And so, you know, we’re joking about, you know, who’s gonna want to go to Disney World. Take your children to Disney World if everybody there is unvaccinated. Maybe it’s the alternative. Maybe that’s the place to go get exposed—like you remember when we were kids? We used to be told to go over and play with the kid who has chickenpox so that we would all get chickenpox. Well, maybe we’ll all just go to Florida so we all get measles, mumps, rubella, and polio—and other things like that.

So, who knows how this well-trained person has got it in his mind that this RFK Jr. sort of “vaccines are evil” is part of his mantra, and he’s applying this across the state of Florida.

So, I am so anxious about this because I think the next step is access to medical care in general. Right? We know that there are major cuts to Medicaid about to happen—influencing the shutting down of hospitals. Even in the state of Virginia, if we apply the current Medicaid cut recommendations that the new big bill signed, seven rural hospitals will have to close. Those people will not have access to hospitals in their area. Right? Also talking about reducing Medicare support. So, okay, fine—we're gonna reduce the amount of healthcare that’s available to people out there.

But what about medicines? What’s lifesaving, and what is a hoax that causes autism? Right now, the CDC and RFK think that vaccines are a hoax that cause autism. Okay, what about immunotherapy for MSI-high patients, right? Is that a hoax, or is that amazing, life-saving therapy? And so we’re splicing and dicing all of these things to the point where we’re not gonna have access to things that we know help broad populations avoid bad infections and death.

When is that gonna start to trickle down to other healthcare access, and who’s going to be making those decisions?

I think about the HPV vaccine. Right? This is available to both boys and girls. We think—we’re pretty sure—that if everybody were to get this, cervical cancer, head and neck cancers, and others would diminish dramatically because so many of them are caused by HPV infections. Are we gonna do away with those? That’s, in essence, a cancer vaccine—a prevention-of-cancer vaccine. Is that next on the chopping block? So that now our incredible discoveries of the linkage between HPV and cancer are undone—because we can’t prevent it anymore?

So, I am very unsettled. The people around us in healthcare are very unsettled. Pharmaceutical industry is very unsettled. Healthcare providers—small hospitals, rural hospitals—are very unsettled. Yet we are being led by people who do not represent the population, who do not represent the 80–90% majority of parents that want their children to have vaccines. What these people are representing are the 5–10% of people who are convinced that vaccines don’t do anything and are crazy to give.

And so we need to figure out how to push back, how to represent the majority against these people—to stand up against these people. Both sides of the aisle are uncomfortable about this. And my fingers are crossed that if enough of us get out and scream, if enough of us go up and hold a sign over a bridge or out on a walk somewhere, that enough people will hear—and we will rise up and take back our healthcare, take back our successes so that we can at least not step backwards. More people dying. More people suffering—when we’d already figured out how to prevent it.

I am hopeful, hopeful, hopeful that the months ahead will be better than the last eight months.

John Marshall for Oncology Unscripted.

[00:13:02] Main Topic: Running Into Risk: Colon Cancer and Marathon Runners

John Marshall, MD: We have been preaching on Oncology Unscripted about the very cool new data showing that if you had a personal trainer, you had an improvement in survival in colon cancer compared to if you were just told to go exercise. Right? What an amazing abstract that was presented at ASCO this year. And so we're all wondering whether Blue Cross Blue Shield should go out there and start covering personal trainers. And maybe the answer is yes.

But follow-up data on that says—and these are things we all knew before—is that too much of a good thing can be bad. A very good friend of mine and colleague of ours, Tim Cannon, here in the Northern Virginia area, actually has been doing a study that made the big time—New York Times published work that they had been doing—showing that marathoners and ultramarathoners actually had an increased risk of colon cancer. So yeah—personal trainer a few times a week, improving your cure rate. Whereas if you go too much, you strain the body. Maybe it’s an alteration in diet, maybe it’s microbiome—we’ll talk about it. You actually can make things worse.

So, I want you to listen in to our interview together. Dr. Tim Cannon and I discuss this way cool science, with an idea of trying to figure out what the heck’s going on.

Join us for Oncology Unscripted.

[00:14:38] Interview: Running Into Risk—My Interview with Dr Timothy Cannon

John Marshall, MD: Hey, everybody out there—John Marshall for Oncology Unscripted. You're frittering away more of your time, but we've got something that is clearly worth your effort. You know what? I have run, myself, three half marathons. I hated every one of them. I did it 'cause I thought I was supposed to. I trained up for it—it took a whole season to train up for it. I didn’t hurt anything too bad, which is good. I wasn’t fast—let’s be clear. I was always glad to not be doing the other half of the marathon.

So why do you care about this? Well, there's been new evidence—it’s been building over time—and it's been really led by and championed by a very good friend and colleague of mine, Dr. Tim Cannon, where too much exercise—or too much strain on the body, maybe we should rephrase that—might, in fact, be bad for us, specifically around colorectal cancer. We already know the data—'cause we've talked about it—around a personal trainer improving your survival if you had colon cancer. But what about joining an ultramarathon team?

Dr. Tim Cannon has something to say about that. Tim, introduce yourself and tell the gang your science.

Timothy Cannon, MD: Sure. So, I'm Tim Cannon. Thank you so much for having me, John. This is a study that you cite, that we've just done in the DC area, on ultramarathoners. And I had seen, in the course of about a year, three different ultramarathoners—actually, two were ultramarathoners, one was a triathlete. They had both done dozens of those types of races. And they had stage IV cancer in their 30s.

And I thought, you know, there may be a connection here. They were all describing bleeding after they run. I had heard a lot about runner's trots, or bleeding when you run long distances. And I can see how there could be a mechanism—that this could cause cancer if you run so much that you're having repeated insults to your colon, and bleeding.

And so, we decided to start a study. We opened our Cancer Prevention Center here, and that's what we're here to talk about today. I'm really glad that you had an interest in this.

The study was of 100 long-distance runners. I would call them all extreme. They had all run at least five 26.2-mile marathons. Most of them had run ultramarathons. Many of them had run 100-mile ultramarathons. They had to be between the ages of 35 and 50, not have a known familial syndrome, and not have inflammatory bowel disease. And we screened them to see if they had precancerous polyps.

John Marshall, MD: And, as you found—they did. And some of them had an increased risk for cancer. So, fascinating work. When people were doing what they thought was gonna keep them outta trouble, they might've been getting themselves into trouble.

And I know you, you and I and others have had discussions about the “why” of this. And you just described sort of a trauma. I was always thinking like watershed—not enough blood flow, maybe hypoxia. There's also the other side that I’m, you know, obsessed with—and that's microbiome. These ultramarathoners eat all sorts of funky stuff. They do these protein gels, and they do all sorts of things that are not your classic Mediterranean diet.

If you had to put your quarter down, what do you think's the reason for it?

Timothy Cannon, MD: Yeah, and we haven’t proven anything quite yet. But I'm believing more and more that there is a connection here. And like you, I thought the watershed idea made the most sense to me initially.

Since this came out, everyone is emailing me with their own ideas about it. And some of them are pretty compelling. Microbiome, I think, may be among the most compelling. You know, I've been reading about differences in abundance in people who do endurance sports. There’s a bacteria called prevotella, for instance, that's more abundant in runners—and it may be related.

Sure, there's so much we don't know about this, but that's what we're hoping to explore in part two—analyzing the microbiome. And then, of course, there’s the lifestyle. Things that characterize long-distance runners—the goos, the... you know, I’ve worried about everything. They drink a lot of electrolyte drinks out of bottles, and maybe they have high exposure to BPA. Or maybe it’s the high-protein diet that was highlighted this week in The New York Times. Who knows? It could be any of these exposures that could cause it. It’s hard to know, hard to study. To isolate any one of these variables is tricky. But I think it’s important to try to get to the bottom of it.

John Marshall, MD: We're into prevention, right? We tell people not to smoke. We tell people to eat right. Should there be some sort of sign at the beginning of a marathon that says, “You're running at your own risk”?

Timothy Cannon, MD: Yeah, like the Surgeon General’s warning. I'm not sure we know enough quite to recommend that yet. And of course, I want to emphasize what you did first at the beginning here: that exercise is—by and large—going to be a good thing. We’ll have much bigger problems from there not being enough exercise. And I think we know fairly definitively that exercise reduces the risk of cancer recurrence. So, I want to emphasize that from the beginning.

But the question is whether there’s a dose of exercise that is too much. I believe there is. I’d like to get more evidence before we start putting signs on marathons or discouraging people too much. But I could see a future where there is something like that out there.

John Marshall, MD: Breakthrough work, in my opinion. Dr. Tim Cannon, thank you so much for, I’m sure, taking time out—when you're in The New York Times, you're much needed on the interview circuit. So, it's a real honor that you’ve taken some time to talk with us and our audience. Dr. Tim Cannon—

Timothy Cannon, MD: No way. This one means the most to me, John. Thank you.

John Marshall, MD: I love being lied to on a Wednesday. Hang in there everybody, and we'll see you next time on Oncology Unscripted.

This transcript has been edited for clarity.

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[00:05]

John Marshall, MD:
John Marshall for Oncology Unscripted. Big paper coming out of _JAMA_—it's actually a review article. Really, really smart people and friends up in Boston looked at this. We all see it: this emerging trend of younger and younger people getting all kinds of cancer. This particular paper wasn’t about all kinds of cancer, but we’re clearly seeing it in GI cancers. We don’t really understand what’s going on, but we see it—it’s impacting our clinic. Maybe it was first recognized in the colon cancer clinic, but we’re seeing it in other clinics as well.

We have two kinds of schools of thought on why this is happening. On one side, we’ve got this sort of traditional “here’s who gets cancer” list. So, you have a gene, you’ve inherited it, or you have some behavior that increases your risk, or you’re overweight or something, right? You have some known risk factor that we all learned in medical school that’s causing this cancer.

Now, if that were true, then our normal 60/40 split of cancers—40% on the right side, 60% on the left side—would hold true in colon cancer. But in fact, most of these young people with colon cancer—up to like 90-something percent—all have rectosigmoid cancers. So, what the heck’s going on? And most of the patients that we see, at least that I see here in Washington, DC, don’t have any of those things on the list that we all memorized.

They’re all very fit. They have no real reason to have this—no strong family history and certainly no gene. So, we are looking for novel explanations. The leading one right now has mostly to do with microbiome and understanding what that’s all about. We’re not going to drill down on that today, but we are looking for the explanation as to why.

Now, the other piece that goes with this is: if you’re a young person, is your cancer better? Well, it actually doesn’t look that way. If anything, it looks like it might be worse. We know that we fail to diagnose it earlier because it’s not on our radar. If I’m in an urgent care clinic or in an ER or something—or even if I’m a patient with the symptoms—you don’t think to yourself, “Oh, I could have colon cancer,” because you’re 40 years old, and it’s too young to have colon cancer.

So, it isn’t a better cancer. But on the flip side, because you’re younger as a patient, doctors tend to be more aggressive. They tend to push treatments harder because young people can take it well. On the flip side of that, they also have much longer to live if we give them some sort of permanent toxicity—say, neuropathy from oxaliplatin.

So, it is clearly its own thing. It has its own impact on day-to-day living for these people, because they have to keep working, because they need health insurance here in the United States. They have to tell people about it. So, the impact on their lives is much bigger than, say, if you’re a retired 73-year-old with a good support system.

So, that impact is a bit worse. The disease probably is worse. The failure to diagnose is worse. We don’t really know what the biology and the cause is, and more isn’t necessarily better. So, there’s a lot to talk about and think about. Take a look at this paper, see the emerging trends, and share it with your colleagues in other areas of healthcare so that they’re aware of it, too.

John Marshall for Oncology Unscripted.

[03:51]

MedBuzz: Fellows, Funding, and Fewer Radiologists

[00:05]

John Marshall: John Marshall for Oncology Unscripted, with a little bit of buzz, a little bit of gossip, a little bit of stuff that's trending.

You know, this is the end of July when we're filming this, and the squeaky-clean new fellows are here. Don't you love July? New residents and new fellows—you get to teach 'em how 5-FU works and where the bathroom is, and all of those things. But it is—I love this time of year with the new fellows because they're very eager and very interested in learning everything they can. They're not too tired. Everything is good and positive as they learn and go forward. And so, it's just been a great month for us here at Georgetown, and I hope if you work with new trainees—residents, fellows—that you too are having a positive time with them.

I've also—the month of July—been struck by a certain late-night TV host who was fired, let go, because his message was to counter the sort of government message that is going on right now. So, I've been really anxious about having any sort of counter message that's out there, because you know what? You might get canceled if you are caught too often with this sort of counter message.

How that's affecting us here at an NCI-designated cancer center—or wherever you are—is that I'm not sure what the NCI is gonna look like too long from now. We know there are gonna be cuts. We know the payline—there have been predictions that it'll drop as low as 4% for grants. So, if cancer research was being—most, or a lot of it—was being funded by NCI, and that is being cut dramatically and refocused, how does anybody doing the kind of research that we're doing continue? And so, we spend a lot of time at our center—and I'm sure it's true at your center as well—trying to understand how we evolve from here. Is it gonna be philanthropy? Is it gonna be public-private partnerships? Are we gonna work in a different way to keep the progress going that we are seeing?

Now, the other component that's affecting all of us—or gonna affect all of us—is changes in public health. So, if Medicaid cuts are dramatic, then a lot of patients won't have access to cancer care in general. It'll be too expensive or unreachable for a lot of patients. There are certain regions of the country where there is a lot of Medicaid—not just necessarily cities, could be rural places as well. So, those of us who have oncology practices are also trying to understand what the future is gonna look like if we have fewer patients able to get cancer care. So, changes in academia, changes in practice that are coming ahead because of all the changes that are top-down happening in our nation today.

One that is affecting me—and I don't know if it's affecting you as well—is that there has actually become a fairly dramatic nationwide shortage of radiologists. Now, radiologists right now often work in their basements at home. They have shift work. There is support from AI, but it's also a threat from AI. Could it take their jobs eventually? Is the support that it's providing making their job easier or less easy? But regardless, we don't have the same number of radiologists. And so, instead of having a scan being read in a day or two—which is fairly standard for the industry—we see it now taking three, four, five days. And our patients are nervous because they don't know why their scan hasn't been reviewed and the like. So, I'd love for you all to share with me if you're having the same issue too. I meet with my radiologist. We love them. We consider them very tight partners with us, and we are supportive of trying to make their increasingly stressful job less stressful. But that's one of those things that we're gonna have to figure out before too long. Otherwise, we are gonna be stuck without radiologists to read our scans—or we're gonna let Elon Musk read all of our scans. One way or the other, we'll figure it out, I guess. But a lot of changes have occurred just in the last month of July. A lot of those are affecting our day-to-day practice and our ability to deliver the best cancer care and the best research opportunities for our patients in our communities.

I'm not sure what August holds, but I think I'll go to the beach and take a break from it all. John Marshall**,** Oncology Unscripted.

[04:40]

The New Face of Colon Cancer: A Patient’s Story

[00:00:05]

John Marshall, MD: Hey, everybody—John Marshall for Oncology Unscripted, and this session is all about a really big problem that I hate. It's changed my clinic. I really don't like anything about it. It is not what I signed up for. It is young people getting GI cancers. And, you know, the deal was that they were all supposed to be 60, 70, 80 years old with colon cancer, and now close to half of my clinic is under the age of 50. It's a totally different impact, a totally different disease.

There was a recent JAMA paper, which we are featuring, about the statistics around not just colorectal cancer but all GI cancers showing an increase.

And I am lucky enough to have, as one of those young patients, Chad Leo, who has taught me as much about this whole thing as I've taught him about the management of this. He was first diagnosed when he was age 42, and it was out of the blue. So, first, Chad, thank you for your willingness to jump onto this risky venture of Oncology Unscripted. Tell us a little bit about yourself and how they first found it—the sort of "out of the blue," something on your list that was never on your list before.

Chad Leo: Well, first let me say, Dr. Marshall, thank you very much for having me on here. You know, through this entire journey, I'm just overly grateful to be able to kind of give back and share my experience in the hopes that maybe it'll help other people my age—and, unfortunately, people even younger than me—that are being diagnosed with colon cancer.

So, when I was first diagnosed, I was going through some severe abdominal pains. I later found out that was sort of similar to the symptoms that other people diagnosed with colon cancer were going through as well. I was reluctant to really get it looked at, and as time went on, the symptoms progressed. Finally, I was convinced to go to the ER.

I think the way that doctors first saw me—they go, "He's 42, there's no way that this could be anything that severe"—and it was almost a detriment, to the point where I wasn’t fully examined to the extent of what should have been part of the full checkoffs that probably should have been done.

John Marshall, MD: So, what did they think it was? Just like constipation or something else?

Chad Leo: Yeah, their initial thought was that it's probably just Crohn's disease or some type of colitis. That was in my head—I was like, "Okay, that's probably what it is." And then a month later, I'm back in the ER again. The scans indicated that there was, in fact, a mass in my large intestine.

John Marshall, MD: Well, when I went to medical school a thousand years ago—you probably weren’t even born—we were taught that only older people got colon cancer, so it shouldn’t even be something we look at. There has been a growing message about young people getting the disease, but for a lot of folks, it's just not on their checkoff list. So, the patient doesn’t know to ask about it. The physicians are saying, “That can’t be that,” as you just said. To your knowledge, did you have any known risk factors? I mean, your family, your other medical issues—anything that would’ve teed you up for colon cancer?

Chad Leo: No, nothing would’ve indicated that—especially in my family history. I think I had a grandfather who had bladder cancer. My paternal grandmother had ovarian cancer, but nothing along the lines of colon cancer. It wasn’t on my radar. It wasn’t anything where I was directed to start getting screened early.

John Marshall, MD: One of the reasons I’m asking is that this paper we’re featuring lists the standard risk factors. We’ve got to look out for those people. Those people are kind of being followed—or they should be already—because they’re in that risk factor category. But most of my patients are more like you, where it’s just out of the blue. Very fit, obviously, otherwise very healthy, and then—out of the blue—with a diagnosis of colon cancer. So, message heard loud and clear that we’re sending out to the medical community with this discussion.

Tell me what it was like to—out of the blue at 42 years old—all of a sudden have colon cancer, surgery, chemo. How disruptive was all of that?

Chad Leo: It was a huge disruption. So, my job—I’m a detective with the DC Police Department—requires me to be very active. And so, going through the treatments meant that I had to take a break. I planned essentially to use my sick leave as much as possible just so I could focus on getting better.

All of these thoughts start going through your head at 42. I was single then. You start kind of thinking, “What have I done? What have I accomplished with my life?” That plays a heavy toll on your psyche.

Also, I think—being a little bit further removed from some of this—it pushed me to really take a look at my life and not take anything for granted.

John Marshall, MD: Yeah, I would rather you not have to have had that life stress to do that, but I hear you loud and clear.

Chad Leo: Neither would I. But I guess, you know, you’ve got to take everything with a grain of salt. There's always a silver lining to something, and I think that sort of mindset just kind of kept me going and just being hopeful. I think obviously having a terrific care team—such as yourself and the team you had with you—made a huge impact. I felt like my best interests were at heart.

John Marshall, MD: Yeah. And did you tell the gang at work? Did they make accommodations? Did people try and help you? Or did you feel like you wanted to keep it quiet?

Chad Leo: I basically told my close friends and obviously my supervisors what was going on. Pretty much everybody from work was super supportive, and would reach out or come visit, and every once in a while send encouraging messages. I couldn’t have asked for a better support system.

John Marshall, MD: Yeah. So, you went through surgery, did some chemotherapy. We were in follow-up. You've been getting the fancy ctDNA test as well as scans. Describe a little bit about that, because you’ve had a rollercoaster there too.

Chad Leo: It was. The initial surgery I had was to remove the mass, and then I was affixed with a colostomy bag. And, you know, no pun intended—I don't know if we're allowed to curse on the podcast—but I won’t. Oh, okay, I’m getting a thumbs up. So, pun intended, it was a very shitty situation. That was a huge adjustment, where not only did I have a colostomy bag, but I had to learn how to do daily activities with that.

And just the sheer embarrassment of looking at myself in the mirror with this stoma poking out of my stomach. You still want to go out, still want to try to be somewhat normal, but then you have this colostomy bag. I remember at times meeting up with people, and you start to smell something, and you’re like, “I gotta go—it’s a leak or something.” So, I would limit my exposure with my friends to a few hours just because I didn’t know what could happen.

Once we got to a point where I was essentially no evidence of disease, I think I was kind of encouraging—or pushing—you to, like, “Hey, maybe we can look into getting this resection surgery.” So that was good to get to that point.

Then the follow-up tests and the blood tests post-surgery just kind of set up a platform, if you will, of, “Okay, let’s just keep banging out whatever the next steps are.”

John Marshall, MD: Yeah. I know we talked about the role of exercise. One of the big studies we featured in a previous episode was the dramatic impact that having a personal trainer had.

I don't know if I’ve shared this with you yet, but half the patients got a pamphlet that said, "Go exercise," and the other half were assigned a personal trainer. There was actually a survival delta between those. You're already very active, but when you talk about the ostomy—if we’re recommending exercise—an ostomy is exactly counter to that. It makes it very, very difficult to do the kind of physical activity that I know you like to do.

Chad Leo: Yeah, that was—so, I had started an intense workout routine before I even got diagnosed. So, to have the ostomy, basically, my exercise routine just consisted of lots of walking. Maybe just some push-ups. I tried hard not to do anything that would disrupt where the ostomy or the bag was, just because I was so self-conscious. I didn’t even want to go to the gym. I didn’t want to deal with the embarrassment of people seeing the colostomy bag.

But overall, I felt it was just important to stay active and move no matter what.

John Marshall, MD: Yeah. You're a few years out now. With each new scan, with each negative blood test, we’re a little bit further off. You know where we’re gonna be. All right.

And fingers crossed—we’ve had some nervous times still. You’ve got an audience of docs right now, all around the country, all around the world, other people in the industry. What sort of message would you like to share, given your experience? Is there anything you’d like us to hear about?

Chad Leo: I think most importantly—and you do a great job of this—it’s giving your patients hope. Giving someone like myself hope, even through the early stages where you feel like everything is at a loss. The way that you would say, “Hey, look, these are the steps that we’re going to take to try to get you to a point where you can hopefully live as much of a normal life as possible”—I think that’s one of the key things. Because if you have hope in your mind, who knows the benefits that provides the rest of your body? Your body may just continue to keep on fighting.Despite the chemo treatments or even the subsequent blood tests and scans that we go through afterward, you’re still clinging to that hope. Even though you get that little bit of anxiety every time a blood test or scan comes up.

Like I mentioned before, I know that I’m in good hands, and if something does come up, we’ll be able to treat it as early as possible and just give myself a better chance. Again, from my own personal experience, it’s about trying to live your life as normally as possible after going through an experience like that. You and your team have afforded me that ability.

John Marshall, MD: We’re happy to do it, and there are a lot of people out there who can do it well too.

One of the things that was fairly new when you were getting your chemo a few years ago was three months versus six months of chemotherapy. At a young age, you have a physical job, you need to be able to use your hands. The reason for three months versus six months was the cumulative neuropathy of oxaliplatin. We had those discussions about that. There are a lot of docs out there who might be listening in, who, as a young guy, might think, “You can take it because you're young,” and push it to the six months. But right now, one thing I’m glad about is your scans—you’re good. You’re good. And no neuropathy, or limited neuropathy.

Chad Leo: None that I can detect.

John Marshall, MD: And you’re a detective!

Chad Leo: Yes! I mean, I gotta do a lot of typing too. So, it’s important that everything works—at least where I can type. But yeah, I remember there was a point where I started feeling some neuropathy in my hands.

Subsequently, whatever happened after that, it has now since subsided.

John Marshall, MD: Chad, thank you so much for taking some time to discuss this with us.

We all hate this trend. It’s why there’s a big, important paper on this. You are the real kind of person who’s being affected by this. And for you to share all of this with us means a lot to us—and teaches us, as I said at the opening, maybe more lessons than we’ve ever taught you.

So, Chad Leo, thank you very much for joining me on Oncology Unscripted.

Chad Leo: Thank you so much, Dr. Marshall. It’s my pleasure.

[00:14:00]

The Rise of Young-Onset GI Cancers: Interview with Dr Thejus Jayakrishnan

John Marshall, MD: Hey everybody, John Marshall for Oncology Unscripted, and I promise there is no script anywhere in front of us right now. As you know, what we are focusing on this edition is: why are young people getting cancer all of a sudden? I thought we were supposed to be getting healthier.

We just blew up the EPA earlier this week, so I guess we're all going to die of cancer sooner rather than later, if that all works out to be true. But even before we blew up the EPA, some very, very smart people have been watching and monitoring this increase in young people getting colorectal cancer and other GI cancers.

And I am honored to be joined by the lead author of a very, very important review paper that looks at this.

That's been going on all around the world and in the United States. Thejas Jayakrishnan has just joined me today from the mecca of all knowledge—that would be Boston—at Dana-Farber. So, Thejas, thank you very much for joining us, and maybe give us a little bit of an introduction and a little bit about what drove you to put together this paper.

Thejus Jayakrishnan, MD: Thank you very much for the kind introduction. I am a gastrointestinal medical oncologist at Dana-Farber Cancer Institute, an instructor in medicine at Harvard Medical School and Brigham and Women's Hospital, and I work closely with the Dana-Farber Young-Onset Colorectal Cancer Center. I predominantly do clinical research and also translational work, trying to identify what are the biomarkers or molecular characteristics associated with young-onset GI cancers.

I finished my fellowship at Cleveland Clinic, and I had wonderful mentorship there with Dr. Khorana. I spent a lot of time during my fellowship trying to understand the molecular characteristics of young-onset GI cancer. It's mainly during the fellowship that I noticed there's increasing incidence, and the mentorship was helpful in getting me more attuned to recognizing those aspects and realizing some of the unique characteristics of this population. That led me to get involved in research related to the microbiome and metabolomics—trying to integrate different aspects of early-onset GI cancers. I've continued that work since moving to Dana-Farber Cancer Institute.

John Marshall, MD: I'm an old oncologist, right? And so, I didn’t sign up for a lot of my clinic being 20-, 30-, and 40-year-olds. Back then, they were all what we later found out to be Lynch syndrome patients and had genetic inherited syndromes, etc.

Nowadays, that’s not who all of these people are. They are very fit, very healthy, with no real strong risk factors that are showing up. And I think early on, people like the American Cancer Society and others were saying, “Oh, that’s just because they have bad behaviors,” or, “They have the wrong parents,” or something was causing it.

And I noticed that in your all's review, those things were mentioned again, but also, to your acknowledgment just now, we still really haven’t uncovered what the heck’s going on. Let me ask specifically—'cause I did a lot of work with our molecular database—we could not really find any clear next-gen sequence differences based on age. Have you guys got any more insight into the genetic piece of this?

Thejus Jayakrishnan, MD: Yeah, I mean, you're very right, Dr. Marshall. Genomically, we do not see a huge difference in early versus average onset. Certainly, there's a higher prevalence of germline predisposing syndromes in younger people, but that doesn't explain the increasing incidence over time.

The vast majority of these cancers are sporadic, meaning they are not inherited-type syndromes. We do see certain subsets of early-onset GI cancers—for instance, early-onset cholangiocarcinoma—where there’s a higher prevalence of _FGFR_2 fusion. That has been described and is a targetable mutation in cholangiocarcinoma.

In pancreatic cancers, there’s a higher prevalence of not having th_e KRAS_ mutation in early cancers, but having other targetable mutations like IDH1. But again, that’s not a standard targeted therapy in pancreatic cancer. These are still very small percentages.

So, what we really see is also the fact that most patients with young-onset GI cancers present with more aggressive disease. There’s a higher prevalence of, say, signet ring cell cancers or poorly differentiated cancers across the different early-onset GI cancers. A lot of patients present with stage IV disease at diagnosis, which could be partly from delays in diagnosis. But then, we also see higher prevalences of these aggressive variants.

Even with aggressive treatments—younger people, you can imagine, don’t have a lot of comorbidities that may prevent them from getting intensive treatments—we do not see a proportionate improvement in the outcomes. So, there's definitely more molecular factors at play that we need to understand better.

John Marshall, MD: Yeah. So, bad cancers—not necessarily better cancers. Yes, they're younger, and you can beat ’em up more, but that doesn't necessarily mean it's translating into improved outcomes for those patients.

Let’s sort of talk a little bit about current theories as to why. One of the things that only recently—in the last three to five years—that I recognized is that for colon cancer, and it's not necessarily the other GI cancers, instead of the normal sort of 40% right, 60% left, we're seeing this very high percentage of rectosigmoid tumors.

And so, I've been sort of thinking, this must be some sort of microbiome issue. My God, I hope it’s not Starbucks. And I hope it's not bourbon, because then I'm just gonna get it too—those are like my two favorite things.

But, you know, some people are looking at exercise, antibiotic use, or other kinds of components. Microplastics—people are out there.

Thejus Jayakrishnan, MD: Absolutely.

John Marshall, MD: If you had to put a quarter down right now and bet, what do you think the common sort of theme or molecular pathway that’s causing this would be? What would you say?

Thejus Jayakrishnan, MD: I think it is an interaction between environmental factors and the microbiome. That’s what a lot of our studies are trying to do—like a deconvolution—to understand how much one component is contributing.

We definitely have seen an increase in obesity over the last 40 years. Childhood obesity is increasing, and it has been shown that early exposure to adult and maternal obesity can be a risk factor for early-onset GI cancers. But, you are right. I do see a lot of people who do not have these risk factors, so there have to be other factors as well. Physical activity correlates—lower levels of physical activity are associated with higher risk for these types of cancers. But again, we see people who are athletes who do develop early-onset GI cancers.

I do think that exposures play a role. Dietary patterns have changed over time. We see associations with Western-style dietary patterns, which include higher intake of processed meat and sugar-sweetened beverages. Even if someone may not have obesity or metabolic syndromes, they may still have higher exposure to unhealthy diets. Another common factor that connects all of this is microplastics. There are actually studies that have shown microplastic exposures in experimental models lead to higher rates of growth of colon cancers.

There's also synergism between high-fat diet and microplastics, which has been demonstrated in experimental models. We need more epidemiological data and tissue-based analyses to really understand how this may be contributing.

Studies—including ones I’ve been involved in—do show differences in microbiome characteristics, both tissue-based microbiome and stool microbiome, in early-onset versus average-onset GI cancers.

Now, some of it could be associated with the development of cancer, but there are unique differences. We have also identified that these microbiome differences correlate with the metabolites in the body. So, there are a lot of connections between exposures, microbiome alterations, and metabolic changes in the body.

What we are trying to do—through the young-onset colorectal cancer cohort—is prospectively collect tissue, blood, and stool from young-onset patients, along with exposomal data. That includes dietary exposure, physical activity, and other lifestyle factors. We’re really trying to integrate that to understand how different factors may be interacting with one another in the development of cancer.

John Marshall, MD: Part of the reason we're focusing on your great paper is that we don’t have widespread awareness in primary care and urgent care clinics that young people can get cancers. Our screening is not well established. We did drop it to 45 for colon, but we don’t screen for cholangio. We don’t screen for pancreatic.

So, we need to think about: is it enough of a problem that we need to begin shifting screening?

On one level, you’re trying to figure out who’s getting it and why, so we can intervene and reverse whatever it is that’s causing it.

Thejus Jayakrishnan, MD: Mm-hmm.

John Marshall, MD: On the other end, from a public health perspective, we’re trying to say: should we be looking more aggressively, as a healthcare system, at a time when our system is already stretched to the nines?

But let’s go one other place. You’re 42 years old, and now you’ve got stage III GI cancer. You have to work to pay for your insurance. It’s disruptive, because none of our treatments are easy.

Talk a little bit about the impact of cancer for a 40-year-old versus what we all signed up for, which was a bunch of 70-year-olds.

Thejus Jayakrishnan, MD: Yeah, you know, that’s what makes it even tougher to manage. A lot of the people that you diagnose with this cancer are at a stage where they have a growing family. They may have recently gotten married or had kids or just started a new job.

They’re gradually progressing in their careers when they’re faced with this diagnosis. Many of the young patients I see don’t have previous exposure to the healthcare system. So now they’re going back and forth to the hospital for biopsies, chemotherapy, managing complications—and it’s all new to them. That’s combined with other life stressors—managing a career, a family, everything. So, we do see higher psychosocial distress.

John Marshall, MD: I gotta throw this in. You know, 70-year-olds don’t complain about any side effects, but 40-year-olds complain about every single side effect that we cause. It’s always interesting to say, yeah, you're young, you're tough—but they list them all—whereas that 70-year-old is just used to feeling that way.

Thejus Jayakrishnan, MD: That’s also something that’s part of our research—trying to figure out if there’s a biological mechanism that may be responsible for a higher risk of toxicity. But it definitely impacts the ability to deliver the treatments we want to. We do want to give intense treatments, but then you see significant side effects, whether it's nausea, vomiting, or even neuropathy from oxaliplatin.

And then, we have to think about long-term side effects—even in curable colon cancer, where you have to receive adjuvant, postoperative chemotherapy to decrease the chance of recurrence. But then you’re faced with having to deal with some of these side effects.

Even post-surgical complications, like low anterior resection syndrome after rectal cancer surgery, can have a big impact on quality of life. So, there are a lot of considerations there.

John Marshall, MD: You know, part of it—being the end of July—is we’ve got our brand-new fellows coming in, and we’re teaching them as much as we can.

I think when it comes to young people, for example, young patients, we often say, “We want to be very aggressive.”

Thejus Jayakrishnan, MD: Mm-hmm.

John Marshall, MD: But I keep trying to swing us away from that word. Being more effective is really what we want. And this young group—I was thinking mostly around colorectal, but it’s true in other diseases too—there’s increasing interest in organ preservation, avoiding radiation. These are the kinds of strategies we’re using because if you’re going to have this problem and you’re going to survive it for the next 30 or 40 years, we want to optimize your quality of life.

I know your center does a lot of this. We do a lot of this. It’s less easy to do as a generalist or someone out there who doesn’t feel quite as comfortable, but I know we’re all out there to help them and offer advice to try and optimize that patient’s quality of life—to be the most effective, not necessarily the most aggressive.

Thejus Jayakrishnan, MD: Yes, totally agree. With the PROSPECT trial and the OPRA trial in rectal cancer, we have more evidence that we could potentially avoid radiation or help a portion of people avoid surgery altogether for rectal cancer.

Over time, I think we will see increased adoption of these approaches. There are also studies looking at early-stage rectal cancers—T1, T2—whether we can use chemotherapy or chemoradiation and avoid surgery in those subsets of patients.

There are newer immune checkpoint inhibitor combinations coming up. So whether those translate into opportunities for non-operative management in microsatellite-unstable tumors remains to be seen.

And can we develop effective immunotherapies for microsatellite-stable rectal cancer that can also help us avoid the risks of some of these other treatment modalities?

John Marshall, MD: I can’t thank you enough for taking the time. I know you’re busy—I know we’re all busy—but this is such an important topic. Your paper got the appropriate big national recognition—on news channels and the like.

I just wanted to make sure that our audience also had a little bit deeper dive on this issue, because we’re the ones that are going to be meeting these people across the exam room table from us.

And we want you to know out there as much as we know, so that we can make it a little easier on all those folks out there. Thejus, again, thank you very much.

And for Oncology Unscripted, this is John Marshall. Thanks for joining.

[15:26]

This transcript has been lightly edited for clarity.

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[00:00:05] John Marshall, MD: John Marshall for Oncology Unscripted. Really no script at all, but we are post-ASCO here in Washington, DC, trying to take all of those major innovations that we all get so excited about—curves with big deltas that we saw in all sorts of different cancers, including the humblest of them all: GI cancers.

So, now the question is: how do you take those innovations and those changes—some of them are added to NCCN, some of them may be FDA-approved, some of them in The New England Journal of Medicine, some not—and apply them to our patients? Many of them are novel tests, maybe not covered by insurance.

Many of them are new drugs that don't have a label and may not yet be approved by healthcare coverage. Many of them, as we will talk about, are not available to most of the world. In fact, they're only available to us here in the wealthy corners of our planet. And so, how do we go from that innovation to the patient to realize those benefits?

I want to highlight two papers because, thematically, they go along with what we are talking about this cycle. So, you've probably seen this journal before—it's called The New England Journal of Medicine—but I want you to make sure and look at this paper by Andrea Cercek. You know about it. This is using IO therapy in MSI-high positive primary cancers, and of course the rectal cancer data. This bar plot right here: 100% of patients with rectal cancer, MSI-high, had a positive clinical response and didn't need surgery. It's not quite 100% in some of these other cancers, but it's dramatically positive, and we here in the United States have access to those therapies for patients with these dramatically positive benefits. But, as you will hear, not everybody has that access and, therefore, they don't even really want to know what their MSI-high status is, because they can't do anything about it.

A second paper, also from a journal you've probably seen before—recent cover change; I kinda like the old cover better myself—Journal of Clinical Oncology. This is also a GI cancer paper. This is from a European consortium group, and there are also some US folks here. They took samples from adjuvant clinical trials in colon cancer and developed a sort of digital path–generated signal of risk, and were able to sort patients into their risk categories so that we could know who needs chemotherapy and who doesn't—who's going to benefit from chemotherapy and who doesn't. Similar to what we are seeing with the MRD ctDNA testing.

This is pretty damn cool because everyone's getting surgery, or most of the world who has healthcare is getting surgery. The analysis that this requires is actually relatively inexpensive compared to some of the fancier tests that are out there. It enables a sorting of patients into risk factors—so much, importantly, for whom needs treatment. Because, right now, we're treating everybody. But more importantly, who doesn't need treatment? How much value can we find with these tests that actually identify the patient who's already cured or who will be upfront resistant to the treatment, therefore not needing it?

This is really where AI is going. And both of these papers speak to this concept of access and value. When something's a 100% benefit rate, the whole world should have access to that—and that's where you can have MSI for rectal cancer with IO therapy. When, on the other hand, an inexpensive test—a series of tests—can show you who needs treatment and who doesn't, there's incredible value. The whole world saves money if we can apply that kind of metric to decision-making going forward.

So, I think these two papers are really good examples of how the progress we are making improves the value and our efficiency going forward, so that as we approach the next generation of cancer care and cancer interventions, we can do it better, more effectively, less expensively—so that one day we can say, yeah, that was worth it.

John Marshall for Oncology Unscripted.

MEDBUZZ: WHAT IF THE BEST CANCER DRUG IS THE ONE YOU CAN’T GET?

John Marshall, MD: We've been talking a lot and thinking a lot about access to cancer care. And let's start hometown—let's start here in the good old US of A—and talk about unequal access to cancer care. Here, we all know that what color you are, what your race is, what your gender is, who your parents were, what type of insurance you have, urban versus rural—we all know about those differences in access to cancer care. A new one that's emerging is specialization of the team that you're seeing. So, general oncology teams versus disease-specific oncology teams tend to produce different outcomes, simply because everything is moving so fast, the subtleties are something that the specialized team can keep up with, that a generalist would struggle with. And this is an important issue that we need to figure out, as a nation, how to distribute that specialized knowledge to everyone so that we level that playing field as well.

We all know about the threat that's out there right now with health insurance changing—where Medicaid is being threatened. Just yesterday, Planned Parenthood was talking about, well, the Supreme Court says, yep, you don't have to have Medicaid for Planned Parenthood. Like, that's the Supreme Court's decision on—I give up anymore. But so, where's that gonna trickle down to in the expensive world of cancer medicine?

And so, we'll talk about ex-US, but I want to start with us a little bit more, because I was on a call the other day with a congressman—U.S. Congressman from Georgia’s First. That’s the southeast coast of Georgia. It's also where I—so one of my favorite places to escape. But the congressman there is a guy named Buddy Carter, and he was a pharmacist before he became a politician. He was saying—Republican—and he was basically saying that we can't afford, in this country, healthcare. We can't afford cancer care, for sure. We're spending a lot more than we have, which means we're just continually going into debt every time we add a new medicine or do a new CT scan or whatever it is. Yep, insurance is covering it. Healthcare systems are being paid for it. But we're going into overall debt because of that. And his main shtick, which sort of upset me, was all about cleaning up the rolls—making sure that people who don't deserve U.S. healthcare aren't getting it. So, if you're a non-national or you're not working or whatever it is, that you don't get access to the support for your healthcare without demonstrating your worth, your value to the system. So, that sort of got me on my heels. 

What also putting me further back on my heels was that he was ranting about 340B pricing. We all know that that is an uneven system in our country, where certain health system sites get different prices than other sites, making a bigger markup to pay for the infrastructure of cancer care. That was the reason it was originally developed. But, of course, it creates an uneven reimbursement system right now here in the good old US of A—even within the Beltway, we have different rules, different healthcare sites.

He also went on about PBMs, the pharmacy benefit managers, the middle people who are taking their skim off the top for managing cancer care and the expense of therapeutics. So, they clearly, up on Capitol Hill, are upset about this and anxious about this. And they want to blow it all up like they do with everything, but they don't actually have a plan for what they would do in place of that.

As we thought about this, we thought about: okay, if we're gonna blow up the U.S. system that's covering so much of our world's healthcare economy and research, what are we gonna replace it with? So, we thought it would be interesting to talk to folks from around the world and get their opinions about this. So, certainly continue to listen in and listen to those interviews from people who are very well respected around the world.

But one other thing that we thought about is that if you are from a poorer country and you know about these novel therapies, and some manufacturer is willing to make your biosimilar or your generic for you outside of the patent laws that exist—at least in this country—do you know if you're getting a good product or not? And so, there is increasingly data to say that it's inconsistent—that if you're a physician in a less wealthy part of the world and you've ordered some fancy drug that's being provided by some manufacturer, not the original one—maybe it's not active, maybe it's too active, maybe it's toxic. So, it's unpredictable.

And so, in the desire to have access to these very positive therapies, these very positive interventions, it makes people make risky decisions about, well, better to try it than to not try it, because I got nothing better than that.

So, we think this is a major issue for us as a global market as well.

So, lots going on out there as we try and bring innovation forward, try to keep our advantages that we have been able to achieve, and distribute them evenly and more effectively to more people—not only in the United States but around the world.

So, I hope you will continue to listen to Oncology Unscripted as we do a deeper dive into this issue of access and healthcare decision-making around the world.

GLOBAL REALITIES OF ASCO INNOVATION: PERSPECTIVES FROM THE UK, LATIN AMERICA, AND EASTERN EUROPE

John Marshall, MD: Hey everybody. John Marshall for Oncology Unscripted sort of still on ASCO, not letting go of that, and this little bitty series is about I Access to treatments around the world. We all go to Chicago or to ESMO this year in Berlin, and we see new big productions, new data, expensive medicines, but medicines that are having major impact.

And here in the United States we have this sort of perspective that we can have whatever we want. And for the most part, we are the primary market for a lot of these new cancer drugs. And we've talked about that before, but I thought. Post-ASCO. It's really, really important for all of us to pause and think a little bit about rest of world because we don't have the same access around the world.

INTERVIEW WITH DR DAVID KERR

And to help me discuss this is an incredible leader in the world of oncology today. And also, I am lucky enough to call him my friend and have spent some time with him and his family in that beautiful spot over his shoulder there in Oxford, and this is professor Dr. David Kerr, who is down from Scotland, in his current, place of, Oxford. and he's been willing to join us. So David, welcome to Oncology Unscripted. Give the fans here a little bit, background about you, and then maybe just jump right in in terms of access and how you folks there in the public health service figure that out.

David Kerr, CBE, FMedSci, FRCP: Great to see you, John, and of course, welcome to you and the rest of the gang from the dreaming spars of Oxford, which you can see over my shoulder. so I'm David Care Professor of Cancer Medicine at University of Oxford. I, sidekick friend of John for more years than either of us would care to account and probably have lost the sort of distant tracks of time for former president of esmo.

I chaired the ASCO International Committee for a while. Fantastic outfit, and I've just been elected to the board of the UICC, which gives quite an interesting overview globally. About inequity, the, the unfairness, the lack of reasonable distribution of access to. medicines in the uk. many years ago, I served as a health advisor to then Prime Minister Tony Blair, we set up something called nice. This was a National Institute for Clinical Excellence and effectively. a rational means of drug rationing. that's not oxymoron. We can put that into the same sentence. And what it does is it looks at the data.

What are the clinical benefits of it?  How much does that cost? And in the context of a socialized healthcare system, such as our NHS, how does it stack up against hip replacements against vaccinations for children, against smoking prevention programs and so on. The whole gamut of cancer control, but, but placed within the wider context of all of medicine and, and poses a question, can we afford it?

Are the benefits sufficient for us to recommend that all the patients in NHS can get access to it? at one level, I think it's fear and transparent. And it's not a deal done in smoke-filled rooms. The old days was a machinery, a, logic, a statistical approach. All of us could understand, of course it's frustrating because quite often the answer can be no.

We come back from, ASCO, full of the joys of spring, full of the joys of early summer. and of course, medical oncologists wanting to do their very best for the patients that we look after, but frustrated by nice often saying no. And by the time taken, to be honest, it can take months, if not years, for the process to to go through. So, while the gold standard has moved ahead in the United States. But we find ourselves in stages, waiting to see if it can be done or afforded. And there's a frustration in that, as you would imagine.

John Marshall, MD: Let me drill down on some of this because, I've been always impressed by your work and the creation of the NICE committee. First, the transparency. As you say, you publish the analysis in Lancet Oncology of, of a yes or a no. Is that right? And, and the committee is a formal charge on behalf of the nation, if you will, instead of me dealing with the Blue Cross physician. You all are taking the responsibility on the backs of, on, on behalf of your country. Is that, is that the way it works?

David Kerr, CBE, FMedSci, FRCP: It, it, it is, it's a national committee. So, when, when the, the reason that we kicked this off all those years ago with the Blair government, we had a thing called postcode prescribing. So even with NHS there was significant variation. Variation is a word that we might come back to 'cause that makes us nervous. 'cause variation is usually, it's usually leveling down rather than leveling up the NHS was set up, different regions, different districts. you're living in a, a village in England, if, if one side of the village road happened to be in District X rather than District Y, you know, your neighbors might get the drug, but you wouldn't. It was extraordinarily ridiculous. So, we created this national body exactly as you said. That we take a decision on behalf of all the citizens of the United Kingdom.

John Marshall, MD: The other piece that, or a second piece that I wanted to focus on is this, this concept of you take something away, if you're gonna bring a new thing in, if you're gonna bring a new product in, you're, you're trading off something, or on the other side, making some recommendation to raise taxes. Is that true or is that my version of it?

David Kerr, CBE, FMedSci, FRCP: No, so, so you, you've opened up to a philosophical canof worms. One is we're a taxation-based health service therefore, like Moby Dick, it's the ever-open mo that we are a sort of endless money pit. To, to use a sort of term from Hollywood and so on. So, we just go on and on consuming and using, and successive governments health secretaries talk about the form of NHS, improving efficiencies and so on. But this is an organization with 1.35 million employees. I think we're the fourth largest outfit in the world after the Chinese People's Liberation Army, the Indian Civil Service. Then probably is actually, so you can imagine managing that outfit is horrendously complex and we have disconnected hierarchies.

The boss, the health secretary says I've made the decision and he thinks that that will sprinkle down throughout the NHS far, far, far from it. But other thing that you, that, the other thing that fascinates me is the concept of value in the headroom. So, so you're exactly right. If, if I had the. If I hit the national cancer budget under my control, then I wanted to bring innovative. Worthwhile new drugs coming through you, you and I would recognize these, so we're not talking about an improvement in disease-free survival of six weeks, but we're talking about impactful real drugs that make a difference. Exactly. So, we, we make a secret sign But in order to bring that in, how do we create the headroom? Well, by not doing stuff that's useless, should we be giving 10th line breast cancer chemotherapy? I, I dunno why I particularly said that, but you get the point, way beyond the evidence base using I I don't mean this to sound horrible using chemotherapy as an emotional, psychological crutch for me as well as for my patients. It's, it's, it's a trap that we mustn't fall into and those of us older, wiser, I think, often manage to avoid it. But for young colleagues who want to do the best they can to leave no stone unturned, we give quite a lot of actually, ultimately treatment. I'm sorry to say.

John Marshall, MD: I think you're totally spot on.. One thing that sort of came to me, this ASCO. As we talk about the cost of precision medicine, doing the tests, let's just start there. Or could be MRD testing, ctDNA testing, identifying those people still at risk, et cetera, instead of just treating everybody and crossing your fingers you know, how do we identify value to your word? And I like this word. It's like when I see someone presenting a new study at the plenary session, the slide that's missing. Is the value slide. So, if I do a test and it identifies the 9% of BRAF patients in colon cancer and my survival delta is big, what we're not showing and the cost of that, let's be fair.

The added cost of both the test and the new drugs, your, to your point, what we are not showing is the useless medicines that we are not giving. And so, on some level, we've made ourselves. More efficient, it becomes worth it because then we don't give the therapies that don't have the value. So, I, it's always about adding on instead of what is it taking away when we make progress.

You think that's right?

David Kerr, CBE, FMedSci, FRCP: Isn't value an interesting word and it's a double-edged sword. So, all of us want to get value for money. We're buying a new car, we're doing this, we're doing that. You know, the value are usually where you get cheat cuts of meat. It's usually of inferior quality. And so somehow wrongly value can be associated with a poorer effort. A poorer outcome, and a a, so I'm going to plug like crazy, A wee book that's Grain I wrote called how to get better value healthcare, the focus on cancer, and this is trading in some fantastic work coming out of Harvard. And how do we define value? And we defined it in terms of what the inputs are exactly as you said, what all the various costs and elements are, and so what the outputs are, what, what we achieve in some way. And so, it's moving just beyond the health economics of it. I agree with you. That's one element of it, but not, not the most important of it, too sharply focused on, you know, the impact of the new drug and the new test without taking account of the wider picture. 

John Marshall, MD: Let's go to one other area, and this is just the, the cost and the negotiation process. So here in the United States under there’s a law that says we are unallowed to judge value. That whatever the industry asks for, the product we are on, government and Medicare, et cetera, is going to pay that and that markup. Again, our secret sign, that big markup is what is going back into drug development or global drug development. That's part of the budget that these multinational companies have, and since the last administration we have that's been challenged, and so everyone's very anxious that we won't have that money for reinvestment. I also see on your side. A different level of negotiation is that, you know, if, if, if, if you charged, you know, one of the big companies this amount, you could fit in under our budget. Right? So, you are getting a different price hopefully for takes too long. I granted, but you're getting a different price at the end of the day than we are. So on some level, when we talk about the imbalance or the inequity, I think the American public needs to recognize that we, and it's our taxes and other things coming out of our paychecks are paying more for a given thing than you guys are able to negotiate as a collective. And, you know, so I, the individual versus the collective.

What, what are your thoughts about that?

David Kerr, CBE, FMedSci, FRCP: I think if it wasn't for US drug market, with all the elements that you said, I'm sure that there wouldn't remotely be the same drug development expertise going on in the world. the idea about that imbalance being redressed in some way, be fascinating to see how, how your administration will deal with it. Our civil servants are negotiating behalf of the whole, of the, a whole country, you know, 65 million people, so they'd hope to be able to get a good deal. clearly your administration have spotted the huge differential in prices comparing many, if not all European nation states with the, the prices going on. United States, it doesn't seem fair, and I've said that I've benefited from your large s scientific and tax dollars for the past 40 years. I, I, I'd be very honest about it.

John Marshall, MD: I always wonder about the other side of this argument is that only, I think the figure is somewhere around one in seven people on our planet has access to cancer care at this level. And so, I, my sort of running joke about this is that we're selling Lexuses when in fact we could be selling Toyotas and selling it to more people.

And I've never really understood to this. What feels like false economy, and we are in the middle of it of course, because we are counseling and consulting with the industry people. We are providing care. You on a national level, coaching, you know, your country on how best to do this. It would seem like there should be some opportunity here to sell to more individuals and therefore make up the difference in that way and solve.

One of the problems that you and I recognize all along is that so many people just simply don't have access.

David Kerr, CBE, FMedSci, FRCP: If only we knew more about economics of, you know, sell low, something like that, which is.

John Marshall, MD: Behind you, they teach that, don't they? 

David Kerr, CBE, FMedSci, FRCP: No, you're right. There are a couple of Nobel Laureates their people, the Fields Medal. So, there are some bunch of smart people, but they, they, God, you know, they do their own thing. 

So, the UICC. great organization is a multi-member institution. It's a union, international control of cancer. We've got a brilliant program called Atom, working with pharma to make expensive drugs available in low-income countries. And I, I think both you and I would agree that the perfect as enemy of the good, rather than saying that every citizen on earth deserves a gold standard Cruiser, deluxe, NCCN ASCO and ESMO guideline driven cancer treatment. That's that, that cannot be the deal. It just cannot. And I was my president, I was very keen to see what we could do to establish. Functional, sensible guidelines that took account of individual countries could afford. And I would rather that we gave something that was decent but not perfect rather than nothing at all and had all sorts of interesting ideas.

But I ran into a few problems. It was fascinating and that some of my colleagues from low-income countries said that. I was trying to, how did they put it? Quite strong language. I was imposing an imperial, Imperial approach to saying, I'm denying people from income countries perfect treatment.

I said, I'm not, I'm being utilitarian. Let's treat more people pretty effectively rather than. people very effectively 'cause that that was a price differential, low dose metronomic, oral chemotherapy for breast. Why not? It's not, it's not like humdinger. This would do some good for the masses. Vast majority of people. I'm getting about it, but no, I mean, you've hit upon something that. that bugs me. and, and we need to find a better way of doing it. And I think we are the WHO Essential Medicines list, with work that's going on to reorient the guidelines and, and to make them more cost sensitive and to work with colleagues to say, let's reach out to wider segment of our population, moderately effectively, run a tiny sector with cruiser, deluxe drugs. it's a hobby horse, as you can tell.

John Marshall, MD: I could go on for a while, which is why I think they created pubs in your beautiful land. and maybe next time we are together, we should do that. But for now, let us, Call it an evening. thank you one more time for taking your valuable time away to share with our audience actually on a pretty global audience nowadays with electronics and all of that, our reflections and discussion around, the impact of innovation and how do we distribute that innovation to more people. Professor, Dr. David Ker. Thank you very much for joining us on Oncology Unscripted.

Good to see you, John, and delighted to take part. 

John Marshall For Oncology Unscripted

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John Marshall, MD: John Marshall coming to you live Oncology Unscripted, not from my office back in Georgetown, but from beautiful downtown Chicago, Illinois at ASCO 2025. Look at this amazing place. 40,000 of our closest friends.

To get in, you need to have one of these. So, I'm gonna go ahead and badge up. I got a fancy red collar thing here, boy, that makes me stand out even that much more.

But what we're gonna talk about today first is the social aspect. You remember in anticipation of coming, we were a little worried about would people from outside the US come to the meeting, and, yep, they've come, but not to the same extent that they have in years past. So very clearly international travel being affected by the world today, and, therefore, our community, which is so important to get together on a regular basis, probably being a little bit affected by this. But it is an incredible time to get together, to share thoughts, to give a hug or two, to shake a hand or two, and connect with those of us in our community who are dedicated to trying to cure cancer to find positive outcome for our patients for Monday morning, for Tuesday morning, in the week ahead.

So, let's start with some high-level reviews of the most important science. Later today, we will have the plenary session where five abstracts will be presented, each one of which has significant impact on our patients going forward. Let's start, in my world of GI cancer, where immuno-oncology, again, doubling down in the microsatellite unstable patient adjuvant IO in MSI patients with chemotherapy proving to be better than chemotherapy alone. Not tested against IO alone, which will clearly be the next question, but for now, starting next week, MSI-high, IO plus chemotherapy in the adjuvant setting in colon cancer.

What about gastric cancer? Same thing, IO, and this is not an MSI-high, added to chemotherapy showing survival benefit for our patients with gastric cancer. So, as of today, new standards where IO will be added to adjuvant perioperative therapy for patients with gastric cancer.

And the third area where IO has been shown to be a benefit in this plenary session is adding it to radiation and chemotherapy in head and neck cancer, something we've long been needing. Improved novel therapies for head and neck cancer. IO has just entered that field too in the curative intent combo chemo RT setting. So, three major places where IO is gonna have an impact starting today.

Now I'm not even gonna try to talk about polycythemia vera. I'm not even sure I can spell it, so I'm gonna make you look that one up yourself.

But I wanna finish from a plenary perspective on this breast cancer study. Of course, it's always breast cancer. They are the smartest, they have the most money, they have the highest survival of all of our solid tumors, and, yep, they did it again. They actually show that if you monitor patients who are getting therapy and you can use circulating tumor DNA, so a blood test that can demonstrate the emergence of resistance before there's a change in the clinical scenario. And if you add in, in this case, an androgen hormone degrader, that in fact you can intervene and actually extend survival and progression-free survival significantly. So, this is real time monitoring, using novel blood tests for resistance and changing your therapy in advance of any other clinical signal. Clearly, this is the way things are gonna be going more and more as we define therapies for our patients. Not so much using CT scans and waiting on progression, but blood tests that demonstrate resistance at a much earlier time point.

Two other important GI papers. Not part of the plenary. There wasn't room for everything in the plenary, and this is, guess what? It's now good to be BRAF colon cancer. Do you remember when it used to be bad to be HER2-positive breast cancer? Do you remember when it used to be bad to be MSI-high? Well, it's not bad anymore for those two because the therapies work. It used to be bad to be BRAF V600E-mutated colon cancer. Just a bad prognostic sign. Nothing you can do about it. Study just presented showed that the addition of BRAF-targeted therapies and frontline metastatic colon patients with a 30-month median survival. So, that took a bad marker, we can now deal with it. What does that mean for your clinic? I'm gonna be strong here. It now means that it is malpractice,  you are not practicing the standard of care,  if you're not doing frontline molecular testing in colorectal cancer. You are obligated to find Ras mutations, BRAF mutations, MSI, and HER2 before you initiate treatment. So, this positive BRAF study affects standard of care in your practice today, so you have to do that going forward.

There was a study looking at the novel, local therapy for pancreas cancer called tumor treating fields. That showed some positive data, finally, in pancreas cancer, so that's exciting. Tomorrow morning frontline trastuzumab deruxtecan data will be presented for patients with HER2-positive breast cancer, showing dramatic deltas and PFS and OS when you initiate treatment within trastuzumab deruxtecan instead of the traditional therapies there.

Practice changing common cancers. Precision medicine driven, IO-driven. It's a dramatic year for new data; new standards of care being presented here in Chicago. ASCO 2025.

John Marshall, Oncology Unscripted.

Live from ASCO: What the Slides Don’t Show

John Marshall, Oncology Unscripted ASCO 2025.

You know what this is? It's called the ASCO Daily News. They hand you one of those as you enter the building here every morning. And yeah, there's a lot of good science here, a lot of cool things, and pictures of prominent presenters. Even old oncologists get their picture here as well. But there's a whole bunch of stuff that's not in the oncology news that's really important to our future.

On Friday, Trump unfolded his budget. His budget includes a 40% reduction in the NIH budget. It is a huge delta in what will happen at the National Cancer Institute, if indeed this happens. 15% indirect rate officially now on the table. The Cancer Center Directors, NCI Cancer Center Directors, visited Capitol Hill last week hosted by Georgetown’s Lou Weiner, my boss, and they all went up to the hill to talk to various congressional folks about what the heck's going on. If you cut this budget, we will lose ground in terms of America's ability to contribute to cancer research at a time when we know more than we ever did.

Our European colleagues have put out advertisements to attract some of our major thought leaders to go to Europe, granting visas so that they can in fact do their own brain drain of us now that our budgets are being cut. So, we really have to figure it out. What we are doing and the impact this is gonna have day to day, not only on our research, but on our cancer care delivery, for our patients here in the United States. And I don't think folks have really thought that through very well.

Secondly, we of course have no NCI director right now. They're sort of an interim. And one of my friends, a guy named Wafik El-Deiry, who's at Brown, has put his hat in the ring. He had said some pro-Trump stuff coming into this year thinking that shaking up clinical research was gonna be a good idea, but he's sort of like, what are we talking about now? And he said, I'll do it. I'll do the job if you give me $50 billion for cancer research. Well, that's more than the current budget is. And of course, I just told you they're cutting the budget. So, I don't see any way that angle, that argument, is gonna take any traction with our current administration. So Wafik, I hope you get what's on your Christmas list, but my guess is you will not. And my guess is we will continue to go without an NCI Director, and an unclear future about the role the NCI is going to play, in global cancer drug discovery and drug development and looking for cures.

The other major theme that we're hearing here at this cancer meeting is that artificial intelligence is gonna be important. That if you're not doing it, if you're not embracing it on the education level, on the research level, any level you wanna look at, then you're gonna fall behind. And I think most of us probably agree that it's gonna be a very, very important tool.

But you that little thing called Make America Healthy again, that just came out from somebody named Kennedy. Well, that actually includes seven papers that were hallucinating. References in our national policy proposal that never were written that AI wrote instead. So, where's truth? How are we gonna know what's real? How are we gonna know what's a hallucination when we do our Google searches? How deeply does a journal need to review a paper to know whether AI wrote it or in fact, some fellow who wants to get a paper on their CV wrote it, right? How are we gonna prove truth going forward when a government policy paper has seven references that never existed, supporting what we're proposing. How are we as a major cancer community gonna keep track of what's real and what's not real? So, I'm very anxious about AI and how we're gonna manage that going forward. We know we need it. We don't know how to control it. Figure this out. Everybody.

John Marshall 

Oncology Unscripted.

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John Marshall, MD: John Marshall Oncology Unscripted. You know what this is? Yeah. You know what this is. This is my ASCO badge. It is that time of year again where I. I don't know, 40, 50, 60,000 of us and our closest friends all fly up to Chicago, stay in hotels that are overpriced, get bused around downtown Chicago, even on Saturday and Sunday. We get in nice clothes. We go to the convention center. We probably share a virus or two, but we mostly share important new information around the world of cancer. Maybe the most important cancer meeting there is on an annual basis, both from a social but also professional level do we gather to really exchange ideas and hear what's happening out there in the world Now. I also in my badge, got this, a 30-year member, God. know what that means? I got one also called ASCO Ambassador. I'm not even really sure what that means. Maybe I owe 'em money. I don't, I don't know what that's all about. I got my thing that I'm gonna submit to win whatever it is they're giving out, this year at ASCO. So, I've got all my equipment, I'm ready to go.

Titles of the abstracts have been released, and there's a lot of really cool information. I know we've been kind of having a sub-theme around pancreatic cancer, last few episodes and during the oral presentations, there are three very important, probably practice changing abstracts around pancreatic cancer, around perioperative treatment for resectable pancreas, cancers, novel therapies that are being brought to the table for pancreas cancer. So, whether you're going or not, you need to know what happened at ASCO. And so, stay tuned because we're also going to be broadcasting from the meeting, and we'll of course follow up with some of the key data post ASCO. 

Now, most of us, when we think about ASCO, we start with what are the plenary papers this year? And there are five. Two of the five happen to be GI. That's, that's a record. I think for us. Normally it's all breast and then maybe something else. But two of these five are in fact, GI cancers. One is around immunotherapy in the perioperative setting of gastric cancer. Gotta be positive. It's why it's in the plenary session. The other is not news in some way, but, God, if it had been negative, we would really need to rethink things. It's using IO therapy in the adjuvant setting for MSI, high mismatch repair deficient colon cancer. Important study around head and neck and immunotherapy. So, big, continued theme around immunotherapy, incorporation, some targeted therapy in breast cancer. Again, positive. Yet another positive breast cancer study, and the last is around polycythemia vera. Have to kind of throw something to the heme team there. So, it looks like a very interesting year for new data and new research.

But if you are thinking about ASCO, I mean. Will people be going? The United States is not the favorite place to be, particularly if you're from another country right now, a huge number of people usually come from around the world. I'll be interested to see do they decide to come, or do they decide to stay home because they're concerned about being in the US and feeling vulnerable at a time when nobody wants to feel vulnerable.

Have you ever been to ASCO? It's a zoo. It's a huge convention center, like I say, 40, 50,000 people that are there. But you keep crossing people that like, you know, we did fellowship together, or I know you, you're a friend of mine. Let's stop and talk for a second. Or let's just wave at each other and remember that each other still exists. It's a wonderful experience and if you've never been. You should absolutely go. If you've been every year for the last 30 years like me, then you're eager to go back and see all of your friends and show off your new comfortable shoes and your new tie.

ASCO has become more commercial. If you've ever been in the big area, the booth area where all the displays are, they're just remarkable and they have to be divided by US and EX-US because of the different rules. Although still, I've never seen one as quite as good as one I saw early on in my career where they actually had a flowing fountain of water through the entire exhibit. because it was a medicine to help dry mouth and so this water was going to improve your overall feeling, this water in the desert, if you will. I don't even think that drug actually ever really stuck around. But, anyway, they had the best booth, the most remarkable booth that I have ever seen, but it's still pretty commercial, pretty crowded. A lot of people crosstalk on the academic side as well as on the corporate side.

I was talking to a company the other day and they were saying that a very high percentage of their business actually gets transacted while in Chicago. Not just ideas exchanged in a follow up email or a call later, but they actually do the discussion and sign on the dotted line while they're in Chicago. So, a lot more closure at ASCO than I thought. I thought it was mostly openings, if you will.

In one word, what does ASCO mean to me, it's community. reminds us that we are part of a huge, invested, caring global community that's focused on curing cancer, and we get together to remind ourselves every year, recharge ourselves and take that energy back so that we can make it another year doing the hard job that we do. Community.

After ASCO, you definitely wanna tune back into Oncology Unscripted. We might have a couple of interviews that'll be interesting to you, but mostly we're gonna focus on the new data, the practice, transforming data that's out there that we're gonna want to, know about for everyday practice for you and your patients.

So, if you are a busy clinician. Maybe a generalist. Almost always the answer is 'no, I don't have time to go to ASCO.' It's not an efficient use of your time. Right. So, you would rather go on a Saturday to the best of ASCO and hear the best of, in one afternoon, one day. So, that, that's the practice changing stuff you need to take back with you. And I don't blame you one bit. I think it is the responsibility of us specialists to go to ASCO. like that and pull out all that we can pull out in our area. So, I'm not gonna go to the breast meeting and I'm not going to the lung meeting. I'm gonna focus on the GI meetings So, I can learn every little bit I can to help me be a smarter parson So, that I can help develop the next study and help those around me provide the best GI cancer care we can.

ASCO's a really, really special time for many of us. Usually, the weather in Chicago is pretty nice. We get a chance to meet new people that do what we do. We get a chance to check up with old people to know that, hey, you're still out there and you're doing okay, and you're making progress in the world of cancer care.

So, it's really an incredibly busy time. Sleep is out of the question. You just don't do it. You work all day long. You party until the wee hours, and then you get up and do it all over again, usually four days in a row. some of the busiest and hardest days of the year. But also, I would say some of the best days of the year. I can't wait to see many of you in Chicago at ASCO.

Crumbling Crown: The Collapse of America’s Research Backbone

John Marshall, MD: How's your week been this week? What's the federal government done to you in your world this week? I've been doing a little bit of math and I've been tracking my patients coming through clinic, and yes, I'm in Washington DC, So, my numbers are going to be higher than yours are in this regard. But right now, about one out of every five patients I'm seeing has been directly affected by changes in employment due to the changes that the government's putting into place. One in five. Either they've lost their job, they chose the fork in the road, or they're feeling eminently threatened by their current job status. Their current job status is vulnerable, if you will.

I sit in section 309 at the Nats Park. I have a half season. I'm there a lot. I drink an occasional beer while I am there. Baseball is my escape. The nice woman who sits right behind me, who's been sitting there for years as well. She, every time I go to a game, is there, and I said, did it happen? And so, last night I was at the game, and she said, no, not yet, but she thinks this week. So, it's everywhere around us, this dramatic downsizing that's just sort of sweeping the country, and we don't really know how it's going to have an impact on any of us going forward.

Now we, in the academic world, we in the cancer world are feeling this in a dramatic way. So, we have discussions every week at the leadership level of will grants continue to exist? Will funded grants be paid? We have examples where they have been withdrawn, right? I happen to know if somebody who was offered a cancer job at a prominent, stable, large, old academic institution withdrew the offer because they were uncertain about future budgetary issues because of the changes in grants. I've never seen that happen in my 35 years of being a faculty member. So, clearly a change in the world. you start thinking about the job that we have, this drug development and new discoveries. How will we go forward? Let's say I'm industry. How can I reliably continue to invest in this front? When I'm not sure how things are gonna go. If I'm an investigator based at an academic institution, how do I decide that that's a logical career path forward for my brain and my intellect if I don't know that there'll be this source of funding to do the research, to set the standard, to change the standard of care? 

In many ways, what we're hearing is that the United States is becoming increasingly irrelevant and untrustworthy for sure. The whole point of what we established in establishing the National Institutes of Health and the National Cancer Institute was to be the gold standard, to be the rock that was always going to be there, to be the constant stream of new data and new resources that will the actual improvements in many diseases, not just cancer. We know that that's why people would come and want to train here. So, the best brains on the planet would wanna come and train and be trained by us here in the United States because of this resource. And, of course, all of this is going away.

The Georgetown University faculty, my daughter, who is my sage. Yesterday, that our faculty, I somehow missed the memo, is now gonna hold a weekly vigil for one of our graduate students who was deported because according to the federal government, his visa status was not right. But really, we know it was because the research he was doing was not in line with what the current administration feels is important.

I don't know if you saw this, but the New England Journal editor in chief received what was perceived to be kind of a threatening letter basically accusing them of not publishing "competing viewpoints." A randomized clinical trial. Patient got treatment A versus treatment B, and the accusation is that the authors may be misleading the readers. So, is this an assumption that the science was fraud? Is it an assumption that there's a counterpoint to their hypothesis that was not listed in the science? I don't know. I don't even know where it comes from. So, this is where we are, is that the federal government is trying to undermine the veracity, the solidness, stableness of the data being presented by the New England Journal of Medicine, one of the journals that we have in highest regard, and it is their strategy, of course, right, is to doubt, to cause doubt, in things that we hold, to be the solid base and the truth, if you will.

Now, you all know that, talked about before on Oncology Unscripted this, this concept that the federal government sent Harvard a letter, which we talked about already, that basically said, we're freezing your funding. So, $2.2 billion of funding to Harvard has been frozen with an additional billion dollars in grants. And basically, threatening the education of international students. They're talking about removing Harvard's tax status.

And, of course, Harvard is the one group that has quite publicly stood up and essentially said, look, you don't have the rights to do this. And their president, Harvard's president, wrote this response, and I do wanna read it to you in specific.

It says the consequences of the government's overreach will be severe and long lasting. Research that the government has put in jeopardy includes efforts to improve the prospects of children who survive cancer, to understand at the molecular level how cancer spreads throughout the body, to predict the spread of infectious disease outbreaks and to ease the pain of soldiers wounded on the battlefield. Opportunities to reduce the risk of multiple sclerosis, Alzheimer's disease and Parkinson's disease are on the horizon. The government's saying, "no, we don't wanna know that." And the victims, will be the future patients, so writes their president. And their loved ones who will suffer with a heartbreak of illness that might have been prevented or treated more effectively.

So, this indiscriminate slashing of science, medical technology research is essentially undermined our role and our ability to help, not just Americans, but people around the world. The accusation, again said by Alan Garber, who's the president of Harvard is that this was the government's reaction to the university, Harvard being antisemitic Alan Garber is Jewish and American, and he basically says, look, we understand our role in all of this. They take their work very seriously, and they'll continue to fight hate with an urgency that it demands. And they will comply with all their obligations under the law they say, he says, it's not only their legal responsibility, it's their moral imperative. Such a strong pushback counter statement to that.

But then, you know, our Secretary of Education? No, you don't know who that is, but She's become famous really for a couple of things. One, she was at an AI meeting. She kept referring to it, because she can't read the teleprompter as A-one. Which of course the reason you know this is that every steak sauce joke in America comes from this statement, statement, this lack of understanding of even where she was.

But then she also was, in theory, the signatory or author of a response to Dr. Garber at Harvard for his letter that he had just sent, that I quoted there. And if you haven't seen this, this has been getting a lot of social media press just because of the quality of writing. You would think that our Secretary of Education could write a letter, particularly if you're writing it to somebody at Harvard that at least is grammatically correct, if not at least readable and understandable. But as you can see, and as I'm sure you have seen on social media, the people in charge aren't up to the game.

And that's how they're doing this. They're undermining education. They're undermining those sources that are our foundation of knowledge of truth, So, that we can get on with curing cancer or whatever it is that our cause is. But by undermining us, causing doubt on us, they can then bring their agenda forward.

And I want to restate what I've shown you before is that there is an ad out there. claiming that the current administration under the President's leadership will cure cancer by 2029. why does it matter what we do? Why does it matter where truth resides? Because the real truth is gonna come forward over the next four years, and we will no longer have to worry about cancer.

In the meantime, I hope to see you at ASCO in Chicago, and I hope you continue to do the right thing, to build truth, to build for the future because we know it's gonna be back on our shoulders soon, and in fact, the load will be heavier when it's back on our shoulders. So, be in shape, get ready because it is gonna come back to us to solve the problems.

John Marshall, Oncology Unscripted.

The Fellows’ Forecast: What First-Timers Expect at ASCO

John Marshall, MD: Hey everybody, John Marshall for Oncology Unscripted. We are getting all ready to go to ASCO and we thought it would be really interesting to talk to some people who are going to ASCO who have never been. I was thinking back, my first ASCO was in a year that started with 19, just to give you an idea, and it used to rotate around different cities. Been at Chicago, same place, same bat channel every year for many, many years at this point.

I was actually able to coerce some of our fellows who are making their first trip ever to ASCO to come on and for a quick interview, introduce themselves, give us some thoughts about what they're anticipating, and then if they're nice enough, maybe we'll grab 'em after ASCO to see what they learned and what was different than what they were expecting. So, listen in folks for what, you might reflect back as to what you thought before you went to your first ASCO.

Tina, introduce yourself and maybe give us one word of what's ringing around your head about what you're anticipating for ASCO.

Tina Roy, MD: Hi, I am Tina. I'm one of the second-year fellows at Georgetown, second year hematology oncology fellow. I did med school back in Scranton, Pennsylvania at Geisinger, and I did residency and now fellowship here. The one word that, I think of is, overwhelming because of how packed it is.

John Marshall, MD: That one's gonna come true. That one's gonna come true. Christian, introduce yourself. Give us your thoughts.

Christian Agbisit, MD: I went to med school in the Philippines, but then my residency in Illinois, and then ended up in Georgetown for fellowship. And my word is something big is at ASCO.

John Marshall, MD: Good. I think big, it will feel that way for sure. And last, but not least, Nikita.

Nikita Chintapally, MD: Hi everyone. My name's Nikita. I went to medical school in India at Kasturba Medical College, did my residency here in DC, and happy to be at Georgetown. I'm a first-year heme/onc fellow. My word for ASCO, as I'm a baby fellow, I still like to think of, is just ready to get inspired, I guess.

John Marshall, MD: That's awesome. And, let me tell all of you out there listening, and these are three of the smartest people. It's such an honor to work with these folks who have dedicated their entire lives and they know so much more than old people know, and I'm dependent upon them. And they're great partners for us, and they're nice enough to spend time with us. Actually, I snuck them out of somebody else's clinic right now to do this, so, I'm in trouble with their current clinic mentors. But anyway, let's get right into it.

Tina, let me pick on you first. When I first went to ASCO, I thought it was all about fun. I wanted a hotel with a good pool, in the, in the range of fun versus work. Where do you think this is gonna be? What's your impression of what it's gonna be?

Tina Roy, MD: I think it's going to be in the middle. Work because there's so many different events to go to. I've tried to make my schedule multiple times already and I can't decide for some of the sessions which ones to even go to. So, I think I'm going to even have to watch some, like on demand after. And then fun, there's a bunch of dinners planned already. I am planning on getting deep dish pizza, So, I think there'll be, it'll be fun too.

John Marshall, MD: There is a lot of fun. There is booze involved at ASCO. Sleep is not one of the big things. Christian, work-fun. Where are you in this balance? Here? 

Christian Agbisit, MD: Yeah, I think it's gonna be both. Basically, because I'm graduating and going into a community practice, I wanted to kind of soak in all the new stuff. 

John Marshall, MD: I wanna come back to you maybe afterwards about the community practice piece because you'll notice just that there aren't many community practitioners who go to ASCO but do get a feel for that when you're there. As you look at that, because it becomes not worth it to community docs to go to ASCO, which is always one of—and they go to best of ASCOs on a Saturday somewhere, later. So, I'd be interested in your feedback on that of the value that you see, as a rising community practitioner, in the future.

Nikita, where are you? Work fun.

Nikita Chintapally, MD: I am hoping it's more on the spectrum of fun for me. I'm hoping to, you know, do maybe meet some people, meet other fellows, happy to just branch out, network in any way possible. I'm really excited to see more people do like oral presentations. I think it'll be really inspiring, and it'll be a good way to get a sense of how people present their work in an effective way. So, I think that's what I'm looking forward to the most.

John Marshall, MD: One of my partners and good friends, and one of your mentors, Dr. Isaacs, is giving a. Big oral presentation, you gotta show up for that and see what it's like. Because it is, it does make you nervous when you get up there in front of, what is the largest room you will ever be in for a medical meeting. So, just so get ready for that is one piece of it.

Christian, let me pick on you. Have you thought about packing yet? Carry on. Are you gonna check? I mean, it's what, three, four days, right? So, what are you gonna do?

Christian Agbisit, MD: Well, basically just gonna pack like some shirts, and shoes, comfortable shoes for walking. 

John Marshall, MD: That is such a boy answer, isn't it? Mm-hmm. let's talk, I, you know, I'm a married man. I know about packing that it's different by gender, although some boys are more about their packing than others, but ladies, have you thought about it? 

Tina Roy, MD: Comfortable shoes.

John Marshall, MD: Heels? Let's start there.

Nikita Chintapally, MD: I'm doing sneakers.

John Marshall, MD: Sneakers. 

Tina Roy, MD: Definitely practical shoes.

John Marshall, MD: Okay.

Tina Roy, MD: I also am going for a day extra because I have a lung cancer event to go to beforehand, so I actually have thought about how many outfits, and I think I might need to go shopping this weekend. 

John Marshall, MD: So, it's remarkable. I will wait to see what is going on this year, which is how dressed up people are. This is just a warning. particularly when we see people from other countries, they tend to, there's a lot of heels when you and to Christian's point you, you know, you, you put a lot of steps on, right? I mean, you, you, one meeting to the next could be a quarter mile, in terms of just distances. So, practical shoes is a good piece of advice. Nikita, do you have a particular, have you already put it out on the bed? Know what you're gonna take? 

Nikita Chintapally, MD: I'm probably just gonna need to pack maybe like a blazer or some layers, because I know conference centers can get super cold.

John Marshall, MD: Cold. It's totally true. It's totally true. And you don't sleep by the way, just so you know. So, you, you party until late and then. You get up early because the next session that you really feel like you should go to is at 7:30 AM. And by the way, you're gonna be taking a bus with a bunch of other nerdy oncologists from downtown Chicago to the convention center sipping coffee. Don't spill it on yourself because you had to be careful with your pack, right? This is just advice, To go out there. it is a contact sport ASCO. So, you're also gonna see for the first time, Nikita, I'll start with you. It's like we've all been to meetings where pharmaceutical companies display stuff, right? So, I don't know if you've been to a big meeting before, but they have these halls where they have their booths and their maps, their actual maps. And so, any idea about what that's gonna be like?

Nikita Chintapally, MD: I have absolutely zero clue what that's gonna be like. I'll probably see the, you know, drug names that we use in clinic, and that'll be the extent of my excitement, but maybe I'll be, it'll be different. 

John Marshall, MD: Have you all had, have you been to one of these meetings where you've seen this kind of huge booth? 

Tina Roy, MD: I haven't seen huge pharmaceutical booths, but even some small ones can be pretty exciting. I'm expecting a, because I've heard about it, I'm expecting a lot, I think. 

John Marshall, MD: Well, one thing you'll notice, this is it'll freak you out—and you'll go, Dr. Marshall? The carpet is thicker, so they make fancier carpet to slow you down when you're on the booth. So that's one thing you'll notice. There are two sides, US and not US because there are different rules around regulatory, they hire people who are not real reps to stand on the corners to welcome you.

So, there's this big thing, the wildest booth I have ever seen. I'd be interesting if our listeners might chime in. many years ago, and it was a medicine for dry mouth, and they literally had a fountain flowing through a sand desert in the middle of this booth. So, when you all go, we always try to pick our favorite or maybe, worst booth that you, you went to go see. So maybe when we follow up later, you take a, share something with like, you were just like, whoa, that, that was, that was something.

Let's do something more important while we're really going. am, and maybe I'm back to Tina. So, what do you wanna learn? What are you expecting to learn?

Tina Roy, MD: I'm really excited about the trainee and early career lounge because of meeting other mentors, meeting other fellows. So, I’m hoping to learn a little bit more about the job application process. See different people in different practices. I am also really excited to see what interaction is between pharmaceutical companies, oncologists, what kind of atmosphere there is.

So, I think I'm kind of, of course, those big like plenary sessions, oral abstracts. I'm excited about learning the nitty gritty about what's happening, but also just like that atmosphere and interaction between the different groups that are there.

John Marshall, MD: That's great answer. Christian? 

Christian Agbisit, MD: Kind of same thing as Tina. How I can treat my patients, plenaries and which are the, well, the new stuff that comes out in.

John Marshall, MD: You know, if it's in the plenary, it's positive. So that's one of the things you can pretty much bank on, going forward. Nikita, what are you hoping to learn from all of this? That you really wanted to be a surgeon? No, no, no. Something different.

Nikita Chintapally, MD: Never, yeah, definitely similar to what Tina said about the early career and mentorship, as I'm going into second year, we have more research time, so hopefully trying to see, you know, you know, what could be feasible from my standpoint. Get some ideas and just again, big, big picture. Get really inspired, hopefully.

John Marshall, MD: I think you'll be surprised. By the number of people that you actually recognize. You'll, you'll cross paths, maybe, you know, through your training at other institutions or just you'll see people you recognize. And of course, it is when you're as old as I am. You recognize lots of people. I think. So that's one thing that is fun too, is that you connect to people that you don't see often or regularly.

It is time to connect, the internationalness of it is quite striking. So, you'll see people from all over the world. are certain countries that do not allow, or we don't let them in. To be blunt. And so, they will go to ESMO or other meetings so that you will notice the absence of certain people, maybe, you know, over time because their countries don't allow, or we don't allow their immigration in.

But very much of an international feel to it. It's both exhilarating, I think. But it's exhausting too because you are learning. There's a lot of new stuff you're drinking in. There is a lot of business that's transacted during the meeting, and a lot of new data that's unloaded on us.

And so, what we then try to do is take this information as say just a GI specialist and try to integrate it into how does it affect treatment on the Wednesday, when we get back on June 4th. So, from there. So, any last thoughts? Christian, you got a plane ticket,

Christian Agbisit, MD: Yeah.

John Marshall, MD: okay, you got a hotel? Okay, then those are the two most important things, Nikita, any thoughts?

Nikita Chintapally, MD: What are you most looking forward to, Dr. Marshall?

John Marshall, MD: Well, so my problem is, is that I'm overbooked and so, I, I, you know, which meeting will I actually go to, and will I actually go and see any data being presented? So, I'm at a place where I almost never go into the posters or to the presentations because I got too much other stupid stuff going on in my world.

It’s an enjoyable event because so much, it is our community. It is a celebration of our community. It's, it's an excitement. You all talked about being inspired and, you know, reaffirming what you do so you leave, you leave charged and ready to, to move on to cure cancer. 

Thank you, guys, very, very much. I know you gotta keep running. We'll get back together in a couple of weeks and see what you learned when you went to the 2025 ASCO.

John Marshall for 

Oncology Unscripted

Talk to you all soon.

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John Marshall, MD: John Marshall for Oncology Unscripted. Let's talk a little science and cancer medicine. I’m gonna come at you from a little bit of a different angle. Yep. A GI cancer angle, but a little bit different.

We have long felt in order to cure GI cancers, we had to do surgery, that it was the only way to ultimately cure people. But we all know that when we do neoadjuvant something could be chemo chemoradiation. we operate. A certain sub portion of the patients have no evidence of disease in their pathology specimen, and we sort of say, we just put somebody through a big operation gastrectomy, esophagectomy, could be a Whipple, could be a rectal surgery that they actually didn't probably need or benefit from, but we had no way of determining that until we did surgery. And so, as you know as well, there's increasingly neoadjuvant therapies for a bunch of different cancers. People are having good clinical responses where after the neoadjuvant treatment, by scope or by scan, and now by new blood testing, we can't find evidence of disease. We're torn about whether we can simply watch and wait that patient and see their cancer comes back, or do we have to operate anyway.

And there's a new paper that just came out, that I used actually in last week's tumor board here at Georgetown about watchful waiting in esophageal cancer versus surgery. So basic story, neoadjuvant treatment, everybody got it. If you had a complete clinical response, you were randomized, so not done in the United States. We'd never pull it off here, were observed for clinical recurrence and not operated on unless they had a recurrence. The other half were operated on, and then they looked for survival. And believe it or not, there was no difference survival outcome. So, some of those people avoided a surgery that they didn't need in the end and no impact on the survival. Now we still need to do better because it's still pretty crummy survival in this group of patients whether you had surgery or not, but still no difference.

In rectal cancers, we are increasingly not doing surgery. I've got a 35-year-old woman who had a very good initial response, a very good response to chemoradiation, no clinical evidence of disease. Doesn't want a colon surgery and a permanent ostomy, as you might imagine, at 35 years of age. And we've been doing watchful waiting, including doing MRD testing, and so far, nine months with no evidence of disease. And I'm sure all of you have patients like that. 

We are also, of course, doing this in pancreatic cancer. And the reason for obvious reasons is that it's a difficult operation. A lot of people don't want the operation. More often, it's because of where the tumor is. It might be grabbing onto a blood vessel that the surgeon doesn't really think they can get around. Or it might be that the risk of the surgery is just too great for that individual patient. So, we are doing neoadjuvant treatment. We are doing radiation, sometimes maintenance after, sometimes not, and observing. And you, like me, have had over your career some patients whose tumors never regrew and maybe just maybe got out of the need for surgery. So, this then brings up. What are the right treatments? How do you pick which patients should have surgery, which you're not. The current neoadjuvant study that's in the cooperative groups here in the United States is surgery first versus chemoradiation first, followed by surgery. Should we begin thinking about a no surgical arm in this group of patients? As our drugs are getting better, as we are learning more about targeting RAS and BRCA and the other molecular targets that we have. Will we get to a place where we can actually increasingly avoid what is fairly morbid surgery? Let's particularly think about pancreas cancer, in this regard, because remember. It's very good at sowing early seeds. It's very good at metastasizing early, and in fact, only one out of 10 is found with resectable pancreatic cancer at initial diagnosis most have already spread. So, the value of that resection, don't get me wrong, it is the way we cure people, but the relative value of that resection in the global scope of pancreatic cancer is increasingly in question. So, as we pick therapies, highest response rate, three drug combinations, 5-FU, irinotecan, liposomal irinotecan, and oxaliplatin. Highest response rate, highest survival in the books for metastatic disease. As we use regimens like that in the neoadjuvant setting, as we add to those regimens with new targeted therapies, I do think what we will see is more and more opportunities for observation in that patient population.

We held a think tank here at Georgetown back in the fall where we invited people from all over the country who were experts in this field to think about this issue and the consensus among, what I think are some of the smartest people in the world around this subject was, that yes, indeed, the improvement of chemotherapy, the advent of precision medicine, the increasing role of immunotherapy in this space will get us to a place where, in fact, we are curing more and more people with pancreatic cancer. We need to get there. We need to make the progress. We need enrollment in clinical trials, but I believe we are going to see it. I believe we're going to see progress in 2025 and 2026. So, stay tuned for more positive papers, more positive data in the world of GI cancers and in pancreatic cancer, specifically.

John Marshall for Oncology Unscripted.

MedBuzz: This Isn’t Just About Harvard—It’s About All of Us

It has indeed been a busy couple of weeks here in Washington and around our country. Specifically, the relationship between our new federal government and academic institutions. I mentioned this previously about the issues between the government and Columbia University. And as everyone knows who's listening in, the most recent confrontation is between the federal government and Harvard University. You know that recently Harvard has refused to comply with the government's demands. There's been a countersuit back from Harvard to the federal government, so I guess discussions are ongoing, Harvard did release the letter that was sent to them lead signator of this letter, I have it here in my hand, is a guy named Josh Gruenbaum, who is a government appointee by the new administration. He's the commissioner of the Federal Acquisition Service. He's co-signed by a couple of other people, I wanted to just make sure that our audience out there knows about this document can read some of the language that is in it because as a professor at an academic institution, as a member of a, a medical community out there trying to advance science, trying to be inclusive and not only who we take care of, but also who is doing the care taking. This I thought was worth bringing in short, but some high level discussion. It's a multi-page letter. You can find it online yourself first from the government. An investment, their grants, is not an entitlement, it requires that you uphold the civil rights laws, whatever those are. And they get to be the judge of whether you're holding those, upholding those civil rights laws. So, the first point they come forward with is government and leadership reforms. They want to reduce the power held by faculty, whether tenured or untenured, and administrators who are more committed to activism than scholarship. It's all it says. So how do you decide, how do you judge a faculty member's commitment to, you know, in their words, activism versus scholarship? Aren't those two in some ways connected? That was the first paragraph no longer can you hire based on race, color, religion, sex, or national origin. They're gonna contradict themselves here in a minute. No longer can you admit students based on that. No longer can you admit students, and here's the contradiction, from countries hostile to the American values, institutions inscribed in the Constitution and the Declaration of Independence, including students who are supportive of terrorism or antisemitism. So how are you gonna not do sort of biopsies of who people are, but at the same time not allow students who represent terrorism or antisemitism? They bring out this thing called viewpoint diversity. Which again seems to me to be contradictory. They were asking Harvard, not asking, telling Harvard to audit their student body, faculty and staff and leadership for viewpoint diversity. They're supposed to produce quarterly reports.

It's supposed to be by an outside group that the federal government approves. So, they're gonna have to hold up standards quarterly so that they're meeting this rule. there could be no program. with Records of antisemitism or any other bias. Pretty broad. One that's we are all struggling with is discontinuation of DEI. So, it can't be part of anything. And that students must be disciplined are not complying with all of this. So, it then puts the role of the leadership of the institution, the academic institution of overseeing and monitoring their students for compliance with all of these rules. And Mr. Gruenbaum signed that along with some others.

Can you imagine being the academic administrator who opened this letter and began to read it? You know that there are billions of dollars at stake with this relationship between just Harvard and the Federal government, and we as institutions are struggling with, do you just comply with these things? Because that's the new law of the land. Do you push back and say, that isn't the law of the land? Do you have to prove that? What really is the truth here and what do we have to do? But you can understand why this is threatening to what is truly been special about United States education, and that is the freedom of speech, the freedom of thought, the challenging of each other, and our thoughts. Acknowledging what we know, acknowledging what we don't know, whether that's around science or other fields, and investing in improving our knowledge and our understanding in that we make the world a better place for us all. 

I worry about this letter a lot and I'm pretty sure you do too. For Oncology Unscripted, this is John Marshall. Let's keep our heads up. Let's keep figuring out the truth and let's make sure we share that with others. Every day makes the today a little bit better for someone nearby. That one little rock you throw in the puddle that makes the ripple, you never know how far that ripple will reach. And I'm convinced that if we keep our heads up, and, if we keep tossing those rocks in and keep making those positive ripples, that we will keep the world headed in a better direction.

John Marshall Oncology Unscripted.

Truth, Science, and the Next Big Leap: A Conversation with Dr. Mace Rothenberg

Welcome back everybody out there and wherever you are, might be video, might be audio, might be both. This is John Marshall for Oncology Unscripted. And it's been a busy week, as they say on the John Oliver Show. There's been a whole lot going on out there in the world of oncology, healthcare, relationships between the government and healthcare providers, et cetera. So, there's tons to talk about, but I want to focus right now on keeping truth and science alive. And so, I am lucky enough to know one of the world's experts. In both truth and science. Not only the creation of truth and science, but the maintenance of truth and science.

And this is a longtime friend. We won't say how long, but a longtime friend and I would actually go as far as. I refer to him as my Obi-Wan Kenobi, one of those people who had a major influence in my decision making early on in my career around GI cancers and clinical research, et cetera. And this is Dr. Mace Rothenberg. And Mace thank you first so much for being willing to be interviewed and join us on Oncology Unscripted. Welcome.

Mace Rothenberg, MD: Thank you, John. Thank you for the very kind introduction.

John Marshall, MD: I am not done because at first you started. As sort of a dumb GI oncologist, a little bit like me, but you were into drug development. You were into caring about the patient. You were into connecting your academic institution with the state of the art science, and, you were one of those folks who coached me and mentored me, as I said. But then, you surprised me, you surprised many of us, when you made a decision, back before it was something that was done regularly, of joining the industry. And I was wondering if you could just start a little bit of talking about that decision, however many years ago that was about leaving academic, medicine and cancer and going over to industry.

Tell us a little bit about that process.

Mace Rothenberg, MD: Well, it actually starts when I was training at the National Cancer Institute. So, the first part of my oncology career was actually spent in government. I did my three-year fellowship there, and then I stayed on as a junior faculty member the NCI. And then I developed some great skills, great interest in drug development, and then I got a call, one day from Dan Von Hoff at San Antonio who invited me to join academia at the university in phase one drug development. I didn't really anticipate this, but it was a call that I received, and I said, you know what, given my interests, this is the next natural step in my career. So, I moved from government to academia for seven years we were in San Antonio. The next 10 years were in Nashville at Vanderbilt. During that time, it was an opportunity to evolve as the field, as opportunities presented themselves. So, when some of the drugs we had worked with in San Antonio, like gemcitabine and irinotecan ended up having applications in GI cancer, that became my area of focus. As I developed skill in designing and running clinical trials. Had a chance then to run the phase one drug development program at Vanderbilt, and then as translational research, linking the laboratory in clinic came along, and things like SPORE grants were designed to really encourage that. I branched out into that and became co-principal investigator of the GI SPORE grant at Vanderbilt. So, I think throughout my career there was always a recognition of what I liked doing and what I was good at. But also, recognition when the new opportunity came along and I was ready for, and that happened again through a call in 2008 when I was at Vanderbilt about a new opportunity at Pfizer. Now, we've all gotten calls throughout our career from industry, and we usually say thanks, but no thanks.

John Marshall, MD: I'm too much trouble. They never call me Mace, just so you know. They're like, no, not that one. 

Mace Rothenberg, MD: And, and so they were reorganizing one of the business units to be focused on oncology. They had a really great pipeline, nor known as an oncology company at the time, but they were making a real commitment. So, I decided that even though that was unanticipated, that I felt that this would be a next opportunity for me to contribute in a way I hadn't been able to before, so I decided to take that big plunge and I, I had a, a tremendous experience at Pfizer for the first 10 years, running clinical development, for the

John Marshall, MD: Let me, let me interrupt you there. Because you, because you, that, that's that decision. There are a lot of clinicians who do get that phone call.

Mace Rothenberg, MD: Yeah.

John Marshall, MD: And they think, okay, I'm gonna, this is gonna be a very different world. 

Mace Rothenberg, MD: Mm-hmm.

John Marshall, MD: You're trained, you've done your whole life about seeing patients delivering care to patients. That's your world. That's your culture. Give me a little flashback on how unsettled that was, or were you excited? Was the excitement more than the unsettled part of that?

Mace Rothenberg, MD: I think with, with all big decisions, we have to think about what we're getting and what we're giving up, and I had to go through that whole thought process because what I love doing, seeing patients, being able to bring ideas from the laboratory to the clinic, being able to design the clinical trials, having the opportunity to, grand rounds to be the discussant at professional meetings like ASCO. I had to think about whether I was ready to give up those things in order to take on new responsibilities of running a large global program. Being able to prioritize the drugs within the portfolio to be able to identify where the opportunities were for us to make a big difference with the drugs we brought forward. I really had to think about that, that trade off. But as I, I've been fortunate in the big decisions I've had in my life, both personally and professionally when I sat down and thought about it, all the indicators pointed in one direction. And that was for me to move from academia to industry because I realized.

John Marshall, MD: Let me poke at one that, because when I thought about this in all sincerity over, over career. You know me, I'm a big mouth. one of my biggest worries was I was losing my ability to write my own script and was now being given a script. And you've, you've, you have, you're different in that you, you're like, you say you're my Obi-Wan. You have this sort of good, deep rudder. You're centered; you're focused. So, when you had to take on a company script, if you will. Did you feel that way? Or coach me a little bit on that experience.

Mace Rothenberg, MD: You know, I didn't feel that way. I felt that they were recruiting me because they needed my critical thinking abilities, my ability to be able to, to take the information that was available to sift through it, to analyze it, and then to be able to come up with a recommendation.

John Marshall, MD: Let me go, let me go a little deeper then. So, what, what if I was younger, you got a really cool high-level position too,

Mace Rothenberg, MD: Mm-hmm. Mm-hmm.

John Marshall, MD: have some junior people listening to us today. So, what if your job is at a lower level, you're given one drug, you're to develop that one drug or whatnot. It is a very narrow focus that you now have. I thought of that as both a positive and a negative as an individual, as you've seen other folks come along. And as the culture has shifted that more and more, industry is hiring physicians, do you see that as a, a distinction or not?

Mace Rothenberg, MD: Even though you may be assigned to one project or one drug, you are not defined by that one drug. Your career does not depend on that one drug. In fact, when there were failures in our portfolio during my tenure at Pfizer, no one lost their position because the drug they're working on failed. In fact, we needed to be very honest and recognize what the drugs we thought they could do and what they actually could deliver and then be able to re-deploy those assets to areas where they're more likely to be successful and to help patients. And so, what I would tell people in my team is that your skills are too valuable to spend it on toiling on a drug that's never gonna help a patient. We need to redeploy you in drugs that will help patients. And that's, that's the way we're able to operate. So, I don't want anyone to ever feel that they're defined by the success or failure of one drug. Your career is more than that. You are more than that.

John Marshall, MD: So, you had a remarkable first career developing new medicines that have had an impact on patients around the world. You had a remarkable second career where you then were able to deploy this and develop even more pipeline, with your commitment to Pfizer. And now, I recently figured out that you got a third career cooking now as someone who's going to be a keeper of the truth or helping to provide others with the truth and this concept of building an essentially a science or medical or biotech museum.

And our audience would really love to hear about this. So, I'm gonna shut up and you tell us what your newest career is all about.

Mace Rothenberg, MD: So, something I'd been thinking about for, for a while even though there were some tremendous advances in science and medicine in the course of our careers and our lives, all the places and venues that you go and see these things. Museums of medicine, for instance, were very static. Basically, displaying artifacts behind glass that you read about. And we know how exciting and wonderful and wondrous and joyful medical research can be. Scientific discoveries can enable us to gain insight into health and disease and from those insights come new medicines and interventions that change our lives and change the world. Yet there was no place that captured that excitement, that wonder. So, I began talking to people about it. And for several years people said, interesting idea. Good luck. It was only in late 2021 that in the conversation I was having with Larry Marett over dinner, he was at that time, Dean of Basic Sciences at Vanderbilt. Someone I had known for 25 years whose response was different.

After I told him about this idea, he looked at me and said, great idea. Let's do it. So that's also something that's been critical in my career is having people who believed in me, believed in the idea and were willing to help along the way. So, this was one of those moments, and thanks to his belief and the resources, he was able to garner the, the people he was able to bring to the table. We took this nebulous idea and began to refine it to identify what the problem was we were trying to address. What the vision was, what the mission would be, because we needed something that could be able to convey this not just to other professionals, but to the general public whose belief and trust in science and medicine have been eroding for the last five years. Despite all the things that we've done, all the great renowned researchers and scientists and government officials who speak to the public. That has not gained the trust and respect and traction that we should have. So, I began thinking about other ways we could do this, and out of that, sprung the Museum of Medicine and biomedical discovery.

John Marshall, MD: Do you think that the trust imbalance, right as you, as you allude to, is that we are learning more and more about how things work? and the public is increasingly skeptical about what, what we know and what we don't know. True.

Mace Rothenberg, MD: Yeah.

John Marshall, MD: do you think that's because it's more complicated? Do you think there's counter voices that are being heard more strongly? The idea around this museum, around this information, resource is to try and level that field a little bit. And when we first talked. I was thinking about how I learned. I learned once I can see it in my head, once I can create a visual, once I saw in my head DNA spinning around, or once I saw a protein docking, then I got it and, and I could under, I could read it and see it at the same time and believe it. Whereas many people don't have that skillset or never really don't learn that way, for example. So, give me a sense from your angle. The problem of why the distrust, and why you think this strategy will help bridge that.

Mace Rothenberg, MD: I think for far too long we as professionals have spoken to the public as if there were other scientists and researchers and medical professionals, and that they were purely fact-based. That's what we like to think of ourselves, we're evidence-based. But the public. Isn't wired that way. They take the facts that we provide and put them into context of their own lives, their community, their political affiliate affiliations. lots of different factors that come into how much, how they process that information. And we've not been responsive to that. And one thing that I've known about myself is that I don't learn just when I'm presented with a list of facts. That's why I really wasn't very good medical student for the first two years where it was just rote memorization. It was only in the second two years of my training when we actually got into the clinic and got into the hospital and I could see patients who had those symptoms, and those symptoms put together into diagnosis that it began to stick with me. And so I think the same approach is needed in trying to convey the progress we've made in science and medicine by telling stories that engage the visitors and to do it in a way that uses 21st century technology, like immersive interactive platforms, to be able to take them on the arc from that scientific discovery in the laboratory all the way through how a medicine or intervention was developed and the impact that that's had on, on, on people.

John Marshall, MD: I really love you.

Mace Rothenberg, MD: that'll

John Marshall, MD: You know, I get you. I'd really love your opinion on, on, on this or reflect on this. We, in healthcare and science in general are quite proud of what we know, but it's only as we get older, you and me are actually comfortable in saying what we don't know. And so, I wonder on some level is that if, if we, if we came clean on what we don't know. Better. Would it also help legitimize those things? We do know, and I, I was thinking about, you know, putting together exhibits. Obviously, you're gonna put together things of what we know, of what we've learned of new, of, of knowledge, but isn't it also equally important to understand the list of things that we are curious about, or we don't know.

Mace Rothenberg, MD: Yeah. that is perfectly described from the perspective of a researcher. But when you, you, you take away that and look at it from a lay person's perspective, they want to know what is it, what's true? What should I do? And, and I'll do it, because they trust you. The problem is what they, what, what's often not conveyed is that you know this to be true as of today. Yet because of science and research, we're gonna know more tomorrow. And the next day. And the next day. And some of the things that we believe to be true today, may be proven to be not as true as we think they are tomorrow, or next year, or in five years. That's the nature of discovery. Whether you're talking about medicine or space exploration, we are constantly learning more, and that's something that we haven't conveyed to the public very well.

Think about the COVID pandemic when we talked about social distancing, cleaning services because we are concerned that COVID could be spread in that way and how later on we said, no, actually it's more spread through aerosol root. And people were confused. They said, wait a second. You told me one thing yesterday, another thing today, what, what makes me certain that if I do this today, it won't be reversed tomorrow? So, we didn't really get through to the lay public that this is, this is the nature we're giving the best advice we have based on the information we have today.

John Marshall, MD: I want you to, I want to spend the closing moments that we have together of telling us where are you with this idea? I know you're pretty far along. How can we as a scientific and medical community help accelerate your progress? Obviously, very important project that could benefit all of us, all of humanity.

Tell us where you are. How can we help you?

Mace Rothenberg, MD: Well, we've been in existence for about two and a half years. We have had receptions in major cities. We have launched a website. We have engaged with museum design and planning firms, and we actually have a three-phase plan for development. So, the first phase is going to be creation of an exhibit. In fact, the topic for the first exhibit is gonna be cancer, and it’s tentatively titled Cancer, from Despair to Discovery to Triumph. And it'll actually take visitors on a journey, not just throwing facts at them, but by drawing them into the story. So just as, as an example, when a visitor enters the exhibit, they're gonna be met by people, people of all ages and ethnicities and backgrounds, talking about what their lives are like as a truck driver, as a third grader, as a business person. And then, their lives were changed by one word, cancer. That brings people into the story, putting a human face on this, not just throwing facts at people. And then going into the exhibit, what is cancer? And the, the 12 essential characteristics that Hanahan and Weinberg described, which will allow people to explore and delve into that deeply. And in fact, understand why cancer detection is better because the cancers haven't developed all those characteristics yet, so they're caught early stages when they're treatable and curable. what? What we do to help the body fight cancer beyond just chemotherapy and radiation and surgery, but things like immunotherapy, cellular therapies, protein degradation, and again, imagine being able not just to read about what a CAR T cell does, but to actually climb in one. See how it's created. See how it's trained to recognize the cancer and travel along through the bloodstream. To see it find and kill that cancer cell. Those are the kinds of immersive experiences that that aren't available elsewhere and that we need to tell in order to engage people. Another thing is that we're not going to be trying to convince people of anything. What we're gonna try and do is open up what's currently a black box to the public to say, this is how science is, is performed. This is how discoveries are made, and this is how it's translated. We're gonna be very open about the fact that we're not always right. We make mistakes. There's a role of serendipity. There's the ethical aspect as well where we have, we have made mistakes over time. What were those mistakes? How were they detected and what steps were taken to correct them and prevent them from happening in the future? So, these are the things we plan for the museum, and I'm just, I can't wait. We're able to bring that forward and show people what we can do and tell these stories.

John Marshall, MD: I know you didn't ask, but I just can't resist. I think the CAR T thing needs to be bumper cars. You actually get in one and you bump into other cells, if you will, and you, you.

Mace Rothenberg, MD: right.

John Marshall, MD: There you go. I, you, you can just have that one for free. You, you,

Mace Rothenberg, MD: That would be great.

John Marshall, MD: We need to help you do this, and we'll certainly help promote the activity. We know it's both a fundraising effort, but also an awareness effort, that's out there to make this be a reality. And I,

Mace Rothenberg, MD: Yeah.

John Marshall, MD: know that all of our listeners hear the need and hear how your strategy and your project and all your past successes are funneling into a new one that'll be left for generations to come.

So, Dr. Mace Rothenberg, I cannot thank you enough for taking the time today to join us, and we really, really appreciate your time and we only wish you success in your third career as a museum developer. Mace. Thank you.

Mace Rothenberg, MD: Thank Really appreciate.

John Marshall, MD:

 I cannot thank Dr. Mace Rothenberg enough. First at NCI, San Antonio, Vanderbilt, and Pfizer now in the next phase of his career is going to build out a museum that's gonna change the lives of all of us in our understanding of science and help keep truth alive. So, Mace, again, thank you very much for joining us.

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John Marshall: Welcome to Washington DC. My name is John Marshall. This is Oncology Unscripted. There is a whole lot of stuff going on out there, seemingly unscripted, seemingly without much in the way of a sense of motivation, really a plan. It's just blow it up. Let's see what'll happen after the fact. 

But let's stop for just a second and think about what science, federally funded science, has accomplished over the last many decades here. Because a lot of us, including a lot of the population as well as the government, feels like, it was really business that did everything, not the government. So, we should shift all of this money over to business and take it away from the government. So, they're firing all sorts of people here in Washington and around the country with the science community.

But let's start by acknowledging what science has done for our health. So first, we know that cancer mortality has fallen dramatically. If you think about when I first started as a fellow a thousand years ago, really the only investment in clinical translational research was through the National Cancer Institute, occasional company here and there, and all of this improvement that we're seeing today comes really from that beginning, and so we've had a clear, positive influence. But let's look at some of the details here. The concept of, I don't know, rituximab, immunotherapy, and multi chemotherapy treatments, and the cures for lymphomas comes out of government invested research, bone marrow transplant comes out of government investment research.

How about understanding HPV and using vaccines? I know. Vaccines are crazy things that we shouldn't be giving because they're terrible things, right? According to the current government. But let's talk about the discovery of HPV and vaccines, which is going to get rid of HPV-mediated tumors. 

What about imatinib? Remember that drug that was really out of the beginnings, of government research? But you know what? One of the ones that's my favorite is actually HER2. HER2 was discovered with government funded research, the therapies for treating HER2-targeting, transforming it from just a bad target, prognostically bad target, to something that actually is good news nowadays because we know how to treat it well. That was all done with government research, right? And so then here comes swooping in a pharmaceutical company under the name of Genentech that took it and made it into a billion-dollar profit that helped to fund other research.

And so, we have failed to value the innovation that comes from the government world, and there's just so much of it out there. And over the last month or so, there's been this dramatic downsizing of grants, grant applications, payment for grants that are funded, downsizing the number of people who are at the National Cancer Institute and other places around the world where there is federal funding for these with the, with the idea being that that's just wasteful, I guess that's the thought. 

We know that the NIH investment has fueled a great deal of economy in all of the places that it's ongoing. So, not only is it producing science and our understanding of the biology of cancer and other diseases, it is also helping the local economy. Then what really got me going on, this was an ad. I'm pretty sure you're probably seeing them too, at your home for our new president and our new, folks that have taken over, ruling our country in a completely different way. And in fact, this team had the boldness to put out an advertisement that in four years they will cure cancer. You should watch it. It's just unbelievable. If they're going to fire all of these people who are the brains and the brain trust and the innovators and they're not going to fund the science that's teaching us what we need to know in order to actually cure cancer. We're going to get rid of all of those people and somehow through some other mechanism, they are going to have cured cancer in four years. So, what have we got to worry about? Right? This is going to be all fine because don't you worry our boss is going to cure cancer.

Speaking of cancer that we need to cure. We've been talking a lot lately about pancreatic cancer and what a difficult disease it is, and despite great deal of investment and positive input around it, we've made some strides, but not the kind of strides we need to make. But I do want to reinforce the progress that we have made. I've been thinking a lot about pancreas cancer comparing to colon cancer. I'm still giving the same adjuvant therapy I've been giving in colon cancer for 21 years. That's an embarrassing statement. On pancreas cancer, we have made progress. We know the drugs that are working there better. We are curing more people with pancreas cancer. One of those innovations is liposomal irinotecan, and the idea that you could take existing drugs and improve their performance by modifying their delivery and the formulation, and that's what liposomal irinotecan is all about. So, we now have pretty clean data that frontline incorporation of liposomal irinotecan in a FOLFIRINOX recipe is in fact better than other options in frontline.

And so, it really begins to fall on us more and more to make individual decisions about which drugs we're going to use and when. And so, this pushes down onto each of us. A sort of plan or a strategy of what regimen do you give in frontline? What do you give in second line? Which of the drugs do you combine? I think the best data we have is with NALIRIFOX, if you will, in frontline. 

How much of this is going to be under our control? We are all feeling the pressure. How many peer-to-peer reviews are you having to do every week for what is essentially standard of care? I'm doing too many of them I have to tell you. So, we are clearly feeling an outside pressure in healthcare today about incorporating what we see as best of care for our patients, and so I want us to make sure that we are connecting, that the experts in your area and the generalists in your area are talking. And that we're sharing advice and optimizing individual patient care for all patients throughout our communities, because we know that if you do that, you get better outcomes. It's not necessarily about being more aggressive. That's often the term we use. It's honestly about being more effective. 

As you know, we've been interviewing some of the leaders in the world of pancreatic cancer and we thought it would be appropriate to reshow some of these key comments that leaders have made, such as Julie Fleshman, who started and runs the biggest advocacy group for pancreas cancer, PanCan.

[00:08:13]

Pancreatic Progress: Revisiting our Discussion with PanCan CEO Julie Fleshman 

John Marshall, MD: Welcome everybody back to Oncology Unscripted. No script at all on this one and the person who's joining me right now, really, doesn't need a script because she wrote it. She was the one who really defined, in my opinion, what advocacy is all about. Taking maybe one of the most difficult, if not the most difficult, cancer, inspired by a personal story to change the outcome for people with pancreatic cancer. And I'm proud to say she's my friend, but she's also one of my mentors, as she has shown the way for so many as to how to really move the bar in advocacy. And this is Julie Fleshman, who is coming to us live and we're so grateful, Julie, for your joining us. So, first, welcome to Oncology Unscripted.

Julie Fleshman: Thank you so much for having me. 

John Marshall, MD: You are so awesome. And you know, I think that, but let me start from the beginning, because a lot of people were coming up on a change in our world. And we know that advocacy is a critical component to our success in making advances in healthcare. It's not just handed to us. We have to push the forces around us to make it happen. Maybe give us your Quick version of, you know, what inspired you and the value of advocacy in the world of pancreatic cancer. 

Julie Fleshman: I have a personal story. 25 years ago now, my dad was diagnosed with pancreatic cancer. 52 years old. Died four months after diagnosis. And I was devastated, and I didn't understand why there was nothing offered for him. Why were there no options? At the same time PanCan was founded and I was lucky and privileged to be hired as the first employee almost 25 years ago.

And I've really just watched, you know, the field, the pancreatic cancer field back then, there was nothing. There was no federal funding. There was no philanthropy. There were no, there's nobody studying the disease. There were no resources for patients and families. And you know, I really believe PanCan has been a catalyst for changing that. And today there is a robust pancreatic cancer research community. And I think a lot of exciting things on the horizon for patients. And so, you know, I believe advocacy being the voice of the patient, not backing down when everyone tells you this isn't the way that we get things done, but it makes the most logical sense for overcoming a hard disease and you keep at it and you keep chipping at it. And I believe advocacy is what gets us to where we're going and accelerates the rate of progress. And in this case, I think it has really helped to build a field that just didn't exist before.

John Marshall, MD: You did all that stuff. Let's talk about the important stuff. Why did you pick purple for the ribbon?

Julie Fleshman: So actually, our founder who lost her mom to pancreatic cancer, her mom's favorite color was purple. That is the story.

John Marshall, MD: I love, I love that.

Julie Fleshman: So yes, so you know, and it was one of the colors not taken, right? You can't, you need to have something different than the other cancers, but it is a great color.

John Marshall, MD: But all kidding aside, yeah, I actually have several purple ties now because of the of the purple ribbon. But all kidding aside, I mean, you have you and your team have built an incredible infrastructure, not just a Hill presence and an advocacy there. Not only a clinical research infrastructure that we'll talk about in a minute, but also operators standing by patients can call in, and get advice about what they should do with your team members. And in fact, I think that feeds back to the practicing clinician, because there's a lot that we don't know that's going on out there, particularly the general oncologist in the world of pancreatic cancer. I'm assuming each one of those was a decision and you needed to have the bandwidth to do it. Like how, how much struggle was that to get all of those resources together?

Julie Fleshman: Yeah, I mean, you looked at and said, okay, where are the gaps, and 25 years ago, there were a lot of gaps. One of the first and most obvious areas was, you know, when someone is diagnosed with this disease, there's no place to go for information or resources. So building that patient services program in the early days, you know, was so critically, I believe, important for helping patients be informed so that they can make the right decisions about their care and go in and be an advocate with their, you know, doctor. Just as you said, many physicians don't see hardly any pancreatic cancer patients. And so, to have someone come in and ask you questions about clinical trials, about testing, about these different things, and hopefully it is also helping to educate the health care professionals.

John Marshall, MD: Yeah. And you've given these folks a home, a club, if you will, where they can share thoughts. And I think with our, you know, the bad cancers, there isn't that sort of survivorship that you see in some other cancers. So you've, you've provided that place where people can interact and teach each other, which to me is just critical.

Julie Fleshman: Everybody needs a cheerleader, right? Whether you're a researcher, a doctor focusing on this tough disease, patients and family, someone who's lost someone. And I think that's what PanCan does. We rally the troops. We make people feel good about the work that they're doing and that there is hope and that we're going to get there. We just all have to work together to do it.

John Marshall, MD: Let me, let me kind of drill down on something you and your team were clearly setting those standards when you develop the concept around precision promise. This was an understanding that molecular abnormalities occur. There are different ones in different patients. We have targeted therapies. Could we drive progress in pancreatic cancer through that? And you, a lot of work, a lot of investment, a lot of science went into this, but it didn't turn out the way you want to maybe reflect a little bit about that and that experience for others, because, you know, for me personally, I think it's exactly the right way to go. And lessons we could share for others trying to do this and other diseases.

Julie Fleshman: Yeah. Yeah. So Precision Promise was an adaptive clinical trial platform. And so, you know, basically the goal behind it was that you could develop a drug with fewer patients, less cost, less time, a way to accelerate new treatments for patients. All of that's true. And I think we learned a lot about sort of that process, and does this platform concept work? And I think the answer is yes. However, in order to make it financially work, you have to constantly have new drugs coming into the pipeline on the platform. And that was the part that turned out to be the, the challenge. Part of that was, you know you were convincing a pharmaceutical company or a biotech company to develop their drug, that PanCan was going to develop their drug, they were going to lose control. So that proved to be an obstacle. The pharma and biotech companies, you know, changed their priorities and their strategies. And so maybe at one point they were developing this drug in pancreatic cancer and six months later they were deprioritizing the asset. And so all of those things became challenging.

 The trial will go on. another organization that is going to launch a new, you know, basically Precision Promise version 2.0 and learn from all the things that that PanCan learned over the last, you know, four years. And, you know, Some people have said it was before its time, you know, now with there's so much excitement around drug development and targeting KRAS and all of these things that maybe, you know, if we were launching it today, it would be a different story. We launched it in 2020 in the middle of COVID. It was, you know, couldn't have been a worse time to be launching a, a big, you know, basically phase three clinical trial for an organization like us that had never operated one before. So, you know, we, we didn't have all everything working with us, we did this, but we certainly learned a lot.

And I think, you know, the, the investigators that were a part of the network and the sites that were running Precision Promise, really, that part ended up being pretty amazing. That network, and the camaraderie and the sharing and the learnings. and you know, I think that those things will continue far beyond.

John Marshall, MD: Yeah, no, I totally agree with you. You know, we, held here at Georgetown at the Ruesh Center, a think tank around pancreatic cancer. And we, we invited a bunch of very smart people. some of the smartest people in our country around this disease who've made a lot of progress. And the whole point of the think tank was to say, why haven't we cracked this nut? Why have we had a few new medicines? They've helped. Yeah. But we really haven't cracked the nut the way we want to. And it was interesting. One of the participants got up and said, but wait, we have done it or we have about to do it and all we really need to do is give it time and ongoing investment. But we're about to reap these rewards in pancreatic cancer, whether it's targeting or new understanding of immune therapies, understanding, how to control. cancers and the like I went into that meeting discouraged thinking there wasn't going to be much in our summary document of what we were going to be able to share, but I left that meeting maybe as excited as I've ever been, and I'm an old GI oncologist, as excited as ever been about the future of where we're going in pancreatic cancer reflect a bit where you all are on that and that stance and The one concern I had again is how do we make sure that that investments there to your previous point? How do we make sure that patients have access to these trials and new medicines around the country? So that all can move this faster. What are your what are your thoughts on that?

Julie Fleshman: I've heard multiple physicians and researchers say that they feel we're at a tipping point, and I've never heard, you know, that kind of talk, before. I mean, 25 years, I've been told KRAS, RAS and KRAS, super important. but it's undruggable. And suddenly, it's druggable. And so that's pretty amazing and exciting. you know, there are multiple, multiple companies with targets for KRAS for pancreatic cancer. The first phase three trial just launched last month. and then lots of phase two, phase one trials that are in development. So, I mean, this is exciting. This is really important.

John Marshall, MD: Yeah, I was going to say that we saw I saw a bunch of waterfall plots. Everybody knows what those are, where I'm used to seeing one patient and being excited about that. This was half the patients were below the line. We were seeing lots of, responders in those patients.

Julie Fleshman: Absolutely. And, and most likely it won't be the silver bullet. I think we've learned that in this disease. So the next step is what do we need to combine it with? What is that going to look like so there's durability, and, and we get, you know, even we extend patients lives even longer. I think that'll be the sort of immediate next step that we need to begin working on. But I was really heartened, at the AACR pancreatic cancer meeting That already it feels like the field is thinking about that, and they're working together across institutions. They're getting together in groups and trying to solve the problem based on different expertise. And so, I do feel like we have a very special community that knows this is hard. That this isn't just going to be the answer, and we're going to have to continue to work together. And PanCan wants to play that role. Whether we're funding, advocating, educating, you know, whatever that looks like to ensure this moves, moves forward for.

John Marshall, MD: I would go one step further, Julie. I don't think we would be where we are today with that progress without your work and PanCan's work, and we are all looking forward to the future in large part, thanks to you. So, I very much thank you for taking the time to talk with us today and, and wish you well as now we watch that survival curve improve.

Julie Fleshman: Thank you so much. I always appreciate your passion and enthusiasm, and, and all you do for patients. So, thank you.

MedBuzz: Who’s Next? Cancer Research in the Crosshairs

John Marshall, MD: If your world is like mine, you're spending a lot of time thinking each day about the impact of governmental changes, administration changes, and their impact on us as healthcare providers, us as humans. Us as educators, us as researchers in the world of cancer care today, and we know there are dramatic events occurring every day that we are sort of figuring out what's the impact, how do we preserve what it is we wanna do?

So, for example, as little as one week ago. Some of the fellows that matched in our area here in Washington DC weren't sure that they were going to be able to start in July because their positions were those kinds of positions that were under the current hiring freeze that just was thrown out there and it took until last Thursday for the leadership to realize that oh, uh, we didn't mean them. They could come on and join in July. But those same fellows we're given an option to say, well, if you don't believe that, that's gonna be there for very long. In which case I'm talking about the NCI. You can go and maybe get a job for some other place, but there aren't gonna be other jobs. Right? So, these are people who their entire lives have dedicated to this prospect, have thought that they have just matched and what might be the most stable organization around the country, the National Cancer Institute, to only find out it might be one of the least stable.

And I was reflecting, as many have been reflecting on these just callous, huge government cuts that have been made just over the last week or so at the FDA. Some of the best minds there gone at the NCI, at the NIH, some of the best minds there gone. Let's think about that a second. So the director of the Institute of Nursing Research gone, the head of the National Institute of Minority Health, health Disparities gone. The director of the Institute of Child Health and Human Development gone along with many others just on a dime, right? 

They're using a model of a game show, a TV evening show, where the answer is you're fired. So we just fire people because we don't like what shirt they're wearing or where they park their car or some stupid answer like that. And I know it's so disruptive to everybody figuring out what does tomorrow hold? When's somebody gonna come and knock at your door? et cetera. So we are all in shock as an academic institution. 

Who's the next Columbia? Apparently, it might be Harvard. They're going after them. How do we work together? NCI designated cancer centers to make sure that the administration and the house, et cetera. Understand the importance of our collaborative research and how we have contributed and will continue to contribute to the cures for cancer and other diseases.

Now the last piece of this is that, you know, as we talked about before, don't worry because Donald Trump and his administration is gonna cure cancer. Now, if you believe that, then sit back and let all of this just go. Leave them in charge. Let 'em do what they wanna do, because don't worry. Trust me, they're gonna cure cancer in four years. My argument is that that's unlikely at best, right? The kind of investment, the kind of people that have been fired, the kind of things that are going on is gonna reverse this process. If anything, and don't get me wrong, I would love to be wrong about this, but I don't think I am. And so how are we as a community, a medical healthcare community? How are we as a research community, how are we, are we as a drug development industry? To ensure that we keep the bar moving forward, that we provide care for our patients, that we innovate, and that we indeed do reach the same goal that our administration is seeking, and that is to cure cancer, but actually do it in as fast a timeline as we can.

We're gonna have to step out of our foxholes. We're going to have to look down the street, talk to each other, collaborate. Scream out loud when it's important. Stand up in front of Congress for 25 hours in a row and make sure they know that we're not happy with what's going on. The rest of the world is extremely unsettled. We are extremely unsettled. I think we should not just sit back and let it be. I think we should figure out how to work together, how to make larger voices, push back and say, there are some things that you are doing that are just not right, and we want it fixed. 

John Marshall for Oncology Unscripted. ​

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John Marshall, MD: John Marshall, Oncology Unscripted. It's unscripted because you can't make this stuff up. I don't know if your week or the last two has been anything like mine, but our country and our science and healthcare, and all of that stuff, is really undergoing an incredible number of changes so quickly that we can't even catch up with what the impact will be. And maybe It's only because we're in health care, but I gotta believe that the impact that all of these changes these edicts that are coming out on Friday afternoons are going to have are going to have on science on the future of discovery on curing cancer we're really feeling that threat. And so, what I wanted to do is talk a little bit about that uh, today in our current episode. 

Now, our main theme today is about the imbalance of credit in the scientific community. And we've really drilled down on the topic around women in science. And how they, over the decades, century, has not really been able to get the same credit as men. 

But we have to talk about all that's been going on just in the last one to two weeks. You know, we went from the freeze that we've already talked about to now this cutting of people, just firing a bunch of people. A bunch of people at the FDA. A bunch of people at the NIH. A bunch of people at the National Cancer Institute. And these are essentially all levels. Some of them leadership levels, some of them mid, some of them are the earliest hires, those within their first couple of years were fired on a dime, no matter what role they were playing. 

One person that I know, I used to coach her in basketball when she was a young woman. Now she's a grown woman and she's an epidemiologist working at the FDA. And because she's only a year and a half into her career, she was fired on Friday afternoon. And what she was doing was reviewing medical devices to make people better able to get around. Accessibility was what she was all about, and now no one's doing that job. So, I don't know, will there be no improvements in accessibility because those people are not there?

We then had the cap on indirects applied. All the cancer center directors got an email around that. All the medical center leaders and academic center leaders got the email. And so, we're all scurrying around to see what can we still do moving forward. What do we have to stop on a dime in order to keep the books open and to keep everything going the best we can. What will be the future of research and science in the current world without all of this infrastructure?

Diversity, equity, inclusion, and accessibility. Gone. Right? So, if we can't have that, how will we acknowledge and credit those folks whose role it is to make sure that we are hiring the best person, not the person who looks like the last person, right? So, quality and qualifications are what DEIA was all about. Not about what others seem to think it's all about. So how are we going to maintain that and will the quality of those folks that are in these positions therefore fall because we're not hiring the best people.

MedBuzz: Welcome to the Healthcare Hunger Games

John Marshall, MD: In our world here in Washington, we've been on this wild swing back and forth where, one Friday, we think that our fellows are no longer going to be hired, that they're going to all be fired. All trainees within the NIH are going to be fired. That was the word. Then it was like, no, we think they can stay, but then, later on this week, it's back on the table. So, we're being called to immediate meetings to say, well, are we going to have fellows from the NIH or not going forward? And if you think about what that would do, not only to them as individuals, but how about all the people that they are taking care of, all the people that are on clinical trials that are getting lifesaving care for cancers and other illnesses that those fellows are critical in providing their care and learning as for the next generation, and so I don't really know. where we are. I've been in cancer center meetings all week long about what we can keep, what we're not going to be able to keep. What sorts of progress can we make? Is it worth writing grants anymore? Should we just give up on this for the moment, tread water and wait, and see? 

My wife went down to one of the protests, and I know they happened all across the country and there were a lot of people there, who came out all across the country to say, none of this makes sense. This is not good for each other. This is not good for us. And most of us are sitting around thinking, well, who is it good for? 

Why is this being done? Is there a methodology? Is it just random? Is it just random rich people who are playing with us? Is it random rich people who are reducing government so that they can reduce taxes so they can have even more money? We don't know. We don't know if there's a strategy here versus just a bitterness and a randomness to it. But it's something that none of us has ever lived through before, at least I know of or anybody I have met. And so, we don't know what to do. I don't know what to do. I can't make light of it. I try to make light of everything. I'm really good at making light of cancer, by the way. But this I can't make light of.

And so, I want you to write to us. I want you to comment to us what you think is going on. What you feel is the right language we should be using. What is the right way to make sure our positions are heard and that our other government leaders are helping to influence in a positive way how we move forward, because for most of us day in and day out, we don't know what to do.

And as leaders, there's nothing more awkward than not knowing what to do. So, for Oncology Unscripted, I want you to help provide some of our script for the future, because if you're like me, you're worried. You're worried about what's next. You're worried about those people who are being fired on a dime. You're worried about those people who come from different backgrounds or have different barriers to enter the workplace or to succeed themselves. We're worried about a new medical head, RFK Jr., who's saying that nobody can be on certain antidepressant medicines, etc. just wide sweeping statements that threaten people's existence and productivity, on a dime like that. And so, how do we defend against this? How do we maintain those things that are good so that we can move forward together? Share your thoughts on Oncology Unscripted, John Marshall. 

I hope you have some good answers. 

One area that we have made clear success in is progress for women in science. Most of my medical school class, I think more than half of my medical school class were women. More than half of my residency program were women. More than half of my faculty here at Georgetown are women. When you look at leadership positions though, when you look at credit for academic productivity, there's still work to be done. And we need to make sure we're hearing all the right voices and those that have been successful and those that have struggled so that we can better balance, make even, our world today so that women have the same opportunities and credit that we do as men. 

So, our focus today with incredibly smart people is to drill down on the issue of women in science and how to ensure balance and parity for all. 

Candid Conversations: Science, Struggle, and the State We’re In—My Interview with Dr. Lucile Adams-Campbell

John Marshall, MD: We have been talking about how disrupted the world is. And in particular, we've been focusing on women in science and how not only is the world disrupted, but women in science have all had a long history of disruption, of steeper climbs, of more difficult challenges ahead and I am so pleased to introduce and welcome, another incredible voice, another incredible person who has had dramatic impact on cancer and cancer outcomes for us here in the D.C. area, but frankly, on a global scale. Dr. Lucille Adams-Campbell and I have been working together for a long time now, and neither she or I will say exactly how long. We first met when she joined us here at Georgetown having come from Howard University where she directed the Cancer Center here in Washington D.C. We had some partnerships even before she joined Georgetown, but since coming to Georgetown she has continued her work and dedication to serving those who are not equally served, if I could just put it that way. But she's also, as you can see, a woman. She's also a woman. I don't know, what does one say as a white man of color? She's a Black woman, and she has had a strong, mature, consistent voice. about what it is to be a woman in science, what it is to be a black woman in science, and we're just honored that she's joining us today for some of her thoughts. So Lucille, with all of that preamble, welcome, but give us a sense of your take on all of this. Is this real? Women have a steeper climb? Is it worse for Black women? What are your initial thoughts out there about this topic?

Lucile Adams-Campbell, PhD: Thank you for having me, John. And I will say that women in science, and women of color in science have an incredibly steep climb in this world. And the reason being is they often are looking for mentors and role models. You don't find many role models of color. And the role models that I have sought out even in my latter days in my job recently, have died. So, we have a dearth of mentors, role models that we can look up to. So, we have to really do a lot our own. We also have to do a lot with society, which means I have had white male mentors throughout my career. I started in engineering, which was a male dominated field. I spent four years in chemical engineering. 

John Marshall, MD: This mean you actually know how to use a slide rule? Do you know how to use a slide rule?

Lucile Adams-Campbell, PhD: Yes, but those days have changed. But I did use a slide rule for many years. But at the same time, I've had phenomenal male mentors. Including someone named Baruch Blumberg who won the Nobel Prize in 1976. That spurred me on to become an epidemiologist. I've also had people during my training predominantly male and White institutions at University of Pittsburgh, for example. The only Black female in the program at a point in time for a PhD. So, for me the curve is very steep, but at the same time, you have to ground yourself. You have to really study. I felt like I worked ten times harder than all of my classmates. I feel that even today, I work harder than many people are working.

John Marshall, MD: Can you tell me a little bit about what that is, why that is? Is that because white men aren't listening? Is it because there's additional barriers? Give me a little sense of why you are working harder.

Lucile Adams-Campbell, PhD: Well, I'll tell you, coming through my training, one of the faculty members said I should be dismissed. I should not be allowed to get a PhD. Only because of the color of my skin.

John Marshall, MD: Seriously?

Lucile Adams-Campbell, PhD: Seriously.

John Marshall, MD: Did they say that out loud to you?

Lucile Adams-Campbell, PhD: They said that out loud, and my chairman, who was my staunch supporter, said, ignore this person. You don't work for this person. You don't take classes with this person. You will get your PhD. You are staying in the program. But I always had to make certain I worked much harder than everybody else. I'm an epidemiologist. We did a lot of biostatistics. We did a lot of computer programming. People would run computer programs. What was I doing? I was writing the programs that people were running. I always had to go to another level, just to fit in, just to fit in.

John Marshall, MD: Let me, let me drill down on that a little bit more because, you know, I think about today. And diversity, equity, inclusion, and all of the vulnerability that that's there. Because you went from a world where someone could say out loud to you, a mentor or a boss could say, you can't do this because you're a Black woman.

To now, to for a while there, that was no way anyone would be able to say that. To now, I think it's okay to say again.

Lucile Adams-Campbell, PhD: Now it's okay to say, and I can tell you that I have witnessed white medical students, I'm not calling any places, that say Black people are just taking up space. We can do better without them. So, these things are now made very easy to say. There's no punishment, nothing. You just said it. And so that's a, that's a really big change. And right now, Black and Brown people are almost invisible. And we watch the administration just wipe it out. Wipe it out. Anything that even is remotely linked to minorities. It's taken away, and that's very demoralizing feeling. They know that. So all you can do is stay pigeonholed, do your work, don't go out of your little square domain because of what's going on.   

People don't understand what DEI is. It's supposed to be enhancing diversity, equity, and inclusion in the workforce. Did you see the Super Bowl? Did you hear the comments after the Super Bowl? The halftime show performed by All Blacks what did the white women complain about? There were no whites in it.

But you don't want diversity, equity, or inclusion. So, an all-Black performance should be applauded because that's what you are asking for. Blacks and Browns are really being removed at an alarming pace. Without any rationale. 

John Marshall, MD: Let's talk a little bit more about mentorship. Is it different today? Are there specific, mentors that are bringing forward women? And women of color and people of color. You know, I was thinking about my own medical school class, my own faculty here. It's about half and half men and women, many more people of color than certainly we had 10 years ago.

Do you see that trajectory of mentorship changing?

Lucile Adams-Campbell, PhD: I think we will strive to continue in the same vein that we're going now. I think we have external forces that might try to slow us down, but at least mentally, I think we are there to see. Increases in women, increase in minorities, in the whole arena for oncology, for medicine, I think that would be the norm.

John Marshall, MD: Let me ask a very biting question. If you put training grant money out for specific subgroups, let's say women, or let's say people of color, one argument is that that's making the hill less steep and that you're identifying the right person and overcoming them. The discrimination, if you will. The counter argument is that you're setting aside money for maybe people who are less qualified and my argument has always been the former and that you're allowing people through that would not have gotten through otherwise.

But do you think there's any legitimacy to the qualification issue?

Lucile Adams-Campbell, PhD: You know, I've heard this discussion about qualifications, saying, can't remember who said it, but on national TV, if I get a Black surgeon, I know that they're less qualified. Standards have not changed. So my, my take on that is, We have a training grant. We do want to make certain that we bring on minorities. But guess what? If they do not come up to the bar, we do not bring them on. So we believe that people of color, they excel just as their white counterparts. There are people that aren't of color that don't do well. But we put all the pressure and emphasis on minorities are always at the bottom of the, of the, of the poll. So I believe in targeted recruitments. But not just as a handout. People that deserve to be in. Now, do we ever make exceptions? Not really when it comes in terms of what they can do. If there's no way this person can do this job, not hiring. Not hiring them. So, I think I've been true to that. People that come on and they can't do the work, they have to be let go. I think it has to be fair system across the board. 

John Marshall, MD: I was just in a country, New Zealand, believe it or not, where it was the first Western country where women were given the vote, quote unquote Western country. And then I was thinking about that women in this country have only frankly recently been given the vote. Black women, you know, the last of the group.

And then, but then now this swing back the other way, that basically, as you say, to make them invisible again, 

What's your advice to our folks out there who are listening in to me as a white man? What's your advice to us to how do we push back against this?

Lucile Adams-Campbell, PhD: Well, I think there will be a revolution one day. I think it will be televised. We always say a revolution will not be televised, but it will be televised.

John Marshall, MD: Or it'll all be, you know, filmed with this, right? Yeah.

Lucile Adams-Campbell, PhD: Filmed with your phones. 

I think it's really important that we stay the course. We cannot back up. We cannot back up and back away. We have to stay the course, and we have to start fighting more for what is right. We know what's happening is wrong. Now, my mother, as you know, who died, was 101 years old. She said to me one week before she died, ‘I am sorry that you're getting ready to live the life I lived when I was growing up.’

I think we have to fight, but we're in a very awkward position right now. We have the oligarchs, we have the, the, the authoritarian approach, and in that type of system, it's very dangerous as well. So, we have to stay the course with our science. We have to keep doing as much as we can to promote ourselves, but we still have to collaborate and work, and we have to be inclusive. This not work in silos, it's not just about Blacks or Brown people, it's everybody. And the difference now, and I'll say this out loud, the difference nowadays is the fact that oppression has been felt by Blacks. I have felt oppression, racism, discrimination all my life. I have had different people over time, even here, say comments that they don't realize are really offensive and racist. But you understand all of this racism going on, you still have to function. You still have to keep working. You still have to do what you do. But you hope that the people in power will not just sit back and let it happen to our institutions, to our universities. Don't take away our academic freedom. We have to be certain that we're fighting for the right things. And what's right is not what's happening in this world.

John Marshall, MD: I see you as one of my mentors. I know we're peers as well, but I also see you as an important mentor to me. And you've taught me many things over the years, and you continue to even with our discussion right now. Still keeping the job going. I get that. You know, try to keep your head up, keep looking forward, but it feels to me, I feel like, as, as a voice, you're a voice in this world, that it needs to, in fact, at our level, be even a little higher at the leadership level of a tone setting or, not just show up and do the job, but to somehow not accept what's going on at the same time, and that's a fine balance, right? Because we work for institutions that need to keep existing. Is there any advice that you would give me or share with others about pushing that envelope further than just showing up and being inclusive and being accepting? Is there something more that we should be doing in your opinion?

Lucile Adams-Campbell, PhD: We need to stop labeling. We need to just do the work. We label DEI, and it gets struck down. But we need to get rid of the labels and do the work. If you're going to build your community, build your scientific world, build your labs, whatever you're going to build, it being inclusive of people. And that's really not what's happening. People say it, they say those words, but it's not happening. I think we need to be involved and engaged at every level. So, you're in leadership roles, I'm in leadership roles, but who's really in leadership in academia? It's the lawyers, not us! We want to fight for it. I just had a grant that was taken from me, but it wasn't because of DEI.

John Marshall, MD: Well, it had the word woman in it, didn't it?

Lucile Adams-Campbell, PhD: Women, Women's Health Initiative.

John Marshall, MD: That's out!

Lucile Adams-Campbell, PhD: It's out. But also it was with Columbia University. And they are a hot target right now. So, I really don't have a solution. Because we have to keep fighting. 

But you know, I look at the farmers as an example, and it's really intriguing and very sad. We have been oppressed for so long as people of color. Now, what's different? The difference is, now, everybody is feeling it. Before, you've never felt this before. And I think that's the difference that's happening right now. That White people are feeling that they are being oppressed. Even those that voted for this administration never thought it would come back and hurt them. So, for me, I do sit back at some point and say this what we've always gone through. Now, there's a change in mentality across the board, across all races and genders. You know, it is a change. So, that's, that's different. That's different. Have you ever felt like this before? 

John Marshall, MD: No, I keep saying that too. I've never lived at a time. I mean, we keep equating ourselves with the Jewish people in 1937, right? And the Black people in, you know, slavery and post slavery. and, and now white guy, Presbyterian White guy from, you frigging Mayflower is now feeling it, right?

Lucile Adams-Campbell, PhD: That’s the difference.

John Marshall, MD: Yeah.

Lucile Adams-Campbell, PhD: And that, and that different feeling, I think, is going to help us regain what we need, because it is now oppressing everybody. And when I go back to the farmers, the white farmers are outraged because they are not getting the money that was promised to them. But they never cared. The Black farmers never got a penny of the money. So now, the Blacks have always struggled in farming. But they made it. Now the Whites are struggling, and they don't know what to do. 

John Marshall, MD: Will we ever stop scoring people based on their skin color? And do you think this is an opportunity for us to get there? Do you think that's ever going to happen?

Lucile Adams-Campbell, PhD: In this administration?

John Marshall, MD: No. In our lifetime, how about that?

Lucile Adams-Campbell, PhD: A lifetime. Well, I think there's beauty in skin color.

John Marshall, MD: Me too.

Lucile Adams-Campbell, PhD: I think that there are so many hues that we have to look at. I don't think it would be really a nice fit for everybody to look the same. So, I think the diversity in color tones and hues is so important. So, for me, we win. with the score with all the different shades of gray, literally. I think we really win.

John Marshall, MD: I'll tell our audience, I'm hoping you watched all of this. Dr. Lucille Adams Campbell, an amazing voice, an amazing mentor to me, and I hope now to you, Lucille, thank you very much for joining us today on Oncology Unscripted.

Lucile Adams-Campbell, PhD: Thank you.

Candid Conversations: From Lab Coats to Leadership—My Interview with Dr. Caryn Lerman and Dr. Deborah Schrag

John Marshall, MD: Hello, everybody. I promise you famous people to interview. And I'm lucky enough to know, they won't admit that they know me, these two people, but they are incredibly famous, successful people in the world of cancer. Dr. Caryn Lerman on the other coast out there, where it's probably warm and sunny out in Southern California. Dr. Deb Schrag, who is just up 95, somewhere up there, who is up curing cancer, GI cancer person from up there. These are leaders in the cancer world and they have agreed to join us for Oncology Unscripted today to talk about something we've been dancing around in the last few episodes, and that is women in science, women in professions, and the fact that over time, since sort of modern science, I guess we'd say, the DNA and things like that discovery is that women have not consistently been credited with their contribution with their success with their leadership in this world.

And so, they were nice enough as successful leaders in this world to join me today to share a little bit about their perspectives. Caryn let me Let me pick on you first, if you will. I mean, you've made it to leadership role in an NCI designated comprehensive cancer center in the biggest city in America, right? That's still the biggest city in America. So, tell us a little bit about your perspectives and your thinking about women in science. 

Caryn Lerman, PhD:Well, first of all, thanks for having me, John. I totally admit that I've known you for decades and I'm really excited to be here.

I started, In the mid-80s. So just to give some context, and I was fortunate to have an absolutely exceptional female mentor Barbara Rimer, who ultimately became Dean at UNC, Dean in the school public health. And so, I was fortunate to have a wonderful female leader, role model who took me under her wing and helped me. And I will say that as my career advanced and I had the opportunity to work at other institutions, it became very obvious to me that there are very few women in leadership roles as role models as mentors, and I've had great male mentors as well, but I think it's very important because there are unique perspectives and it is more challenging as a woman. 

If you look in the cancer center leadership space, you know, and in the research space, this is where I live. Even now, there's just a small minority of cancer center directors who are women. Okay. And, and then you look at the next level down, you know, associate directors and deputy directors, and it's still like 80, 85 percent are men still at that level. So, 10, 15 percent are women. 

John Marshall, MD: Can I, can I drill down on this mentorship thing?

So, when you have a good mentor, I, I, this is white man looking from the outside in. Okay. So, I want you to mansplain back to me what the reality is. Are there some women mentors that just say, tough it out. You're not. You're not strong enough or so or are you all actually is the mentorship of recognizing that this is an unfair world and here's some strategies for getting there or is it both?

Caryn Lerman, PhD:Well, like anything, there's a lot of variability, right? And I think there is some folklore and there's probably a kernel of truth in the fact that the farther you go back. The harder it was so there's a little bit of I had a battle my way through with all my male colleagues, who treated me differently, didn't let me into the old boys’ network, who felt that I had to always be charming and not push back and had different expectations. So, you do have sometimes women coming, you know, moving up the ranks, feeling like you do just tough it out, tough it out, tough it out. And I think as I mentor people for me, it's really about how do you be authentic to who you are? It's not about trying to be one of the, the, the guys, it's about, you know, being authentic, being authentic to your personality, showing compassion, being nurturing and being tough when you need to be tough. So, I think there's some great female mentors out there, but there are also some who are pick yourself up by your bootstraps because it's tough out there, and I had a tough. So just deal with it. 

John Marshall, MD: Yeah, Deb, let me get to you, because I think about, you know, I'm a member of the GI old boys club, right, and I think part of the reason why I'm still giving the same adjuvant therapy for the last 20 years, and no other cancer is that true, but colon cancer, is because of it some old boys that didn't want to move things. But you have in fact changed standards of care and in the backdrop of an old boy’s club through innovative clinical research and taking a stance that, you know, was impressive and you stuck to it and succeeded. So maybe reflect a little bit at that research level and, you know, disease orientation and clinical leadership roles. You know, some of the struggles or feedback you would have in this space.

Deborah Schrag, MD, MPH: Yeah. So let me start by saying that, you know, Caryn and I have different roles, and we have different jobs and have had somewhat different trajectories, but I agree with everything she said. I think it applies to people who are focused on wet lab research, dry lab research, you know, basic biology, behavioral, clinical trials. It spans the gamut because these are fundamental human sort of issues about how we work together and what people's expectations and biases are. I think as women leaders, we have to get comfortable with ourselves. 

I completely agree with what Caryn said about authenticity. Women lead differently. We just have different styles. There are certainly women who lead like men and men who lead like women, but as a generalization, and this is a generalization, you can find many exceptions. Many women have a more male style, and men have a more female style. It is really hard for us when everyone is angry with us when we feel like everyone is hating us for making difficult decisions, not to staff, not to grant, not to fund to say no, that is really hard. And those are hard skills to learn. And women struggle with that. Some of it's very cultural. 

For us to learn how to be comfortable with power, to navigate conflict, to communicate clearly, to sit with the discomfort, and again, that is with people who are above us in positions of power, people who are our peers with similar levels of, as well as with trainees and mentees and team members because science is so these days to do anything really impactful and involves a team. And you have to inspire and lead a team, and you have to make tough calls. You know, we were going to do this project, the budget was cut by X, and we got to chop off an aim or we submitted this grant. And it had four components, and this part scored really badly. And so now we are cutting your project loose. That is something that women leaders, I think, that's something that women really struggle with. I think men have the same struggles, but I think they sometimes experience them differently or feel the pain, a little bit less. 

Would Caryn agree? I'm curious if she agrees with me or not. 

Caryn Lerman, PhD:I agree 100 percent and I'll just add that I think that still in this day and age. And there's research to back this up. Women are more likely to experience the imposter syndrome, more likely to downplay what they have to offer. And I would just tell you, I've run a lot of searches, and you have women, you know, reaching out to people say, are you interested in being chair of department X? I don't know if I'm qualified for that. Yes, you are, come on. I don't know. And then. It's just a very, it's very different for people to even consider their candidacy or whether they are worthy of roles like that. The system has created some of that and I 100 percent that. 

John Marshall, MD: Let me lean in on that, because on the other end of Pennsylvania Avenue, just down that way, this is only going to get worse, right?

I mean, right now the public tone is very male driven, women minimizing, almost dehumanizing tone. So do you feel like that the gains that have been made in science and medicine are even more vulnerable now than ever before?

Deborah Schrag, MD, MPH: So, so John, I want to just quickly respond to that question, Caryn I don't mean to interrupt. Women should not interrupt each other, but you know, are we all terrified and worried and distraught about the immediate future? Yes, sure we are. We are. Noone in biomedicine is happy, whether, no matter male, female, junior, senior, east coast, west coast, blue state, red state, we're all concerned, alarmed even. But when you look at the long game and look at the arc of history and how much progress has been made, women are too central. We are too critical to the biomedical research enterprise. It cannot function or run without us. If you look at PhD graduates, medical schools, yes, at the top echelons, I completely agree with Caryn about it still hasn't penetrated up to the top-level C suite. But I believe that in the long run, that is going to happen because the talent is there, the training is there, the motivation is there, the skills are there, and we are in it for the long game.

So yes, we're in a bad patch, but long game? We're going to prevail. I know. I believe nothing can prevent that from happening because it's so powerful. 

Caryn Lerman, PhD:I have to agree. And I love your optimism. I agree. But I do at the same time, these the efforts to dismantle programs, you know, in the name of efficiency, reducing staff at NIH, reducing indirect costs. This is going to affect all of us. And that means that this is the time where we have to band together as scientists of all of all genders and all backgrounds, because we're going to lose the tremendous breakthroughs and scientific gains that we've made over the decades. And, and that to me is the biggest threat that's out there right now. 

John Marshall, MD: But let me lean in on that just a minute for the last few comments from you guys. And that is, when we went back and looked at literature around women in science, one of the very strong themes that came forward was the lack of credit. Those people who had done the work were not on the papers or were tucked in the middle or, and the like. And I, there was part of me that didn't understand that there, is this right, even today that if you that as a woman, you might not get the proper credit because of your gender. 

Caryn Lerman, PhD:I don't feel that I've experienced that personally. Obviously, I feel it's wrong. I feel people should get credit and there should be transparency about individuals’ contributions and agreements up front about authorship and who's going to be PI, and so forth. I guess I've been fortunate to not experience that. 

Deborah Schrag, MD, MPH: I wish I could say the same as Caryn. I have experienced that, and I think it continues to be an issue, but it relates to the comment I made earlier, which is that women are more likely to be conciliatory. We have that hardwired in us from pre-kindergarten. So, when there's a discussion about authorship, sure. Let's have two first authors and two last authors and you can be, I'll be second. In other words, I'll be the one, I'll be the co first author, but you can go first, I'll go second.

But women are also wily and strategic. We're in it for the long game. We're not going away. I think we have to support and coach each other. 

but I think that we are really making great strides. I've seen it, and I think that when there are more women who are directing cancer centers, and who were sitting on panels, whether study sections or other things. That is a really important corrective because they help ensure that awards. Resources grant funding is allocated according to merit, which is what we all want, right?

That's what we all want. We want merit-based systems. We really do. 

John Marshall, MD: You guys have been awesome. I know you both have lots to do, and I've interrupted your busy day and the world's gone to hell. We all know that we're trying to hold on to what we can. So let me, on behalf of everyone, thank you guys for sharing your thoughts and your feedback on this.

And I know that your comments and your success, personal success and collaborative success will have an impact on women in the future.

Caryn Lerman, PhD: Thank you very much. 

Deborah Schrag, MD, MPH: Thank you, John. 

John Marshall, MD: It's just amazing to talk to such smart people who have made so much progress, not only for cancer and cancer medicine, but for women in science. And so, I'm very grateful to them for joining us. And to all of you out there for sharing and thinking about these issues in front of us, not only the, the parity in individuals, women versus men, diversity, equity, inclusion, accessibility, but also in the increasing threat day in day out threat that is to science from our current administration and how we will keep innovation going forward. We all have to work together to ensure that success. 

​[00:24:32]

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How Do Middlemen Impact Our Practices? [00:00:00]

John Marshall, MD: Welcome back everybody to Oncology Unscripted. It is August and if you're lucky like I am, August is vacation time for me. I am at this beautiful place somewhere in the south, somewhere near a golf course and an ocean; a little river flowing right over there, some egrets and an occasional pelican flying by. There are fruity rum drinks, most evenings, which makes for a very pleasant time away from work. So, I'm on vacation, and I hope you guys have gotten some time away.

We're going to focus on in the second part of our series of three programs on the middlemen in our lives. The last episode, which many of you have commented on and have watched, is around pharmacy benefits managers; their role in our healthcare system and how they've inserted themselves and made a bunch of money and not necessarily adding value. 

Today, we're going to riff a little bit along the electronic medical records, certainly a middle thing in our lives that many of us are sort of frustrated by. And then our next episode will focus on clinical research organizations that I know many of you can be frustrated about, as well. 

Silent Crisis: Can You Admit You're Burned Out? [00:01:27]

But, to set up this EMR vacation setting. I think we ought to talk a little bit about the concept of burnout. Now I'm on record as having officially burned out. It was in, really, 2018, 2019. I didn't really know it. I just thought I was grumpy because I had good reason to be grumpy. But it was actually my wife and my daughter who noticed that I just wasn't my same old self. I had lost my sparkle. And I thought a lot at that time about my own personal burnout: therapy, I ended up taking a sabbatical, my wife and I wrote a book. We had to get away for a while in order to deal with that. 30 years of being an oncologist is a big deal. 

And then I started to look into this issue of burnout and realized that lots of us in our space have a lot of burnout. There's some studies that have been done and basically looks at, sort of, not only our burnout, but how are we dealing with burnout. And given that I'm on vacation, I thought it would be kind of useful to look at some of the data for us around vacation. And we don't take very much vacation. And when we do, we actually work. Like this morning, I actually have already seen four patients in tele visits. God help us. So even though I'm on vacation, I'm still working. And I bet many of you do that the same way. 

So, in this survey. 60 percent of us as physicians, we're only taking 15 days or fewer per year. That's terrible. With 20 percent of us, one in five, taking only five vacation days a year. And most of us, when we're on vacation, like me right now, 70 percent of us work every day of a typical vacation. We do something. We check email; we do something while we are on vacation. And a third of us will spend more than 30 minutes a day on work while on vacation. 

Now, looking at subspecialties, oncologists are a little bit better because 60 percent of us were taking about three to four weeks of vacation. But you get more vacation than that!

Is Relaxation Worth Sacrificing RVUs? [00:03:46]

I know as well as you know that we're disincentivized to take vacation, right? Because we are RVU-driven, and every week I'm not getting RVU's, I'm actually getting less money. So, if I take vacation, I'm actually making less money.

Now, the other thing that sort of started happening more recently is this concept of paid time off PTO, right? Didn't used to be called that. It used to be called vacation. If you're in a business where when you're on vacation, you're paid, you're supposed to call it PTO. For those of us who don't have that sort of tracking system, we call it vacation. but it still makes me feel guilty, I guess.

Are Your Patients and Staff Mad When You Go on Vacation? [00:04:32]

Now, one other perspective that I learned the hard way when I took my sabbatical is just how angry patients get when we're on vacation. Our staff also is angry at us when we're on vacation because we're not immediately available and they depend on us in order to, you know, do the day-to-day stuff we have to make decisions here and there. And our patients, particularly when we take a longer vacation, do get kind of fussy at us. Well, you know, as soon as you get back, let me get in to see you, or I need to see you right away. So right before and right after vacation, we clearly pay the price, by, you know, all the catching up that we have to do when we are away.

PROMISES UNFULFILLED: THE EMR PARADOX

Do You Love or Hate Your EMR? [00:05:17]

Now, the new one that I think is the most kind of creepy of all is that of course our patients have access to their electronic medical record, right? Our topic for today. And so, they can look up their results or they can wait on, you know, they can find what their CT scan showed or their CEA level or whatever it is. They can see and now they know this result. You're on vacation. You don't really want to get into the discussion. They've got to wait until you get back. And of course, that just generates more anxiety for everybody. You have to decide whether to stop everything, pick up the phone and call Mrs. Smith and tell her about her scan and talk it through. Wait till you get back or do as I did this morning and schedule four tele visits with your patients while you're on vacation in order to catch them up and make sure they're okay. Which for me in the end was a good trade off. I feel better about what I did. I'm happy for the patient. I won't have to get creamed when I get back, but I had to eat vacation time in order to do it.

Now, I'm old enough, maybe some of you out there are old enough, to remember charts. They could get really thick in some patients, and you would carry them around if a patient was inpatient. Often in our shops, you could find the chart up on the floor, which is not where it was supposed to be, or they couldn't quite find it. Or the last person just stuck something in the chart, and you didn't know whether the result was going to be there or not. So, we didn't really like our charts either. They were inefficient and we were hoping that the electronic medical record was going to be this, this great savior. But in many ways, it has become the primary thing that we do is enter data into the EMR. 

More EMR Screen Time Than Patient Time—Is This Your Reality? [00:07:12]

It's very, very common—I catch myself all the time, really common with the younger physicians, is that they stare at the EMR the whole time. The patients over there, they're staring at the EMR. And they're just typing right and entering in data and not really paying attention to the patient over here. 

We've seen a clear fall off on physical examination because it's all there. You don't need to examine the patient. Everything is right there. We collect money, we bill, based on how much we documented in this EMR. And, you know, what's interesting is the EMR is not really that great at being able to find the data, right? So, I think about genetic tests, for example. they could be scanned in somewhere, and they could be in the right portal where I could find it, or they could be under, like, outside records, page 37 of 130 of somebody's outside records. So, I can't find the genetic data. So even though it may be supposed to be in there, I can't find the data that's in there. So, we've separated ourselves from our patient. We're totally driven to entering data. And the world is really excited about this data that we're creating.

Who Owns the Valuable EMR Data? —Certainly Not Us or Our Patients… [00:08:27]

The reason I think of the EMR as a middle person, a middleman, is that the data that we are entering has value, worth something, because it's clinical outcomes, it's behavior and usage and money spent and, opportunities for improvement in healthcare. So, I have been jokingly calling us physicians, you know, highly paid data entry specialists because that's kind of who we are. What we enter into the EMR has value to someone else. We're being paid to enter the data. Someone else can mine that data in order to make money off of it, to watch us, to oversee us. You know, it becomes a new way of tracking our own metrics, our own benchmarking, how good are we, how fast are we, what's our charge lag, all the different things that we have to do so. It’s an oversight of us. It's how we get paid. It's how we interface with the patients. It’s someone else's value in the end. 

So, the EMR is a big deal. We spend tons of time entering data focusing on it. We spend tons of time trying to find information for our patients. Our health care systems value that data very much, and third parties value it very much. But, in essence, we have to recognize that we're in this awkward ménage à trois between our patient, the physician health care team, and this computer system that runs our lives. So, we need to think about how to make a better world around the EMR. To make it more efficient, to make it more clinically friendly, to make it shareable across all health care systems. I think we'd go a long way to improving our health care out there.

EMRs AND BURNOUT: A CRITICAL INTERSECTION

How Much of Our Burnout Can We Really Blame on the EMR? [00:10:27]

So, we're focusing on burnout. We're also focusing on the middleman, the electronic medical record. Why are we focusing on these two? Because clearly they are linked. 

We did a quick literature search and found a bunch of articles that focus on burnout and the electronic medical record. I'm going to put my readers on to share with you one conclusion from one of these papers. it says, "the volume and organization of data, along with alerts and complex interfaces requires substantial cognitive load and results in cognitive fatigue. Patient interactions and work life balances are negatively affected by the time requirements of the EHR tasks during, and, of course, after clinic hours patient portals and, EHR messaging have created a separate source of patient care outside of our face-to-face visits. It is often unaccounted productivity and not reimbursable." It's no wonder that we're burning out. 

As I told you, I am a burnout victim, if you will. Maybe a recovering burnout person. I'm always on the verge of it at this point, but I've learned a little bit better how to manage it. Vacation can help, by the way. 

But, 59 percent of respondents in a survey that was taken did report some symptoms of burnout, and this was compared to only 34 percent back in 2013. So, essentially a doubling of those who are complaining of some symptoms of burnout. Now we are burning out with high levels of emotional exhaustion. And if you think about oncologists, we bring a lot of emotion into our patients. Patients are very emotional themselves. We deal with very high-end kinds of critical moments for patients’ lives that we're walking along with them. So we there's no way we can't not feel that day in and day out. And we feel burned out regularly, right? And that's really up, quite a lot from even just 10 years ago. So, we're getting more and more burned out, more and more, influence of that burnout on our emotional well-being ourselves. 

My health care system just did its annual and maybe it's every other year survey saying they care about my well-being. And so, they've sent out a survey. They set a deadline, September 9th, to fill out this health care form, and they basically claim that what we're going to give them is going to give them a better idea about how to support our well-being and professional fulfillment. Now, this is the same group that's also monitoring me and tracking each of our performance levels and our Press Ganey scores and all of the different components that we are judged by in today's electronic world are. You know, they're going to have this other data that says that that's stressful. So, I'll be very interested to see this. I'm sure your health care systems have done the same thing. How do you bring those two things together. How do you take what stressing us out is the monitoring that you're doing but continuing to monitor us in a way that balances that out so that we get to a place where we can maintain our careers long term, avoid burnout, or at least manage the burnout in a way that's healthy and positive, and mentoring those that are, behind us, if you will. And, and making for a better overall product for our patients and for our teams around us. 

Closing Out Your Vacation—Is it the End or the Beginning? [00:14:17]

As you might have already figured out, the problem with vacations is that they do end. You have to get on that thing back there and fly home. I already looked at my week ahead, it's very, very full, with patients, of course, and meetings, and catching up. That stuff I didn't do over the last week, and it is a stressful week as you look ahead. But I have to say that the tradeoff for the break from all the action and doing what we do as oncologists, administrators, researchers, all the things we do, the break from that was so totally worth it. So, I encourage you out there to make sure and take all of your vacation. Your partners will cover for you. The RVUs, in the end, you won't remember, the vacations, you will. So, make sure, don't trade off those RVUs for those days away. Take those days away. Enjoy your family. Make your life better. Avoid that burnout. 

And by the way, our lack of burnout and our progress and our innovation, maybe some of which comes during a vacation, will one day make it so you got cancer cured. 

Until next time. See you later.

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We now have a really cool function called ask a question. Click on that. Send us something. We hope to get back with you with an answer.

Most of the time, you know, you see these things and it's all nailed down, and you know exactly what you're about to get. Not so much with this. We’re really trying to bring to you the current days news. What's going on in our world in the world of cancer, both in the science world, the social world, and the business world. And you know what? You just can't script that kind of stuff. It just happens as it happens—so a little bit of Oncology Unscripted. 

OncoBuzz

First, the news of the day. U.S. News and World Report just came out again. Guess which one was the number 1? Of course, it's MD Anderson. Number 1 again. The top tier teams, it's like the Yankees going against the Dodgers. It's always the same teams year after year. But congratulations to that fabulous group down in Houston, Texas.

We here at Georgetown are just pumped that we got our NCI renewal; our comprehensive status for a fresh five years. Always a good moment for NCI Cancer Centers, either to get it or to maintain it. So, thank you for all the hard work that went into that. 

Big news out there. Friends of Cancer Research gave out annual leadership awards—Monica Bertagnolli, our new head out at the NCI doing a fabulous job, as well as Brett Guthrie. So great people who well deserve the Friends of Cancer Research Leadership Award. So, kudos to them. 

Just some business news out there. 

Lei Zheng, MD, PhD, who was a UT San Antonio person all along, just named the Executive Director of their fabulous Mays Cancer Center.

Mark Burkard, MD, PhD, he's a good human as well. University of Iowa, just named him their new cancer center director. He was at University of Wisconsin. So, he moved kind of, I don't know, south a little bit. Still will not be such great weather, although it was probably a little better weather than Wisconsin. We'll see how it goes there. So, congratulations to him. 

On the clinical research front, some news that maybe doesn't really make it here to the U.S. so much, is that the E.U., which has been doing a lot of our major clinical research lately, making up for some of the gaps that we certainly haven't been filling as well. They've had a sort of sudden halt to clinical research because of some new regulations around devices and things one uses to test and measure stuff. So, you can imagine scans and other things like that. So, there's some new regulations there that is sort of thrown a monkey wrench into E.U. clinical research. And my guess is, it may take them a bit of time to figure that out, but hopefully they will figure that out fast. 

The one piece of news that really caught my eye this cycle was not something you would see in the journals that hit your door. Maybe not something you'd see in any of your feed, and this is from the Federal Trade Commission. So, there was a Federal Trade Commission report that had to be voted on, and it's all about the anti-competitive harms of pharmacy benefit management industry, PBMs, pharmacy benefit managers, PBMs, and we know in the cancer world, these things have become huge. But on July 9th, not too long ago, the FTC voted 4 to 1, I'm reading this to not get it wrong, to release an interim staff report around pharmacy benefit managers, the powerful middlemen, inflating drug costs, and squeezing Main Street pharmacies.

You and I know this is going on out there. We're feeling it. Our patients. Maybe not. Interestingly, they're a little bit on the sideline about this because in the United States, we don't judge value around here. 

PBMS: THE POWERFUL MIDDLEMEN

John Marshall, MD: This is going to kick off one in a series of the middlemen in our world. We are going to talk about CROs, clinical research organizations, certainly going to talk about electronic medical records. They're sort of our data middlemen. But for this episode, we're going to talk about pharmacy benefit managers. 

Now benefit. I love that word. I get benefits for my job here at the university. It's in my benefits package. What these pharmacy benefit managers are taking advantage of is that that's money that I don't really feel. I don't really see. It's going to pay for things and they're getting, of course, their cut. So, we're going to try and drill down on this. 

Now, as we usually do, we did a pretty extensive literature run, and there are some papers here and there. There's a JCO paper. It was a little while ago. Lancet had one, but nothing really recent about the impact of PBMs on our medical world.

So, what we did, because we went out and found a couple of really good experts that we're going to be interviewing. 

But let me talk a little bit about just these PBMs and the impact that they are having. So, for example, a couple of or three PBMs or at least these are now big companies that are of course vertically integrated, but they've gotten so big that they're thinking about buying practices.

And one of the practices that's out there being considered is Florida Cancer Specialists and Research Institute. Now, I know a lot of the people at Florida Cancer. It's a great health care system. The cancer community is outstanding, McKesson, Cencora, and Cardinal Health, not commenting, but there are suggestions that they're out trying to buy this organization, and they're worth about 3 billion out there in the open marketplace. And then what you could see is you've not only got, you know, pharmacies and hospitals and all of that. But now you own the physicians as well in this. So that's going to be an interesting thing to watch out for is that. 

But let me show you another sort of side mark of this. And this is this thing that I recently heard about called Lilly Direct. Now, Eli Lilly, right? They are solid company. They've been doing a lot. They've got a lot of innovative drugs that are out there. But they had something called Lilly Direct, so I went on to their website. You should do this too. And what it is, is a website for patients who might not have a doctor, or whose doctor might not be willing to prescribe a medicine at Lilly sells. There's some weight loss drugs in there, by the way. And you can click and it says, do you have a doctor or don't you? And if you don't, they give you one and you have a visit, I assume, with that doctor. But then Lilly mails you the drug. There is no in between pharmacy. So now you're even being sidelined as a physician to where Lilly will be providing the physician through some mechanism and then will be mailing you the drug directly to remove this middleman. A different kind of strategy to cut out that PBM and now your own pharmacy or your local pharmacy from that pathway as well. It'll be just coming direct from Lilly. 

Now the big ones, of course, are CVS Caremark, Express Scripts, and OptumRx, and those three companies have nearly 80 percent of the market share. And of course, this is a subject of a recent House Oversight Committee review to look at that and see if there is any, you know, is that clean? Is that what are the rules in there? Are we getting the best for our buck there? 

On the other end of the country, Blue Shield of California actually kicks out CVS Caremark as a PBM, and they basically are starting up their own new pharmacy model.

So, there's a lot of big, moving parts in this space. Some of you out there are familiar with PBMs and all of this world, I was not when I started to get into this world a little bit more in my roles. And so, there's a lot to learn a lot to know. And I do think we represent an important voice in this process, not just victims of it, but part of it that we can influence some change.

I encourage you to listen to it. A couple of interviews that we did with people who are really smart about this subject, so you too can be a little smarter about it and maybe have some influence on this in your own way.

THE PBM IMPACT: INTERVIEW WITH STACEY MCCULLOUGH, PHARMD

The first of our two interviews is Stacey McCullough, PharmD, and Stacey's just amazing. She is the Chief Pharmacy Officer at NCODA. 

As I promised, I have got a world expert on PBMs to come and join us. Now, I didn't know this person until pretty recently when I started working with a group called NCODA. They were silly enough to invite me to be part of the group. Of their oversight group, and it's been an incredible eye-opening experience for me to understand so much more about this important aspect of the business of oncology.

So, with me, shutting up, let me introduce Stacey McCullough. She is the chief pharmacy officer of NCODA, and she is our sort of guru, if you will, of understanding what's going on out there in our oncology world and the impact specifically on access to drugs and the impact of PBMs. So, Stacy, first, let me thank you very much for, as usual on short notice, being willing to jump in and share your thoughts on this important topic.

Stacey McCullough, PharmD: Dr. Marshall, happy to be here and thank you for serving with us and bringing all your expertise to NCODA. It's a pleasure. 

John Marshall, MD: As I said, I've learned more from you than I've taught back the other direction, so I'm keeping going that direction. But, you know, here at our hospital system in Washington D.C., I had no real PBM awareness until really more recently, I used to think of PBMs as maybe a good thing, as a maybe a cost savings thing, a way to manage prescriptions on a higher level for patients who needed chronic prescriptions. But more recently, I've had  actually now, I think, up to 4 episodes where I tried to order a medicine for colorectal cancer for a patient on label, a perfectly straight indication where I was told I couldn't. I was trying to figure out who, in fact, told me I couldn't, and I couldn't get a peer-to-peer review. None of that, but I was told I had to order a different drug 1st before I could order the drug that I wanted to order so now my recommendations were being dictated by some really, I don't know who, out there, telling me what I could do. And so, my PBM awareness. Changed on a dime. So maybe if you could give us a little bit of background on all of this and how that could have gone from something that we thought of as good to something, maybe not so good.

Stacey McCullough, PharmD: Absolutely. So, I think what you reference is, is maybe the experience of a lot of people and probably started a decade or so plus ago when as you know, being a giant with an oncology space, we started going from infused products to oral products.

So instead of, you know, a buy and bill model, we introduced the pharmacy benefit. And what we saw in kind of that deluge of specialty products coming out, Oncology led the way, in that growth of specialty products. And so, we saw pharmacies and PBMs start to compete, not just within specialty pharmacy, but with an eye on oncology specifically because it was a leader among the field.

So, PBMs, integrated in 2018 or so, where the payer and the PBM had their own specialty pharmacy. And so probably that would have been the entree into your world more specifically, all of these new oral oncology drugs. And then in addition to that, specialty pharmacies, maybe within your institution, as well as specialty pharmacies that are owned by the plan and the PBMs now competing for the control of your patient from a pharmacy, dispensing the drug perspective.

John Marshall, MD: We've been talking about being a middle person, middleman, but you know, it's today. So, it's a middle person in the chain of events. Often middle people add value. To the chain, if you will, and I think that was the initial intention is that this was going to be value added, maybe save some of our staff some time and effort, maybe speed the delivery of medicines. What's your take on the value added of the middleman of the PBM.

Stacey McCullough, PharmD: Yes, I think the value added is services offered. So, ideally the definition of a specialty pharmacy would be that you do prior authorization to help the patient find copay assistance. You utilize manufacturer copay cards, but really every step in the process. You know, your teams, you have an internal pharmacy there. And so, your teams are set up to do that. They have access to the EMR. They can go in and get the patient’s information. So, you've created your own efficiencies, I guess. The benefit would be if you're asking for a benefit versus if you've already established the process, and then it's an intrusion basically, on your current workflows.

And that latter case is probably what has happened with the PBMs in that they then insert themselves between the physician and the patient. Oftentimes, the services that they offer may be difficult to offer without access to the EMR. So, they're kind of offering, I guess, education as well as benefits that maybe are outside what you're aware of, often confusing to the patient because you introduce another party into their care. And then, you know, your oversight really is lost a little bit. You don't know when the patient is getting their refills, if the patient calls the pharmacy to report a side effect or an issue with the medication, how does that get back to you? So, all well intended potentially. But now, the complexity of oncology care is definitely an impediment a lot of times to the care versus a benefit.

John Marshall, MD: Yeah, I mean, there's a lot of money involved. I mean, here in Washington, we get ads about PBMs on bus stops and on the morning news. So, it's obviously an important political. issue as well about how this is going to go.

What's your take or maybe what's in NCODA's take on, you know, how this should evolve or what the recommendations are to improve this process further? Because the orals are not going to go away. They're going to only increase. So, we need to figure this out. 

Stacey McCullough, PharmD: Sure. I mean, the complexity of oncology care, in itself is enough. So, fragmentation of care should be avoided. You know, the pharmacies that are in your institution, the medically integrated pharmacies.

There's accreditations for specialty pharmacies out there and NCODA has an accreditation as well. These accreditations are intended to ensure operational as well as patient care. So, with those accreditations, that is the establishment, if you will, of good sound practices that should buy a pharmacy access to dispense these medications.

Basically, what you're showing is that you're helping patients get access, you're making it affordable, and you're able to manage the patient from a side effect educational profile. So outside of, of having that in every pharmacy, kind of showing those competencies. Specialty pharmacies mandating that it go to their mail order pharmacy, or it go to their specialty pharmacy is really without validation. There's no reason other than the economic benefit, as you mentioned in that. So, you know, we support the continuity of care. We support the physician being the overseer of all of the care and the medically integrated team so that when you prescribe a medication, you have expectations of what your pharmacy team is going to do. You know that that patient is going to get access to the medication. It's going to be affordable. It's going to be dispensed. They're going to be educated in it. They're going to have tools that are going to empower them to be adherent with the medication. And any glitches in any of those steps in the process, you're going to get a notification back through your EMR to let you know that. Outside pharmacies aren't able to do that. And so, what goes on the outside of that, not only are they not able to promote optimal care, but some of the actions that they take may actually derail the care. As you mentioned in that, you know, you chose a product for a patient, and an outside entity tells you that you need to choose a different product.

Typically, we all know these are very expensive products. As you mentioned, list prices are about the same. And so why the choice of one agent over another? I think, you know, even within a class of medication, distinct side effect profiles and your experience and your conversation with the patient to understand what's going to be the better choice. Anybody coming in and inserting themselves without knowing that conversation is really outside the benefit of the patient.

John Marshall, MD: Yeah, and dictating a therapy based on a price they got not on the medical recommendation you're giving.

Stacey McCullough, PharmD: Well, and you know, you bring up one point that we hadn't talked about, and that is the difference in buy and bill and the pharmacy side buy and bill you, you get the, the bill on the backside at the pharmacy, you pay at the register before you get your prescriptions.

So, any of these price concessions that are on the back end, the patient is often paying a higher price because they're paying it off that list price, not off the net price sans any of the rebates or discounts that are in that. So that bubble pricing effect really does impact the patient often as well.

John Marshall, MD: And of course, no transparency to that. You would never know what actually happened behind the scenes on all of that. Right. 

Stacey McCullough, PharmD: Absolutely. And that's where, you know, the resources that manufacturers often put out to help the patients, the copay, the patient assistance programs, we've seen, you know, copay maximizers and copay accumulators that redirect that benefit from the patient, you know, back to the PBM. We've seen alternative funding models and that, you know, patients are effectively uninsured because the preferred drug list is nonexistent. And so that actually qualifies them for manufacturer copay assistance or patient assistance programs, even though they're paying for insurance. So, there's no transparency, but the level of deception is very high within that too, and so patients are often caught in the middle of that, and you as their prescriber trying to get them medication, that's the downside.

John Marshall, MD: Stacey McCullough, Chief Pharmacy Officer at NCODA. As I promised you all out there, she knows what the heck she's talking about and the vision going forward of what we need to do, what we need to make sure and emphasize as practicing physicians and all of us in this business of oncology, we need to figure out and evolve this PBM process further so it's in the best interest of our patients. So, Stacy, again, thank you so much for joining us. 

Stacey McCullough, PharmD: Dr Marshall. Oh, it's a pleasure to see you. 

John Marshall, MD: That was amazing. I hope you agree that Stacy's insights and thoughts about how we need to move this stuff forward is really useful to us. 

THE PBM MONEY TRAIL: INTERVIEW WITH ANTONIO CIACCIA 

But we actually got also a 2nd interview in a 2nd take on this. I do want to introduce you to Antonio Ciaccia. Antonio founded several things along the way, as he'll share with us, but he works at a place called Three Axis Advisors which spends their day thinking about this issue of pharmaceuticals in the United States and ways that we could evolve it so that not only is there more transparency, there's more access and improved market system in place for all of us. So, I am pleased to introduce Antonio Ciaccia. Antonio, welcome. 

Antonio Ciaccia: I study drug prices for a living. We track manufacturer price changes. We track Medicare expenditures, Medicaid expenditures. We look at publicly available data sets that demonstrate utilization and pricing trends and what we have learned over time is that, between those moments of money going in and money squeezing out, there is a lot being lost in translation.

John Marshall, MD: Okay if that's the problem, where do we go? 

Antonio Ciaccia: Well, in a number of directions. First and foremost, I think everybody believes that we should move toward a system of value-based medicine. I'm a big believer in the philosophy of value-based payments and value-based medicine. Problem is, is that the architecture of our system today is not aligned in that direction. We buy medicines based on volume, not value. The bigger you are, the bigger discounts you achieve. Thus, typically, the greater financial rewards you will yield. Everything I said there has nothing to do with the quality of the service rendered, the outcome to the patient, et cetera.

The key driver of volume-based payments and volume-based reimbursement, starts with our exemptions to federal anti-kickback laws that allows PBMs, and health insurance companies to collect big kickbacks. from drug companies in exchange for preferential treatment on the formularies. Those exemptions create an arms race, to become larger and larger, thus, to extract larger and larger kickbacks, which results in significant market concentration and also insulates drug companies from the traditional competitive forces of lowering prices. Instead, incompetent competitive environments, they compete to raise prices. To create more bandwidth for kickbacks, which increases our reliance on the intermediaries to negotiate our way out of the problem. 

John Marshall, MD: Do you see us ever getting to value-based? I always, I've spoken for years on this subject because I've lived for 32 years as an oncologist. I've watched this business evolve. And I regularly say like, would you swipe your own visa card? Maybe I should say now tap your own visa card for it. And then because that would say, all right, well, let's connect the magnitude of benefit with the cost. And I can decide value-based medicine as a consumer, but because the consumer is in essence removed from the formula, they're not able to judge value ever.

Antonio Ciaccia: The consumer has no meaningful impact on the business practices of the health care delivery system as it stands today. In general, decisions are made for them. And as a result, those who provide goods and services in our health care delivery system calibrate their business model and their offerings in the direction of the desires of the payers. Not necessarily the origin of the payment, which is the individual patient. And a good example. And you could see in pharmacy pharmacies don't compete to lower prices. Pharmacies don't often compete to increase their staffing, to attract a patient to come there instead. The PBM decides where you'll go.

Right. And if they don't have complete carte blanche to decide where you'll go, they can heavily influence through cost sharing pressure, you name it, where you ultimately go. I know pharmacies that have very low prices. And here in Columbus, Ohio, we have a pharmacy called Freedom Pharmacy.

They don't accept insurance. Their prices are a fraction of what any other pharmacy offers. Mark Cuban's Cost Plus drug company. His list prices, his sticker prices, meaning the prices that are offered to everybody are a fraction of what you'll find in other pharmacies. It begs the question that if the people that we hired to get us out of this drug pricing mess really had our interest at heart, they would be crawling over one another to get those pharmacies to be not only a network, but preferred.

The opposite happens, right? They don't want them in network because they mess up the math. Instead, PBMs incentivize higher and higher usual and customary prices charged by pharmacies, and they negotiate big discounts off of those bogus inflated prices. The challenge though is, is that because of the way that PBMs contracted pharmacies, they actually incentivize them to charge higher and higher prices over time because of the disparate way that they pay them in the most favored nations clauses in their contracts, et cetera, which I don't need to bore you with, but trust my shorthand that PBMs incentivize pharmacies. To charge higher and higher sticker prices. And so what that leaves us with is greater necessity To use the PBM to put out the very fire that they're partially responsible for creating And so what is our way out of it? Well our way out of it is having a system that actually incentivizes drug companies and pharmacies to lower their actual prices to increase the quality of their goods and services rather than the opposite. Which is getting bigger and bigger discounts off of increasingly inflated prices without any sort of quantification of value for the actual service that's being rendered by the provider or the quality of the product that is being offered by competing drug companies. 

John Marshall, MD: So, let me ask one more angle on this is that from the work that you are doing, one of the principles that we've been talking about is lack of transparency. So, if you're going to then report to a government or to whatever that's asking for this information, how do you find it? Where is it? 

Antonio Ciaccia: I often complain about the lack of transparency in this marketplace, and to be clear, there is not enough. However, relative to other forms of other types of things that we buy in healthcare, pharmacy is relatively very transparent. My introduction into this world, in a formal drug pricing research capacity was in my home state of Ohio, pharmacies in our state were complaining about underpayments within our Medicaid managed care program.

PBMs were driving lower and lower rates of reimbursement that was causing a lot of pharmacies to go out of business. Meanwhile, on the other end of the transaction, the state of Ohio said we're spending more for medicines. Those two things didn't make sense. How could pharmacies be getting paid less? How could the state be getting charged more when they're ultimately involved in the same transactions?

Well, what we started doing was downloading very boring Excel files off of CMS's website. One being the National Average Drug Acquisition Cost, which for those that don't know, is a benchmark that is provided by the Centers for Medicare and Medicaid Services where they survey pharmacies on a month-by-month basis and they simply ask them the question, what did you pay to put the drugs on the shelf?

And so we took that data set and combined it with another data set called state drug utilization data, which is a quarter by quarter, state by state, drug by drug accounting of how much every Medicaid program is buying and for how much they pay for those drugs. And so we were able to stitch those two data sets together.

One being the real cost of the drug as purchased by pharmacies. The second being what Ohio Medicaid and every other Medicaid program across the country was being charged. And what you saw was this divergent experience over time. Well, we took all that information and gave it to state officials at the time, who I felt didn’t do what I thought they should do with that information. And so, I turned it over to local reporters. I sat down with reporters at the Columbus Dispatch. I flew out to New York to meet with folks at Bloomberg News. And I gave them all this data and they said, we think there's a big story here. The state of Ohio eventually followed the trail. Our state auditor, Dave Yost, decided to open the books and, voila, they found that there were $245 million worth of hidden PBM spreads where they were buying low, paying the pharmacies very low, billing the state high and pocketing the difference.

All of that was started thanks to the accessibility and availability of limited, imperfect, but very valuable drug pricing data. What we have learned since then is that there's even more data out there. Medicare Part D has a ton of pricing information available on its site. You have folks like Mark Cuban that are publishing their prices. Costco publishes their prices, and, before, you know it, yeah, we have a black box in drug pricing, right? But the beauty of a black box is that it's multi-sided and there's a lot of things that you could find around it. Right. And, and so in answer to your question, there's not enough transparency, certainly. And I would argue that when we do work on behalf of state agencies or employers. They're not given the itemized receipt that they deserve. However, the limited amounts of transparency into the system we do have often helps us uncover the latest and greatest drug pricing schemes that are being cooked up by the various intermediaries in the drug supply chain.

John Marshall, MD: You've done a great job of pulling this together and really serving the community at large, because the money that we're talking about. Is not really, I mean, whether it's government money or insurance company money or whatever, it's our money, right? This was money that we paid into these banks, these quote unquote banks for them to then distribute and cover this. And so, there couldn't be honestly, a more important way to try and make our health care system more efficient and find the fat in it so that we can deliver more services.

I mean, it's just crazy how much we spend and still how much we're limited by what we can do. 

Antonio Ciaccia: Let me let me depress you just one little bit more. 

John Marshall, MD: Go for it. 

Antonio Ciaccia: It's an oncologist. Our story is very relevant to your line of work. So, the very first report that we ever issued was in August of 2018, when we launched 46Brooklyn Research as a nonprofit dedicated to what I would call drug pricing journalism.

The very first report we released was called The Cancerous Design of the U.S. Drug Pricing System. And it was all about generic Gleevec, okay? Which I would argue is the poster child for drug pricing dysfunction. It was a huge part of the Federal Trade Commission's report that was released within the last month.

But basically what we found was that Medicaid programs across the country were getting charged thousands of dollars for something that had been declining in its underlying cost significantly over the last few years. Fast forward the tape and again, this shows you the value of drug pricing transparency.

We still see to this day Medicaid programs being charged thousands of dollars per prescription for generic Gleevec. We see employers being charged thousands of dollars per prescription. Patients in those commercial programs having cost sharing based upon those bloated prices. We just released a report in July, where we were looking at pricing information for generic Gleevec in the Medicare Part D program and the beauty of the Medicare program is that they will show you the prices of every single Medicare Part D plan. And within those Medicare formulary and pricing files you can see it within every plan the parent organization of those plans as you well know PBMs aren't really PBMs anymore. They're part of large vertically integrated companies that are often health insurers. Well, if you take all the prescriptions for generic Gleevec across all the different Medicare plans and roll them up to their parent organization, what you'll see is a company like CVS Health, which has hundreds of Medicare Part D plans, despite the fact that this drug has been generic for a long time and is very cheap. Still to this day, you will find CVS Health Medicare plans setting 597 different prices across all of its plans. The lowest price is around $2,600 per claim. The highest price is $8,200 for prescription. Okay. Now to give context here, not only do you have 597 prices, not only do you have about a $5,500 difference between the lowest price that they offer and the highest that drug can be bought from Costco or Mark Cuban for less than $40.

Okay. So the games that we find, right, are not limited to that drug, but it is a demonstration of I think how much risk there is When there is not an aligned approach for how the prices of medicines are set at the pharmacy counter and when there are raging conflicts of interest within the companies that are setting those prices.

John Marshall, MD: Are we the only country that does this? 

Antonio Ciaccia: We are the only country that does this. Other countries have a much more heavy-handed approach to drug availability and pricing. They say, look, these are the drugs we're going to have in, and these are the prices they're going to be. Sometimes that means that they cut off a lot of the inefficiencies that our system has.

In other ways, they disincentivize manufacturers from bringing certain products into those marketplaces. That's a double-edged sword, and those are policy tradeoffs that I think everybody has to, has to consider. I personally am not as much of a fan of that heavy-handed approach, because I think sometimes it can, throw cold water on the access to medicines in the in the innovative churn that we rely upon to get access to those medicines but regardless I think the U.S. System hasn't been given a chance to flourish the way that a traditional market based approach could Because we have all of these special rules for Medicaid rebates, 340B rebates. We have these GPOs and exemptions to kickback laws. We have all these things that make the U.S. marketplace special. Aside from the price controls that separate, you know us on paper I think that the U.S. marketplace can be materially different than what it is today without having to go all the way and say hey, we just need to take this over as at a government level.

John Marshall, MD: So the free market could handle it if really it was a free market and when I hear in the spectrum of sort of, you know, government heavy, quote-unquote, socialized medicine. You're not really there because of the level of restriction. But, you know, I think about the British health care system and the nice committees that oversee new drugs or new therapies, and they put a value proposition to it. So, they say, okay, here's what you're going to charge for it. Here's the magnitude of benefit. Medical people make a judgment. They have a certain fixed amount of taxes they can spend on health care, and they make a decision in or out. So they actually, and then publish the data, the decision in Lancet, for example, but, but that's often criticized because they, you know, there's a lot you can't get in Great Britain, because of that public health service system, we can get it all, but it's a very disrupted system, as you say.

Antonio Ciaccia: I think it's important to remember that there was a, there was a market-based system before PBMs, right? And certainly, it was not nearly as robust as it is today, but it is important to remember that there was a time where our wallets and purses are what guided this, this marketplace. And if a medicine was too expensive, we sought alternatives. If a pharmacy was too expensive, we sought alternatives. The second, that third party payment governed the marketplace. All right. That's when things really started to get out of whack. And that's not me saying we don't need third party payment at all. It's not me saying that we should go back to a system where people can't afford their medicines. But I think it's important to understand the traditional forces that we rely upon in a free market are not present in the environment we have today for medicine. 

John Marshall, MD: This has been perfect. 

Antonio Ciaccia: Have a good one.

PUTTING PBMS IN PERSPECTIVE  

John Marshall, MD: I hope you all watched both of those interviews. I learned so much from both of those people about our world. Every time I click on an order in my EMR and send that prescription off into the ether somewhere, you know, how many people are touching it? How many people are skimming a little money off of it?

How many people are valuable in the process? How many people are unnecessary to the process and just making a dime off of this game that we play? It is so important that we fix this. Our patients are literally dying for better treatments and new treatments. Our industry partners are spending great resources on developing new therapies, most of which are today are going to be oral therapies. And so we have to fix this. We have to fix it. For progress. We have to fix it for our national, frankly, security. We have to make this cost less. We have to make it have the value that it really has so that the money we're spending is going to the appropriate cures for cancer. And, you know, the reason we want to do this is that the next time you see a patient with, you know, say, metastatic cancer, you say stage 4 metastatic cancer. Don't worry about that. Because we can cure that. 

This transcript has been edited for clarity. 

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John Marshall, MD: Hey everybody, this is, believe it or not, episode four of Oncology Update, where we're really trying to get to, God should we say it, the truth in oncology. There's so much going on out there. It's a complex business. There's a lot of really cool science. There's a lot of progress going on. We're affecting a lot of people's lives, including our own. 

So, let's jump right in and see what's going on out there this week. 

Remembering the Father of Tamoxifen

[00:00:31] I don't know if you saw this, but a guy named V. Craig Jordan, PhD died. If you don't know who Craig Jordan is, he actually worked here at Georgetown briefly. He invented tamoxifen. You think about the impact of understanding the estrogen receptor and being able to intervene on it and have an impact on people. Talk about somebody who's had an impact on a whole lot of lives. That is Craig Jordan, and his impact will always be felt. But as a human, we will miss having him around. 

DOD Gives Colon Cancer Research Thumbs Down

[00:00:58] Up here on Capitol Hill, kind of a bad day for colon cancer. We've been lobbying to try and get colon cancer as a set aside in the DOD budget. Remember that breast cancer stuff that's in there? A couple of other cancers are in the DOD budget as a set aside, but colon is not. A set aside. It's in the pot. You can do colon research with DOD funding, but we didn't get our set aside. Even though we are among the top five in terms of common and seriousness and cost and all of that. We think we should be in the DOD budget, but we didn't make it. 

NCI Budget Challenges

[00:01:33] Dr. Kim Rathmell, new director of the NCI, she's got a lot of work in front of her. Budget being slashed up there on the hill. But there's this ARPA-H thing, which is this new kind of designated money for more, I don't know, inspirational research might be the right way to put it. Whereas NIH is kind of incremental research that gets funded, ARPA-H is looking for that leap of research. 

Time to Unionize Oncology Practices? 

[00:01:59] And then, I don't know if you saw this. This is kind of interesting. We'll have a little bit of a theme on this today is that out in California, there are 400 residents who work for a Kaiser organization there, and they actually formally filed to unionize, and I want to think a little bit about unionization and practice and the like. 

Merging Oncology Practices: More Guidelines, Fewer Choices

And let's talk a little bit about the business of oncology. So there was a recent paper by Mike Milligan, it was actually one of the ASCO pubs, and it was looking at U.S. oncology practice patterns. And, just very briefly, what they showed is that there was an increase in number of oncologists by 14 percent over, say, 2015 to 2022, but a decrease in number of practices by 18%. Well, you can do the math on that one. What it means is, is that more and more practices are getting bigger and bigger. And in fact, here in Washington, D.C. I work for a 7000-physician practice here in Washington, D.C. And our oncology team is all 1 big team, if you will, and work together. So, we're working more and more for someone and we're working in larger and larger groups. And what it sort of suggests to me is. Maybe we need to start thinking about unionizing. 

[00:03:28] Now, I'm not trying to be some socialist, although I was in England when the Labour won their vote over there. Now, they know how to have an election. That was way cool. We should take a tune from them. They know how to have an election, but we still don't. But, you know, we are being asked more and more to follow guidelines, to basically be on the assembly line doing what we're expected to do and less and less freedom. And I think the way that we will regain some of that independence is through collaborative sort of bargaining, if you will. And so, I do think I see that trend increasing, as more and more of us work for one individual. Or one company, if you will. 

Dr. Ferris Heads to Lineberger After UPMC Layoffs

[00:04:10] Other news on the headlines is that a guy named Robert L. Ferris, MD, PhD, a very prominent runner of the UPMC Cancer Center has just moved down to, a great cancer center as well, down at UNC and North Carolina at Lineberger Cancer Center. He's a great guy and, and he's going to do very, very well wherever he is. But then it made me sort of think, well, what's happening up at UPMC? Because I think about that as being a great place. They turned out to have lost over the last year, 200 million bucks in, unbalanced budget, if you will. And they had to let go 1000 people. And so, we understand that our business is indeed fragile. Makes me wonder if Dr. Ferris made the trip out of there knowing that things weren't going to be very good at UPMC for the while, but we do need to take care of each other, in our business of oncology.

Science of the Week: Risk Reduction vs Absolute Change

[00:05:01] What we're going to really drill down on today scientifically is a single paper. This is a breast cancer adjuvant paper published in JCO not too long ago. And the drug that was added to hormone therapy in a big, randomized trial was abemaciclib. So, Priya Rastogi was the principal investigator. The full manuscript is out there. And what this was, was the five-year survival, the five-year update of this group. So, half got traditional hormone therapy for ER/PR-positive, HER2-negative, breast cancer, quote, unquote, high-risk. Breast cancer. I'm going to come back to that. Versus the same group getting the same treatment plus two years of the CDK 4/6 inhibitor abemaciclib. 5600 patients.

Let's think about what they call high-risk over there in the breast cancer world. Well, the control arm of this patient population had a 90 percent 5-year progression free. So, I mean, it's just a huge number, right? They're all doing very, very well, even though high risk. And it was, it's node positive. It's bad features on the tumor. So, as we, it is bad cancer, but they've already figured out so much now that the many of most of those people are cured. And certainly in 5 years, it's a very high number of people who are doing well, but to try and make that even better, they added 2 years of abemaciclib. And this drug comes with diarrhea and neutropenia, sometimes severe, sometimes requiring dose modifications. 

Would you take it or not? Well, let's look at the data. Well, the data, um, and the curves do show an improvement in distant relapse. Okay, of about 7 percent with a hazard ratio of 0.67, right around there, and, by any study in my world, this would be a home run. And I think it was pretty positive in the breast cancer world too, but you could think of it a couple of different ways. Remember, Already, the vast majority of these patients were cured or certainly disease free, with just the hormone therapy that they were on, and so to add on this, you know, you could say, well, you reduced the risk by a certain amount. You know, the risk was already small, 7%. You know, such a small number. So, if you treat 100 women for 2 years, you pick up a few. 

But then what this paper was all about was overall survival. And I'm going to try and show you that. You see that curve? That's the bottom curve there. That's overall survival. And of course, at five years, there was no difference in overall survival. And even though this paper does, sort of engender changing the standard of care, you treat a hundred women with this situation. You give a bunch of them side effects, there's cost. And in fact, you haven't changed the overall survival. And most of them were already okay. And you did bump it a little bit. 

How do you present that data to a patient? Do you use hazard ratios? Do you use treat 100 people? It only helps one. Do you present overall survival and say it's not worth it? Or do you have sort of a risk avoidance for yourself where you don't want to have been wrong. You have a patient on the other side who's afraid and will do almost anything to get out of this. Right? So, they're willing to risk toxicity, even for a very low percentage, or at least most people are. And so, it’s all aligned. The stars are aligned. to add this medicine for everyone. And so, we are really dramatically overtreating most of these people. If we were to add this drug to everyone, because most of them didn't benefit, most of them don't need it. It's only a small proportion of the patients who really get benefits. So, I think as we are presenting new science or as we are presenting options to patients, we need to be aware of this.

Patient Perspective on Risk vs QOL: Interview with Zach David

[00:09:24] So what we did is we found a patient. I happened to be walking around a golf course with him. He wanted to share his story of his decision making, where he actually decided not to do it—to take additional treatment, risk a higher risk of relapse, in order to keep his taste, to keep his saliva, and to keep his quality of life.

So, let’s hear from him now.

Just a few days ago, Zach David, who, as we were walking and talking and comparing life stories on a golf course, was telling me about his recent experience with his own cancer, head and neck cancer with radiation and chemo.

And what he told me was a fascinating story. So, I want Zach to do a brief introduction of himself and really tell us about the process and the decision making. And in particular, this one decision towards the end of his treatment, that was a tradeoff between quality of life and maybe survival. So, Zach, thank you on such short notice for being willing to join us, but take it away Give us a little blurb on who you are and what you've been through and maybe a little bit more about that decision 

Zach David: Sure, Dr. Marshall. Thank you very much for the opportunity to help in any way that I can. Zach David. I was diagnosed with squamous cell cancer in my neck when I was 48 years old. Three children, obviously a big, big shock to us. Otherwise, I seemed very healthy. And then, you know, the decision trees that you talked about, you know, which process. I started off with a surgical removal of the tumor in my tonsil. And then they did a radical, um, where they took out, I forget the name of it Dr. Marshall, 

John Marshall, MD: Radical neck dissection, I think they call it.

Zach David: Yeah, that's right. 

They took out all my lymph nodes where they thought I'd gone on the side of my neck. I had to decide whether to get a feeding tube before, we went through this process because the radiation was going to impact my swallowing.

We ended up doing that. Seven weeks of radiation and three courses of cisplatin, which was a, you know, an all day event. of hydration, cisplatin, hydration. And by the end of my second cisplatin, I think it was about week five and a half, six of the radiation, I was fully dependent on the feeding tube, was being admitted into the emergency room because the cisplatin was wreaking so much havoc. No taste. High fever. And I went to Dr. Deekin, who was my oncologist. And I said, do I have to take this last dose of cisplatin? He said, well, you don't have to. And actually, a lot of people don't get to that last dose. I said, what are my percentages of survival? He said, your survival rate goes from 96 percent to about 90%.

My next question was my quality of life will have a chance of more saliva. Well, I have a chance to regain more taste and all the side effects that go with that chemo, and we decided after he told me that my chances were 90 percent versus 96 percent to not go with that. Today. I, you know, I do again, taste a good wine, taste a cheeseburger versus, uh, no cheese, et cetera, et cetera. 

John Marshall, MD: that's a really great story and very helpful to our discussion today. So, thank you for sharing. But when you think back on that, obviously you're in good shape, right? There's no evidence of the cancer returning. Do you sometimes have sort of chills or what goes through your mind about that 6 percent that you were sort of willing to give up, for the tradeoffs that you mentioned. 

Zach David: The biggest thing that I think about was that I had advocates. And I asked the question. And you're faced with so many different questions through this process without advocates and lots of people to speak to and ask about the decision points really, you won't know until you ask or are faced with these decisions. Obviously, you know, everybody's a little bit different, and everybody has a little different decision tree that they need to make.

John Marshall, MD: If you hadn't asked Dr. Deeken about that, you would have gotten that last dose, right? He wasn't going to come forward. It's not natural. I'm not picking on John. I know him very well, but we don't naturally come forward and say, do you want this trade off from the patient?

Zach David: Yeah. I mean, this was, this treatment was recommended, by lots of doctors, you know, nationally, worldwide. So, this was the prescribed treatment for my particular cancer.

John Marshall, MD: Maybe one last thing, because you, you know, a lot of docs, a lot of oncologists around the country and really around the world are watching this right now. So, what would you tell us as a patient? You know, what advice would you give us about communicating these kinds of issues to patients, these kinds of tradeoffs to our patients who may be not quite as good a self-advocate as you were? 

Zach David: That's a really hard question. But one thing that my doctor, Dr. Deekin did, he, he took a lot of time with me and just taking the time to slow down in your decision-making process and educate, which not everybody has that luxury. and talk to people, I think that's, that would be my, my number one thing. 

John Marshall, MD: I love it. I love it. Zach, David, thank you so much for joining us as we discuss this really tricky subject of these tradeoffs, decision making, shared decision making to optimize patient outcomes.

Zach, thanks a lot. 

Zach David: Thank you for having me, doctor. 

John Marshall, MD: Zach certainly has an interesting story where he made the decision to not do a dose of cisplatin in order to try and optimize his quality of life, even though he knew that there was about 6 percent delta. Just like our women in our breast cancer study had of having a relapse. He made that decision and so far he is happy with it. 

Talking Truth with Patients: Interview with Mark Lewis, MD

[00:15:42] But what I think we need to do is drill down with one of the world's experts on decision-making. And so right now we're going to cut to an interview with Dr. Mark Lewis 

We are very, very lucky today to be joined by Dr. Mark Lewis. He is the Director of GI Oncology at Intermountain Healthcare in Murray, Utah, which is, I'm assuming, a place somewhere in Utah. He does a lot more out there, but he's really one of the key thought leaders in the world of decision making and oncology and he comes at it from a couple of very important angles, both sides of the exam room, if you will. And it really takes that perspective to, I think, make us all better at what we do. And so with that, let me welcome Dr. Mark Lewis, and we're going to drill down on this concept of decision-making.

So, Mark, thank you so much for joining us and maybe just open this up a bit. What's your take on how we're communicating with patients? These complex decisions, these complex pro and cons for adding drugs, length of therapy, toxicity versus benefit. Where are we with that in your head?

Mark Lewis, MD: Yeah. Thank you so much, John, for having me. And this is a topic that's near and dear to my heart, both in professional practice. And as we might discuss a little bit, even in how I've made decisions about my own care as a patient. So, I'll start by using an analogy. I love figurative language. And one of the things we're talking about here is how to communicate with patients. So, one of my tools is analogies. So, I think a pendulum has been swinging where on one extreme we have sort of the old paradigm of paternalism. You or I would walk into a room with a white coat on and we would sort of try to project confidence. I think sometimes that maybe became almost kind of overbearing or imposing. And, you know, the, you know, idea there was that you and I have done this long enough that we know what we're doing, and we basically just prescribed to the patient what they were going to do. 

And then I think the pendulum has swung potentially a little bit too far all the way across the other pole, which I call a la carte oncology. Which is the patient comes in to consult with you or me, and we basically give them a menu. And we say, would you like option A, B, or C? And I think the problem with that, while it does respect autonomy, to be very honest with you, it kind of abdicates our responsibility. Again, there's a reason people come to us. And I think somewhere between, you know, sort of, uh, bravado and, you know, complete abdication, I think there's a place where the patient wants to know our opinion, or our recommendations.

So, what I do is, I do like to present options, but I also feel like I'm not doing my due diligence for any given patient if I don't tell them at the end of the visit, Hey, listen, this is, this is what I'm going to recommend that you do. One tool I found really helpful is sort of trying to take the patient's pulse on an individual level as to their, not just their scientific literacy, and I don't mean that in a condescending way. You and I both know how easily we lapse into jargon and the alphabet soup of oncology. But even how they view risk, because I think a lot of what you and I do actually is we're trying to mitigate risk for people. And what I've learned over the years is just percentages, might not, especially if we just say them verbally, might not have the same impact as, again, trying to figure out, you know, what do numbers mean to a given person, or do they prefer visuals? And it's interesting, John, we're all products of our training. I trained; I did my fellowship at the Mayo Clinic. At the time I was training, there was a huge emphasis, as you might imagine, on how to counsel patients on adjuvant therapy. And You know, the two diseases that I think made the most impact on me, were breast cancer, and colon cancer. Now, breast cancer was interesting at a time, there was a software tool available, not just at Mayo, but elsewhere called Adjuvant! Online. You may be familiar with it. And it was beautiful, especially for a fellow, because you could essentially sort of plug and play with a given patient's data and you could show them in, in visual format, the added benefit that they would get from say endocrine therapy. And I know you're talking about, about abemaciclib which is, you know, a little bit different. But then, endocrine therapy plus chemo, like if you maximize your odds of risk reduction. And what was it worth? And I guess what struck me, John, was with those patients I was counseling, and again, it was at the very sort of outset of my oncology career, there were some patients who would incur literally any toxicity that you consented them for. If it resulted even theoretically in a 1 percent greater chance of being alive at five years. 

And so I had that perspective from my breast cancer population, and then I developed actually a completely different perspective from treating patients with colon cancer. So, you know, again, I trained under some really wonderful GI oncologists, and the first day of my entire fellowship, one of them who was a true expert in colon cancer said to me, Mark, if you do nothing else as a practicing oncologist, whether you're going to GI or you're doing general practice, I want you to respect oxaliplatin, and I know that you know why, why he said that, and I've certainly learned it over the years. 

So, I think one of the great advances of the last several years in our field, John, meaning GI oncology, was the IDEA trial. I don't know if we'll ever see its like again. Almost immediately as I was sitting at ASCO hearing about it, I think it was the plenary session in 2018, if memory serves, I remember thinking, I can use this the day I get back to clinic. The question is, how am I going to relay these findings to, my patients in a manner that really matters to them? 

So again, without getting too much in the weeds of that study, but you know, you and I both know, and I'll just repeat for the audience here, really a fascinating trial. Again, really looking, I think, at the risk benefit of oxaliplatin in particular. So, Looking at this huge, internationally pooled group of about 12,000 patients with stage three colon cancer. Looking essentially at what was the tradeoff between three or six months of oxaliplatin containing chemo. And there was a lot more nuance to it, but what I came away with was, okay, the disease-free survival of three years, which was the primary endpoint, was actually roughly equivalent, depending on some risk stratification. And what I came away with was to tell patients, listen for perhaps a 1 percent greater chance of being alive at three years without your colon cancer coming back, you're incurring triple the risk of neuropathy that I probably am not going to be able to reverse for you. When I, when I put it that way, rather than just, you know, saying, oh, the three-year DFS was 74 versus 75%. And especially when I put it into visual form. So, I've started using pictograms rather than seeing percentages, actually printing out a picture of a hundred theoretical patients usually, and usually coloring them and showing, okay. It's almost like a spot the difference. I literally just spot the difference. So, on one side I had. like all the colors of the people if they did three months of oxide applied containing chemo. On the other graph, I had the one with six months, and I said, hey, spot the difference. And I had, you know, colored it pretty subtly, but if you looked carefully enough, you see that there was one extra person alive without their cancer having recurred at the three-year mark on the six months.

John Marshall, MD: But even with all of that, we still see our colleagues feeling like, you know, if the cancer came back, what if I had given you three more months, right? You the 1%. And so, this sort of regret avoidance pushes us, I think, to do more than and many of us. I mean, you take the time, which is valuable. You show in a clearer way. What it is to a patient, but a lot of us don't either have that skill set or have that level of knowledge on an individual decision. And so, they say, well, the NCCN guidelines say this, that's what I'm going to do. Right? Because you have to, it's the playbook. Right? And so, you know, we have to figure out a way for us as healthcare providers to increasingly be comfortable with the de-escalation concept and the traits that come with it.

Mark Lewis, MD: Yes. So, two things there, John. Thank you. And you're giving me so much credit and I'm really flattered. One is that the concept you are, important notion you raised about time. So, I agree with you. Uh, the greatest premium needs to be placed on the time that we have, especially face to face with our patients. I don't know how your practice works. I get an hour with new patients. I get 30 minutes with follow ups. And that first hour, as you know, there's like, you want to be present, but there's a to do list in your head, right? As the oncologist, you know, you have to do X, Y, Z. And by the end of the visit, you're supposed to, you know, lay out a treatment plan and explain the intent. And I think one of the things that's really tricky about say adjuvant therapy in particular is it's all risk reduction. There, there is no 100 percent foolproof guarantee that the cancer is not coming back. So, in regard to the time aspect, I am actually a huge fan of, and I'm just throwing this out as a practical tip for our colleagues. I really like One aspect of the EMR, okay. The electronic medical record is largely a billing and compliance tool. I’m well aware of that, but the part I like, and I think it's available in most systems now is the patient portal where I can exchange information with them, almost like a secure email. And it's nice because it's asynchronous. Like they can send me a message at midnight, and I can answer at five in the morning when I'm prepping the next day's clinic. So, we can have that almost immediate interaction. We can exchange information and I can send them resources. I can send them pictures or articles that I think are helpful, whatever issue they're grappling with, especially if it's this one.

And then the other thing I would tell you about, you know, decision or regret. It is a hundred percent real. There have been times in my career where the weight of decision regret has been so crushing that frankly, I've had a crisis of confidence and said, oh my gosh, like, am I really cut out to do this? And, you know, I think if any of us are honest with ourselves, like it's appropriate from time to time to sort of. step back and sort of survey your own acumen. But frankly, John, and this is gonna sound strange, to me that that one percent who recurred because I gave them three months versus six months, I see that a lot less often than the people I see who are struggling with, and I'll use the word very carefully, crippling grade three or above neuropathy because I gave them, quote, too much oxaliplatin.

I have had so many of those people in my career, especially pre 2018 and pre-IDEA, that all those things that my attendings told me the first day of fellowship, they have absolutely, you know, rung true in my head. I probably give, I have given thousands of patients oxaliplatin, and I've given a substantial number of them, and it weighs on my conscience considerably, neuropathy that I sometimes wonder, I sometimes lay awake at night thinking, gosh, did I need to do that? So, you're absolutely right. The decision to regret it. sort of very black and white is, okay, did I, did I affect mortality risk reduction? But the other decision to regret is, you know, first do no harm is a very difficult principle for an oncologist to follow. Like primum non nocere with the drugs that you and I are dispensing is very, very tricky.

John Marshall, MD: Now, those surgeons cut people open and let's give it, you know, they have to do that. Listen, we could go on all afternoon, but I want to really thank you for coming in and sharing your thoughts on this decision making and the complexity and some of the strategies that you've used to make it better for your patients.

I couldn't agree more with that. We need to be voting on what we would recommend to our patients more than we are today. And just put up with that decision regret because it's us that know more in many ways than our patients. So, Dr. Lewis, thank you so much for joining our program if we want to go quite so fancy as that.

And I can't wait to see you in person soon.

Mark Lewis, MD:

Likewise, John. Thank you so much for having me. 

John Marshall, MD:

That's a wrap on episode four. I hope together we are working to find not just the news and oncology, but deeper than that. What's the reality of what we do? What's the truth in our world? And once we get the truth, we'll all be better at what we do.

See you next time. 

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John Marshall, MD: Welcome back to Oncology Update. My name is John Marshall here from Georgetown University, Washington, D. C., the land of freedom. I don't know what it is the land of anymore, but welcome back to Episode 3 of Oncology Update. 

Our theme for this session is going to be, how do you stay up to date? How do your patients stay up to date with all that's going on in the world of oncology? And are you, in fact, delivering state-of-the-art treatment? Or are you, in fact, maybe delivering something, some recommendation that maybe AI created? So, we do want to, you know, Be careful about that. 

Oncology Update: New and Noteworthy [00:00:40]

But before we do, let's kind of start with some of the news of the week. You know, everyone knows who Dennis Slamon is, an amazing scientist and clinician who, really, his group really defines the whole HER2 targeted pathway, defined the use for trastuzumab in more than one disease and turned HER2 into something that you didn't want, to, now, something it is you want, in certainly in breast cancer. And he, of course, rightfully receives another, major award from the National Foundation for Cancer Research, so a big shout out to Dennis Slamon for the incredible progress that he has made and the impact he's had on so many people. You think about how many lives that man and that science has saved just through that research that he's done. It really is impactful.

On the other side. I want to give acknowledgement to Dr. Harpreet Singh, who worked at the FDA in drug approvals, right? So, the whole idea of giving back to the government, working for not very much money to try and establish the metrics, et cetera, for FDA approval for medicines. But just recently, Dr. Singh took a job as the CMO for Precision for Medicine, which is a, basically a research CRO. And that's very much similar to what we see here in Washington of that kind of revolving door between working for the government and then working for industry. Taking the skills and the inner inside knowledge and the like that's important out to the rest of the world to try and improve the process there. So that's a little bit of what's going on in the world of drug development.

But, maybe most importantly, this is Juneteenth. Actually, we are recording session 3 here, episode 3 here. And it's also part of Pride Month. And so, we have a lot of folks who are out there, who really are underrepresented in our research, underrepresented for access to the treatments we have, for a variety of reasons. Not just here in the United States, but everywhere around the world. And I know many of us are working to try and level that playing field. I always think about this as a really difficult subject, is health care a right or is it a privilege? And we try to dance both of those here in the United States with the private health insurance and other government health insurances underneath that  are clearly not providing the same level of care. And these kinds of months that we think about those who are less fortunate or those who have struggled with their own personal world in a world that's not necessarily built to—ready to receive them. And so, I do think we have to make sure we're taking care of everyone and acknowledging all of that that goes on. So, it's an important month, the month of June for us all to stop and reflect a bit on all of this, particularly in health care.

Oncology Update: Vetting Medical Information [00:03:47]

But let's look at the science of the week. Now, you're going to think, this is, you're waiting for a Nature paper or some major JCO paper. I'm actually going to show you a minor JCO paper. It was written by a very good friend and a person who I really go to for my sort of ethics checks. And this is Dr. Paul Helft out in Indiana, and his team put forward a survey paper that was published in JCO looking at what patients are doing on the Internet, what they're going to see on the Internet, and then what they're bringing into us as information they have found on the Internet. Again, sometimes it's supportive care things, but often it's therapies that someone has posted somewhere on the internet that might be helpful for their cancer. They're looking for a better answer than the ones we are giving them. And it comes to mind is how many times a week does somebody come in with, you know, I've heard that ivermectin can really help cure my cancer. Or, you know, if we just allowed more medical marijuana. This would solve the whole problem. People wouldn't have cancer. Maybe they wouldn't care about having cancer, but they wouldn't have cancer is what they think. Or turmeric is my favorite one. You would think that whole, you know, populations would never get cancer because of the turmeric that is in the diet in certain populations. But no, that seems to be a popular one. Acupuncture and other sorts of mind-body approaches are of course very popular. But many times, you know, we in the healthcare industry aren't really qualified to comment on the things that are being brought in, or they irritate us, or they just take time, and we spent time then waving off the things that patients have found on the Internet. And there's an entire, you know, burgeoning literature around this, and we clearly see that social media and the Internet are actually promoting this sort of alternative oncology all the way to what we would call quackery. And the publishers want this. You know, in my position in academia, it's very common that I'll get emails from some new journal that's just coming out that they need new reviewers, and they want an editorial board or something. And I see that mostly as spam email myself. But, you know, somebody’s saying yes to that. And somebody then is publishing stuff that may not be up to the same scientific rigor that we're used to. And we might come across some of those things on the Internet searches and not really be able to judge what it is we're seeing. And this has created these so-called predatory journals that are out there to just make a living having medical information, no matter what quality of medical information is out there. And a nice recent paper did summarize a lot of this that's out there to be careful. Because when we're going online ourselves, we really need to figure this out. 

Now, where do you go for your information to stay most up to date? Well, I bet you go to UpToDate sometimes. And that's obviously a much fuller annotated version of things. It requires you to do some reading and thinking in order to apply the knowledge there. But most of us are going to NCCN. It used to be that around here, at least, that we would not allow our fellows to cite NCCN as the reason to do a treatment. That was not the source document. The source document was the study on which the NCCN guidelines were based. So, you had to know where the NCCN guidelines came from so that you could interpret that. But somewhere along the way, we sort of slipped off of that. Don't you think that if it's on there, then it's legit. And the payer on the other side is like, well, if it's on there at the right level of evidence, we'll cover it. So, it's almost more important to be on NCCN than it is on FDA. Once you're on the market, NCCN will get you covered. So, it creates a sort of new target that's separate from the FDA, different levels of evidence. 

Did you look down in six-point at the very bottom of the NCCN guidelines on every one, it has the disclaimer and I'm going to read it just so you guys can read, hear this out. NCCN explicitly disclaims the appropriateness or applicability Of the NCCN content, the guidelines and any derivative resources or the use of or application of the NCCN content, the guidelines or any such derivative resources to any specific patients care or treatment. 

That's exactly how we use it. Right. We look up a patient who. You know, we're not quite sure what the rules are. We're not quite sure if that drug's got approval or you covered. We're not quite sure what to do next. So, we open up NCCN and make an individual patient decision based on what's on that, even though they in fact, say that that's not what we built it for in the baseline. So, I just want us to remember that that's where that sits. 

Now, in the old days. I used to be able to know pretty much everything I needed to know to be a practicing oncologist. I could study it; I could remember it. Nowadays, I can't. And there's so many new drugs, they have so many new names and funky names that I can't remember, that in fact, I'm constantly, even in my own space in GI cancer, needing to reconfirm or look back up in the internet of some place—NCCN, UpToDate, or even just Google, to figure out where the answer in fact is. 

Oncology Update: Tracking FDA Decisions  [00:09:45]

And so, I just did a little looking myself about, new drugs that were approved, but now have been withdrawn. It came through my inbox that a, a drug infigratinib (Truseltiq), which you may know as an FGFR fusion molecule for cholangiocarcinoma, was withdrawn. The approval was withdrawn. Originally approved in '21, just in May 2024 was withdrawn. And so, if I had one of those FGFR fusions, even though this drugs on the market, I can't use it for cholangiocarcinoma. But if I looked that up, and I didn't see that it was withdrawn, I might not. I may only see the FDA, the positive FDA approval, but there are a bunch of them here. And in fact, there were 29 drugs withdrawn that had initial approvals within cancer medicine.

Some of the others that we noticed was belantamab mafodotin-blmf (Blenrep). Okay, so Blenrep is a drug for multiple myeloma. It's been withdrawn. It was withdrawn back in 23, but new data, we think it may be coming back on. So, it depends on when you looked up what your reference pops up in your search of whether that drugs in or whether that drug is out. In my world, pembrolizumab (Keytruda) was originally approved for gastric/GE junction cancers. Now that's been withdrawn, depending on what your PD-L1 status is, etc. And then also a really interesting one that maybe, you know, you younger people don't even know the arc of, but gemtuzumab ozogamicin (Mylotarg), was originally approved in 2000, withdrawn in 2011, but then back on the market in 2017. So, you get my idea of what really is out there, what really is FDA approved, and these accelerated approvals give us access to medicines, importantly, but then sometimes they are pulled back. 

Now, just in June. There were a bunch of approvals. There are six new approvals. I want to read you a couple of them because they're pretty pedantic, if you will. One of them is a drug called blinatumomab (Blincyto). You've probably heard of that one. But the approval is for adult and pediatric patients one month and older, CD19 positive, Philadelphia chromosome negative, B cell precursor, ALL. How about this one? repotrectinib (Augtyro)? This is for 12 years and older for patients who have NTRK gene fusions. Now, I've only found one of those in my entire career, but you need to know that there are drugs that that just got added to the list of other drugs that are out there. Another one is a drug called lisocabtagene maraleucel (Breyanzi), I believe it's how you pronounce that. And this one is for adult patients with relapsed and refractory mantle cell lymphoma, who have received at least 2 prior lines of systemic therapy, including a BTKi drug. 

So, you have got to really know what's going on. If you're a general oncologist, how would you know what's going on? So, you're dependent on looking stuff up. You're dependent on our education resources and other online resources to keep up. 

So how about this one? This is real or not real? This is a paper that a search found and it's for entrectinib (Rozlytrek), you remember I talked about repotrectinib, this is for entrectinib, for NTRK fusion positive solid tumors after a larotrectinib (Vitrakvi) or repotrectinib, so as third line, if you will, for entrectinib. Now, this paper is from the Journal of Clinical Oncology, says it was published in 2021. And in fact, one of the authors is one of my partners here at Georgetown, named Mike Atkins, and Rick Pazdur is listed as an author on this paper, Michael Slayman, Jeff Weber, a lot of prominent people are authors on this paper. And you would think if this came up in your inbox that this is real, right? And so, you might even take this paper and send it to the insurance company, to the guy at Aetna, and say, look, I got a JCO paper here that says I got a response rate that's very high in this patient population. It's already an approved drug. Let me give it to my patient in front of me. Except, it's not real. This paper was created. By an AI search engine, and it says it's a JCO paper. It was completely the right format, the right color scheme, the right font, the right references. But what made us all suspicious was the author list. Why would Rick Pazdur, from the FDA, be on a paper such as this? Mike Atkins doesn't do this kind of research, technically. And then we went one further step. And in fact, showed that the page numbers from this JCO paper didn't line up correctly with the journal. And so, this really suggested that we were getting a bum paper. This was a made up what they call hallucinated paper. So, we also have to be careful at that level.

Oncology Update: Maintaining Certification in Today’s World [00:15:03]

All right, so how do you keep up? And I want to kind of shift gears a little bit to our maintenance of certification, or MOC. Now, I'm in internal medicine. It's originally boarded in medicine, then oncology, and I've only maintained my oncology after a while, my 4th go-around, and this 4th go-around, because I do it every 10 years, this go-around, I decided not to sit for the exam and to take the maintenance of certification, questions. Those of you who are doing this out there know what this is all about. But maybe most some of you do. Some of you don't. So, every quarter I get 30 questions in a portal. And these questions are heme/onc questions, onc questions, med onc questions. And the way I do it is that I put 2 hours on my calendar each quarter. 1 hour I do 15 questions. Next hour. I do another 15 questions just so I make sure and get it done. But you also know that when you go on to this, you have 4 minutes to answer the question. And there's a clock running up in the corner there. And you can use any online resource that you want, but you can't talk to somebody. So, when I originally started this, I thought, Division Chief, we've got a big fellowship program here, maybe I should do this in front of the fellows. And they're like, nope, you can't do that because this has to be just you and whatever internet resources you have. So, they're giving us the internet. to do this. So, what I do is I have two screens. I put the question over here, my little clock running over there, and open here, I've got, what do I have open? I have NCCN Guidelines, and I have UpToDate open on my computer screen, and I read the question. It's always a leukemia question or one more breast question and the like, and I don't know a lot about that, so I really need to understand what my answers are. So, I look it up, and I'm doing pretty well. Every 30 questions, I might miss three or four. But that's with all of these resources, and I get nervous about the clock running down, and I am pressed for time. And so, in the end, I just hit one and say, I hope I'm right. And most of the time so far, I'm right. Except the GI questions. I'm getting killed on the GI questions because I really know the medical literature in GI cancers. And one of them recently was a case where a patient had liver mets that was resected, had not had adjuvant therapy a couple years before, and there's no literature on what to do with that patient. None at all. And so, I put, you know, you observe the patient, which is to me, what would be a standard of care. If you had an isolated liver met, it was removed, you don't know what to do. But then I missed the question. Missed it because it said I should give chemotherapy. There's no data for this. In fact, the data does suggest maybe progression free, but no overall survival benefit, no true adjuvant effect. So, I go on to their reference, which was the NCCN guidelines and down in the small print, some branch point way down here. It basically said, look, if you've never given adjuvant, consider giving adjuvant. That was the correct answer by the ABIM version of the process, which, in my opinion, is a very controversial answer. And, yeah, I could see the argument for, but there's no literature to support that. And so, you know, this is why I'm kind of frustrated. Now I'm getting nervous every time there's a GI question that comes up because, you know, do I know too much? Do I not know enough? What's going on here? Why am I missing the GI question?

So, it is clear that we can't know everything anymore. There's too much coming at us. There's too many funky words. There's too many subtleties to genetics and the drugs, etc. So, we need to get better. I need to get better at online access. I need to have trusted sources. Sure, UpToDate and NCCN are very good sources. I don't hear anything different than that, but we also need to have that sort of inside baseball knowledge about what the right way to do it is. What's the right way to dose things? This sort of thing. Right? So, we need good, over our shoulder help that the Internet can provide to make sure that we're providing state of the art care for the patient in front of us with all of its complexities and all of this changing that's going on so that we're dependent on it just as much as everybody else is. So, we need to get better at it. 

And so, with this, I just challenge all of us to think a second time when you're going on a search, and you find a paper that supports what you want to do for a patient. Do some cross referencing. Think a second. Was it created? Real? Is it on guidelines? Is it cross referenced with other sources before you then go forward? If it's a therapy you've never given before, try and find somebody who has, and talk to them about what is the right dose, what is the right way to monitor for side effects, et cetera. Because those kinds of subtleties are awfully hard to get off of the internet and find, phone a friend and figure it out. Because I think with that, we'll all be better doctors and using this great tool, this great knowledge base that's in front of us, using it wiser for the patient.

So, to really try and dig down deeper on this issue of the ABIM and MOCs, there's a lot of confusion about that. We are lucky enough to have a guest visit us for a brief interview. From the inside, one of the leaders at the ABIM 

MOC Ins and Outs: Interview with ABIM Chair Suresh Nair, MD [00:20:53]

So as promised, I have a world's expert on how we get board certified in oncology, and we're lucky enough that Dr. Suresh Nair has agreed to spend a little bit of time with us. Now, if you don't know who he is, you should. He's an important guy. He was the physician in chief at the Lehigh Valley Health Network and Pennsylvania, just north of where I'm sitting. When I look through his resume, the guy likes Pennsylvania for sure. He's been from the east side to the west side with all of his training, and he's trained in some of the best places in the world, and he has dedicated himself to building just an incredible practice there. Part of his busy life as well has been to be involved in the ABIM. The process and certifying us all for our licensure. He's an oncologist, and in 2022, if my numbers are right, he actually took on the leadership role in the ABIM structure over medical oncology and having somebody like that to give us a few minutes is really special.

So, Suresh, let me first say thank you and welcome. 

Suresh G. Nair, MD: John, I feel honored. Thank you so much. And to be, as I said, being with a legendary oncologist who I respect highly. Thank you. 

John Marshall, MD: Well, I get in trouble a lot, as you know, so hopefully we'll keep each other out of trouble on this one. Because for the first time, this was number 4 for me on going around on, on a, on a getting recertified and I thought I had been doing it right. But it was December 15th of 2023 that I realized that I wasn't doing it right. My CMEs weren't MOCs, for example. And so, I had to very quickly figure out how I was going to do everything by the deadline so that I maintain my board certification. So, I had a panic moment here as a senior doc.

I wanted to talk a little bit about my choice, for example, to take the test. Sitting down formally number two pencils, no longer, versus the orderly tests as a way to maintain and just to get your high level that those of us in oncology are doing this. Who's doing what? Everybody, or is it a gemish all over the place? 

Suresh G. Nair, MD: I've been on the ABIM med onc board for the last five years, and as you said, the last two years as the chair. So, I was there as the board responded to diplomats that sometimes the 10-year exam took time out of practice to go to courses, and it was very stressful. And especially I feel like in oncology where things are changing, you know, by the week, by the day for some of the questions. I know you probably had the same experience, the areas that I spent a lot of time in like melanoma, kidney, I was getting some of the questions wrong because the test questions were written five years ago. And they have to go through verification and standardization and all of that. So, the longitudinal knowledge assessment (LKA) was launched. We have about 14,000 board certified oncologists, 85 percent of them are engaged in the LKA, once they become eligible for it, and about 15 percent are choosing to do the 10-year. I also did the 10-year exam about two years ago. I've decided to do the 10-year in oncology and I'm doing the LKA in hematology and in internal medicine. I don't practice much hematology anymore, but I was originally boarded in that at the University of Pittsburgh, and I thought I would try it out, and it's been a bit humbling, but I'm gradually—I have a barely passing score and continue to improve in that. We are finding that, we're continuing to listen to the diplomats and we're looking at making some changes because, I too, the week of Christmas and the new year was reading a lot of up to date to get my MOC credits because I too had a deficit and, you know, I didn't have the hundred that was needed and So at the board level, we're looking at giving—there is credit for the LKA. You do get MOC credits for that, which I think more and more a lot of diplomats are going to, but we're working with ASCO, working with thought leaders in all facets of CME and maintenance of certification credits. 

John Marshall, MD: Yeah, no, I think that's really great. And it's, it's, you're having to live it yourself. You know what it feels like when all of us are out there, because you and I are pretty specialized. A lot of generalists might do better on some things, but still need the props you know, resources and source things to help with the questions. When I first started, I did really badly on the first 30.

I have to share with you that the four minutes was stressful to me. I kept watching. I wasn't. very good actually at looking things up. And as I've done this now for a year or more, I actually realized that I've gotten better at looking things up. Now what I'm not sure of is, is that making me a better doctor or not? I mean, I can find the answer what's being asked, but I don't necessarily have any familiarity with What I'm talking about so I can match the words up to get the right answer But how much feedback have you had in that way that people because I do feel smarter I actually used to dread the time when I was doing The questions to now sort of looking forward to it because I do leave knowing more than I did before. What's been the feedback so far to you at your end?

Suresh G. Nair, MD: The feedback's been very similar to you John in that the four minutes is stressful. There is a time bank that you can click on for extra time for certain questions. I, I too, on, on the hematology, which I don't practice as much and I'm doing it for pure learning I didn't do that well in the first two, and now I've been engaged in about two years and keep getting better.

One of the things it's made me do is areas that I feel weak, and I do when I have some time read up on that area a little bit. And I'm noticing my scores going up and getting expertise. We are, you know, kind of wrestling with certification versus education. So, it's not a pure education tool. When we go to ASCO and we sit at the education sessions, that's a pure education tool. This is also a summative assessment, and there's a lot of science at ABIM. I've been very impressed with the test gurus there. There's a lot of science that basically about 96 percent of us end up being certified, but it is stressful to some degree. But I think all of us believe in lifelong learning. And there is, there is some science that when, when the test has some stakes. We actually learn at a higher pace.

John Marshall, MD: No question. My juices go up on when I'm doing those questions. No, no, I totally they do. And, and I believe I take away things that I wouldn't normally have ever learned if I hadn't come across the question.

Let me come back to the, you know, you miss questions, I miss questions, but in our own field, right? So, I'm getting the leukemia questions right, but I missed, there was a question the other day, where it was a resection of a colon met in the liver, and the question was, do you give chemo afterwards? Well, I happen to know there is zero literature to tell you what to do one way or the other. And when I got the answer wrong because I said to observe the patient and done in the subtext was the reference was NCCN guidelines. So, I went to the NCCN guidelines and saw that said, well, consider this. And so of course, you know, you know too much, right? And so, it's a frustrating moment. How do I miss that question? When I know the literature there and you and I talked a little bit before about How does the ABIM keep up to date? Where are the sources of the questions and that sort of thing? 

Suresh G. Nair, MD: So, so we have a test writing committee and a test approval committee, and our board has given feedback for instance in the LKA, okay, there's 30 questions. There's usually at least one or two that the standard of care has changed, even if the question was written, you know, two years ago. I think a clear case would be in melanoma at the plenary, the neoadjuvant change from pembro to, you know, ipi/nivo now the two doses and our, our, we have a, you know, there, there's been test questions that, that If you do what we heard at ASCO, what's in the New England Journal, you probably could get it wrong. So, so one of the, one of the suggestions at our last board meeting was to have a group of experts. Literally, the, the, the week of go live of LKA go through with it with the fine-tooth comb, because it is very frustrating to diplomats. 

John Marshall, MD: But I was thinking to us in my head was like, could you put the date up there? Because I remember we were talking about. You know, if I go on a Google search for something, and if I find an answer I like, but it's an older answer, it might not still be correct, but it's what I was looking for. And so, I don't keep looking. I'm done. I validated what I thought I knew, and then I move on. And, and so, as you say, we're, this is assessing a moving target. So, there is a time, but I think your strategy is perfect. It's just making sure that folks, Have a good look.

That still wouldn't have solved my problem. 

Suresh G. Nair, MD: No, and we acknowledge that there's just some bad questions. That that question you were you were right, you know, based on the literature based on studies. And NCCN sometimes it's just more opinion rather than studies. And so, unfortunately, there are on the board, you know, so they are looking continuing to look for more test writers. We are starting to get a good number of applicants. And then what one other important direction that the board is going and based on listening to the ASCO survey of the diplomats is to tailor the exam so that 70 percent of the exam will be general content, 30%. We can't hit every narrow specialty, but the major specialties that we have that physicians in the future could say, I specialize in GI, or I specialize in lung, and so, so it can be more tailored to them. Because this is a summative assessment and the science has to be intact, right now we're working on what's called practice profiles and kind of focused assessment and we'll be having the fall meeting where our committee will present a lot of stuff to us.

We have Furman McDonald is the new CEO and president of ABIM. You know, had a distinguished career at Mayo Clinic was at Penn and really is, is a strong listener and I heard his vision at the ABIM Council last week. There was always this feeling the board was a bit tone-deaf to the diplomats and I, I see that changing. I'm a practicing community oncologist who has been lucky enough to have partnerships and stay involved in NCI trials. I'm supposed to be 40 percent clinical, but I ended up being 80 percent clinical in my 40 percent time. So, so I hope I bring the practicing physician perspective to the board. The board has been receptive and sometimes it does seem like it’s turning a plane around. Because they have to keep the science and the validity that the board certification means, you know, that that it means something to the public. One of the things we want to do is to celebrate maintenance of certification but continue to evolve. 

And one of the areas we're grappling with now is the, you know, quick adoption of AI. Now Siri soon going to have AI on our phones you know, pretty much any, any Google search, you know, there's an AI running in the background. We know we can't run away from societal innovation. So, we just need to continue to see, you know, what's the most important thing to try to test. And more and more we're actually finding, it goes back to John, how you started, I think trust and being able to trust your physician because patients are going to be confused, there's going to be misinformation, there's going to be a lot of things. So how do, how do we test for, you know you know, trust and, and, and the things that makes a human physician different from a, from a robot. 

John Marshall, MD: Totally right. I'll be quick, but the AI thing you mentioned, there was some complicated gene in one of the questions and I, instead of typing it, I tried to swipe and copy it and this alarm went off and it basically says, if you do that one more time, we're going to do something bad to you. So, I haven't done it again. Okay. But anyway, you have put some checks and balances on the ability to just cut and paste that question over and put it in AI and see what the answer is. But listen, I know you've had a busy day already. And you're giving us extra time on short notice to talk about a really important question about how do we keep up to speed and you are the sort of overseer of truth in many ways. And, like you. I am proud of my certification, and I am proud to be part of that club. We were all worked very hard to get the 1st one, and so we should continue to maintain that. And I think it's great to hear how both receptive you are, but at the same time, holding our feet to the fire to make sure that we're providing the public with a trusted human on the other side who knows what they're talking about and knows when they don't know what they're talking about. Maybe more importantly and knows how to figure it out for the patient in front of us. 

So, Suresh, thank you so much for this. And good luck as you continue in your leadership role.

Suresh G. Nair, MD: John, I really appreciate it thank you so much. All right. Thank you. 

John Marshall, MD: Thank you all for joining us for episode three of Oncology Update, where we focused on the whole concept of how do we stay up to date. I'll see you in a couple of weeks for episode four. 

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ASCO Buzz

[00:00:13]

We're just back from ASCO, so you know how everybody's doing. You're still trying to pile out of your emails and figure out if you're actually going to get reimbursed for that dinner or not try for it. You never know. It might work out. 

Let's start and kind of reflect a bit on this meeting, that is ASCO. You know, is it really a medical meeting, or is it really a celebration? Let's think about this. You walk into that place, there's signs everywhere. You get out at O'Hare Airport, there's signs everywhere. They're welcoming you to ASCO. You get a bunch of cancer centers marketing their cancer centers that aren't in Chicago, in the Chicago airport. And then you get to the meeting itself, it's like a celebration. You go in to where the booths are now. This makes it look like we have won, that we have cured cancer! The lights are going off, everything is all shiny and sparkly, the carpets are extra cushiony when you get onto one of the drug company booths.

I asked people while we were there which booth was by far the over-the-top booth and there is a clear winner here. We're going to give it to AstraZeneca. Amazing booth. Also, the most likely to cause a seizure was this booth, the lights and everything going on; most likely to cause a seizure for sure.

But there was also a really fun booth. I'm not going to name the company where it came from, but they had the most funky lights. There were these huge tubes that were bigger than a human. And all the lights were hanging from the ceiling from these huge tubes. All I could think about as I was walking by is that, somehow, those things must be really for erectile dysfunction, right? I mean, that's kind of what it looked like—it solved that problem. I went to the booth, turned out, no, they were just decorative. Not any erectile dysfunction problem at all. But, you know, go figure. It's what it seemed like to me.

It was clearly a super spreader event. We pretty much figured out that the best COVID comes from Western Europe, the sort of romance language part of Europe. The Germanic language part not so good, their COVID is more serious, the romance language COVID is the best. 

There weren't many community oncologists there because they had to make a decision to go there, lose RVUs to gain CME. And that trade off just wasn't there for them. If you remember from the first episode, when we really drilled down on the RVU and its value, it's going to be a disincentive for somebody to go to a medical meeting like this to try and learn the state of the art of cancer care. So, clearly that's not who was at this meeting. 

Probably the wildest thing I heard somebody say was that when I was asking about the booth, and a typical booth, even a small, modest booth might cost half a million dollars, is that they came back and said, ‘you know what, this is a good use of our money.’ Wait a second, half a million dollars, that could fund a phase 2, small phase 2, clinical trial for goodness sake. So, you know, is that the best use of your money is to have this big booth, and then the other part is who's paying for those booths? That's our health care dollar at work, whether it's the National Cancer Institute's booth, which is our tax dollars at work, or the pharmaceutical industry and all the money that they have because of the health care industry. So, that's our money they're spending in there on these celebratory booths that we need to kind of come back and think about why is that the right way to go.

Our theme today is going to be all about costs and expense, and why is it so expensive? Why is cancer care so expensive? And we're going to really drill down on a few main areas around that, the cost of drugs and the cost of clinical research.

ASCO Wins

[00:04:17] Let's start with looking at the success, amazing success, of the clinical research that was presented at ASCO. There were three standing ovations among the five plenary abstracts that were presented, and the one that probably deserved it was a drug called osimertinib. You know, this is for EGFR-targeted non-small cell lung cancer. And the benefit was dramatic. A huge delta between the curves. And all of a sudden, everybody said, this is the way to go. I think probably yeah, there's a terrible disease. It's a therapy that works very, very well. Huge improvement in outcome for patients in the curative setting. All in, right? We're all in in that group. Worth standing up and clapping for. 

But, did you know that the rumor is, a little gossip, that, uh, that the other two standing ovations also, drug therapy studies were actually started by plants from the companies who wanted everybody to stand up for their therapies as well. I hope that's not true. I really hope that's not true, but it might be. You never know. Could be true that they're trying to get more standing ovations to applaud this victory that everyone is claiming that we have in cancer. 

[00:05:40] I can't resist telling you about one other study was done in colon cancer. My baby. A study that could only be done, where they have the best COVID, in France. This was a study led by a brilliant surgeon who has set so many standards for us all around the world, a guy named Rene Adam. And believe it or not, liver only metastatic colon cancer, half the patients got standard chemotherapy, The other half got a liver transplant. Do you think you could ever do that study here in the United States? No way. There is no way you could ever do that study here. What patient would allow you to randomize them to a transplant over there or continued chemotherapy over there? If you were eligible, I want that transplant, baby. I'm American, I can have whatever I want. They pulled it off over in Paris, and what they were able to show is again a dramatic difference for the transplant. Something like 70% versus 15%, a huge delta between the two groups. And even though it was a small study, it was very well done, very well, conceived and followed correctly. So, setting a new standard for in the right patient liver transplantation for metastatic colorectal cancer. 

Clinical Research Reality Check

[00:06:55] This has made me reflect a bit about clinical research in general. What is the value of clinical research? Well, one of our lines has always been that if you're on a clinical trial, you live longer; that somehow patients who participate in clinical research live longer.

There was a recent paper that was in JAMA that actually did this. They took a bunch of studies, and they pulled it apart and they actually did show that there was some benefit to being on a clinical trial. So, you're okay in saying that, but then the authors went a little bit deeper and actually compared it to what if you were on standard therapy, and, if they pulled out those clinical trials where the control arm or whatnot was a standard therapy that was in place right now, there wasn't any survival advantage. So, it was only when you compared it against other kinds of approaches that people showed that survival advantage. So, it was a little bit of a mixed message of, yeah, there's a survival, but maybe not so much as we thought before. That was a little bit of water on our flame. 

[00:08:03] And then a second approach that was, was presented in Cancer Medicine actually looked at how we've done not a very good job of increasing accrual to clinical trials. There are all sorts of strategies and studies and education and all of this that we've done to try and increase awareness of clinical trials; increase participation in clinical trials. And, yet we really haven't made too much out of that. 

So, on the backdrop of all of that, we’ve still got a lot of work to do. I don't think we have a victory just yet. 

Drug Price Negotiations

[00:08:41] Let's get back to this value question. You may not know that there's a law in the United States that says, I can't judge value. I can't put together the cost of something and the magnitude of benefit. We're the only country in the world that has this law. And so, to begin to undo that law. A year ago, the folks from the government said, we're going to put out 10 drugs. We're going to give you a list of 10 drugs that we would like to negotiate price on. And we want to start this discussion. Well, lots of people said, this is never going to go. It wasn't just cancer drugs, but some of them are cancer drugs. People said, this is never going to happen. We're not going to have that discussion. It's just going to go away. There's too much going on that’s good with the way the current system works. So, we're not going to mess with that. 

The reason this has come back to mind is that it didn't go away. Just about a month ago here near me, in Maryland, the state legislature had a meeting. They put together a committee and had a meeting. And in this case, they picked eight of those ten drugs, and they began to talk about how are we going to think about this. Now, I worry a little bit because who's on this committee? Who's making this decision? Well, we do have people from the pharmaceutical industry, we have insurers on that, we have medical communities, and unions, and patient representatives, etc. So, you know, probably pretty good representation to discuss the impact of should we or shouldn't we. And you must remember that Maryland is quite, I don't know if you want to call it progressive, but it's out there with regard to government healthcare, has completely different laws around Medicare than any other state in the country. They might just take this on and think about it in more detail.

You know who I really find missing in all of this discussion is the payer. So where is Medicare on a huge pot of money over there? Where are the Blue Crosses and Blue Shields in all of this discussion? Because the way I think about it, we are each paying into those banks, whether it's Medicare or your own health insurance company. Each month coming out of your paycheck, taxes going into those banks, and you haven't gotten a raise in a while because companies are putting in more and more on our behalf. So, the bank's getting filled up, and then they guard it. The insurance companies guard the bank, but distribute it to people as they need it. And that's the model of insurance, of course. We hate our insurance companies because they're always fighting. We don't like the way they guard that bank. We want them to let everything out of there if they can. But on the flip side, we don't want our individual costs to rise. So, we kind of talk out of both sides of our mouths. 

I've been thinking like a crazy idea. Go with me on this. What if you just got diagnosed with, I don't know, say metastatic colon cancer? And your insurance company calls and says, sorry, you've got metastatic colon cancer. We'll offer you today half a million dollars, five hundred thousand dollars cash, to not take treatment. Would you take the money? Who out there would take the money? I see you. Who out there would not? Turn it down and take treatment? Because in fact, we're about to spend more than half a million dollars on you. And so, I never understood why insurance companies don't offer you a buyout to get out of all of this and just pay some cash and go, but that's never going to happen. We know that. 

So, we are in fact having the discussion. We probably will over time begin to whittle away at this concept of negotiating drug prices so that that component of our over-expensive health care system can at least fall into line. That yes might make for less fancy booths at ASCO. We're going to have to realize that you won't be able to get quite as good a cappuccino at that favorite drug company booth that you got when you were in Chicago this past weekend. But I think we'd be willing to make the trade for, some sort of better pricing, better access to drugs, in our country and around the world. 

I want to shift gears to a really, I think, even bigger problem than the expense of new drugs. Because one of the arguments that the companies make is that clinical research has gotten really, really expensive.

And there's a law that you might know about sort of a theoretical law called Moore's law, that I think, came around building computer chips, that with every year, with every five years, it not only got cheaper to build the chips, the chips got dramatically better. They could hold more data, they were faster, etc. So, that Moore's Law of it gets cheaper and faster, is how much most things work in the development world. Well, in drug development, jokingly, they call it Eroom's Law, it's Moore's Law backwards. And essentially this says that with each passing year, it is getting more expensive and less efficient to do clinical research. And this has been going on, as an old guy, this has been going on for gosh, 10, 20 years.

We thought we'd do is deep dive into this subject, and we have invited maybe one of the brightest people on the planet with regard to clinical research. And not only smart about it, but is determined to do something about it. We will meet Dr. Laura Esserman right now.

Smarter Clinical Research: Interview with Dr. Laura Esserman

[14:40] As I just promised you, I have found maybe. the smartest person on the planet about how clinical research has to evolve in order to actually cure cancer. Because remember, that's what we're here to do. And Dr. Laura Esserman is a professor of surgery at the beautiful UCSF out in San Francisco. And for the last while she has built this incredible program around breast cancer research, and now other cancers are starting to follow suit. And she's nice enough to take a bit of a break out of her own clinic day to come and join us and talk about this. 

Dr. Esserman ,Laura, thank you first for joining, but right away, what the heck happened to clinical research? What happened over the evolution of the last 10, 20 years that's got us in this bad state? 

Laura Esserman, MD, MBA: In an effort to try and make it more consistent, I think we took a wrong turn. I have two words to sum it up, misplaced precision. We have two systems, one for clinical research and one for clinical medicine. They're both terrible, and, what we need to do is improve both with one better approach. People say clinical data isn't good enough for research. Really? So, it's really only good enough for patient care?

What is that? Right? You know, who would accept that? There are a certain set of facts that you would not forego if you're taking care of a patient with colon cancer. Same way for me with breast cancer. The surgeons want a little bit more detail on this, and the medical oncologists want a little more detail on this, the radiation oncologists might want something else, but all of us know what it is that we need to collect. We need to get to the business of collecting the right data once. And just having a commitment to high-fidelity, high-quality data as we go. And then you've got all the data you need for clinical research. Now we've got these CROs who are coming in and combing through the data, and they make money every time you find a discrepancy. So, our incentives are completely misaligned to make things better. And everything's gotten so bureaucratic that no one wants to do any of this stuff. This is crazy. 

John Marshall, MD: I kept thinking that we become highly paid data entry specialists, right? And even then we don't do it correctly, as you say, and they in the CRO thing. I remember the day when a clinical trial might be $2500, $5000 a patient and you could abstract out from the data, and cooperative groups accepted this, the FDA accepted this, this was good enough. And then this CRO thing came in, and what is it, one-third of the total budget of most trials is this data discipline over top of us that's paid, as you say, to find us making mistakes. If we don't make any mistakes, then they don't have a job. 

Laura Esserman, MD, MBA: That model, I think needs to go, I've dispensed with it. And you don't need it. And the thing is, there's already data you can extract. We've developed these tools called OneSource. You can pull the data out. I mean, why, why are we having data coordinators extract lab values from one electronic system to another?

One of the things that isn’t going to break the bank is the patient reported outcomes because the patient's only going to report them once. And we only need them once, and, again, the patient should report what they know best. You don't need the clinician or the study coordinator to report what the patient's going to know. They know if they are having aches and pains. And then, the clinicians should focus on grade three and grade four adverse events, adverse events of special interest, and immune related events. And anything that causes a dose delay, reduction, or discontinuation, and that is it. Are we collecting adverse events so we can report them to the FDA? Okay? Are we collecting information so we can get them to the clinician to manage, improve and minimize toxicity? Again, a complete lack of focus on what matters, what's important to patients. 

Imagine if you had a trial where you were constantly learning and evolving and figuring out the best sequence of therapies, trying to learn and manage and optimize the management of toxicities as they arrive. Everyone would want to participate in such a trial. And that's what I-SPY is. That's what we've done.

John Marshall, MD: you brought it up, the I-SPY, and I have watched you. I was your IRB reviewer here at Georgetown for many years, so I know it well. and as you know, I'm really interested in it for us in the GI cancer space. I think it is a great model for us all to follow. Getting back that control over decision-making, simplifying, expediting; all the things you talk about. So maybe, those of us who know, know, but there are a lot of us who don't know about your solutions for this, and so maybe some highlights of that for our audience. 

Laura Esserman, MD, MBA: Let me just sort of give you a quick summary. And again, I think there's plenty of complexity in the trial, but it's focused on clinical decision-making, not on, you know, the nitty gritty detail of every last event.

All disease is heterogeneous. And all of us really know that, and we'll say, oh, well, it's a heterogeneous disease, but then we go ahead and treat everybody the same. That makes no sense. And then people are like, oh, well, you can't do subset analysis. I'm like, okay, fine. So let's start. We started, actually, I started in the cooperative groups, and I left the cooperative groups because they weren't moving at a pace that I felt was appropriate. I mean, the cost of drugs and the cost of development is astronomic because we've allowed it to be so.

John Marshall, MD: And time is a factor in that 

Laura Esserman, MD, MBA: Time is a factor, and If you think about it, the person sitting across the table from you does not have 10 years for you to get your act together. So, what we started with first was, let's take the fast-growing, molecularly high risk, stage two, three breast cancers, where we showed in I-SPY 1 in the cooperative groups that, you know, if you could actually start with the therapy first, and you could make that tumor go away, you've got your intact biomarker. By the time you operate, you're getting in the course of care. The important information that tells you what to do next. So, if the tumor's gone away, that is strongly associated with event free survival and distant recurrence free survival, which is what kills people, right? So that with a hazard rate of 0.2, that is an amazing early surrogate marker.

So, your goal should be to try and figure out what are the different disease subtypes? How do you start figuring out what the right drugs are for the right patient at the right time and constantly learn and evolve and improve the algorithm so that you can optimize everybody's chance at getting that good outcome. In the first 10 years of the trial, we studied 23 drugs in control and 10 of the arms graduated. And some of them are on the market today or were superseded by other drugs. We had Taxol (paclitaxel) with a novel therapy, plus or minus any one of a number of therapies, followed by ACE, adriamycin, which is a terribly toxic drug, then followed by surgery. The next person coming into the trial would get the benefit of what we learned from that. That's actually not what patients want. They want to know that they're going to be on a trial that is smart, and that will actually give them some agency and some learning.

At the beginning, we couldn't do that because we didn't have the drugs, but now we're running the trial the way I'd envisioned in the first place, which is three blocks of therapy, three shots on goal. Again, everybody starts with the systemic therapy first. I'm a surgeon. I'd love to be here, but you know what? You know, everybody would love to do much less surgery. I can do less if the tumor is gone but if the tumor isn't gone, my surgery isn't going to fix them. So, you've got to figure out the next drug. I think everyone's like, ‘oh my God, you're putting them at risk.’ You're not putting anybody at risk. I think we've learned that. Right. And that's how you found, you know, in colon cancer to some remarkable treatments for immune drugs in the right patients, but you don't bring them to the wrong patients because they have a lot of side effects. So, the idea is you give them the first set of drugs, but you make that a non-standard chemo. It can be, you know, bispecific antibodies. It can be anybody drug conjugates, you know, any number of things. 

John Marshall, MD: What's so crazy about that from most of our traditional thinking is that this is curative. In this neoadjuvant, I mean, think about the old days that it would take 10 years to find an adjuvant therapy because you had to wait forever—you've developed a system where you can change the standard of care within a year or two based on neoadjuvant pathologic complete responses, right?

Laura Esserman, MD, MBA: Right. So, here's the thing, patients care about efficacy and toxicity. 

John Marshall, MD: Exactly. 

Laura Esserman, MD, MBA: Right? Not just efficacy, you know, and I think a lot of clinicians are like, I just don't want to be blamed for making a mistake. You know, 

John Marshall, MD: Regret avoidance, 

Laura Esserman, MD, MBA: You’ve got to come up with a strategy that makes people feel comfortable. So, what we did was we've been using MRI and quantitative imaging, not RESIST criteria, that it's like doing some two dimensional thing when you've got really, you know, rich data.

John Marshall, MD: You created a new endpoint of essentially pathologic complete response that ultimately gets regulatory approval, right? So, you changed the rules on, you know, the old established rules that weren't doing us any good.

Laura Esserman, MD, MBA: Right. As you know, we have to let go of some of the rules stuck in our heads because you can't improve without that. The thing is, we need to not be afraid to do some safe experiments. You know, it's true, you might make a decision that you might find that something's wrong. Okay, just set it up in a way that you've got your safeguards built in, but you're giving everybody the chance for benefit. These new drugs, you don't know if they're going to work, but six weeks, no one's going to die in six weeks. And there's a huge upside if they work in avoiding future therapy. And, if by 12 weeks it really works, you can skip the toxic chemotherapy and go to the OR. Same thing for going on to block B. So, you've got some agency in the middle, and we have good algorithms, and we keep working on making them better. If you want these companies to build these new exciting therapies, you've got to give them a place to test them and to do it much more quickly. You know, the whole Silicon Valley, the whole dot tech tech revolution is about systems-based learning and, you know, rapid learning. You know if it's not going to work, learn fast, fail fast. If it's going to work, great, build on that and move on. 

John Marshall, MD: You've done it, right? Got it. And the way I think about…

Laura Esserman, MD, MBA: People are following it. 

John Marshall, MD: Yeah, we're coming after you.

Laura Esserman, MD, MBA: And now we're working with the FDA on developing a regulatory strategy around it. We haven't finished we haven't gotten there quite yet, but we will. 

John Marshall, MD: It really is Innovation and individualization are the two priorities, that you want to make sure that that patient in front of you, their individual tumor characteristics are recognized and optimized, the therapy for them learned from that through innovation. And you bring those two things together and then you create a new way of practicing medicine and cancer.

Laura Esserman, MD, MBA: So, the basis of this new trial is a smart, sequential, multiple, Assignment randomized trials, 

John Marshall, MD: You certainly sold me as a GI oncologist of how we might partner with your team for similar things you have learned. You've already done it. You're doing it with COVID vaccines as well 

Laura Esserman, MD, MBA: During the COVID trial, you know, the, one of the agencies that was sponsoring us was concerned. I said, look, we do not need to have, every time there's an adverse event, someone doesn't have to fill out an adverse event report because when people are dying of COVID, they have ARDS, they're dying. They have multi system organ failure. I mean, you could be filling these forms in all day. Here's a checklist of 10 things that happens to every patient. Do it the same on every single patient. It'll take you two minutes. That's a much smarter way of going about it. But they were concerned that we were hiding things or not collecting information. And they made us do this full audit. And you know, we spent six and a half million dollars doing this audit. And we didn't find one adverse event. 

John Marshall, MD: You know, you say that that would have bought a kick ass booth at ASCO, six and a half million dollars. That would have been money well spent, is to take that money on your audit and spend it on a fancy booth.

Laura Esserman, MD, MBA: I'm trying, I'm trying to get this published, but, you know, it's going to be very threatening to the industry, but it should. But, to us, it's like we need to take back control of our profession. We need to, like, develop better systems for clinical care that actually help us with research because the goal of clinical medicine, what are we practicing for? We should be practicing to improve, but if you don't know what you're doing, you can't improve it. So that's my story and I'm sticking to it. 

John Marshall, MD: I think we should just leave it right there. Dr. Laura Esserman taking a break out of her clinic from UCSF Department of Surgery there and the leader of the I-SPY program, transformative. Dr. Esserman, thank you for joining us. 

Laura Esserman, MD, MBA: Oh, you're welcome. Thanks for having me. 

John Marshall, MD: I hope everybody enjoyed this episode of Oncology Update. My name is Dr. John Marshall and maybe while you're out there, think a little bit about why is cancer so expensive?

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Shifts & Shocks: Layoffs, Dose Reductions, and Drug Withdrawals

[00:00:27] There’s been a crazy lot of stuff happening. First, I don't know if you saw this, but Bayer laid off a thousand plus people or will do that over this year. And it's going to be at the management level, pretty high level. They say they need to thin down, become more lean and mean. They got a bit top heavy, but this is not the only company doing it. Biogen and Novartis are also in the process of downsizing their sort of corporate offices. So, look out for, I don't know, people looking for jobs as these folks get laid off and need to move on to something else.  

https://www.fiercepharma.com/pharma/bayer-reduced-1500-roles-new-organization-takes-shape   

[00:01:01] Another fascinating thing that's going on is that there's this recognition around dosing of new medicines; that we're using too high of a dose of medicine. That's the ones that were tested. We didn't want to miss any effect, but that means we're giving too much of a dose. New studies are looking to see if we can we use significantly lower doses of a lot of our cancer medicines and still have our best bang from the buck? And so, this is critically important as we become better physicians. So watch out for that research. 

https://www.washingtonpost.com/health/2024/05/04/cancer-chemo-drug-dosage-fda/

[00:01:32] The next, and I don't know if you saw that just this last couple of days, FDA announced that, infigratinib, now this is one of those fusion molecules for FGFR2 that was seeking to get approval at the FDA level. It got initial approval based on early clinical trial data, but you know why they withdrew the request for approval. They couldn't get it because they couldn't get patients to go on the study. And that means we're not doing good molecular profiling and we're not enrolling patients into clinical trials. This is a shame that this has happened. So, we need to be better about this because now we've lost a drug that could have been useful for our patients with FGFR fusions.

https://www.fda.gov/drugs/resources-information-approved-drugs/withdrawn-fda-grants-accelerated-approval-infigratinib-metastatic-cholangiocarcinoma  

Redefining Cancer Center Operations: Strategic Mergers and Leadership Changes 

[00:02:19] On the big medical corporate front, the news that's out there is that Rush, up in Chicago, has become the seventh internal in the U. S. partner with MD Anderson's network. And this is quite a network. You've got Banner Health in Phoenix, you've got Baptist in Jacksonville, you've got Community Health in Indianapolis, in Camden, New Jersey, a site, Ochsner, Down in New Orleans, Rush in Chicago, and, of course, UT San Antonio, and you think about just the size of this. I happened to be down in Houston to do grand rounds. Actually, only four people showed up live for that. Everybody is virtual. Will grand rounds ever be live again? But nonetheless, I was down at MD Anderson, my wife and I giving grand rounds and lo and behold, it is huge. It's shiny. It's beautiful. And now they've got even more size to go after. 

[00:03:13] So why would you do this? Well, of course, from MD Anderson's perspective, this is a great thing for them. This is connections to cancer centers around the country. They can do more studies, for example. They probably get paid for this brand.

[00:03:26] Why would you want to be this? If you were in New Orleans or in Phoenix? Well, you're trying to compete in the marketplace, and the MD Anderson brand carries a lot of weight for people out there as they're seeking cancer care. So, it seems like it's a win win for both of these groups or all of these groups to get together. But it also means we're getting bigger and bigger conglomerations of cancer care providing, and so, you know, there'll be less variability, less innovation is what I worry about in that space. 

https://www.bizjournals.com/houston/news/2024/04/29/md-anderson-cancer-center-rush-university-chicago.html  

[00:03:58] One last point around the business of oncology, if you will, is that for NCI designated comprehensive cancer centers like ours here at Georgetown, it is increasingly really impossible for one individual to run that shop because cancer medicine, particularly at the NCI level, has two, at least, major components.

[00:04:22] One is a research component, and one is the business side of this. And the latest to join this splitting of the leadership is out in Oregon. You know, Brian Drucker has been running that shop for a thousand years, and he's just the greatest cancer center director there ever was. But he basically said, look, I need corporate help to run this, and he brought in Tom Sellers, and they split the head office into these two different sections, and it really speaks to the times that we have. You need that research, mentor leader on one side, the scientists coupled to the business side of things. Moffitt did it. Huntsman did it, and they've now done it. So, a lot of action out there in our business world today. 

https://news.ohsu.edu/2024/03/14/ohsu-knight-cancer-institute-announces-leadership-transition   

ASCO's Pinnacle Presentations: The Path to Plenary Recognition

[00:05:08] Let's shift gears and talk a little bit about what's going on in the research world. Well, it's May 22nd today. And so all of us are getting ready for the big show in Chicago. 45,000 of your closest friends will be assembled in Chicago. There isn't a hotel room to be found, so don't even try.

[00:05:28] And, we'll present a bunch of data. I mean, a lot of what the meeting is about is other meetings to try and move some balls along, if you will. Let's hope it's not a super spreader event. I think hopefully we're done with that kind of thing. But, you know, there's big data that gets presented. And I've been on the review committee for ASCO for many years over in the past, and I was fascinated at how the abstracts get chosen. You know, the disease teams get a dump of 300, 400 abstracts per working group. They review, they prioritize, and up bubbles the top 50, the top 100, the top 25, top 10, the top 10 of the orals that get presented by colon or non-colon or breast or whatever, and then from all of that, the subcommittees nominate an abstract to be in the plenary session. We now have five abstracts in the plenary session. We don't know what they're going to show yet because they haven't released those abstracts yet. They're all called late break abstracts. 

https://meetings.asco.org/2024-asco-annual-meeting/15848?presentation=234899#234899

[00:06:33] So, I took a look, see what we're about to see coming forward at ASCO this year. And of the five, three of them have to do with lung cancer. One small cell clinical trial using IO, one non-small cell using osimertinib. And interestingly, one that's palliative care, whether you should give palliative care remotely or in person, who knows what that's going to show, but it's a positive either way. There is no placebo arm on that. There's nobody not getting palliative care. It's just how it was delivered. How that made it to the plenary session, I don't know. It better be a big impact. 

[00:07:08] There's an immunotherapy study for melanoma, adjuvant. Got to be positive, right, got to be practice changing. 

[00:07:15] And, then the GI one, my world, was actually two not very good treatments. No new fancy drugs compared head-to-head. FLOT, which is a three-drug regimen for upper GI cancers versus the CROSS regimen, which is chemoradiation for esophageal, and this was looking at adeno. And, how this became the top abstract of the year. I don't know, not a new drug, not anything, not even that common of a cancer. But what we're going to see is a head-to-head of two competing standards, where I'm assuming one of these wins. Now, If the FLOT regimen wins, that's one less place where we're giving standard radiation to people. And, we have to recognize that as chemo and other systemic treatments have gotten better, radiation certainly gets less impactful. But if the other way wins, it means that some of our systemic chemos that we're using in gastric and other cancers may not be optimum treatment either. So, I'm interested to see what happens. I don't really see a standing ovation like we've had in previous years around breast cancer ahead of us, but you never know. Maybe the data will be that transformative that we'll get that standing ovation at ASCO. But I hope to see you, many of you, there, and, of course, on our next episode in a couple of weeks, we'll reflect a bit on what data actually did cause the stir, what bubbles up to be the most impactful out there for us.

The RVU Rundown: Interview with Kashyap Patel, MD

[00:08:48] Now, as our final section, I really wanted to talk about something that is near and dear to my world as an administrator. So, I'm director of a division, and I work in a big healthcare system, and the metric that we use nowadays to incentivize, credit physicians, and other providers, is the RVU, relative value unit. I sort of think of it as our cryptocurrency. And how do we really understand how that came about, and how we're going to use it? Should we be using it? Should we be tailoring it in some way? And I don't know enough about this. So what I have done is invite somebody who does.

[00:09:34] I promised you all a world expert in the world of RVUs and there is no one smarter or more experienced about it than Dr. Kashyap Patel. He is the CEO of the Carolina Blood and Cancer Care Associates. He's the chair elect for clinical affairs and the trustee of the Association of Community Cancer Centers, ACCC. Huge organization is the immediate past president of COA. And, more important to me as a coauthor, he has written a brilliant book that I think everybody out there should get called between life and death. It's a beautiful set of stories about his relationship with patients, and all oncology teams should, should read this. Great book club book for that. But that's not why we're here today. We're here for a much more important topic than patient doctor interaction. We're here to talk about money and in specific, the RVU. He and I are both giving up maybe one or two RVUs right now to be here with you guys. 

  https://betweenlifeanddeath.org/

[00:10:31] Dr. Patel, let me first welcome you, but jump right in. You know, what is an RVU? Why was it created? Let's get into the weeds of this a bit. 

[00:10:43] Kashyap Patel, MD: First of all, it's my honor to be Speaking with you, John, I think you're a big personality.

[00:10:48] You have name all over the world. And my first memory goes back to when we meet at the Ballantyne Hotel back in 2002, when you came and spoke on colorectal cancer as an expert. I remember that. So, I'm so honored to be here with you. 

[00:11:01] And coming back to our core point here, the RVU, Relative Value Unit, It's actually one of the methods that CMS has organized to identify a way to compensate physicians, and it looks into the training time. For example, if you're oncologist in primary care, it also looks into something called GPCI, which is geographical practice cost index. It has a lot of inbuilt adjustments within that. And so, it's a way to define the time that a doctor spends, the overhead cost for the practice, and other logistical expenses. And then what would be that cost plus physician time be combined together, and how does the American Medical Association CPT Committee and CMS decide together. And it also applies to not just the patient, it also applies to procedure as well.

[00:11:58] John Marshall, MD: So, would you and I actually get different RVUs? I'm in Washington, you’re in the Carolinas. Would you, would we have differences or we're the same? 

[00:12:07] Kashyap Patel, MD: No, we are different. So, so they, they adjusted with something called GIPC, which is Geographical Practice Costing Index. And they make adjustments based on the cost of living, based on the cost of hiring employees, and the cost of the rent . So, it's adjusted based on where you practice. You may be having highest RVU when you're in New York, and the lowest when you're in Alabama, like South Carolina, because CMS perceives that the cost of running business is low there. 

[00:12:33] John Marshall, MD: And so, but then we've got the differences between like, orthopedic surgeons who are making 10,000 RVUs a year, and we oncologists who average somewhere around, you know, 4,000, 5,000, depending on what kind of practice you have, some more, some less. Is that because we're different busyness or we get different credit for what we do? 

[00:12:55] Kashyap Patel, MD: So, it's very interesting. The RVUs forcing patients is one thing, but if an orthopedic surgeon does a procedure where they do surgical procedure, there's an RVU tied to that as well. Now the big limitation is that going back to like 20 years back, when technology was not so much evolved, we didn't have robotic surgery.

[00:13:15] If you had a procedure that, you know, somebody did surgery and spent four hours, technology evolved, time become very efficient. The same thing could be done in one hour, but RVUs still four times. So that's a discrepancy there itself, that with the evolution of the time and technology, the RVUs lag behind adjustment. That's why you're somebody said this may be getting paid 10,000 hours for the RVU versus us probably 4,000. 

[00:13:43] John Marshall, MD: So, you think that it's a good system? Do you think in general, it's a fair way of giving credit where credit is due? Because I remember the good old days when you got a salary. Right. You just got this much money. You might get bonused if you were really busy or there was some sort of extra way to make money here or there, but this really does credit you for the individual part of your role in the health care system, you know, one patient, one doctor encounter versus your role as a sort of leader and organizer of a practice. Do you think it's a pretty fair way to do things?

[00:14:22] Kashyap Patel, MD: I think at the beginning of the career, it may be pretty fair way to do that, but then people like me and you, we spend a lot of time outside seeing patients. For example, you teach so many students, you do so much research, you publish so many papers, and it doesn't come free.

[00:14:38] I mean, you give up something. time that you can never reproduce. Unfortunately, the CMS as well as AMA committee that looks at RVU has not factored in the length of experience, the type of experience, and the administrative time. So to a certain extent, people who go beyond their call of duty of seeing patients, doing research, bring new technology in particularly into the medicines, elective specialties.

[00:15:08] We may be treated unfairly because the time spent in teaching research or experience is not factored in into the compensation. So it's almost like if you started your career with a fresh MD from the same school at the same hospital, John Marshall will still be within the same money that he started making, but your MBA colleague becomes CEO and he probably will get 50 times more than what you get. 

[00:15:32] John Marshall, MD: Well, we went through this, right? So, we went from this salaried, you know, differed by rank here at the medical center, you know, different rank, you made different money, um, to where everybody essentially got the same pay, whether you were right out of residency, or if you were a 30-year senior physician, and so it normalized that. And there was a lot of initial pushback on that, of course, is that you don't get any credit for your seniority, as you mentioned, your experience. But also, as you get older, you have more duties, and, so, our docs are now pushing back and saying, well, if this is how you're going to pay me, then that committee I'm on or whatever else I need to be doing to keep a practice and a hospital going, you need to credit me for that. And I think that part of our compensation hasn't caught up. Do you think that's right? 

[00:16:24] Kashyap Patel, MD: That's absolutely right. I think they need to factor in the extra clinical duties that you do other being a part of the committee or part of the NCCN coming to write guidelines for part of the ASCO committees. All of this should be factored in within the legitimate kind of time frame to ensure that people who want to give back in a different way are not disincentivized.

[00:16:46] And let me tell you one more thing here, John, that, for example, seeing a patient after 20 years’ experience and make a clinical decision is a lot different than seeing a patient right out of college. So, there's definitely a wisdom to aging and maybe, you know, people like us with gray hair and wrinkles. But I do feel that RVUs should factor in that element, even in the clinical side as well, in addition to the extra clinical duties. 

[00:17:12] John Marshall, MD: Yeah, I think there are a lot of places around the world that do acknowledge that expertise. And, you know, there might be a base healthcare system for everybody and then kind of a premium healthcare system for those with more experience out there.

[00:17:27] And so, again, we don't, right now, we don't, everybody's treated the same, uh, in most of our healthcare systems. And I do think RVUs seem to be the dominant way it is done, although there are still Those that have kind of a more traditional thing, let's look at it from the health care system because I know you're big into that too on that side.

[00:17:48] You understand that part of it. Is it fair from the health care system? There's some people come to me and say they're making money on us. Because what they're paying us, they're making more money in revenue than what we're doing. So in fact, we're not being credited for that back in the day when people owned their practices, they could pay themselves what their practice could make.

[00:18:11] And so do you think that's fair under an RVU model? 

[00:18:16] Kashyap Patel, MD: No, I think you're right. Because once again, I think, you know, the RVU probably ends up in people work hard to earn some bonuses based on RVU, but then RVU produces more and more revenue for the health systems, which unfortunately ends up going into the administrative costs without having a lot of other kind of rewards to the person who does it. So, I feel that it's important to have a base as an RVU, but then they should, they should evolve. From my perspective, RVU space has failed to evolve to keep up with the changes of the time. And if you don't change with time, you may become like a dinosaur. 

[00:18:57] John Marshall, MD: Last sort of point about this that I want to bring out and then whatever you want to share is that, you know, when you're driven by these RVUs, you don't take a Friday afternoon off anymore to go to a meeting or to go to a CME event or, um, or frankly go play nine holes of golf and clear your head because you're driven to see more patients.

[00:19:20] And so I worry a lot about our sort of mental health, both emotional, social health, but also our education and keeping up because we're so driven by these RVUs. Are you feeling that happening? 

[00:19:35] Kashyap Patel, MD: I do feel because, you know, we experience compassion fatigue when you deal with the patient over and over again. And if you don't have time to take a break, to attend a meeting, shake hands with people who know something may be better than what I know, or maybe, you know, take some time off to unwind. It's only going to make mental health crisis worse. I think we are in the perfect storm between the post COVID recovery phase, between the RVU world, and between the push to do more and more and more without getting time. I think we are entering into a whole different era of healthcare delivery systems.

[00:20:10] John Marshall, MD: I can't thank you enough for joining me today. I hope everybody listening appreciates it. I think it's you and me and people like us that need to keep this conversation going so that we allow this system to evolve to take care of some of the issues that you and I brought together. So, thanks very much for joining. 

[00:20:29] Kashyap Patel, MD: Thank you very much, my friend. I look forward to learning more from you, my brother.

[00:20:33] John Marshall, MD: And both of us back to clinic so we can stay down for the long haul. 

[00:20:36] Kashyap Patel, MD: Get some RVUs. 

[00:20:38] John Marshall, MD: So that's a wrap. Oncology update, John Marshall, May 22, 2024, a week ahead of ASCO. I hope this has been useful and I hope these insights and our world of oncology will make us all better so one day we indeed will find the cure for all cancers.

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John Marshall, MD:

Hey, everybody, John Marshall back for oncology unscripted. If you've been silly enough to further away your time with me, we're now on the 7th episode, believe it or not. Goodness gracious, the sponsors of this are crazy to let me keep going. 

But we do have some really cool stuff to talk about today, and I hope you'll listen in as I review not only sort of what's going on in our world, a little bit of gossip, a little bit of business, we're going to talk about the latest science, but as you remember, this is the third in three parts about the middle men, the middle people in oncology. And so, we've done pharmacy benefit managers. We've done the EMR. Now, the next one is Clinical Research Organization, CROs. So, stick around for some discussion about the impact of CROs on us, on clinical research, and maybe, are they helpful or not? You'll have to decide after you listen in. 

[00:01:11]

Vermont Sues PBMs

But let's start with a little bit of gossip. So, if you remember, we talked about PBMs before, and just so happened that the state of Vermont, their attorney general has sued the pharmacy benefit managers for illegally driving up drug costs. You thought that was just me saying that? No, the Attorney General of Vermont also thinks that. 

[00:01:29]

ACS CEO Steps Down

Sort of on a business note too, Karen Knutson, who's a really very prominent member of our cancer community, was or still is briefly the CEO for the American Cancer Society and the American Cancer Society Action Network. She has decided to step down, she's going to do a lot more work in that space. So, we will be seeing a new ACS leader. I always want to think about the ACS. It is the largest private nonprofit funder of cancer research in the United States. And, so, we do want to make sure and hold them accountable for their product beyond their journals and the like and what comes out of their science, but I think they've had a great impact over time. So, congratulations to Karen and we look forward to the transitions ahead.

[00:02:16]

NCI Puts Millions into AI Efforts in Breast Cancer

Sort of a crazy thing we came across is that, you know, there's a lot more AI in health care today. But the NCI just dropped 3. 7 million in an effort for AI to predict breast cancer risk and also sort of to try and wrap in health disparities to try and level that up a bit. But there's another one looking at AI outperforming conventional methods for prostate cancer. management. So, we're increasingly seeing AI being used, just like every time you drop something in your Google browser, AI being used to try and help us be better at what we do.

[00:02:59]

Honoring Dr. Jeff Weber

I do want to give us a bit of an update. There's a really important obit that I'm sure you saw a guy named Jeff Weber. Jeff Weber was 72 and he died. He actually. died of pancreas cancer, but we will know him forever as one of those people who's made a major impact in the world of cancer. His work in melanoma, his work in immunotherapy, frankly, his work as a mentor and making sure that for generations to come, we are going to see that kind of high quality clinical translational researcher, educator, the whole bit. We lost a big one when Jeff Weber died of one of my diseases, sadly, pancreatic cancer. I wish he was working on this one, because maybe he would've solved that one. I feel like we let him down, but here's to him and all that he has done and all the lives that he has touched.

[00:03:48]

McKesson Wins Bid for Florida Cancer Specialists

Just one little bit of business news. You may remember a few episodes back, we talked about sort of the interface about the You know, our industry and how groups are buying other groups, etc. Well, I mentioned Florida cancer specialists was being looked at by a bunch of different parties. Well, we now know McKesson, I guess, won the bidding for a low 2. 5 billion. McKesson bought Florida Cancer Specialists. And then if you think about everything from patient care all the way up the business chain is owned and organized by one group. And so, I do think we need to watch this space carefully because are things going to improve? Are they going to get more expensive? Are they going to get more efficient? We really need to see how this kind of structure works, because we know more and more of that is going to happen. In fact, I've heard some people predict that not too long from now, the entire United States might be covered by just 10 different health systems that there'll be mergers and acquisitions up and down the chain. so that will be just about 10 of us nationwide. We'll see if that comes too fast. But there's the 1st pass at it with Florida cancer specialist and McKesson working together. 

[00:05:06]​

John Marshall, MD: 

What Did We Learn From the 2024 ESMO Congress?

So, let's look at a little science at this point. As you may not know, 34,000 of our closest friends gathered in Barcelona. Have you ever been to Barcelona? It's one of the greatest cities on the planet. The food is fabulous. The weather is fabulous. The views are spectacular. So, if you ever have a chance to go there, go to Barcelona. 

Well, 34,000 heme/onc docs descended for the annual ESMO meeting. It moves around, unlike ASCO, which is always Chicago. ESMO moves around this year to Barcelona, and I thought it would be useful just to take a look.

I'm going to show you a few high-level abstracts and make sure you guys have seen these. You probably did. Because both the New England Journal of Medicine and Lancet Oncology had featured publications with the full articles that reviewed some major new science that was out there. So, I encourage you to browse both of those editions because there's a lot of practice changing stuff that went in there. But I thought I would actually feature a couple that maybe didn't make it; were still high value papers, 

[00:06:15]

Enzalutamide + Ra223 in mCRPC with Bone Mets

So, one is a prostate cancer study, and this is where enzalutamide was given either alone or with radium 223. As you know, radium 223 is good for painful bony mets and things like that. So here was the question of what if you put the two together on initial treatment and the punchline was. It worked. So, you got a progression free survival of 19.4 versus 16. So, you got a three-month bump by combining these therapies. And I think the conclusions of the authors are probably accurate to what we will see in guidelines and the like is that this will become certainly a new standard option to patients with hormone refractory, metastatic prostate cancer. 

[00:07:00]

Retifanlimab + Carboplatin-Paclitaxel in Anal SCC

Now, you don't see a lot of stuff around anal cancer, do you? We haven't made much progress in this space in a long time, and we've tried all sorts of different things. Well, we did get one clinical trial, and I'm going to screw the name of this drug up. It's retifanlimab basically another checkpoint inhibitor in combination with platinum and carbo taxol in patients with metastatic or inoperable squamous cell cancer, the anus and has not been treated with prior chemo. So, these are not common. This is a cancer I take care of. So fortunately, we take care of them most of the time, but this study actually demonstrated an improvement in outcome.

[00:7:43] 

Pembrolizumab Plus Chemoradiotherapy for High-Risk Locally Advanced Cervical Cancer

And related to this a little bit further north, I don't know, is pembrolizumab plus chemo radiotherapy in cervical cancer, similar biology, similar risk, chemo radiation treatment, similar this kind of thing. Well, this study did show an improvement, but here the delta, it was not so great. So, if you added the pembro to the chemo radiation, you got 82.5%. Whereas if you just did the chemo radiation, it was 75%. A bump. Most people were cured. The bump was small. Giving everybody pembro for that small bump will be the decision we have to make going forward in cervical cancer patients. Big study, statistically significant. Got to think about the magnitude of the benefit. Is that worth it in these patients? 

[00:08:23]

TACE + Lenvatinib and Pembrolizumab in Intermediate-Stage HCC

Another one back in the GI space, which I thought was important. We're seeing more and more HCC around the world. We know about lenvatinib. We know about IO therapy here. Well, what about if you gave TACE? So, you injected the liver lesions and gave the lenvatinib and some pembro. So, some TKI and IO concomitantly. This was the LEAP 012 clinical trial. And guess what? It was positive. It was positive by 4 months. So, 10 months versus 14 and a half months. So, I expect that we will see that moving very quickly to the front line setting as well when you're doing TACE early on in diagnosis. Current standard would be TACE alone. Now it's going to be TACE with combo therapy. So that's a good study. That's moving the bar forward in HCC. 

[00:09:21]

Neoadjuvant Pembro Plus Chemotherapy and Adjuvant Pembro for High-Risk Early-Stage TNBC

Breast cancer cannot be left out. Triple negative breast cancer. You give Pembro to chemo in patients in the neoadjuvant setting with triple negative breast cancer. Overall survival. Of course it was positive, but here again 82% of patients were cured with the old standard. Adding the pembro to this, bumped it to 86%. So, you got five percentage points more. You gave a hundred women pembro for those five extra points, but it's a bad disease. My wife had it. I'm glad she didn't die; 5 percent may be my wife next time. So, we do understand the importance of adding that to treatment. 

[00:10:04]

Neoadjuvant Durvalumab in Muscle-Invasive Bladder Cancer

And then the last one I want to talk about is again, an IO clinical trial. They featured it as well, plus chemotherapy, and in the adjuvant setting, neoadjuvant setting for bladder cancer. So, do you give it before or only after the treatment? And so, basically, the answer was by giving it before you did have an improved event-free and overall survival. So again, I'm expecting that we're going to see more and more neoadjuvant therapy coming in bladder cancer, clearly a trend and almost every cancer there is out there. 

So, I sadly did not make it to ESMO, but I wanted to bring just a little bite of ESMO to you. I got no beautiful Barcelonan food to offer you, and you know, to make you feel more at home, but I hope you one day will go. And maybe not when ESMO is there, maybe just go with your family and have some fun.

[00:11:03]​

Main Topic - Complexity Overload: CROs and the Rising Cost of Clinical Research

John Marshall, MD:

Let's shift gears now to our middlemen series. And the next area we really want to focus on, as I've mentioned, is clinical research organizations. And I have two outstanding folks that we're going to interview to talk about this sort of from all angles, but I want to just set the stage with a very brief history of what all happened. I've been around since before CROs were really much of a thing. They only came into play in the 1980s. And this was because of the worries that clinical trials were getting to be more common and that we needed to have our data cleaner. The FDA was, in fact, tightening up in some way. The way packages would be submitted to them for approval or not. It wasn't just the trial, yes or no, on a curve. You needed to have all of the data in there together. It needed to be highly qualified data, good quality data. 

You know, I always joke that even the National Cancer Institute, you would think they could handle this. They went out and got a CRO, and they partnered with Theradex. And they have for many years. What the issue here is, is that the sponsor, somebody who wants to do the trial, needs to get access to that patient who fits their trial. And traditionally, they just needed us, the clinician, who did clinical research, to identify and enroll that patient on the clinical trial. But, we apparently didn't do a good enough job of maybe managing the data, is really where we got in trouble. We're good at finding the patient, not good at managing the data, maybe, or at least to the quality that we need. And that's what CRO's who now get inserted into all of this will do. They came in as the savior for all of this problem. They said, don’t worry, sponsor, we'll find you the best sites. We'll make sure their data is the best. We'll train them and we'll make sure your package is great, and we will, by the way, add a whole lot of money to the overall cost of the clinical trial. Some say as high as one third of the per patient costs goes to the CRO to manage this. 

These are for-profit companies. We need to remember this. These trials are going through the roof in terms of numbers of trials, complexity of trials, so that as a result of this too, the number, the value of per patient accrual. So, what it costs to put a patient on study is going through the roof and it's a competitive marketplace.

Back in the day when I was young, you know, you could put a patient on a study for, I don't know, 2,500 bucks a, a head. And that was enough to do all the data analysis. Of course, that was old money. New money, you need to add at least one zero, maybe two zeros per patient. and so, the cost of one patient on a clinical trial has gone through the roof in large part due to this additional administrative oversight. So, we get analyzed. We get trained. We have to hire up all the people. They hire up all the people to cross check one another. That actually, made it incredibly expensive so that, it's actually made it not very much fun.

So, I was the associate director for clinical research here at Georgetown for a long, long time. And I just got to the point where this got to be crazy. Even I as a clinician didn't like it very much. I was signing forms that said I had to sign a form. Just the burden of documentation was so much. Today, I saw 4 patients on clinical trials, and I was noting that with each 1 of those, it cost me about 10 extra minutes of documentation to make sure that I had all the data that was needed for the audit and, our own people to enter the data, et cetera. And remember, back when we were talking about EMRs last week, they're not really built for clinical research, are they? So, we have to hand do and then hand enter a lot of the data from clinical trials into some other EMR for the CRO to give to the sponsor.

So very, very inefficient. So, what do we do? Like everything else? We offshore it. One of the consequences of CROs has been that the U. S. market can't handle this. And so, lots of clinical research is done in parts of the world where they're dying to get on clinical trials, right? We're a rich country. We have access to everything. Lots of places don't. So, if they do trials, they actually get that investment there locally and their patients can have access to newer therapies. So, we enjoy FDA approvals on the backs of studies done in other countries where the price differential is better for those sponsoring and managing the clinical trial. We need to think about that as we move on to the next FDA approval. A lot of the work was done by other patients who probably in the end won't have access to the drug that we will have access to. 

And then the last piece of this is that. You know, the specificness of a patient to enroll into a clinical trial. We already have the precision medicine piece, so they have to have the right gene test, but they also have to have a very good, what we call, performance status. Their labs have to be perfect, so much so that the patients who are on trials don't actually represent the patients that we will end up using the drug on. So, to get these pristine results, we have to test pristine patients, then apply the drug to the less pristine. And so, we have a disconnect there in all of this.

And then the last part of this, of course, is, is the patient interested in participating? some are, yep, we know that, but we are still well below where we need to be as a nation, as a world, in clinical research. Because let's face it, we haven't figured out cancer. We could argue that almost every patient should be on a clinical trial. And yet patients are not really incentivized to participate in clinical trials. And I think actually, there needs to be some change in that space too, but not from my perspective, an old grumpy guy whose kind of a little burned out on the clinical research world. Let's talk to some experts.

[17:23]

Do the Complexities of Clinical Trials Demand CRO Support? 

Interview with Dr. Gwyn Bebb

John Marshall, MD: As we promise for Oncology Unscripted we bring the best voices, the brightest minds on all of our subjects. And so, we are very, very lucky to have Dr. Gwyn Bebb join us today. He's the Senior Vice President and Franchise Head and Global Therapeutic Area Head for Oncology from Parexel International, one of our world's greatest organizations CRO institutions. And he's nice enough to join us early in the morning from the West Coast to talk a bit about CROs today. So, Dr. Bebb, welcome and thank you for joining. 

Let me start right in by. So, you're saying, where are we today with CROs? You know, a little bit about the evolution of that, and maybe even wax poetic a little bit about where we go in the future. I know I've just asked a lot, but. Fire away. Tell us what you're thinking. Okay.

Gwyn Bebb, MD, BM, BCh, PhD: Well, John, first of all, I want to say thank you very much for inviting me to this forum. 

I was just chatting to one of my colleagues recently, and we were commenting on how protocols for clinical trials have evolved from being fairly simple, you know, maybe three or four page documents to being the kind of encyclopedic tomes that we see today with many hundreds of pages, and I think that sums up some of the aspects of the evolution of clinical trials in general. Which essentially, is an increase in the need to be precise about the endpoints, to be precise about the design of the clinical trial, to understand the regulatory bodies perspective, to understand the nuances of the endpoints and the measurements that we take in trying to prove that these new treatments are better than what we have. And as a result, I think, however innovative and exciting your new molecule or your new therapeutic approach is, and however motivated we are to get these promising new things into the clinic for our patients, there is a very, very important need of maintaining the rigor required to demonstrate that what we are proposing is safe and is going to be better than what we have. And in there, I think, lies all the complexities. And for, say, a small team from an academic institution that has promising data who now want to bring it to the clinic. It is a very daunting prospect to try to conduct a clinical trial in today's environment. So therein, there is an immediate need, if you see, for somebody who has the expertise to run clinical trials, and that in some ways is where the clinical research organizations come in. 

John Marshall, MD: Let me jump in there. You know, you and I have watched this evolution occur. So, I remember one of my first protocols is, as you say, maybe a four-page document. And, and now they're, they're incredibly long. I'm thinking about the escalation of that complexity. It’s multifactorial.

The way I think about it is that cancer has gotten more complicated. There's more and more subtypes of patients and the like. Okay. The drugs have gotten more specific, so I get an element of complexity there. But we've also started to measure more and more things in order to prove that safety that you talk about. You have that you have the sponsor wanting to get to the patient. Before that was just through the physician, and now the CRO, because this is this middleman kind of discussion we've been having, the CRO has joined in on this to identify and train and oversee the clinical site. Can you talk a little bit about that piece of it, and the importance of that in in the overall flow of things?

Gwyn Bebb, MD, BM, BCh, PhD: So, that kind of sums up a lot of the challenges we have. There's many paradoxes in here. I think. The world of clinical trials is so exciting and so promising, seeing the new ideas that are coming through. Gosh, you know, everybody gets very excited and very motivated to bring these to the patient as quickly as possible. But as you say, cancer as an example has evolved very much. We have a very specific slivers of classification of patients with, for example, lung cancer. It wasn't just used to be maybe just lung cancer. We have small cell, non-small cell, and then we have all these molecularly defined categories of lung cancer, each with a potential molecular marker that can be targeted for benefit. Now, if you have an agent that, it targets one agent. But if those patients don't have a, that marker in their tumor, then we're not going to have an effect. And so, including too many patients in the clinical trial that are unlikely to benefit will mask the positive effect. On the other hand, trying to get too specific, maybe it limits your, the number of patients that you have accruing the right number of the required for the statistical design may be challenging. And so, these are all components where it is very important. to invoke the help of a body of expertise that can help you through the clinical trial trajectory. And that's essentially what clinical research organizations are. When I was a physician, when I ran my own lab, my expertise was very limited to those particular areas. And if I had been lucky enough to bring something to the clinic from my own lab, I would not have been able to do everything that was required to conduct that clinical trial. And that need, you know, I’ve said it's particularly required for small Innovative teams from academia, but the same applies for innovation anywhere and the same applies for big pharma they have a lot of internal capabilities, but sometimes, whether they're overloaded with their current, requirements, whether they're pivoting to a new area, where they're doing something completely different. Sometimes the expertise provided by a clinical research organization, such as Parexel, is exactly the expertise they need to invoke to move things forward. Everything included in that package, from the identification of the biomarker, all the testing that's required to do that, the clear delineation of which patients is the investigator in the trial going to bring into the trial. How do we meet the regulatory body requirements to make sure that the test we use to identify the patients is a valid and reliable and reproducible one? How can we help design a trial in such a way that it can run uniformly across many countries? How can we make sure that the statistical design is going to meet the criteria required of the regulatory bodies to demonstrate that what we have is better than what we had? And so, these are not, this is not a range of expertise that you can just pluck out of the air. And, you know, I think that's one of the things that makes me very excited about working for Parexel is that we have this expertise that can slot into this critical area to drive innovation forward while maintaining the academic rigor required, and of course, most importantly, protecting the interests of the patients who are kind enough to volunteer their time and their bodies in a way to take part in what is a scientific experiment.

John Marshall, MD: I think that's great. I was going to ask, and you just answered was sort of your perspective on the value of what the CRO brings to the table. And I think you did a great job of describing that. As you were going to, I want to kind of go to the patient side of things. So one of the worries we have in the clinical side is that the patient who now is eligible for that trial in the end is so perfect is so squared off at the corners to fit, that that doesn't end up representing the ultimate patient who will be treated with this therapy because there's, you know, patients are not that clean in general, if you will, so, you know, softening the edges around eligibility for us would be good to increase accrual and also therefore represent that patient at the end. 

And one other angle on this is, you know, the patient is volunteering. A lot of clinical trials, that are not so cancer therapeutic, we've actually ethically understood it's okay to incentivize a patient to go into a clinical trial. We do ask a lot of them. It is extra visits. It is extra time, extra biopsies, sometimes, things like that. So, they are volunteering their bodies at a sacrifice of some quality-of-life component. And I wonder what your thoughts are. Ultimately, could we get to a place where we are incentivizing that patient? So, softening the edges of eligibility, is there a role for incentivization of patients?

Gwyn Bebb, MD, BM, BCh, PhD: Well, thank you very much for bringing that up because the patient centricity of clinical trials is a very important theme. It is something that we at Parexel are very, very aware of. We have a patient officer who is part of our company whose task is to maintain a focus on the patient as we look at the design of clinical trial. And as you say, these patients are volunteers. A very important part of clinical trials is the moral and ethical framework for essentially conducting experiments on our fellow human beings. And this is, this is a very, very important area. I have a lot of passion for that. And, you know, the history of experimentation of fellow humans is a terrible one. And so that's just why we have international agreements, we have ethical review. An awful lot of regulatory input on how to go about attracting patients to clinical trials. 

Let's address the inclusivity to start with. I think this is an important point. One of the things I like about clinical trials is the tension that we get when we, when we have slightly opposing forces trying to drive us forward.

So, as you say, on the one hand, we do want to create the biggest possible chance of deriving the positive signal that we're looking for and so we have to be very rigorous about the patients that we put in a clinical trial. Otherwise, we will lose the positive signal that may be there in a very, very important, new, therapeutic, agent. On the other hand, as you say, we don't want to be too restrictive. There's many, many examples of this, you know, performance status, for example, clinical trials have always honed in on performance status 0 or 1. Because the outcome that we associate with performance status 2 and 3 can actually compromise the signal that we're looking for. So, trying to soften those edges is something that many of the regulatory bodies are trying to drive us forward in doing. Another example, for example, is the inclusion of brain metastases in our clinical trials. Very often it has been the case that patients with brain metastases from their primary cancer were excluded from clinical trials and we know that that is a very unfortunate paradigm, and I think that too is now evolving and changing. But as we said at the beginning, you know If you're looking at a new agent that targets a particular therapeutic target including patients in whom that therapeutic target is not present is not going to be useful for anybody. It's not going to be useful for that patient and it's not going to be useful for that clinical trial. 

Now let's turn to the incentivization of patients. I think this is a very difficult area to navigate very often, and, as you say, incentivizing patients is not the main theme of our approach to clinical trials. Many patients, when I was in clinical practice would ask me, you know, why would I, why would I join this clinical trial? And I would say, broadly speaking, there are three reasons for a patient to take part in a clinical trial. One of them is for the opportunity of getting new, exciting, innovative therapy. That is very, very good motivation. Another one I think is overall, there is a body of literature that suggests that patients participate in a clinical trial. Generally, do better than those who don't. And there's lots of reasons for that. And that is possibly, as you said, the more intense follow up, the more supervision of their whole clinical experience probably helps drive those, those data of survival forward. And then the third reason, this is very altruistic indeed, there are some patients who just want to contribute to the general body of knowledge about their disease for those who, as I say, come after them. 

Now you know a very important part of this having made having looked into their heart and realized what motivates them, the next thing is if we are patient centric, we have to make the burden of the clinical trial as minimal as possible. And I think one of the major things that we see happening is that the increased visits the increased procedures they Don't make your quality of life better, right? They take a lot of time and a lot of energy for the patients. And when it gets to the point where you're missing work, you're missing the opportunity of giving care to those who depend on you, then that is a significant detriment. And so, making sure that there is what we have termed fiscal neutrality, for example, participating in a clinical trial is very important. So, there is a drive to make sure that the costs incurred by patients, whether it's food, travel, care costs, those such things are very much part of, of what we provide to, to make sure that it is not too much of a detriment to the quality of life. I think those things are probably slightly different from actually incentivizing patients to take part in a cancer clinical trial.

John Marshall, MD: Thank you very much, Dr Gwen Bebb for sharing all of your experience and knowledge around the world of clinical research and in the role of a clinical research organization in making sure that we do it right. And we do see the clearer value, but as we've talked about, there are still lots of issues that we need to address as we evolve this relationship further.

So, again, thank you very, very much for joining us on Oncology Unscripted.

Gwyn Bebb, MD, BM, BCh, PhD: Absolute pleasure, John. Thank you for hosting so gracefully.​

[31:11]

Are There Alternatives to Traditional CROs? Interview with James Palazzolo

John Marshall, MD: As I promised you, I have experts in the world of CRO and clinical research, and not just experts, really visionaries about the problem and about how we can move forward. And I'm honored to be joined today by what is becoming a pretty good acquaintance in this world of clinical research. So, James, James Palazzolo, is out on the West Coast right now and he has joined us from Quantum Leap Healthcare Collaborative, and I'm going to really leave it to James to describe, to us, the CRO, in a sense, that he and his team has created in large part response to the problems we have been talking about with CROs. So, James, welcome.

So, you get to tell us whatever you want to say about CROs. Tell us a story in the background of what you've created.

James Palazzolo: Yeah, thank you, John. So, it's an interesting world, right? We all want our medical decisions to be made based on data. And the ultimate way to do that is with a randomized control clinical trial, an RCT. And as the practice of medicine became more and more data driven, of course, more and more trials are needed to be conducted. RCTs by themselves are the pinnacle of how this data is collected and the results are generated, but there are some downsides. The downside is it requires extreme precision. Data collection needs to be done in a way that's meticulous. And it creates also a form of a Hide-Bound system where we can only do things one way. And frankly, I think there are alternatives. Alternatives can include things like using game theory, Bayesian statistics, platform trials, master protocols, and the list goes on...decentralized trials. We can make a long list. Of innovations, but these new innovations haven't always penetrated the traditional world of the RCT. The RCT is driven heavily by government regulation, but also by the routine of practice. So, the people or organizations that conduct these are usually called CROs. They're professional data collectors and can put that data together for people who wish to have an R C. T. conducted. The downside, though, is that it really doesn't benefit us to have all these innovations over and above what we can provide to RCTs. And so maybe we need a new form of an organization to make that happen. And that's what we've done at quantum.

John Marshall, MD: Yeah, tell us a little bit about that. I mean, you know, part of what the concern is, is that there's this ever-ending escalation of precision. If we can look for more data. If a CRO came and audited us here and found no problems, then that would put them out of a job. Right? So, part of their essence has to be to find some problems to justify their existence. So maybe tell us a little bit about how you've evolved this for your team.

James Palazzolo: There's no doubt that misplaced precision is everywhere, right? We could focus on all the wrong things, but we tried to apply a bunch of newer tools to make this better. So, one is we set up a platform clinical trial that once it starts continues to run. So, it'd be like if you brought the Olympics to the same city, every 4 years, you wouldn't need to build more stadiums. And some people would love that because the public would have access to these things. Other people would hate it. Like if you're in the stadium building job, it would be bad for you. So, it's going to depend on where you sit on this issue. In our case, with a platform clinical trial, we can run cancer trials over and over again with the same infrastructure, but that's not all we can do. Right? We're also going to listen to veteran clinicians like yourself, who guide us into what is the most important. We no longer use misplaced precision. Parameters that are most important, but we're also going to provide these results to patients in in plain English in digestible form. So, whether you participate in the trial, or you're curious about the results, we're going to make them available to everyone. 

Another thing we've done is put this in not in a not-for-profit company, so that the company itself isn't doing this. We don't have a vested stake and who wins or loses. We're not looking for the next contract from the next pharmaceutical company. Frankly, we're working with groups of very curious, but also very experienced investigators who want to learn more about it. their particular, area of oncology, and then we're going to grind on that, not just for two or three years in a trial, but maybe decades until we find real lasting solutions that make the problem better for the patients who suffer from it.

John Marshall, MD: I want to kind of come back to a couple of things you said so this idea of having experts be part of the decision-making. So, I remember back when we were involved in decision-making and design of clinical trials and running them. And then something happened where Industry actually hired the physicians.

So now instead of borrowing us when it was time to design a trial, everybody went in house. And so, they had their internal experts. And so, we no longer were really being asked what our opinion was about a trial or a trial design. But we were being asked just would we do the trial that's being handed to us? Are we okay with that? I do think that's driven a further wedge between the reality of patient care and this sort of mystical   of precision, you know, data from the randomized controlled trial. So that's one. The second, and I can't help but have this vision of the London underground and this platform clinical trial, like, you know, you could be on the London underground sitting next to Paul McCartney, right?

So, Paul McCartney would ride the London underground, everybody uses the public transportation there in order to get around. It's the most efficient way to do it. You've built, in essence, the, you know, the Piccadilly line for clinical research that everybody can get on and use if they want to try and lower costs and to improve speed of accrual. Is that a fair analogy?

James Palazzolo: I think that's absolutely fair. And, you know, if we're going to improve things like racial disparities and medicine, we need a more uniform tool platform trial where everyone can participate that, of course, includes the high-end academic centers. We're going to provide very useful information, but also safety net and community hospitals where everyone has a chance to participate. Of course, it's up there choosing. But, if they choose to participate, their data will be included, and we'll get more information that allows us to do a better job for everybody.

John Marshall, MD: And so, it's just so our audience knows your basic group is supporting as a CRO in a way for this platform trial and its relatives. Right? 

James Palazzolo: That's right. So, our organization provides the same functions to conduct a clinical trial that a CRO would have. If an industry company, a medical device company, a pharma company did some of their trials in house. They would have these same functions. We have them. But rather than going out and seeking new projects to work on, we built the project with people like you to make sure that it was relevant in reflective current clinical practice and then continuously improved it over time, so that we could enroll patients in trials that more closely reflected their actual routine care and didn't get hidebound in the routine or the tradition of an RCT. It is an RCT. But it is more flexible. And then it collects the appropriate information at the right time.

John Marshall, MD: And we know you guys have been at it a while, and you guys have produced FDA approvals and innovation in how we treat patients in general. You've broken the mold in a way that's allowed us to accelerate our innovation instead of sort of plodding along as we've been doing. So, James, I can't thank you enough for joining us. I know everyone will be interested in hearing more about your success, so be careful. You might get some phone calls after this. James, thanks for joining us.

James Palazzolo: Thank you, John.

John Marshall, MD: I can't thank our experts enough for sharing their thoughts about clinical research, CROs, and maybe some thoughts about how we move forward going ahead, because we need to move forward, and we need to make it more efficient so that we can provide better cancer care for people all around the world.

And I hope you have found this episode seven of Oncology Unscripted useful, maybe a little enjoyable, but certainly thought-provoking as you go forward in your week ahead. John Marshall, thanks for joining.

This transcript has been edited for clarity.

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Hello, everybody. John Marshall from Oncology Unscripted. Do you know where I was this past weekend? I was in San Francisco. It's actually pretty nice weather there in San Francisco. I go pretty much every year. In fact, I have gone to every GI ASCO. 

Skipping This Test in Frontline Metastatic Colon Cancer? That’s Malpractice.

[00:00:24] It's really usually my first business trip of the year. Usually, the weather out in San Francisco is kind of rainy and gloomy in the fifties, but it was pretty sunny compared to here out east where it was cold and snowy. So it was kind of good to get away, but that's not really why I go. It's also not a meeting you go to learn a lot of new science. That's usually ASCO and ESMO and other places. Occasionally there's some data, and I'll talk about some of that in just a minute. The reason most of us go to GI ASCO, and I with my perfect attendance at GI ASCO, is to see the people. The GI cancer community is very, very close. Some of us argue that that may be why we haven't made more success, but we are a very, very close community. And this gives us an opportunity to get together, share meals, share ideas, compare notes, and become better at what we do through our camaraderie and our collaboration. 

But I do want to make sure and give you the highlights of what happened at GI ASCO. Now the first, and this has really been true for many, many years there is I've been very discouraged, as you know, in the progress that we're making in GI cancers. For example, colon cancer, I have been giving essentially the same adjuvant therapy for colon cancer for 20 years. There is no other cancer where we have failed to make some advances in adjuvant therapy over the last two decades. Essentially, until a paper that was presented in San Francisco, I had been giving the same frontline treatment for metastatic colon cancer until now. Yes, we had MSI, but that's kind of its own different disease. But now what we have is a 9 percent wedge of colon cancer that has BRAF V600E mutations. I remember, because I'm this old, when it used to be bad to be HER2-positive for breast cancer. Now, you want to be HER2-positive for breast cancer because we know how to control that pathway, right? It's a good thing when you're HER2-positive. 

BRAF, for a long, long time, was just bad news. We had nothing we could do for it, and it was just a bad prognostic marker. So why would you care about knowing? Now you have to know because now we have frontline therapy, proven combination BRAF, EGFR therapy with chemo, big increase in response rate, big increase in Overall survival, new FDA approval that you have to know about for BRAF patients. So no longer can you wait till later to do your RAS and BRAF testing in colon. You have to, or it is malpractice if you don't- yes, sir, yes, ma'am. You need to do it frontline so you can incorporate your frontline treatment of your patients because now that BRAF has some drugs to target to it, we can, in fact, improve the outcome for those patients. So, for me, that was the biggest data set that was out there. 

Let me share two other high-level observations. And that is one that we were part of, but others have also shown a similar data set, is that does specialized care is only seeing GI and not knowing anything about breast cancer and lung cancer, et cetera. Does that make me a better doctor? Does it make our team have a better product than if you're a general practitioner who's having to see all of the new treatments and understand all of the nuances all at once? And there's a couple of different beliefs in this. One is that as long as you're practicing the guidelines, as long as you're following the rule book, you in fact do just as well as those who are writing the guidelines and writing the rule book. But some new data we presented and others also presented there suggested that if you are a specialist, things like proper molecular profiling, time to treatment, those kinds of things, can overcome even social determinants of health, which, by the way, with our new administration, there are no imbalances in social determinants of health. That's all gone. it's just wiped away. But those of us who know they still exist; specialization might allow you to prioritize that. So then the question becomes, how do we connect our specialists, those who live one disease day in and day out, to our community docs who are doing most of the work of treating most of our patients in this country and doing a fabulous job. How do we help them? How do we help them to do even better out there with making sure our patients get the best care? And that's our next step of going forward. And that was a theme that came out of the ASCO GI meeting. 

But the last piece I want to really emphasize, and this is again back to that frustration of lack of success. Is that there are a lot of new drugs coming for GI cancers. One is that there are some very successful RAS targeted agents that are on the way, with very good response rates in pancreas cancer, colon cancer, and other diseases. The problem this has created is that patients know about them, doctors know about them, but there aren't enough slots for all the patients that are out there. So, I was actually engaged in a bunch of discussions with folks about how do we as a cancer community get access to these agents before their eventual FDA approval that doesn't hurt their eventual FDA approval. Essentially that phase four kinds of study, but before so it doesn't spend all the money of the company doesn't hurt their ultimate package. And this is a really important issue. If you thought about it, it would be true with immunotherapy before. But now with the RAS targeting agents, there's more of it there. But it's not just that there are a lot of people nibbling at the edges of different signaling pathways, improved immunotherapy outcomes, in microsatellite stable GI cancer. So, this is going to get better and it's going to get better fast if we can keep the machine going.

NCI Silenced, Grants Frozen—What This Means for Cancer Care

[00:06:43] And what we really talked about at GI ASCO was the new administration. On Wednesday, the meeting started on Thursday, a good friend of ours, was on a review committee. He's on a normal NCI grant review committee. And during the Zoom, 20 minutes into this review, they'd all done their work. They were presenting their grades, if you will. somebody interrupted the meeting from the grants group and said, this meeting's over. There are no more grant reviews going to happen because of the freeze that a certain president put in place. So, they stopped. Think about if you're a researcher or what not, that grant renewal, that grant application is your career, it's your salary, it's everything, right? And you've spent your whole life to try and achieve that, and now you are uncertain whether it's going to happen at all. so, this was just devastating.

Then I ran into somebody at the airport, a very good friend in the airport, she was saying that their institution interpreted the freeze as there would be no more indirect. So, you know, you get a grant for 100 grand, you get some extra percentage to keep the lights on and the heat on and running water so that you can actually do the science. And that's always the way it's been. But there was some suggestion based on their interpretation that the indirects were going to go away, right? All of that. 

Then we got to the meeting, landed, had the airport discussion. We're all anxious. We get to the meeting, and I ran into one of my NCI friends, and the only reason he was there was that he left on Wednesday, because if he had left on Thursday, he would have been shut down, not able to travel, So there was no NCI representation at GI ASCO, and they do a lot of great science there, right? And they were shut down and said, You can't come at all. And in fact, you can't communicate with anybody. You can't share information. You can't put out your bulletins or the information that is your job basically to do. And that person had to go back. They couldn't even stay at the meeting because they only were there for the day. And then they had to go back because of the freeze. Right? 

So, this has created this wave of uncertainty, fear of panic among many of us out there. So, is there going to be ongoing research funding for us in the cancer world? At a time when we've never known more! At the time we were about to cure this set of diseases, we run into this administration that doesn't believe that science is real or that progress is something that we can have. But it does cost money, but they don't want to spend it on us. 

Then think about the DEI piece of all of this. Every NCI designated comprehensive cancer center is required currently to have a DEI section in it and everybody's like I talked to actually a few cancer center directors in the last week. They're all saying that's gone. They're just going to take that out and we'll just don't worry. We'll keep doing it. We'll fold it into other things. Yeah, right. You know, there are people who are hired at cancer centers in order to meet that grant requirement in order to play out what we need in terms of DEI support for folks out there. 

If you offer institution, any sort of gender affirming care. Right. What touch words those are gender affirming care. Then we're going to cut you off. We're not going to give you any support, which would go to education, medical school, research, other things, right? Progress and science. So, if you do that, you're no longer eligible for this. And so, you talk about dictating and governing. And it's not just gender affirming grants, it's all grants that go to your institution, right? And we all know that the government helps support. 

Now, where's that money come from, from the government? Guess what? It comes from us. I just got my tax form for last year. Just paid the government a whole lot of money to spend. I'm thinking it is on our behalf, right? Not on certain people's behalf, on all of our behalf. So indeed, we have to make sure that everyone knows how disruptive it will be. 

Now, another piece is that communications have been cut off. So you believe what you see on your feed, right? You do from certain sources. You don't from others. Sometimes you're not sure. Well, if communications out of the NCI and the government are cut off, then you have the right not only to invade the Capitol. It's a new right that you have, apparently, but you have the right to die of bird flu. That's a new right you have. And of course, you have the right to die from cancer because we're not going to communicate any new data about cancer and the cures for it. So, let's face it, this was disruptive.

The last story I want to tell you Is this came from my daughter. My daughter is in school becoming a social worker and a minister, and she spends after school time with preteens and kids helping to mentor, helping to guide. And of course, when this all came out, around immigration, these children at school were given a pamphlet on what happens if ICE comes to your door. You all have kids out there. What if your kids came home with a pamphlet that says what are you going to do if ICE comes and knocks at your door? I just want us all to think about that a little bit, what we have done in just one week.

Now, it is the next Wednesday after GI ASCO. This will air a little later. So, who knows what will have happened by the time this airs. But just today I saw on the Washington Post, also owned by a billionaire who was on the podium during the inauguration, so you got to wonder in the Washington Post, it's been rescinded. For all the confusion it has caused. it's confusing because they didn't know what they were doing. They just think all of this is the right thing to do. 

So they're just blowing up stuff and then figuring it out later. we're uncertain here. We are trying to keep our heads down. We are trying to take care of the patients. I'm on service right now. So I'm trying to make sure we manage keeping our eye on the ball of taking care of people who need us in the medical translational research community. but it is very hard not to be distracted by what our world is becoming, what's happening to it, how it's being nibbled around the edges and how it's being exploded only to say, Oh, no. We were kidding. We didn't really mean it, but we could mean it in the future. 

I don't know what to tell you. But I encourage all of you who out there are listening is to throw some comments in shoot me a note, put it in the chat, if you will, but let's get this conversation going and get it noisy so that those people not too far from here on the other end of Pennsylvania Avenue for me, hear it loud and clear and understand that their whims have major impact on our future. What is it to be a great nation? It is to take the success that you have and share it with others. That is really what we have lost. I think with this election is this concept of sharing it with others. It is what we do in the healthcare world. We take the gifts that we have we share them with others. I really hope that you have a chance to share your gifts with others. John Marshall for Oncology Unscripted. Until next time.   [00:14:39]

Why Dr. Marshall Needs a Hug—And Maybe You Do Too 

[00:14:39] You know, our world is getting turned upside down every day. There's a new pronouncement of what's going to be. I sort of am afraid to read the Washington Post every morning for every page. There is something else that I'm like, how could that be? And then you turn the page and like, how could that be? I have been thinking a lot, of course, as we all have about our lives and how they may be changing dramatically. Earlier this week, knowing that our team here at our cancer center is spending a lot of time, we're in Washington, thinking about the changes. We're thinking about the impact on research if they cap the indirects. We're thinking about how are we going to continue with NIH fellows who come here. For their training, if they shut down the NIH, etc. So, there are a lot of sort of scientific research questions. But then over the weekend, what really started to strike me is what's happening to our patients during all of this. You know, they come here for security, for care, for answers in what may be one of the most difficult times of their lives as they face cancers or hematologic problems, they're coming here for us to provide that. And that is what we and our whole team are called to do is embrace that patient in front of us and care for them and try to deliver the best message. But we know that on both sides of that exam room, there's a lot more anxiety underneath all of this, right? We as providers, the back of our heads are like, what's tomorrow going to hold? How am I going to hold up myself when all of this is going on? But at the same time, you have to be outwardly for that person in front of you and focused on the medical issues for the person in front of us.

Let's face it. Our jobs are hard already. Right? To get up and do what we do every day, year after year. But now you put this added burden on us, it makes it even that much harder. Think about who's on the other side of that room. What are they going through as they're confronting life threatening illnesses and side effects of treatment and all the different things that go with that. And they too are dealing with all of this unsettledness that's out there in the world. And so, I'm not sure I have any answers, but I did ask my team um, and I told them, uh, Officially that if they saw me and looked at me and said that guy needs a hug that I would welcome that hug, and vice versa. We need to take care of each other because our job is to also take care of those in front of us. So, what I've encouraged our team here. What I encourage your team there to do is huddle up. Make sure that you are talking and caring with each other so that we can do what is our most important job and that is caring for the person across from us, who knows what next week holds, who knows how unsettled our world will be, but stay tuned because we're going to review it right here.

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John Marshall, MD: What do you guys think? What do you think I'm looking like today here in Washington D.C. In January 2025? Well, What I'm trying to look like is the new administration, which is moving in just down the street from me there. 

There is an unfortunate casket, a hundred-year-old man inside, draped in the American flag. What I think of as a sort of heroic politician. And in a couple of weeks, we're going to have a parade here for next wave of politicians. So, we're all getting ready here in Washington, D.C. For the 2025 ahead. I hope you are out there as well. 

Welcome back to Oncology Unscripted. My name is John Marshall shooting to you live from Georgetown University here in Washington, D.C. 

And as you know, those of you who are following this, we have been trying to drill down on a government thing called the Inflation Reduction Act, and we've had a couple of episodes on that already and interviewed some important smart people in the space, and we've got another important smart person coming to you in this episode, as well. But I want to talk a little bit more about the specifics of how we got here and the problem at large.

So, let's just look at the cost of the product that we in oncology are putting out day in and day out. So, 95% of new cancer drugs in the US cost $100,000 per year, on average, more than that. And the median annual cost was almost $200,000 just for cancer drugs for one individual. And most of that's being driven by, of course, this new cooler stuff, the gene therapies and viral therapies leading the way. But very interestingly, based on an interesting paper, it didn't cost more if your therapy worked better or had some novel mechanism of action. That didn't matter. So, magnitude of benefit was not connected to cost. It's just going up and up and up. 

And, oh, by the way, if you ever watch television or have a phone or have an email, you know that all of these new medicines are being advertised no matter how esoteric the disease is, or the problem is. We have national campaigns, often in the middle of Jeopardy, which makes me think that Jeopardy viewers are having the most illnesses. I know I'm a big Jeopardy viewer. My wife was a Jeopardy champion a long time ago, so I never win at Jeopardy, but I do like watching. But these ads are running all the time. What do you think an ad on national television costs? And every time I see one of those, I'm thinking, well, how many new prescriptions do they have to fill an order to pay for that ad? Based on what I just told you, maybe only one, you know, if you get one new patient at those kinds of prices, maybe it pays for the ad itself. Now, you also know that there is a new group coming to town, and one of the members of this new group, we think, is going to be this guy named RFK Jr., who is compelled to make our nation healthier. So, the first thing he's going to do is get rid of all vaccines that that'll do the trick. But I don't know if you know this one of his big pet peeves is that he would like to get rid of ads. So quit spending all of that money. And by the way, they spend close to 30 billion in 2024 on ads. So, take that 30 billion and quit spending it in direct-to-consumer marketing.

This is what RFK Jr. wants. But he also wants equal pricing. You know we've talked about this before. You're already aware of it. We here in the United States pay more for all of our drugs than anyone else in the world. And sometimes that delta can be a huge difference. And the argument has been, well, we can afford it. And that reinvestment that delta that we're providing the world is going into reinvestment for new drug development. And that's really what the IRA, the Inflation Reduction Act is all about is to try and close that gap. And so, if you thought that might go away under the new administration, it's I think maybe the opposite. They may double down on it if RFK Jr. has his way by taking away ads and leveling the playing field for new payment. And of course, this has got everybody on their heels a bit because they don't know what budgets will look like if they don't have this margin from post marketing, if you will. So, it really put a big wrench in cancer drug development as we've talked about before.

[00:05:12]

MedBuzz: Is Divorce the New Trend in Oncology Partnerships?

Let’s look a little bit of how this is beginning to trickle down into our world of cancer research and cancer care. And I have a couple of sort of high-level things. You probably heard about both of them. One of them is a very, very famous scientist and clinician, Brian Druker, who is essentially He invented Gleevec, got it to come out to treat all the diseases that has been treated, been the head at Oregon for many, many years, a dynamic leader, fundraiser and everything else. Just a couple of weeks ago, on a dime, he resigned. 69 years of age, got plenty of life left in him, I hope. And he basically said, look, we're not aligned with healthcare systems and research. We don't know how the two are going to play together. I work at a big health care system here in the Baltimore, Washington area, and we're trying to maintain an NCI designated comprehensive cancer center inside of a big health care system that values productivity and margin and all of those things. And so, we've been lucky enough at our health care system to maintain that margin, right? But a lot of healthcare systems did not maintain. And so even though there's a big nest of philanthropy that the team there has, the job all of a sudden became too much for Brian. And he said, no, I'm not going to do it anymore. And he's going to go back to his lab and do something different, more focused. It was really rocking our world that news. 

I know you've heard about this, is there's trouble up there in Boston. If you remember, lots of the healthcare systems, Dana Farber, Mass General, and the Brigham were all working together. Well, they decided about a year ago to have a divorce. And so, they're splitting up as general and Dana Farber, but it's interesting because then all going to go partner with different folks. So, they're getting a divorce and then kind of remarrying, in new structure. And, and you know what, this was really a split over is that one of the institutions wanted their own cancer building in the hospital. Not like we have here at Georgetown, for example, where it's all over the place. They wanted their own freestanding building. A hard thing to do in the middle of a busy city. So, they got a divorce over what they thought should be the most appropriate cancer care out there. 

[00:07:38]

I want to just sort of close this discussion about us. talked about the health care system and the troubles it's having. We talked about the Inflation Reduction Act and the impact on pharma, legislation that may come forward about ads and all of that. So, we talked about that, but what about us, the health care consumer? And you know, it really starts with us here in the United States with this concept of insurance. Now, probably everybody listening out there has car insurance, you have house insurance. That model is you put in five bucks a month and if your house burns down, everybody chips in and builds you a new house. And that works because most people's houses don't burn down that often. You don't have too many car wrecks. So, the insurance model, shared risk, works in that setting. 

When health insurance first came along, it was, the only thing that was covered was sort of catastrophic health. You needed an operation. You were in a car wreck. You had something that required being in the hospital. Didn't happen all that often. We all chipped in. And you can pay your five bucks a month and that would cover it. it has evolved to managing hypertension, hypercholesterolemia, erectile dysfunction, and all the other things, you know, obesity, weight loss drugs, etc. All the other things that have become maintenance. We don't have mow-your-grass insurance, right? Where we all agree to chip in, unless you live in a big complex, you all agree to chip in to mow your grass. Then it's everybody's grass, right? So, in healthcare, we're all chipping in to pay for everybody's maintenance. So not catastrophic stuff, maintenance. But then with this health insurance model, we've been removed from the actual costs of what it is to get healthcare. It sometimes feels free. My Medicare-taking father at 90 years of age talks about, well, that won't cost me anything, but wait a second. Yes, it does. pay taxes, my salary here for my healthcare policy, I'm paying. Georgetown who pays the insurance company, right? And they're paying and they would have been paying me. So, what if I instead said, forget it. You're not getting health insurance through work. We'll just increase your salary by whatever you're paying. What we're paying now, you're on your own. To deal with health care costs. Let's go back to cancer drugs. It's $100,000 a year for a cancer drug, and that's a cheap one. If I gave you $10,000 back into your salary and said, okay, instead of health insurance, here's the cash, spend it as you would, you've got to imagine there'd be some competitive pricing. So, this whole price structure we live in in the United States As you know, is a false economy. And it's coming out of our individual pockets to create a bigger pocket, which increases the national debt, by the way, fund our health care and our health care system. So, while I'm very nervous about the upcoming administration, I do think of our health care system as a balloon is continuing to be blown up. And that one day, one day it's going to pop. And so can we be smart enough before it pops to let the air out slowly? All need to talk about this. We need to bring these issues forward. We need to develop a real economy for health care. And we need to think again about the Inflation Reduction Act, the cost of medicines and cancer care and other places as well. Our insurance model and think about how could we reshape that so that it continue to exist to provide excellent health care, but at the same time reduce that cost. And don't let that balloon pop.

[00:11:48]

The IRA’s Ripple Effect: A Candid Conversation with John Newby 

Now, I promised you an interview. And the interview today is with John Newby. Now you will see that Mr. Newby is an expert in this world of drug development and costs here for the state of Virginia and this region. And so, I think you're going to find this quite interesting. So, tune in and continue to listen to our interview. 

I am honored to be joined by John Newby. He is the CEO of the Virginia Biotech Association, and he is joining us today to talk a little bit about a new challenging subject of the Inflation Reduction Act and its impact on cancer care.

So, John, thank you so much for joining us.

John Newby: Thanks, Dr. Marshall. Happy to be here.

John Marshall, MD: Tell us a little bit about your role and, and what's your crossover with all of this and how the IRA may be important to you. 

John Newby: Sure. So, the Virginia Biotechnology Association is a trade group here in Virginia. Our members are life science and biotech companies of all stripes all over the Commonwealth. We have over 300 members and we've been around for 32 years now. We're headquartered out of Richmond, Virginia. We're located on the campus of VCU of the Biotech Park, Virginia Commonwealth University of the Biotech Park.

and our main goal in life is to support our startup companies, survive the gauntlet of this thing called biotechnology entrepreneurship, mainly trying to help them, with obtaining funding from investors for what they're trying to do into putting solutions in the hands of patients and also speaking on behalf of the entire industry from a government relations and policy perspective, federal government, state government to make sure we're protecting our companies anyway we can.

John Marshall, MD: Know, I want to jump right in on that. So, first, thank you for what you're doing. I was just at a meeting this past weekend where a series of biotech companies were presenting to us as colon cancer experts, their ideas. And I used to joke about, there's three guys in a garage, and who are the ones who invented whatever the drug is, or the new approach is, and that's where really innovation is.

Yes, there is some in big biopharma and the like, but a lot of it comes from individuals or small groups that get together, form a biotech company, generate their preliminary data, and that part's relatively affordable, I guess, or there's ways you can get that kind of funding. I used to think that there was just the bucket load of venture capital and others that was around that people were like, let's bet on that one or that one. But that's really been tight lately, as I understand it. And so, to get from that really good idea in this case was around colon cancer too, you know, clinic is a big investment, and that's really difficult nowadays, isn't it?

John Newby: the big investment in time and effort. the larger companies you reference nowadays, typically, like to keep an ear to the ground what's happening in basic science and then translational science and then ultimately, getting that science in the hands of hands of patients, but really on the front end, the risk really is born by the inventors, in some cases, the universities. Before the larger companies come in and acquire those companies, kind of how the ecosystem works. So, it's really on the shoulders of those great folks doing presentations to you to get out there and find the capital, you know, whether it be non-dilutive at the front end with NIH grants or other things all the way through venture capital and ultimately acquisition before a patient can get that therapy in her hands.

John Marshall, MD: And that just takes too long, right? I mean, you know, there in my world, there are people dying down there in my clinic. And how do we get this accelerated so that it's not five to 10 years, but more like one to two years to bring these therapies to market? And I, this, this model of how we found this is, you know, yes some fail, and yes, bets are lost, but it seemed to me this was a very rich pot of, of opportunity that we are unnecessarily delaying.

John Newby: Yeah, we need to do all we can to support this activity at the levels we're talking about. Too many great ideas are left on the shelf, and not funded because the investment environment is challenging always for life science and biotech. We had a good go of it for obvious reasons during the pandemic period, but it's kind of returned to the very difficult periods. But here's, here's the golden rule, good companies will always get funded. Good, good teams always get funded. Good science, mix all that together, get funded. So, we need to support that.

John Marshall, MD: I agree with that. Now, one of the main themes we've been talking about is the Inflation Reduction Act, and our audience has been hearing, you know, how did we get here and, and the current, efforts that are being made to negotiate for drug prices and this kind of stuff. And was in some meetings where those who are doing the investing in new therapies are hesitant right now because of the Inflation Reduction Act and the uncertainty that that's bringing to their bottom line, I guess.

Maybe reflect a bit on that and the impact it's having on the businesses you represent.

John Newby: Well, the bottom line is just talking generically about Any investor, you or I, even on a personal level,  we don't want to put our money somewhere where our chance of, achieving our gains. Are basically eliminated. Here, you know, withartificial prices being negotiated air quotes, is, is exactly that circumstance. You have, you have a company that invests millions, if not billions of dollars more often. in their drug pipeline. And if you have a drug that is now subject to this negotiation at some point in the future, whether it be nine years for a small molecule or, at 13-year point for biologics, The government's going to put a price down and, and lock it there, irrespective of how much money it took to get there. And also more importantly, John, you know, there's irrespective of the technologies and cures and treatments that can be gained from that same drug after that 13- or 11-year point that are now no longer going to be obtained as far as a return on investment. So, this is just a, not a good idea broadly speaking, but if you're looking at investors and the incentives. You're basically cutting that incentive off at the, at the hip.

John Marshall, MD: Yeah, I do, you know, I, we've talked a little bit about. US versus ex US, because I do think a lot of drug development depends on the US investment, and the current structure of how things are going. I also have been a drug developer all my career, you know, I do know that. We don't win every one we go after, so there are many medicines that we do put significant investment in that in the end fail.

So, those are losses. So, on the one side, I was hoping that we could get more efficient, like not turn off drug development altogether, but be better at picking the winners. If you will and optimizing that. But I also thought this was an opportunity for regulators to look at, you know, this relationship of drug approvals, patent half-life, intellectual property, and all of this to think about ways of. incentivizing the investment that we are making so that if you do when you get changes in your, you know, your IP or your duration of your, your patent life or something like that. Do you think that sort of evolution could happen as a result of this?

John Newby: I think the way you describe what will be a commonsense way forward is exactly why it's not going to be done anytime soon. You can't reduce all that you said to a bumper sticker. You can't reduce all that you have just said to, we're going to cut drug prices.

John Marshall, MD: Right.

John Newby: So that's the problem. That's really an issue here. it is a very complicated system that the U.S. has to get drugs into the hands of patients, but it's the best in the world. And I think the world recognizes that. And indeed, the world benefits from what we do here in the U.S. Yes, I do think that all those things that you just mentioned should be done eventually to look at things holistically and get to a better place. but that's not really how it's being approached from a political, political will, if you will. So, we have to deal with each attempt from policy makers to help and try to ameliorate the hurt that they're actually doing in this new system.

John Marshall, MD: But, you know, the other side is, as an oncologist particularly, I do a lot of trial-and-error medicine, right? We try a drug or try a therapy, see if it works. It's not inexpensive. It has side effects. You know, I need to be more efficient too. And I think about the payer side of this. Right. So, there's the private payers and then there's the federal payers that are actually funding health care. That money's coming out of yours and my, you know, our pockets, whether whoever we work for our health insurance or taxes. And. That's to a side of this that I've always struggled with the inefficiency of what we do on the other side. So, and again, this is some sort of idealistic world. I've just painted. Of that there would be more recognition of the inefficiency on this side improved development on the other side to a place where we're actually, you know, spending less money for better outcomes.

John Newby: That's the desire. Let me, let me, also throw something else in there. Not only is it the fact, and you know, firsthand this john, that it takes a lot of money and effort to develop drugs. The chances of success are lower than low in many cases. add on to that the threat of the reduced investment in this space, which is what the IRA potentially could do. So, there was a recent survey that was conducted by PhRMA, by the large Pharmaceutical Research Manufacturers Association that we're all familiar with. 78 percent of the companies that they surveyed said they expect to cancel early-stage pipeline projects that no longer makes sense given the short timelines that are being established in the IRA for setting prices for small molecules, large molecules.

So not only at the outset, is it already hard enough to get a drug. successfully through the pipeline. Now I have now I have companies saying, okay, now we're going to take away project money to begin with, because it just doesn't make financial sense, given these artificial deadlines and price, restrictions are going to be put on the drugs.

So, we're getting it from all ends, both from the scientific end, which is already difficult enough. Now the funding ends and we need to change that funding piece and deal with the uncertainties of the science because it is science. but let's not hurt ourselves with cutting ourselves off from the funders with, with such a regime that we're talking about.

John Marshall, MD: And I think it is important for our audience. I know they know this, but you know, cancer, we've sliced and diced it into subgroups that molecular profiling makes smaller and smaller markets for drugs when we get them there. And so, when we talk about trimming the sales, in terms of reinvestment and development, those small markets are the ones that are going to be lost just at a time when in fact, we understand better how to treat the different subgroups. So, I'm anxious about that along with you. Let me ask you one, one last question. 

So, what's going to happen next year?

John Newby: If I knew that I, I wouldn't be talking to you right now. we don't know. But you know, I wanted to make one more point, particularly when it comes to this audience and oncology experts and the IRA. So, the IRA does something else as well when it comes to orphan drugs. Most, many orphan drugs are obviously small molecule, targeting cancer, rare diseases, you know, those, those diseases affecting 200,000 or, or, or less, Americans. Currently it really, the IRA does, really hurts incentives for orphan drugs that are primarily for cancer. It only exempts from these price setting, this price setting regime, those orphan drugs that only treat one disease condition. Now that should absolutely make everyone's head spin in this community, right? Because we all know many orphan drugs that are approved in year seven, ultimately go on to be approved for 3, 4, 5, 6 more indications in seven years, eight years, 10 years in the out years. Currently the IRA cuts off that possibility because it says only orphan drugs that are indicated for one disease can be accepted from the price setting regime. Virginia bio and many other organizations, big bio pharma are advocating to change that provision. pretty soon. but that's just yet another example specifically how this impacts this community here, given the orphan drugs are really those small molecules that are at issue in your community. 

So, we all need to kind of come together and encourage our policymakers to look at big picture. This is an education process. It's like anything else in our space. Many of the folks on Capitol Hill don't have direct experience in what you do every day. So, it takes time for education, and we have gotten on Capitol Hill and my counterparts across the states and our national organizations have. But it's a process. Who knows what this new administration is going to do? And how, how well they're going to receive, our positions based in science and fact. But all we can do is continue and with your support, get the word out and, and, and encourage our policymakers to do the right thing.

John Marshall, MD: God, let's leave it right there. I think that's a, we, it's a charge and a call to action for us all in the year ahead. This is John Newby. He's the CEO of the Virginia Biotech Association, who's taken some time this morning to share his thoughts on the IRA. 

John, thank you so much for joining us.

John Newby: Thank you for having me. 

John Marshall, MD: I promised you that a good interview. That was a great interview. We appreciate all of the insights he brings forward as we look forward to the year ahead and all of our both scientific but also financial challenges that we have ahead of us in health care. Nowhere is that brighter shining is the issue more critical than around cancer care, where our therapies are getting more and more effective, but they are also going up and up in cost, and we're going to have to figure out how we're going to manage those two opposing factors for more people to get access to these lifesaving therapies, new innovations, new cures for patients with cancer out there. Join me next time for oncology unscripted, where we'll continue to dissect the world of oncology and healthcare in general. And what you're going to see will surprise you join us 

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John Marshall, MD: Ho, Ho, Ho, everybody out there. This is John Marshall for Oncology Unscripted, and we're going to talk a lot about pancreatic cancer today. We're also going to talk about some other things as well, but I thought I would sort of start off with a little holiday story. 

See that stocking? I've had this stocking for a long, long time. I actually keep it right over there in my drawer, and it's a reminder of what we do for a living. So, a patient almost 30 years ago gave me this. It was actually a breast cancer patient I was covering for one of my colleagues who was out on maternity leave, and during that three-month window, I was the one who gave her the scan that showed the recurrence of her breast cancer. And so, I was the messenger if you will, of the bad news. And she pretended like nothing was really a big deal, and it was fine. My colleague came back and managed things from that point on. But then that Christmas season, that year, I got a very beautifully wrapped box. I thought, oh, how nice that this patient I was covering for those three months, many years ago had given me this gift and I opened it up and inside was this stocking. I thought, well, that's pretty nice. I don't really understand it. And then I felt and inside the stocking is a lump of coal. And this was a patient who had taken a lot of trouble to wrap me up a pretty gift with a stocking in it, mainly to make sure I knew that I was the Scrooge for her holiday season. 

And so, as we enter this holiday season with our patients, with our colleagues and our teams around us, remember. It is a special time of year for all of us. It's an important time of year, but it's also a time of year when bad news carries a little bit harder weight with our patients. So, avoid getting one of these from your next patient if you get one of those bad scans, which sadly is common among our pancreas cancer patients.

But before we go there. talk a little bit about one of our past topics, a little bit of gossip that's out there, and that's the pharmacy benefit manager. If you remember, we talked about this a few episodes ago where this group CVS Caremark, and there are many of them now, nearly three big ones, are controlling the pricing of our medicines in such a way that they're ramping up pricing, controlling the distribution, and really kind of undermining a lot of the free enterprise, if you will, out there. And so I'm sure it wasn't our video and commentary that caused this, but there's been some backlash from the PBMs who now are like filing lawsuits against the Federal Trade Commission, claiming that basically they're fiddling with all of this is unconstitutional. And they've had full page ads running in the Washington Post. We always know when there's something going on here in Washington because they'll take out a full-page ad saying we're right. You're wrong. You should support us. I guess it’s sort of subliminal messaging for our Congress people as they go to work in the morning. Nonetheless, there's now this pushback from PBMs to say, stay out of my business. It's not the government's business. 

And so now I'm thinking about what's coming in the year ahead. You don't want regulation. Okay, you voted for him. He's not going to have any regulation, at least as far as I can tell. But this is one of those examples of what's going to happen if we don't push back, it's going to affect all of us going to affect the cost of health care. And we won't be the ones who are benefiting from this. These third-party managers, such as the PBMs, will be the ones that are benefiting. So, it's going to be to see what happens in the year ahead. Just how much changes in regulation, particularly for us in health care, will have an impact on outcomes, cost, access, all those important things that we are trying to get for our patients. So, I don't know. Stay tuned. More stories to come on the PBMs.

What’s Making the Impossible Possible in Pancreatic Cancer?

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Our main topic today is really all-around pancreatic cancer. We just got out of November. And as you know, November is Pancreatic Cancer Awareness Month. Now, did you know that there are about 60, 000 new cases of pancreatic cancer every year? Not that many survivors, right? Because most patients present with metastatic disease,  and is there such a thing as early pancreatic cancer? And so, the teams that have been trying to advocate for new science in pancreatic cancer have made headway. First, you need a month. So, they got November 2nd. You need a ribbon. Do you know what color the ribbon is? Yep. Yep. You're right. It is a purple ribbon. So you got to have a ribbon. You have got to have a month. Got to have a few five K's. You have got to have some money. to distribute out there for research and you've got to create a home for patients to go to,  so that they can learn more about their disease.

And so Pancreatic Cancer Awareness Month has really been something that I would say has been positive for our patients and our medical team in this space. 

I want focus on a paper actually that came out last month in the JCO, and this paper by Ludmir et al, was kind of breaking a rule, but it worked.

Now, you remember that in colon cancer, not pancreas, colon cancer, you can resect metastatic disease. In fact, you should for some patients because sometimes there's only one or two weeds in the yard. And if you remove the metastatic disease, you cure that patient. But generally. We don't do that for other cancers routinely, but this group published their data looking at pancreatic cancer patients with five or fewer lesions, metastatic lesions, randomizing them between just continuing chemotherapy versus this metastectomy or localized treatment, and wouldn't you know it, it seemed to work. So, the next time you're in your GI multidisciplinary tumor board, and somebody, some surgeon usually says, what if we just took those mets out of the liver? And that you would use to say, nah, it's pancreas cancer. There's no data. Now, there is data. So, I strongly encourage you to look up that paper, maybe present it at your next multidisciplinary tumor board so that you too can be cutting edge, if you will, on trying to do a better job with pancreatic cancer.

Now, the other piece that happened in November is we have our annual Ruesch Center Symposium here at Georgetown. We invited people from all over the country to come and start off with a think tank. What do we know? What don't we know? Actually, we know a lot more than we used to know. We then celebrate this with a series of presentations and a CME symposium. And I wanted to sort of really drill down on pancreas cancer for a little bit, because we've made progress, believe it or not. 

So, it really starts with an understanding of there is such a thing as early phase pancreatic cancer premalignant lesions within the pancreas. There's increasing ability to detect these things. Now, how do we prevent them from becoming a cancer? That's another challenge. How do we identify them as a screening tool? There's new data that supports being able to do some of these new screens,  both with blood testing, as well as with imaging, et cetera. So, there is hope that soon we will be able to incorporate routine screening in patients to try and find early-stage pancreatic cancer, even premalignant. 

The second, and this is a big deal, is we have been saying that RAS is untargetable. 90 percent of pancreatic cancers have a RAS mutation. And we basically said, we're sorry, your driving mutation is untargetable until now. It started with G12C and now there are, gosh, some people say more than 20 new drugs that are targeting RAS, increasingly more successful. Some are very specific to a certain mutation. Others are pan RAS inhibitors, but there are a lot of clinical trials, a lot of new therapies, and a lot of investment that's going into this space of targeting RAS in pancreatic cancer. And our hope is that Maybe even by this time next year, we have some positive randomized data that would lead to FDA approvals.

My guess is between now and then, we will also be seeing some phase 2 data that suggests significant positive responses. All of a sudden, we're seeing waterfall plots with pancreatic cancer, not with just one patient, 10 percent, having a response, but now approaching 50 percent of patients having response. And I am really excited about RAS inhibition in pancreatic cancer now.

The last piece of this is that you think of pancreatic cancer as sort of an immune silent disease. disease that there's no treatment for therapy, no role for immune therapy in these patients. But newer studies looking at novel combinations of immune therapies are starting to show some improvement in waterfall plots as well. 

So, when we got everybody together here at our symposium and our think tank, what really came out of it is that It's now on us to figure out how to put together these immunotherapy approaches and these RAS targeted agents along with our existing systemic agents to move the bar in pancreatic cancer. 

Is it about time? Yes, it is. Do we have the right drugs? We at least have a good wave of drugs That will move us forward in this space. So, if you're out there taking care of patients like me with pancreatic cancer, now's the time to be looking out for trials and other options as these agents come through the mix. Hopefully, this time next year we have improved survival and a path forward about how to make that even better. So, I'm optimistic around pancreatic cancer. 

To really get into this area of pancreatic cancer, we've invited not only a good friend, but someone who I think maybe single handedly has had more impact on the outcomes, the investment, the support for pancreatic cancer. There's no one out there on the planet, in my opinion, except this person, Julie Fleshman, who started, founded, grown, this organization the Pancreatic Cancer Action Network. 

Shaping the Future of Pancreatic Cancer: Interview with Julie Fleshman

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Welcome everybody back to Oncology Unscripted. No script at all on this one. And the person who's joining me right now, really, doesn't need a script because she wrote it. She was the one who really defined, in my opinion, what advocacy is all about. Taking maybe one of the most difficult, if not the most difficult, cancer, inspired by a personal story to change the outcome for people with pancreatic cancer. And I'm proud to say she's my friend, but she's also one of my mentors, as she has shown the way for so many as to how to really move the bar in advocacy.

And this is Julie Fleshman, who is coming to us live and we're so grateful, Julie, for your joining us. So, first, welcome to Oncology Unscripted. 

Julie Fleshman: Thank you so much for having me. It's always a pleasure to talk to you and be with you.

John Marshall, MD: You are so awesome. And you know, I think that, but let me start from the beginning, because a lot of people were coming up on a change in our world. And we know that advocacy is a critical component to our success in making advances in healthcare. It's not just handed to us. We have to push the forces around us to make it happen. Maybe give us your quick version of, you know, what inspired you and the value of advocacy in the world of pancreatic cancer. 

Julie Fleshman: I have a personal story. 25 years ago, now, my dad was diagnosed with pancreatic cancer. 52 years old. Died four months after diagnosis. And I was devastated, and I didn't understand why there was nothing offered for him. Why were there no options? And about that. At the same time PanCAN was founded and I was lucky and privileged to be hired as the first employee almost 25 years ago.

And I've really just watched, you know, the field, the pancreatic cancer field back then, there was nothing. There was no federal funding. There was no philanthropy. There was nobody studying the disease. There were no resources for patients and families. And you know, I really believe PanCAN has been a catalyst for changing that. And today there is a robust pancreatic cancer research community. And I think a lot of exciting things on the horizon for patients. And so, you know, I believe advocacy being the voice of the patient, not backing down when everyone tells you this isn't the way that we get things done, but it makes the most logical sense for overcoming a hard disease and you keep at it, and you keep chipping at it.  and I believe advocacy is what gets us to where we're going and accelerates the rate of progress. And in this case, I think has really helped to build a field that just didn't exist before.

John Marshall, MD: You did all that stuff. Let's talk about the important stuff. Why did you pick purple for the ribbon?

Julie Fleshman: So actually, our founder who lost her mom to pancreatic cancer, her mom's favorite color was purple. That is the story.

John Marshall, MD: I love that.

Julie Fleshman: So yes, so you know, and it was one of the colors not taken, right? You need to have something different than the other cancers, but it is a great color.

John Marshall, MD: But all kidding aside, yeah, I actually have several purple ties now because of the of the purple ribbon. But, but all kidding aside, I mean, you and your team have built an incredible infrastructure, not just a Hill presence and advocacy there. Not only a clinical research infrastructure that we'll talk about in a minute, but also operators standing by patients can call in and get advice about what they should do with your team members. And in fact, I think that feeds back to the practicing clinician, because there's a lot that we don't know that's going on out there, particularly the general oncologist in the world of pancreatic cancer. I'm assuming each one of those was a decision and you needed to have the bandwidth to do it. Like how, how much struggle was that to get all of those resources together?

Julie Fleshman: Yeah, I mean, you looked at and said, Okay, where are the gaps, and 25 years ago, there were a lot of gaps. One of the first and most obvious areas was, you know, when someone is diagnosed with this disease, there's no place to go for information or resources. So, building that patient services program in the early days, you know, was so critically, I believe, important for helping patients be informed so that they can make the right decisions about their care and go in and be an advocate with their, you know, doctor. Just as you said, many physicians don't see hardly any pancreatic cancer patients. And so, to have someone come in and ask you questions about clinical trials, about testing, about these different things, hopefully it will also help educate the health care professionals.

John Marshall, MD: Yeah. And you've given these folks a home, a club, if you will, where they can share thoughts. And I think with our, you know, the bad cancers, there isn't that sort of survivorship that you see in some other cancers. So, you've, you've provided that place where people can interact and teach each other, which to me is just critical.

Julie Fleshman: Everybody needs a cheerleader, right? Whether you're a researcher, a doctor focusing on this tough disease, patients and family, someone who's lost someone. And I think that's what PanCAN does. We rally the troops. We make people feel good about the work that they're doing and that there is hope and that we're going to get there. We just all have to work together to do it.

John Marshall, MD: Yeah, I couldn't agree more. Now, the year ahead, we're all pretty sure that the NIH budget is not going to get bigger. We're panicked that it's going to be significantly smaller. And so, I think about a group like yours that has successfully advocated in DOD budget,  negotiations to get pancreas cancer research funded there, there's certainly a high priority around pancreatic cancer in the NIH budget.

What are some of your worries as you look to the year ahead and new administration changes?

Julie Fleshman: Yeah, I was actually just on Capitol Hill last week with Madison Marsh, Miss America 2024, who lost her mom to pancreatic cancer. And so, she's been using her platform to talk about the disease. So, she and I were up on the Hill together and talking about increasing the DOD line item for pancreatic cancer research, and just trying to understand the current environment. And definitely what we heard is most likely it will be flat funding. There probably will not be any increases. And I think there is just a lot of concern about what's going to happen to these agencies and what could this look like. So, PanCAN along with the other cancer advocacy organizations are going to have to stay on top of it. I think the good news is that usually health related problems do better during change like this. And so, let's hope that's the case, but this will be a time where the voice of the patient, the voice of advocates is going to be extremely important.

John Marshall, MD: Let me kind of drill down on something you and your team were clearly setting those standards when you develop the concept around Precision Promise. This was an understanding that molecular abnormalities occur. There are different ones in different patients. We have targeted therapies. Could we drive progress in pancreatic cancer through that? And you, a lot of work, a lot of investment, a lot of science went into this, but it didn't turn out the way you want to maybe reflect a little bit about that and that experience for others, because, you know, for me personally, I think it's exactly the right way to go. And lessons we could share for others trying to do this and other diseases.

Julie Fleshman: Yeah. So, Precision Promise was an adaptive clinical trial platform. And so, you know, basically the goal behind it was that you could develop a drug with fewer patients, less cost, less time,  a way to accelerate new treatments for patients. All of that's true. And I think we learned a lot about that sort of process, and does this platform concept work? And I think the answer is yes. However, financially, in order to make it financially work,  you have to have constantly have new drugs coming into the pipeline on the platform. And that was the part that turned out to be the challenge. Part of that was, you know you were convincing a pharmaceutical company or a biotech company to develop their drug, that PanCAN was going to develop their drug, they were going to lose control. So that proved to be an obstacle. The pharma and biotech companies, you know, changed their priorities and their strategies. And so maybe at one point they were developing this drug in pancreatic cancer and six months later they were deprioritizing the asset. And so all of those things became challenging.

We also had, you know, the last couple of years it's better today, but the last couple of years, I mean the funding for biotech, you know, really dried up.  I still think many of them are challenged and so there wasn't even funding to do something even like this that would be less expensive. So, with all of those things, it became a financial risk for PanCAN was the bottom line.

The trial will go on. another organization that is going to launch a new,  you know, basically Precision Promise version 2.0 and learn from all the things that PanCAN learned over the last, you know four years. And, you know, some people have said it was before its time, you know, now with there's so much excitement around drug development and targeting KRAS and all of these things that maybe, you know, if we were launching it today, it would be a different story. We launched it in 2020 in the middle of COVID. It was, you know, couldn't have been a worse time to be launching a big, you know, basically phase three clinical trial for an organization like us that had never operated one before. So, you know, we didn't have everything working with us,  we did this, but we certainly learned a lot.

And I think, you know, the investigators that were a part of the network and the sites that were running Precision Promise, really, that part ended up being pretty amazing. That network, and the camaraderie and the sharing and the learnings. And you know, I think that those things will continue far beyond. 

John Marshall, MD: Yeah, no, I totally agree with you. You know, we just held here at Georgetown at the Reusch Center, a think tank around pancreatic cancer. And we invited a bunch of very smart people, some of the smartest people in our country around this disease who've made a lot of progress. And the whole point of the think tank was to say, why haven't we cracked this nut? Why have we had a few new medicines? They've helped. Yeah. But we really haven't cracked the nut the way we want to. And it was interesting. One of the participants got up and said, “But wait, we have done it, or we have about to do it and all we really need to do is give it time and ongoing investment. But we're about to reap these rewards in pancreatic cancer, whether it's targeting or new understanding of immune therapies, understanding,  how to control  cancers and the like.  I went into that meeting discouraged thinking there wasn't going to be much in our summary document, or what we were going to be able to share. But I left that meeting maybe as excited as I've ever been, and I'm an old GI oncologist, about the future of where we're going in pancreatic cancer. Reflect a bit where you all are on that and that stance. And the one concern I had, again, is how do we make sure that that investments there, to your previous point? How do we make sure that patients have access to these trials and new medicines around the country? So that all can move this faster. 

Julie Fleshman: I've heard multiple physicians and researchers say that they feel we're at a tipping point, and I've never heard, you know, that kind of talk before. I mean for 25 years, I've been told KRAS, RAS super important, but it's undruggable. And suddenly, it's druggable. And so that's pretty amazing and exciting. You know, there are multiple, multiple companies with targets for KRAS for pancreatic cancer. The first phase three trial just launched last month, and then lots of phase two, phase one trials that are in development. So, I mean, this is exciting. This is really important.

John Marshall, MD: Yeah, I was going to say that I saw a bunch of waterfall plots. Everybody knows what those are. Where I'm used to seeing one patient and being excited about that. This was half the patients were below the line. We were seeing lots of responders in those patients.

Julie Fleshman: Absolutely. Most likely it won't be the silver bullet. I think we've learned that in this disease. So, the next step is what do we need to combine it with? What is that going to look like so there's durability and, and we get, you know, even we extend patients’ lives even longer. I think that'll be the sort of immediate next step that we need to begin working on. But I was really heartened at the AACR pancreatic cancer meeting in September. That already it feels like the field is thinking about that, and they're working together across institutions. They're getting together in groups and trying to solve the problem based on different expertise. And so, I do feel like we have a very special community that knows this is hard. That this isn't just going to be the answer, and we're going to have to continue to work together. And PanCAN wants to play that role. 

John Marshall, MD: I would go one step further, Julie. I don't think we would be where we are today with that progress without your work and PanCAN's work that's driven this and made sure that in the top of everybody's mind is how We're all tired of taking care of pancreas cancer patients with not much to do. And we are all looking forward to the future in large part, thanks to you. So, I very much thank you for taking the time for talking with us today and wish you well as now we watch that survival curve improve.

Julie Fleshman: Thank you so much. I always appreciate your passion and enthusiasm, and all you do for patients. So, thank you.

John Marshall, MD: I really can't thank Julie enough for joining us in our series Oncology Unscripted. As you can see from our discussion, she’s just all there is out there. She has been such an advocate and positive for so many of us in the space of GI cancers and pancreas cancer in specific. So, a great shout out to her and thank everyone out there for joining us today as we've sort of started to dig in deeper in the world of pancreatic cancer, our hope for the future, as we've developed new agents and new support for our patients that are out there. Join us next time on Oncology Unscripted.

Thanks everybody. John Marshall.

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Is the Inflation Reduction Act a Threat or Opportunity for Oncology?  

[00:00:05]

[00:00:05] John Marshall, MD: Hey everybody, John Marshall live from Washington DC where all the action is happening. A lot of moving vans are likely to be coming here soon as the new party comes in to take over maybe everything. We're going to have to see how that goes. We're all living in this crazy state of uncertainty about just how much. Are they saying is going to happen? But we'll see. That's our future. 

[00:00:34] But what I really want to talk about on this episode of Oncology Unscripted is the beginnings of a discussion around health policy in oncology and the reason I'm bringing this up is I just recently came across my radar, something called the Inflation Reduction Act. Well, sure, I knew about the Inflation Reduction Act, but I didn't know how that was going to affect cancer. And then I started to think about, yeah, I do. They're going to negotiate drug pricing on cancer. And there's been this big turmoil about we can't do that. It'll break the system. We need the fixed drug pricing, et cetera, and I want to talk about that because it's starting to be put into place, and it might actually get wiped off the map in a couple of months, but maybe it won't. And I wanted to talk about it because it will affect what I do for a living, and that's to try and develop new drugs for cancer.

[00:01:29] But in order to do that, let's start by at the beginning of when the whole thing needed to be created in the first place. And that is go back to 2003 Bush II, Bush II to put into place a health modernization Medicare Modernization Act, which at the time was praised. Now, remember where we were people with Medicare didn't really have drug benefits. You went and paid cash at the pharmacy. But drugs were getting more and more expensive. And so, seniors weren't able to afford the drugs. And so, we needed to figure out how US health care was going to cover those drugs. And this was the deal that was cut now out of that deal. So, seniors got access to drugs. But for the tradeoff that always happens here in Washington, D.C. Now, the first one was that there was an agreement that we would not import new drugs from other countries. So, in other words, you couldn't manufacture it in Canada and then ship it across the border at Canadian prices. We weren't going to allow that. So, the borders were closed to import so that we could save the price structure here in the United States. And with that rule came another corollary is that we could not negotiate drug pricing with the manufacturer. Whatever they said was going to cost, that's what CMS would pay. And as a result, that was when we could no longer judge value as a nation. So, if you can't connect magnitude of benefit, which is what the FDA judges, did it work or not, to the cost, that's what CMS has to do, you can't judge value. Right? There's no way. Okay, it'll cost $100,000. Okay, but what do I get for that? Well, it could only be 6 weeks. And that would be enough for it to get FDA approval. And Medicare would have to pay. the third component was something called 340B pricing, and that is institutions like mine and many of the institutions around the United States pay a reduced amount for the product, get paid by insurance companies, the delta, and with that extra money that we get as a healthcare institution, we're supposed to provide All those other things that cancer care delivers. A nutritionist, a social worker, nursing support, et cetera, that don't have any billing infrastructure for it.

[00:04:08] And so that non negotiated price, the rising cost of cancer drugs, and this 340 B pricing is our current economy. And with that, all of our industries more or less dependent on that pricing structure. So, the inflation reduction act is a threat to that, right? Because if we're going to start picking and choosing drugs that can be negotiated on price, then how does that affect the revenue stream?

[00:04:37] And how does that affect the reimbursement into research? And so, our whole series on the next few episodes is going to be focused on the Inflation Reduction Act and what it does now, and what it could do in the future. And why we're worried about it. We hope to get some good folks who are in the middle of this discussion to talk to us about it. It's a fairly sensitive subject. So, we are hoping for that. So, stay tuned to future episodes. 

Cancer Care in America: Equal Access or Uneven Outcomes?

[00:05:05] But as part of this episode, I wanted to talk about yes, U.S. health care, but I wanted to talk about. Does everyone get the same U.S. healthcare? Now, the reason this has become important to me is that we just did a study here in Washington, D.C. between two of our main hospitals that I work in. They service very different patient bases and neighborhoods. They're both busy cancer hospitals. They both provide specialized cancer care. That's important. But one, quote unquote, has a lot of issues with social determinants of health. Barriers to access to cancer care, because as we've talked about, cancer care is complicated to receive, it's complicated to give, and if both parties are doing okay, then it's okay, but if one is challenged, then it's not okay, right?

[00:05:54] So what we did is a big study of a thousand patients with colon cancer, and actually extracted from their charts, 400 from one hospital, 600 from another, and believe it or not, We were expecting to see a difference in outcomes that the social determinants of health were in fact going to affect the outcomes for those patients. But not only did we see no difference, we saw that. In fact, our record here in our health care system was better than published national averages. Molecular profiling, time to treatment, survival, all the key points we want. And after an initial sense of pride, I'm like, well, wait a second. That is not what we were expecting, right? We were expecting there to be a difference because of the populations that we were serving was different. 

[00:06:42] And so we then developed a new theory, which we are testing now, that can a general oncologist, nobody out there get offended, keep up. With everything that needs to be kept up with in every disease, and I think if you ask most general oncologists, they would say they do a very good job, which I would agree with, but maybe not as good as it could be. On the other hand, what if you live in a remote part of the world in our country? How far do you have to go to even find a cancer doctor or a place where you can get an infusion? So, we have this issue of general oncologists and remote access, right?

Bridging the Distance: Can Rural America Get Equal Access to Cancer Care?

[00:07:23] And so there have been a couple of, you know, announcements lately about new projects. There was 1 that looks like it was funded by ASCO and it's in rural Montana where they're going to use a hub and spoke model where there's going to be infusion sites around in the. and then they'll be in a remote country, but then there'll be centralized care. It's exactly how Canada does it now, all the doctors live along the southern border of Canada, right? Because that's the only place where there's not snow all the time. And they've talked to, using telemedicine, patients who live up further away. And then there are local nurses and general doctors who administer the cancer care. So that hub and spoke model we know works in the Canadian health care system. 

[00:08:08] , There was recently Iowa, as you might imagine, great centralized cancer care, but how do they care for folks out and around? So, the University of Iowa bonded with Mission Cancer and Blood, 280 million dollars changed hands, but to basically deliver cancer care in a remote areas. Now this is great. This is what we need for our people and for everyone around our country is good access to cancer care.

[00:08:37] But what our little study may be hinting at is maybe this also needs to be done by cancer specialists. Should we begin to divide even general practice knowledge into its subcategories because it's gotten so complicated? The analogy I like to use is if I had a bunch of okay. And the answer is no, I can be an expert in one or two, but I can't know all the nuances of all the different board games. So we're going to have to figure out not only provide cancer care for everybody, but Through these kinds of networks, hub and spoke model, but how do we make sure that we're actually delivering the highest level of cancer care that we can so that our patients can get the best outcomes and the best and the right therapies on time, et cetera.

Is the U.S. Health System Designed to Fail Its Patients?

[00:09:30] So the last point I want to make about all of this health care policy. It really comes from a recent survey paper that looked at the different health care systems and outcomes around the world. And we always think, because we're the United States of America, that we have the best of everything. Well, we do have the best hamburgers that I'm going to give us. Maybe the best fried chicken, too. I would say that's probably true. Best bourbon? Yeah, I think we have that. But in terms of the best care and healthcare, when you look at the top, like richest countries, we don't. We're in fact, of the top ten, guess what number we are? We're the worst in terms of access to care. Bad health outcomes. Bad worse. So, 9th administrative efficiency. I didn't need to tell you that. Equity, we're 9th in that where we are. The best is what they call care process. So if you're in the system, we got all the bells and whistles, but we leave lots and lots of people behind. 

[00:10:40] And so, as we think about going forward, we have the inflation reduction act, which is trying to make cancer care more accessible and more affordable for our patients. We've got administrative and economic pushback on that. We have a new administration that, who knows what they're going to blow up going forward. But we know for sure. One of their priorities is not equal access to everybody around our country.

[00:11:04] So as we spend the next couple of months reflecting on where we've been and where we're going, fingers crossed, that reason will prevail, that we will prioritize the patients in general. That access does matter that we want to level the playing field to health care as much as we can for all of our patients across our great nation. And I think with that, we will show how we can work together and how we can bridge our divides as we walk forward over the next 4 years. John Marshall for Oncology Unscripted. 

Pandemics, Presidents, and Perseverance: A Candid Conversation with Dr Anthony Fauci

You know, I've interviewed a lot of people in my career, but I don't think I've ever had quite the joy of interviewing someone who, honestly, I think almost everybody in this country, there's some who don't feel this way, but, almost everybody, in this country who think is a real modern day hero, and this is Dr Anthony Fauci, and he has agreed to join us and talk about a few subjects that sort of near and dear to maybe both of our hearts and share them with us all. And on a second note, I want to welcome him as he's flying the Georgetown University flag behind him. I've been here on the faculty for 31 years and I'm not sure I've, I don't want to insult any of my other colleagues, but I'm not sure I've ever had quite so, such an esteemed colleague from my own university, join me. So, Dr Fauci, first, thank you very, very much for joining us today. And let me give my own personal Hoya Saxa welcome to Georgetown University.

[00:12:35] Anthony Fauci, MD: Thank you so much, John. Pleasure to be with you.

[00:12:38] John Marshall, MD: Well, you're awfully nice. Part of what has sparked my interest in talking with you just beyond all that you've been through and all that you've led us through over the years, is really some subjects that came forward in your book. It was really an impactful book. If you haven't gotten it yet, gang out there, it's called On Call. It’s a terrific book available on audio as well for those of you who like to walk and listen at the same time. It's really an extensive review of your own life and the impact that you've had in your own reflections on very, very dramatic moments in medical history. And I wonder if you just start by kind of sharing the sort of inspiration to write it and sort of the emotion and what it took to stop and get all of that down.

[00:13:25] Anthony Fauci, MD: Yeah, well, thanks, John. I decided to write the book because when I came to what I was projecting to be the end of a 54 year career at the NIH, Almost 40 years of which was as the director of the NIAID, which positioned me to essentially be in the eye of the hurricane in the evolution of, as you mentioned, the most impactful pandemics in modern history HIV in the early 80s and through the next 40 years, and then followed by COVID-19.

[00:13:57] That started, at least in the United States, we had the impact of it in the early months of 2020. When I decided I was going to step down, I thought it would be important, given I had the unique experience of this, journey through these two major pandemics, but also in between advising seven presidents of the United States from Ronald Reagan through the Bushes, through Clinton, through Obama, through Trump, and then finally the seventh. when I spent two years as the Chief Medical Advisor to Joe Biden. I thought that that was such a unique experience. My thoughts were two-fold. One, I thought from a historical standpoint, I thought it might be useful for people to see what that was like to go through the early years of the pandemic with HIV and then throughout COVID, but also hopefully to serve as an inspiration for younger individuals who might have an inkling they might want to go into science or medicine or public health. And my description of the early years I believe were important because right now with HIV, we have a single pill with three antiretrovirals that can put a person into complete remission by bringing the level of virus to below detectable and keep it there, essentially indefinitely.

[00:15:27] But I hearken back in the book, in the memoir, to those early years from 1981 through the mid-80s, the late 80s. And the early 90s, when we did not have adequate therapy, and I found myself as a physician who, prior to HIV/AIDS, was rather successful in developing remission inducing therapeutic protocols for auto inflammatory disease, where most of my patients who thought they were going to die actually went into remission, then entering the arena of caring for and studying persons with HIV. I describe it in the memoir as the dark years of my medical career and the stress and the strain. Of seeing virtually all your patients, mostly young, otherwise previously healthy gay men who are dying terrible deaths, no matter what you did. And it was like putting bandages on hemorrhages. You know, I described in the book, I still to this day have flashbacks of what I call a version of post-traumatic stress. Because. When you were taking care of these people early on in the early 80s, you could not get emotionally involved in it because you had too much work to do, and your job was to take care of the patients. So, you suppressed it. It only was years later when you reflect on what you've been through that you understand that you didn't have time to burn out because you had too many people to that you had to take care of. But it was an extraordinary experience, which was an important part of the book to describe those early years of HIV.

[00:17:17] John Marshall, MD: Yeah, well, and taking care of yourself was had to be last on the list because everybody else needed you and there were no, you know, it was sleep, eat and take care of people. I remember in 1988 when I became an intern here at Georgetown walking the halls and those floors still exist. There’s new tile, but the floor still exists. And, you know, I remember the faces of the young men that you describe in there and being the guy who had to go in the gown and get the blood because we didn't have phlebotomists back then and being afraid actually to have a needle in my hand and have an HIV patient that I needed to get blood on or to put a line in or something like that, but at the same time they were alone and you wanted to be there with them because the way the rules were in hospitals as they frequently couldn't have visitors and certainly that was traumatic for me and I, like you say, I probably tucked that away. Then I decided to take on the easy task of trying to cure GI cancers. Not done nearly as well as you've done with viruses

[00:18:16] My experience was then my wife gets breast cancer. And I thought she was going to die. And now all of a sudden I knew what it felt like to be a caregiver or to be a patient. when in fact, I had probably tucked that away for many, many years. and when it, then I tried to, back to we're busy and we got to cure people, deliver that care for every cancer patient that was here. I realized there was no way that you can deliver that level of cancer care, the cancer care that we received as patient and caregiver. I couldn't turn around and give that to everybody who walked in the door. And that was in essence my source of burnout because I was feeling the impact. I was feeling the shortcomings, and actually had to get away for a while. And, and part of our book reflects on that. I think the young people today, and I would love to hear your sort of comparison because I experienced both, you experienced both pandemics, but a lot of our gang around here, you know, they cut their teeth on a pandemic. The interns and residents were on call, and you know, burning their clothes at their door on the way home in that same sort of way we felt with HIV.

[00:19:22] Do you have a sense of how they might be different or how they were different for you, the two experiences?

[00:19:28] Anthony Fauci, MD: Well, yeah, they were different for me, John, for the following reasons, that through the early years of HIV, even after I became Director of the Institute, I was very actively involved in the individual care of individuals, which led to that very stressful, emotional experience that I mentioned to you a moment ago. When it came to COVID, for me personally, it was a different experience because I was in a position of public health influence where I was, you know, as part of the coronavirus task force in the White House, making decisions that were difficult because we had an evolving outbreak that was not just selectively impacting a subpopulation, it was global that everyone was at risk. So, we had a true global health and domestic health catastrophe with COVID, and we had to, to the best of our capability, make decisions about what public health recommendations would be that would involve everyone, not just a small subset of people. 

[00:20:45] At the same time I had the responsibility, together with the pharmaceutical companies, to develop the vaccine. And I could say that was one of the things that we're very proud of, is that my group at NIAID, the Vaccine Research Center that I established 20 plus years ago, was the group and the organization that developed the vaccine the highly immunogenic immunogen that partnered with the mRNA platform to create a vaccine in 11 months, which as you well know, that is a fraction of the normal time it takes to develop a safe and effective vaccine, which usually averages, 7 to 10 years. So, a combination of major investments on the part of the government, the scientific input from my group, and the incredible work that the pharmaceutical companies did. We had a vaccine in 11 months. So that was very, very different from the multiple years it took before we could get a drug for HIV. Remember the first patient that I admitted, with HIV, was in 1981. The first drug that had any effect on HIV was 1987, and it wasn't until 1996 that the triple combination of drugs were made available, which actually dramatically diminished the viral capability and viral load.

[00:22:18] John Marshall, MD: I used to say back in the day that the only reason the HIV success happened was that gay men, essentially, became very powerful self-advocates, and demanded this when there was probably a public sentiment that you were up against even then to do this. 

[00:22:34] With the pandemic, even though you did have global support. You did also have to climb a hill over some who thought this was all some sort of conspiracy. We all know that, but so we are grateful for that. But it does require that sort of will to do it. But to your point, if the will's there and the science is ready for it, it can be done. And so to reflect on that, you coaching me as an oncologist, do you think that if the will were there and we spent the money that we are spending every year on cancer care and cancer medicine, if we spent it more wisely, could we in fact have better outcomes than we do now? What's your thought on that?

[00:23:15] Anthony Fauci, MD: I think so. I mean, if you look at the focus concentrated effort that was put into drug development for HIV, it is one of the greatest success stories of modern medicine. I mean, where all of your patients are dying from an infection that you just could not treat at all to years later when you have a single pill that can essentially drop the level of virus to below detectable and keep it there, not only saving the life of the person, but making it impossible for that person to transmit the virus to someone else.

[00:23:51] John Marshall, MD: at the time, we had like 90 percent accrual rate on clinical, everybody was on a trial, right? It was uncool. Not to be on a trial.

[00:23:59] Anthony Fauci, MD: Yeah, that's exactly what it was. I mean, and you know, you mentioned a moment ago, John, the importance of the AIDS activists in getting community involvement in everything from the design of clinical trials to make it more user friendly to them, to challenging the rigidity of the regulatory process to get drugs approved. Because the FDA process prior to AIDS was very well accepted. It provided safety for the American public, and it got drugs out. But it was ill suited to the emergent nature of HIV, where when someone had clinical disease, it was 12 to 15 months before they died, and interventions before they got through the FDA process would take six years, seven years. It just didn't work for them. So, they pushed back, and the scientific community and the regulatory community didn't listen to them. So, they became very provocative, theatrical, iconoclastic, disruptive. And then I finally listened to them. And when I did, it became clear that they were making perfect sense. And if I were in their shoes, I would have been doing exactly what they were doing. So, it's a very interesting part of our history, the very positive role of the activist community. In getting HIV drugs out sooner and getting them out in a more efficient manner.

[00:25:35] John Marshall, MD: And I've always wondered why the cancer community hasn't been able to sort of create that same unified, not just a pink tent or a brown tent in my case, but a unified rainbow tent to go up and say, we need to change how we do this increase, you know, we're at 8, 9 percent at best on clinical trial accrual now accepting bad diseases and not really pushing. And yet, spending whole lots of money on health, you know, on both screening and on therapy. And it's always been a disconnect.

[00:26:04] But, let me shift gears a little bit because one of my favorite interviews I've ever heard of yours was on a Saturday morning driving around for Wait, Wait, Don't Tell Me. It was just the best thing ever. It's a great show, best show ever. And as you know, on that, they bring famous people like you on and they say, well, we're not going to ask you about viruses. In that case, they asked you about computer viruses. If my memory is correct. Well, I'm going to do the same thing and ask your advice to all of us. You know, what are the secrets to avoiding burnout? What are the secrets? What do you do? What are some of the things you would advise those of us behind you, if you will, to do a better job of taking care of ourselves? You know, we have a common friend who, you know, you played three on three basketball with. I know you're a basketball junkie, but what is sort of your, your advice to us on that

[00:26:53] Anthony Fauci, MD: Yeah, I think it has, you have to have an outside, source of, of support. I was very fortunate in my wife, at the time, was a nurse, who was specialized in the clinical care of persons with HIV. She currently is the chair of the Department of Bioethics at NIH, and she actually is a Hoya all the way down. She went to undergraduate nursing school. She got her PhD at the Kennedy Institute of Ethics with Ed Pellegrino.

[00:27:31] She was very, very helpful in grounding me when I would come home after losing two or three people, mostly, as I mentioned, young, otherwise previously healthy, gay men to just get me to realize to focus on the potential good that you can do and not the disappointments. Because if you focus on the fact that you didn't succeed, even though you tried, you can really get very discouraged. So, what you got to do is focus on the positive nature of the effort that you put in, hoping that someday that effort is going to result in something that's much, much, much more favorable. And that's exactly what happened because years later, what went from everyone dying to essentially people leading normal lives on medication. So, support structures are incredibly important. Yeah.

[00:28:36] John Marshall, MD: so disappointed that you didn't list bourbon as one of the options, but apparently that should be lower on my list. And famously, it is 1 of my vehicles, but never, never before 6, but let's make this be clear. But anyway, so. I hear you loud and clear. And I think it's great advice for all of us. Not the bourbon, by the way, you out there listening. That's not good advice. Let's close, you know, you've as you mentioned, and you reflected in your book this incredible duration of advice, you know, the folks that you have provided insights to in our leadership of our country. And one of the areas of focus on our series right now. Is what's called the inflation reduction act, lots of us are not really aware of it, but why it's coming to a head in oncology is in fact, they're starting to talk about negotiating drug price. And so, I'm actually taking our audience back to the beginning when Bush II signed into law. The revised Medicare support bill you know, no importing of drugs and no negotiation of drug price because more and more oral agents were needed, and Medicare didn't cover oral agents. So, we needed a vehicle to do that to now Biden's institution of the Inflation Reduction Act. To now a new administration that might wipe that away. And I realize you, you don't know everything and can't see the future, but I'm just wondering what you're thinking is about what we should look forward to what ahead to in terms of health care policy and changes

[00:30:08] Anthony Fauci, MD: Well, John, that is the big unknown question right now that's causing a lot of anxiety in the medical community. For my colleagues at the NIH, for my colleagues at the CDC, at the FDA, is that, will there be a dissolution of things that were very helpful to us, and will there be new things that are put into the hopper that might impede what our ultimate common goals are. And the answer is we don't know. And that's the reason why we're in a state of somewhat heightened anxiety because of not really knowing what exactly is going to happen. So my only advice would be to, you know, think positively that the better angels will prevail and that we'll have things that are sensitive, you know, to the needs of our patients and to the things that we're responsible for doing.

[00:31:06] John Marshall, MD: But bourbon wasn't on the list for that one either. But I understand completely. Why not? We're all talking to those angels right now to make sure that what we can do and what the progress we have can continue in the years to come. 

[00:31:20] I've kept you long enough. I could keep you all day. Dr Anthony Fauci, who is really a world's leader in healthcare and global health. think of the number of people out th`1 ere in the world that he has saved. He wouldn't take credit for that personally, but we should give it to him. So, Dr Fauci, thank you very much for joining us.

[00:31:37] Thank you, John. It's a pleasure being with you. Appreciate it.

[00:31:40] Amazing to talk to Dr Anthony Fauci on his own personal experience, the impact that he's had as an individual on so many around us, but also his own reflection on his own health and his own well-being and some advice to us all. So, I hope you enjoyed our talk with Dr Anthony Fauci and will join us again on Oncology Unscripted.

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[00:00:05] John Marshall, MD: John Marshall, MD: Hey, everybody, John Marshall with Oncology Unscripted, even though I've got a little bit of a script right here, but don't tell anybody. Today, we're going to talk all about dosing of medicine, and do we have it right or not, particularly with some of our newer cancer medicines. And I'm going to really drill down on a couple that I know a lot about that I hope you will use in your own practice, quite honestly, and make your life a little easier, and, more importantly, your patient's life a little easier. 

[00:00:34] Let's look a little bit at the business side of what's going on. You know, I've been kind of watching this big takeover of McKesson and Florida Cancer Specialists. Well, wouldn't you know what? There's in fact, of course, been some Federal Trade Commission pushback that this creates sort of, how could it not be a monopoly, when you've got everything from insurance to providers to drug people and everybody in the same game. It ends up becoming a monopoly out there. And, you know, I think it's right that we look at this because, you know, we do predict that there's going to be just, you know, just a few huge health care systems out there in our country. And we need to figure out how best to manage all of that to continue to provide the best care we can, for all of our patients and give access to everybody that we can get access to. So. Important stuff going on out there still, of course, in our business world. 

Science Snapshot [00:01:34] 

From a science perspective, I just came across, really yesterday, in the New England Journal, an article that that piqued my interest. Because it only went very nicely with the theme of our episode today, but around dosing, but really value in terms of what's it worth to get a little bit more survival. 

And this was a study as a metastatic lung cancer study in the New England Journal of Medicine. I've got an actual copy of it. Right there. There it is. And this is by Cho et al. It's a very important study. It's the MARIPOSA study. You all know about it. It's amivantamab, there you go, plus lazertinib, which is, I guess, like Lazarus from the New Testament, maybe, maybe not. But this is in patients with EGFR-mutated non-small cell lung cancer, and, of course, the current standard of care is osimertinib. A relatively easy medicine to take has some side effects. The doublet wins in the end of the day, by a small amount, and that's with both PFS and trending towards OS. But I went to the toxicity table because do we have the doses of these medicines correct? And so maybe that's reflected in tox, and I'll come back to this in a little bit, but you know, there's not equal toxicity at all. In fact, the doublet therapy has essentially double the amount of grade three toxicity, and the investigators are fairly bold in saying, however, the incidents of grade four, which is almost dead, and five, dead, or discontinued treatment, were similar between the two groups. So now we've elevated it. Don't pay attention to grade three toxicity, we know that's going to be different here, let's look at dead and almost dead grade four and five and see if that's different. And it really struck me when I looked at the deltas on the advantages, the clinical outcomes, and the deltas on the toxicity that, is this really worth it? Should this become a new standard of care? New England Journal usually doesn't print things that it doesn't think are at least at risk for being the new standard of care. So, those folks out there who take care of lung cancer are going to have to figure out if this really reflects a new change and is that worth it.

Are You Overdosing Your Patients? [00:04:08] 

And really why I picked that paper, it's important, but, to me, it's all about dose. And I think we are overdosing people. I am old enough to remember that when chemotherapy was the thing that we needed to get to what we call the maximum tolerated dose. And this was how much could you give you all know what this means. How much could you give without bumping the patient off, because the principle was that more was better.

I want to reflect on this a little bit because we learned pretty clearly in some cancers, that was true, germ cell cancer, some leukemias, maybe adjuvant breast cancer, but that dose intensity mattered in those diseases. But let's look at adjuvant breast cancer, because when I was a junior faculty member here, we were doing bone marrow transplants in the adjuvant setting for stage two and three breast cancers. So, we were doing marrow ablative, myeloablative therapies because more was better. And if you know that story, you know that the people who were leading some of those papers out of South Africa ended up committing fraud. Their results were fraudulent, and many, many women were exposed to bone marrow transplants because of their data suggesting it might be helpful, when in fact it was not. So, more was not better in that scenario. 

And the other place that I was living at the time, again, 20, 30 years ago, was the advent of capecitabine. Simple drug. You use it a lot in your practice, I am sure, but what dose and schedule do you use? Do you remember, were you around when the actual dose studies were done? Back in the day, we would not only do something called maximum tolerated dose, we would then have a supplemental study of recommended phase two dosing. And very often that meant a randomized clinical trial of different doses and schedules of the medicine looking for both toxicity and efficacy to see which one works the best. Yep, they did that with capecitabine back in the day. And they looked at continuous dosing, right? Just giving it continuously at a certain dose. They looked at 2 weeks on 1 week off with leucovorin. Two weeks on, one week off, without leucovorin. Those two doses were a little different. And guess what? All three had exactly the same outcome in terms of response rate and progression free survival. All of that, exactly the same. The continuous dosing had the lowest toxicity. But guess what? We picked the one that used the most capecitabine pills. Not leucovorin, you could use fewer pills if you threw a little leucovorin in, but this was just capecitabine at what we now know as its dose, two weeks on, one week off. That sold the most pills, not because of benefit, but because dose intensity at the time mattered. And we are still clinging on to that dose and schedule. Many, many people are, whether it's a XELOX regimen or just capecitabine or maintenance capecitabine, but it's not correct.

How Does Dr Marshall Dose Capecitabine? [00:07:34] 

The correct way to give capecitabine by John Marshall. Fixed dosing, never use the small pills, only use 500 milligram pills, size up your patient. Do an estimate of creatinine, clearance, because this is a renally cleared drug. Most patients I start at 1500 milligrams, three pills in the morning, after breakfast, 1500 after dinner. Monday through Friday, because you know what if radiation doesn't work on the weekend neither does chemotherapy, every week. Okay, so if you're a two-week one-week offer, you're giving it 14 days every three weeks. My way, I'm actually giving it 15 days every three weeks. And because you give that little weekend off, the hand foot syndrome is less, it doesn't build up nearly as much. Are you given the right dose? If somebody comes back in within a month or two and starts to have some hand foot syndrome, if it's mild, you're probably at the right dose. If there's no toxicity, you think about increasing it. If there's a lot of toxicity, you need to decrease it. We all are pretty clear on that. Some of us like to decrease it by pill count and keep the continuous dosing. Others like to do one week on, one week off as a modification. One little trick to know that you're giving the right amount, check your patient's MCV. If they've been on capecitabine for, I don't know, a couple months, you'll notice that MCV will be going up because that's the antifolate effect that you're seeing. You got your own little built-in micro-biomarker in your CBC of every patient that you're giving capecitabine. So, I'm telling you, switch out to this dosing and you can give your ox every two weeks or every three weeks. I'll leave that up to you. That's another matter altogether. 

Consider Dose-Escalating Regorafenib [00:09:21]

Tony Saab taught us how to use regorafenib, Stivarga. Because we knew that if we gave full doses, 160 milligrams daily, it was too much, too spicy. Lots of patients said, forget it. I'm not taking that drug ever again. Tony showed that if you started lower at 80 and then inched it up, and then inched it up, you did a lot better

Should We Rethink TKI and Immunotherapy Dosing? [00:09:34] 

Now, what's the right dose of a tyrosine kinase inhibitor? The studies are done with maximum tolerated dose. Give as much as you can give. More is better. Use that in the clinical trial. But more and more, we are seeing that you don't need to give that much. But are we comfortable in dose-reducing? Are we okay with saying, all right, I'll just cut the dose back because Marshall said it's okay. No, we're not. Because we don't want to regret that it was our dose that maybe it didn't work. So, we're feeling compelled to give the dose. Even the insurance companies are mandating that we give the dose that is in the package insert. When, for a lot, maybe most, of these TKIs, we don't need to give nearly that much.

I believe the same is true for immunotherapy. Because let's face it those patients whom we stop for IO toxicities, you know, they seem to be doing okay. So maybe we don't need to do nearly the duration or as often. If the way the drugs work is the way they say they work, then you wouldn't need to have it continuously exposed all the time to patients. So, we're probably overdosing TKIs all the time, and we're probably overdosing immunotherapy. 

What Schedule Does Dr Marshall Use for Trifluridine/Tipiracil? [00:10:56]

 Another colon cancer drug that I think is important to understand is Lonsurf dosing, trifluridine/tipiracil. What a crazy regimen that was. So, five days on, two days off, five days on, two weeks off. It takes forever just to coach the patient on what to take, and there are two pill sizes and all of that, and myelosuppression is the big side effect of that regimen. We just looked at that and said, that's crazy, just give it every other week. So we still stick with our Monday through Friday because it's easier for patients to remember. And instead of two weeks in a row, we give it every other week. And believe it or not, that is essentially solved a lot of the cumulative suppression, myelosuppression, the nausea, all of that stuff that you see with that drug by getting away from the package insert. dose reducing, maybe a little using only one pill size, again, to get your optimum dose and schedule.

So, we need to understand better how to dose these medicines. The problem is, we don't use them that often, many of them, so we're dependent upon looking stuff up, and what the package insert, and what the insurance company, what the guidelines say. We all don't have a person who's an expert on speed dial that you can say, well, what would you do if you were giving this patient this treatment? So, we clearly need an improved resource for all of us to understand what the correct dose is that we need to use day in and day out to optimize our patients, both benefit but also toxicity, so that we know that we are doing the best job possible. 

Up Next: A Candid Conversation with Dr Mark Ratain on Drug Dosing [00:12:36] 

And, so, to that end, I have invited not only a lifelong, career long friend and mentor, but really what I think is maybe the world's expert in this space. And that's Dr Mark Ratain from the University of Chicago. He cares passionately about this and is actually doing something about it. So, listen to this interview with Mark Ratain, MD.

Dose Matters with Dr Mark Ratain

[00:12:58] John Marshall, MD: I only get the best people to interview for every major topic, and I am lucky enough to have known the gentleman next to me right now for almost all of my career. Dr Mark Ratain at the University of Chicago has been one of the world's leaders in not only drug development, but really the pharmacology of novel chemotherapy, novel biologics, etc., of really optimizing dose, schedule, efficacy. He's the real guru of this, and, honestly, is one of the few, let me put it this way, anchors or rudders in our overall cancer development pathway and system that's really keeping us honest about what we're doing. And it's not an easy position for him to take, but he continues to work on this, and I think has had a major influence on many, many cancer patients, and our practice over his great career.

[00:13:58] So, Mark, first, thank you very much for joining and talking about this important topic of dosing treatment. Mark J. Ratain, MD: Thank you, John, for having me.

[00:14:07] John Marshall, MD: So, let, let's just dive in. You and I are old salts. We've been doing drug development a long time. We used to have these great, you know, dose finding trials where we compare different doses that seems to have fallen off by the wayside. So, we have a sort of maximum tolerated dose for everything that gets approved out there. We all recognize as clinicians, it's too spicy, but we also don't wanna cut doses back because we don't want to shortchange patients. So, tell us a little bit about where this is, why that evolved, and maybe some of the newer projects that are going on in that space.

[00:14:41] Mark J. Ratain, MD: Well, it evolved because in the old days of, the start of chemotherapy, we didn't have effective drugs. We were treating diseases like leukemia and Hodgkin's disease and with drugs for which more is better. And so, we did the right thing. But as we began using chemotherapy for less sensitive diseases and with drugs that were less effective, like using 5-FU for colorectal cancer, more is not necessarily better. And yet we stayed with the more is better paradigm for decades and then even worse, when we developed better drugs, including, you know, targeted monoclonal antibodies, tyrosine kinase inhibitors, we kept the same paradigm, despite the lack of scientific justification.

[00:15:35] John Marshall, MD: You think you have a good reason of why we didn't sort of rethink this? Were we afraid that we might lose benefit and patients with cancer?

[00:15:45] Mark J. Ratain, MD: No, I think it's because, the way we've been doing it was quick and dirty from the standpoint of a company developing a drug. It's very quick to determine the maximally tolerated dose. That's an easy study to do. You don't need to be smart. You just need to push and push and push until the patient can't take it anymore. And so, you treat a bunch of patients, and you say, oh, we found our dose. And so that was quick.

[00:16:15] John Marshall, MD: Well, and I also think along with that, I keep thinking every time I see a new presentation of a novel therapy or a clinical trial, they pop that tox table up in front of us. And we've learned to just accept a fairly high burden of grade three toxicities, or a lot of patients getting grade one, two toxicities without really challenging the dose in that. So, we're co-conspirators, in some way, on this of accepting these doses and toxicities. 

[00:16:42] Mark J. Ratain, MD: Well, not only that, we've trained patients to expect these toxicities. 

[00:16:47] John Marshall, MD: If you don't get sick, it won't work. Right?

[00:16:49] Mark J. Ratain, MD: And, in fact, oncologists say, well, that's what we do. We manage side effects of drugs. Like if we didn't manage side effects what would we really do here? And so, no, it is, is part of the culture of both being an oncologist and being a cancer patient. 

And you hear people say, well, cancer is such a bad disease, you've got to push the dose, you've got to accept side effects. Well, in the greatest medical crisis of our lifetime, COVID, I don't recall a single drug development program in which any sponsor said we've got to push the dose. The remdesivir development, which was the first drug approved, did a careful, dose optimization study. The logic is completely flawed, it’s just part of the culture of oncology, and that culture, quite frankly, has harmed patients.

[00:17:49] John Marshall, MD: Totally agree. And you've been really helping to lead this, you know, carry this flag for us and point this out so that we can be better physicians, better, better providers, better outcomes even. And I know you'd had some discussions with one of your faculty colleagues and also FDA lead Rick Pazdur around this Project Optimus. Tell us a little bit about that encounter. 

[0018:11] Mark J. Ratain, MD: These discussions have been going on for many years, but the most recent major interaction was in the fall of 2020 during the pandemic when the University of Chicago Comprehensive Cancer Center gave Rick Pazdur our annual award, and he virtually visited us. And as part of that virtual visit, we had a group discussion, a group Zoom, involving our cancer center leadership and his center leadership at FDA. And during that I said, Rick, I don't know why you don't make companies optimize the dose before approval. And he said, Mark, you're right we're going to make them do that. And about 6 months later, he announced Project Optimus. That in many ways might be the history. I don't know what other discussions were ongoing at FDA prior to that meeting, but some of my FDA friends say that was a major moment for the FDA oncology leadership, that discussion that day.

[00:19:18] John Marshall, MD: Well, take that to the next step. has that been applied anywhere? Where, where are we going with that kind of thinking?

[00:19:24] Mark J. Ratain, MD: Well, the first thing that happened was when, FDA approved sotorasib In May of 2021 at a dose of 960 milligrams, they basically said in the review, we're pretty sure 960 milligrams is the wrong dose. There's no relationship between dose and response. There's no relationship even between dose and plasma concentration because the drug's not absorbed very well. but the only dose of which. There was sufficient data to evaluate, efficacy was 960 mg, so we'll approve the drug, but require the sponsor Amgen to conduct a post marketing trial, 960 mg versus 240 mg.

[00:20:10] John Marshall, MD: But let me interrupt right there real quick. So, if I go on right now as an oncologist and I've got a patient who's been maybe a candidate for sotorasib and I look online, 960 is what pops up on their official website and everything, and that's what that insurance provider is looking to provide. That's what the pharmacy we riffed on PBMs earlier, that's what they're expecting to provide. There's a business around this too. But, anyway, there's a study looking at two different doses,

[00:20:39] Mark J. Ratain, MD: So that study was completed, and that study was published recently in the European Journal of Cancer. And that study was presented last fall at a virtual ESMO ACR plenary session in which I was one of two discussants, the other one Sanjay Popat from the Royal Marsden. And we strongly disagreed with the presenters that 960 was the correct dose. The progression free survival was identical for 240 and 960. The progression free survival was the primary endpoint in the phase 3 trial versus docetaxel. The treatment related adverse events, grade 3 or higher, was significantly increased with the higher dose. And so, we wrote an editorial. That was just published earlier this month about that paper basically saying 960 is the wrong dose, that FDA may think it's the right dose, but they're wrong. The European payers and regulators should do their own due diligence. And it shouldn't be covered at 960. That's what we published in this European journal. Well, about a week or so ago, FDA published their interpretation of the data. The lead author is Harpreet Singh, who is no longer at FDA.

[00:22:07] John Marshall, MD: Right.

[00:22:07] Mark J. Ratain, MD: She left for industry. And basically, in the paper, 

[00:22:13] John Marshall, MD: She's quite a social media person too, by the way. 

[00:23:16] Mark J. Ratain, MD: Well, in that paper they basically don't even mention the progression free survival. That's all. Okay, they say the overall survival was longer with the higher dose, but overall survival is meaningless if there's no improvement in progression free survival, because that's only survival after you stop the drug, that's not an effect of the drug. There's no mention of the clinical pharmacology data. And there is mention of the colorectal cancer data saying, oh, well, 960 was better than 240 in colorectal cancer. They actually tabulated data for colorectal cancer in combination with panitumumab in support of a dosing decision for 960 in lung cancer, not mentioning the fact that in the New England Journal paper, reporting the colorectal study, the pharmacokinetic results for 960 and 240 were indistinguishable. In other words, 960 can't be better than 240 because you don't get more absorbed, and any differences are due to chance, not due to drug. 

[00:23:30] John Marshall, MD: You know, this isn't really that new of a story. The battle that's made me think about this topic is the dosing of capecitabine. I mean, you'll remember back a thousand years ago when we did dose finding studies for capecitabine, that low dose continuous actually was either equal or superior to the two-week-on-one-week-off higher dose, but Roche picked that dose. I always joked, even back then, because it would sell more pills. In the end, they would sell more pills, and dose intensity was still believed to be true back then. And getting folks to get away from those doses, to a more sort of, you know, prolonged and better tolerated dose has been a real struggle for me even to this day.

The newer colorectal cancer drugs, the same issue is there, whether it's regorafenib, or fruquintinib, they all have the same issue of overdosing, if you will. And so, to kind of bring this full circle, I keep thinking about pills, numbers of pills, and pricing. You know, what's your take on this being sort of a business emphasis that, you know, they make a pill size, they get an MTD, they set a price based on that, and there is some objective to sell pills. What's your take?

[00:24:49] Mark J. Ratain, MD: They're going to set a price before approval, and then they'll price it in a way that matches, that's consistent with that. The problem Amgen had was at the time of approval, they had a single formulation, 120 milligrams, and therefore, if the dose got changed to 240 milligrams, they would take a 75 percent haircut. And so, they have steadfastly stuck to 960 milligrams. This got the attention of Senator Durbin. He sent a letter to Amgen in May of this year, basically saying you're putting profits over patients. Now, unfortunately, it looks like FDA actually is part of the problem here that they incorrectly have supported Amgen's, you know, assessment that 960 is superior dose. And basically, on the basis of this, in part, you know, due to these small studies and they say, well, we don't know that 240 is non-inferior to 960. Of course you don't. But that's not the question. The question is, is there any evidence of 960 is superior to 240? And if you don't get more drug absorbed, it can't possibly be superior. Unless, I mean, I'm  interested to see FDA's model for how unabsorbed drug increases efficacy. In defense of the office of clinical pharmacology at FDA, they were excluded from authorship on the paper.

So, it excludes FDA experts, and FDA opinions, and the FDA review of that dose-finding study is not publicly available. And I don't know whether when it will be publicly available. I have a pending FOIA request for it. And I will be sure to make that public once I get a hold of it.

[00:26:59] John Marshall, MD: Yeah, let's sort of close on some advice and actually, I struggle with this myself. So, in my world of GI, I feel like I'm pretty good with the drugs I hand out. But you think about a general oncologist who's seeing these drugs, maybe once a year, maybe not even, and they are trying to figure out what the right dose is, and how best to take care of the patients in front of us. To my knowledge, there really isn't a, a great resource beyond what industry already provides us that would help coach us all on optimizing dose. Do you know of one and what's your advice to the oncologist out there with this stuff?

[00:27:41] Mark J. Ratain, MD: Well, we have a grant from Arnold Ventures. We've completed the analysis. We're building the website, and we'll have it. We've done it for all oral oncology drugs, all non-generic oral oncology drugs, and that will be available next year.

[00:27:59] John Marshall, MD: That's so cool. We're working on sort of a similar one where every drug, every gene, where we do a little short, you know, tick tock videos for our docs out there to say, what would you do, you know, in a patient with a certain medicine and the like? So, I'm glad to hear that you're doing that. Cause I do think we need that kind of resource and we'll be happy to help drive and, and, you know, get, get folks to use that. Because, honestly, in the end, what's going to have to happen is that consumer boots on the ground is going to have to recognize that, maximum tolerated dose isn't always the right answer. and in fact, it's increasingly less and less the right answer. And not only will that be a cost savings but a toxicity savings and maintenance of, of outcomes.

So, Dr. Mark Ratain, you're awesome as always and I know you will not let go of this flag and you'll continue to plant it further and further down the field to make sure that our patients get the best care they can in this cancer world we both live in. So, Mark, great seeing you and thank you for your time.

[00:29:00] Mark J. Ratain, MD: Thanks, John.

[00:29:02] John Marshall, MD: You know, the chance to get to talk to you guys through this vehicle is just really amazing and to get to really share the thoughts that I'm hearing, that I've experienced myself, with you in a sort of an unscripted process. 

I hope that as we end out this year, as we transition leadership in this country, that we are all okay, that we will make it, that we will continue to do a fabulous job in doing what we do to try and cure cancer and take care of patients, but also make sure that every day we try to wake up and say, how am I going to make the world today a little better?

So, I hope this time with me may help you see some way in your own head of how you too could make the world a better place. Until next time, John Marshall for Oncology Unscripted.

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