#133 - Vinay Prasad, M.D., M.P.H: Hallmarks of successful cancer policy

Hey everyone. Welcome to the Drive Podcast. I'm your host Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in depth content. If you want to take your knowledge of this space to the next level, at the end of this episode I'll explain what those benefits are. Or if you want to learn more now, head over to peterattiamd.com subscribe Now without further delay. Here's today's episode. My guest this week is Vinay Prasad. Vinay is a practicing hematologist and oncologist and associate professor of Medicine at UC San Francisco where he focused focuses on not just the treatment of patients, but also health policy, clinical trials, and decision making. He's what some might call a meta researcher. He studies the quality of medical evidence and lately has focused most of his energy on oncology. Of course, he's the author of over 250 academic articles along with two books, Ending Medical Reversal, which was published about five years ago and published this year, the book Malignant, which we spend a lot of time discussing. He also hosts the oncology podcast which is called Plenary Session. I recommend you check it out. And he runs a YouTube channel along with his various activities on social media. He's primarily active on Twitter. That's P R A S A D M D MPH where he writes some really great tutorials related to clinical trials, critical thinking, decision making, et cetera. In this episode we talk a little bit about his beginnings, how he got into medicine, and really how things that he saw during his medical training kind of woke him up to some of the issues in clinical medicine. Probably the first thing that he observed was some of the limitations in cardiology and how there was a disconnect between clinical practice and research. But really that kind of took off once he chose the profession of oncology, which is a field that is really rife with some of these inconsistencies. Now this is a podcast that sort of builds on a lot of the stuff that we discussed in a previous podcast with Azra Raza, but we go a little bit deeper into some of the structural failures. This one goes by quick and yet somehow at the end of it I looked and realized we'd been talking for two hours. I could have spoken with Vinay for Another two hours. We close this by doing kind of a deep dive on what he describes as his six hallmarks of cancer policy. And I think this is a really great discussion. I was just constantly impressed by the way that Vinay was able to kind of articulate things in ways that I even made the comment at one point, if you gave me two hours to explain what you just explained in five minutes, I wouldn't have been able to. So I hope you enjoy this, and without further delay, please enjoy my discussion with Vinay. Hey, Vinay, thank you so much for joining me. Where are you physically today?

I'm physically located in the Bay Area in one of the distant suburbs. Just a temporary place. I'm staying here, but hope to be settled in soon. I started at UC San Francisco pretty recently.

Yeah, I noticed that. And I was gonna ask you about that. That's a soon to be your new permanent gig, huh?

Yeah, I mean, I started the job, but I do not yet have a permanent place to stay. So I'm just kind of hanging out for now. But I'm gonna work on that. And right now, you know, we're in the midst of forest fires and Covid, and so it wasn't a terrific time to move.

In retrospect, UCSF has a dear place in my heart. When I was in medical school, which was at Stanford, we still spent a lot of time at ucsf. We had the option to spend time electively. And Stanford was not a great place to get a lot of trauma experience for a budding wannabe surgeon. But of course, San Francisco General was. And then many years later, when I returned, my wife was an ICU nurse at UCSF before later moving over to run the Coumadin Clinic, which was run by just a solo NP and one hematologist. So up on Parnassus there, it's some of the most beautiful views of the entire city. So one thing I remember her saying was there was this gym up on the Parnassus campus where she would go and work out at like 5:30 before clinic starts. And you'd sort of get to kind of just watch the city as the sun was coming up.

Oh, that's gorgeous. That sounds terrific. I'm actually based in San Francisco General Hospital for my clinic. So that's where I do my clinical time.

Ah, fantastic. So you and I were scheduled to speak, I think, initially. God, probably around the time of the COVID outbreak. And then obviously, everything kind of got derailed a little bit. So I appreciate your patience. There's a lot to talk about here. And I almost don't know where to begin. But I do think it probably helps the listener to understand your background a little bit, because it's a lot of times people who come to medicine through the not so obvious routes that maybe bring in a little bit of a different perspective. So I know you weren't a pre med student. It's not like you grew up thinking, I can't wait to be a doctor. If I recall from reading something, you were actually like a philosophy major in college, is that right?

Yeah, I guess I kind of might have done a little bit of both. I genuinely felt undecided at the time I graduated high school and I thought, I'm good in science, I like science. Maybe I'll major in science. And so when I started college at Michigan State University, I think my original major was in the sciences. Early on, in my second year, I took a philosophy class and it really kind of struck a chord. The professor was very kind and reached out to me and very quickly I added that on as a major. And so I ended up doing a little bit of both. I can't say when exactly I started thinking about medical school, but I remember feeling really sort of uncertain if that was the right path for me. I certainly wasn't somebody who in high school always knew they wanted to be a doctor or anything like that. It came to me sort of on the back end of college. Really.

You went to University of Chicago, is that correct?

That's right. For medical school, yeah.

What was that like? I mean, I know that different medical schools had different environments. Stanford, for what it's worth, was a very relaxed medical school. My guess is University of Chicago being one of the top 10 schools in the country was not relaxed. It didn't strike me as relaxed.

It's so funny you say that. When I was a medical student at University of Chicago, I once visited a friend who was doing his doctorate work at Stanford. And I toured the hospital and. And the windows were open and the smell of jasmine kind of wafted in and I was like, wow, this is a place of healing. And it was really markedly different than University of Chicago, which is a really gritty city hospital feel. A lot of the faculty had trained on the east coast and I think it really had that east coast mentality. It was an intense place. I remember yelling in the operating room was common. Throwing things was common. People getting chewed out was common. So it had all that sort of east coast feel, which these days might be a bygone era, but I kind of caught the Tail of it at least, maybe second generation, but I caught the tail of, I think, that sort of tough east coast mentality which was President Chicago. Yeah.

There's a book that I've spoken about before on the podcast called Forgive and Remember. I don't know if you ever read it. It was written by a sociologist from Pennsylvania University, Charles Bosk. And in the book, he spends 18 months with a group of surgical residents to. To understand the culture of surgical training. In the book, he never mentions, to my knowledge, I don't think he ever mentions where it was. But for some reason, either I spoke with Bosc and asked him or somehow inferred. But I believe it actually was the University of Chicago where it was. And you have to imagine, you take the environment you saw and go back a couple of decades. This was sort of late 70s, early 80s, and you want to talk about toxicity, but you're absolutely right. There's a real East Coast, west coast dividend in medical education. And I think, put it this way, when I applied to my residency on the east coast at Hopkins, there was a real view that no one from Stanford could go there and do general surgery because the last guy, I think, who had gone and done general surgery, who had come from Stanford had committed suicide.

I see. They thought you were too soft.

Yeah, the view was. It was just a little too soft to come from there. Of course, that's such a silly thing to say that this person's suicide had anything to do with that. I mean, the distinction between one versus the other. But it was really viewed as. No, no, no, no. Like if you went to Chicago, you could go to Hopkins. If you went to Penn or Michigan or something, you couldn't. But anyway, that was my view. Having friends that went to medical school in Chicago, that was academically just a tough school and a tough environment. So how did you like medical school?

Well, I guess I probably would be honest with you. I mean, I think I was in the fraction of people that didn't really care for it a lot of the time. To be more specific, when you started medical school, especially in the years in which I trained, you had two, just full years of classroom, almost 40 hours a week of just memorize this, kid, memorize this, memorize this, memorize this. You didn't really get into sort of the decision making of medicine. You didn't get much exposure to patients. You didn't get that side of medicine. What is actually medicine? Those first two years are. I found it really demoralizing. I mean, I wasn't somebody who was used to memorizing lots of things in sort of a disconnected way. I was somebody who liked to think about things and think about them rigorously. And so I really felt, I would say, very frustrated in the first two years. Step one, Studying was a very anxious time in my life, and I didn't quite care for it. And it was only when third year started and I was there on the wards, and I was on internal medicine first as my clerkship, and. And I had some really great and influential practitioners of medicine who would kind of teach me how they think about cases. That was when I started to feel like, okay, that's the first moment that this felt like the right choice for me. So it wasn't until my third year. So I was pretty frustrated in the beginning. And then from third year to fourth year. Fourth year is really sort of an expensive vacation. But there were ups and downs in that process, too.

Remind me where you did your residency.

Northwestern University. I stayed in the city.

You stayed in Chicago.

My folks at that time were living in Northwest Indiana, not too far. And so my undergrad, medical school, residency was all pretty close to where my family was.

Okay, so when is it, like, if we look at the work that you are now basically defining your career by right, I mean, and we're gonna get into this in some detail, where do you think those seeds were sown?

I guess I'd say I was somebody who probably said what I needed to say to get into medical school and get into residency. But the truth is, in my heart, I. I was probably somebody who was thinking about medical school as a route to private practice and that I saw myself as a practitioner. I didn't know exactly what field or what specialty, but I thought I would primarily be taking care of patients in a private practice setting. I think that was true Even when I graduated medical school and even sort of the beginning of the first year, my internship, it only kind of changed for me in the middle of residency. And what made it change for me was I had consistently been put in clinical situations where what I saw we were doing and then what I would read about in the evening, there was a disconnect. There were things we were doing that were not supported by strong evidence. There were some things that appeared to run counter to the best evidence, and it didn't make a lot of sense to me. And so I started just on the margins of that problem, doing a few studies to kind of make sense of what were these things that had become a part of medical culture that ultimately proved not to Work. We ended up calling that medical reversal. We wrote a few papers about it, but. But that was really kind of how I got into it. I got into it from the point of view of a clinician who was struggling to make sense of what was going on around me. And that was really how I fell into research. And I didn't know that research would become my career. But the funny thing about life is you do something long enough and it starts to define you. And so after maybe 15 or 20 papers in this space, people started to say, this is a guy who's doing health policy research in that space. And eventually it kind of just keeps yourself so busy, you're just doing the next thing, doing the next thing, and eventually it kind of starts to turn into a career.

So I think in your book you write a story about a woman who had a stent placed and had a bad outcome and maybe tell folks a little bit about A, what a stent is, B, what her situation was specifically, and perhaps C, and we can probably both elaborate on part C, which is what in the hell was going on with stents.

So I guess I would say I appreciate you looking through my book and reading it. I guess I would say that we try to use composite patients. We try not to base it on any one particular person. But the situation you're talking about, somebody who gets a stent placed for an indication that is kind of questionable, who suffers a complication. Oh, there are many people that come to my mind about that. I have very clear images in my mind of people in that situation. And I guess I would say, I guess there's two parts to this. So the, the first part is like, what is a stent? So a stent is a little flexible metallic tube that expands and it's often placed in a coronary artery when there is a blockage. And for people who come in with a heart attack, an ST elevation, myocardial infarction, a total blockage of the artery, a stent is a transformative, life saving intervention. It's one of those amazing medical miracles that we proudly celebrate in medicine. But it's also something like so many medical technologies that can be used for more broadly, it works really well in a critical situation. Maybe it works well for somebody who just has a little bit of narrowing of the arteries and maybe just a touch of angina. That's that kind of reproducible chest pain that comes on when you shovel your driveway in the winter or go for a long walk. So people would extrapolate from the critical situation. To less severe situations in medicine. And of course, there's a lot more less severe situations than there are severe situations. So it becomes a big driver of market share. So it turns out stents became very popular for chronic stable angina. And I knew in the years in which I was a resident that we had just had a large, mega randomized controlled trial called courage that asked whether or not stents lower the rate of heart attack or improve longevity. And the answer was, for people with chronic stable angina, not that acute heart attack, but this sort of chest pain that comes on when you shovel your driveway, there was no improvement in survival and no reduction in subsequent myocardial infarction or heart attack. Yet survey after survey of patients showed that when they were consented to the procedure, when they had it done, they believed it was being done with that purpose in mind. So there was a disconnect between what patients felt it was for and what doctors knew it could do. This disconnect always played a role in the lives of residents. We're not the people who place the stent. We're the people who manage the patient in the days afterwards. And every so often you place a stent, something bad happens. There can be a cardiac arrest on the table. There can be an occlusion of the stent, a thrombus that forms within this foreign body that's being placed in the artery. And we witnessed several of these sort of complications. These are known complications. All things in medicine have some complications. But the question that kind of plagued me was, it's okay to accept the risk of a complication if the procedure has a net benefit, but if the procedure is questionable as it's being done and the benefit is questionable, you're just taking risk without any upside. So cases like that that we talk about in the book were a powerful, I think, motivator for me personally to kind of look deeper into this issue, to really understand why we do what we do. And that led to a lot of work in this space.

And I think part of it is this gets to how we deal with policy, especially on the procedural side, which I think we'll get to, is because I remember seeing this very tangentially as a resident as well, you couldn't ignore the conflict of interest that existed there, which was when interventional cardiologists were being compensated for the number of stents being placed. And I say that to be clear, not being critical of them, but acknowledging that if I were in their situation, I'm not sure how I would self police. That's the real issue. It's not that they're necessarily bad people, but they're people.

They're just good people. They're just normal people.

Yeah, they're good people. And we all suffer from our own cognitive biases. So what was the next step on that rabbit hole?

I just want to kind of build on what you're saying, which I think is really astute with, which is that these are just people. Interventional cardiologists are just people. Like, we're all people. And they suffer from the same sort of psychological trappings that we all suffer from. And in this case, I think there's two parts to the equation that make stents so seductive. So part one is you place this stent, and the patient comes back in your office nine times out of ten, and they're happy that you did it. They believe you have saved their life or extended their life. They may even believe they feel better. And in fact, we could talk about orbita and whether or not that's a real effect or a placebo effect. We can come to that. But they believe they feel better. They believe you saved their life. So you do this procedure, the patient comes to your office, they say, thank you so much, doctor. You saved my life. And you know what? It doesn't hurt so much when I shovel the driveway anymore. Thank you. So you pair that incredibly powerful feeling of gratitude. You pair that with one other thing, which is you get a little bit of money, and you get more money the more you do. So when you combine that powerful psychological stimulus of gratitude or with a little bit of financial remuneration, I think that's the methamphetamine of being a doctor. That's a highly addictive substance, that whatever we do in medicine, particularly procedures, because that's what pays, we become addicted to that. And then a couple years later, some investigators say, you know what? The patient didn't feel better, actually, when we randomized them to stenting or we made them wear headphones and we told them we put a stent, but we didn't put the stent. We kind of deceived them into thinking they had a stent. They actually both had the same exercise tolerance improvement on a treadmill test. So that's the Orbitist study. So when somebody comes at you and they tell you that, you know, actually it's just a placebo effect, it doesn't actually improve symptoms. It's psychologically unacceptable. How can that be? It doesn't fit with my experience, and it doesn't fit with the way I'VE been rewarded. And I think that's in part why many of these medical practices that have evidence, I think, that goes the other way, are very difficult to dispel. We have become addicted to doing them.

So you're chugging along through your residency, which means you're basically getting to rotate through all the different subspecialties within medicine. Obviously, you're taking care of the critical cardiac patients. Presumably at some point, you're taking care of GI patients, oncology patients. What is this journey like for you now that you've got bit by this bug of. Hey, wait a minute. If the stent thing is a little bit off the rails, is there anything else in medicine that's similarly off the rails?

No. It's like being a kid in a Kanzi store. Peter, you're onto something. I mean, it's kind of a privilege, really, now that I look back on it. As a student, I got to spend a month with neurosurgeons watching what they do. Then the next month I got to spend it with a breast surgeon. The next month I spend it with a radonc specialist. As a resident, it's a GI doctor one for two weeks, then it's a hematologist, and then it's an allergist. I mean, it's really a privilege. I get to be a fly on the wall of so many different situations and see so much of medical practice. And the moment you start to recognize some of the classic, I think, research pitfalls, the evidence pitfalls, you do, as you exactly say, you start to see it everywhere. You start to see it in how decisions are made in one clinic, decisions are made in another clinic. There's a theme that emerges. So one theme might be for mechanical interventions done to. To alleviate a subjective symptom, whether it's angina or pain or dyspnea, which is how you catch your breath or back pain or any sort of discomfort. If you do a mechanical intervention for that, a number of studies show that it is no better than a sham intervention. And that's different than if you compare it to a medical pill where the person doesn't get that sort of psychological benefit that you're doing something for them. So you start to see this theme emerge when you go shadow.

Many places explain to folks what a sham intervention is, because I think we don't do them much anymore. But there was a day when actual sham surgical procedures were done.

Yeah, well, you might know a little bit more about that surgical history than I do, but I guess I would say when I think about a sham intervention. I say, let's just start with arthroscopic knee surgery. So, you know, a lot of people have pain and discomfort and degenerative osteoarthritis of the knee, and they get a orthopedist to go in with a scope and actually debride some of the cartilage, clean up the joint, make it look a little nicer, so hopefully they have less pain and discomfort. And. And lo and behold, if you have that done, people feel better afterwards than they did before. And if you compare that to physical therapy or maybe taking ibuprofen, it might even work better. But when you compare it against a sham intervention, that's where the orthopod goes in with the scope. They fiddle with it a little bit, but they don't actually do anything inside, and they take out the scope and they tell you they did something. There is no difference in outcomes. They both feel better. And what that shows you, it's not the debridement per se, it's the psychological stimulus of having that done. And this is true for injecting polyacrylamide cement into osteoporotic fractures of the vertebra. It's true for a couple of shoulder procedures. It's true for, I believe, stenting chronic stable angina. That's what the orbit trial shows. That's they did it, or they made the person believe they did it. And this is called a sham intervention. And it's a really useful, I think, method to separate what is the benefit from. From doing that final step that you think matters versus from all the other things we do in medicine, which is reassuring the patient, telling them, I'm gonna fix it, telling them that I fixed it, and telling them that they should feel better. What's the added benefit of actually doing.

The thing in orbita? Did they actually cannulate the femoral artery?

Yeah, they did. Yeah, they cannulated the artery. And I believe they performed a diagnostic angiogram. They have all the pictures of it, and they made the patient wear headphones, and they didn't inform them whether or not they had the stent placed. And then the primary outcome that they're looking at is the modified Bruce protocol exercise treadmill. So they put people on treadmills and see how long they can go. And we knew from prior stenting trials that when you stent someone and you tell them you stent them, they're going for another minute, two minutes. And in Orbita study, they're going for a difference of 16 seconds, and it's not statistically significant, and it's not clinically meaningful. So they really do call into question that the benefit of that procedure on this sort of standardized endpoint of subjective symptoms is really sort of what the patient believes it to be. And so that's what a sham study is. And so to your point, which is, you see the theme emerge across many spaces in medicine when you have the privilege of getting to shadow in many spaces. And now, five years into my faculty career, I don't have that privilege too often. I'm in my own bubble. I'm in my own clinic. I'm in oncology and hematology, but in the last year befriended an orthopedic surgeon who I really like. I have a great deal of respect for her. She's terrific. And she let me shadow on a couple of surgeries that I hadn't seen. So I get to feel like a medical student again. Maybe someday it'll lead to a project that we're working on. But to answer your question, I mean, I think you're right, which is that you do get a sense of sort of the broad lay of the land in medicine when you are a trainee and you can see things with fresh eyes and in many places.

So how did you choose oncology as your fellowship?

I guess the first jump in becoming an oncologist is you decide to go into internal medicine. I went into internal medicine because I'd had so many positive experiences in internal medicine. I guess the other options for listeners who may not know are you could do general surgery residency. There are a few subspecialties of surgery you can go into right off the bat, like urology or ear, nose and throat, or neurosurgery. You could also be a radiation oncologist. You could be an OB gyn, You could be a pediatrician. For me, general internal medicine was sort of a very broad category. U of C sent the most kids each year into internal medicine. We had really good mentors in internal medicine. So I knew I wanted to be an internist of some sort. I wanted to kind of have a broad look at the body and think of things very broadly. I thought for a while I might be a cardiologist, not just because that's a stereotype, but because I actually was a little bit interested in cardiology. I thought I might be an intensivist or critical care doctor along the way. And finally, I had some really positive experiences with a couple of oncologists at Northwestern, one of which is Dr. Munshi, who's still there on faculty, but really terrific experiences with sort of consummate doctors. People who balanced. They knew a little bit about the basic science. They really knew about clinical trials. They knew about evidence, and they were really good with patients and great bedside manner. And they made decisions I felt were substantive and important. And so because of that, it's so funny how so much of life is shaped by just the people you meet. I decided to go into oncology, and so I made that decision early on in my internal medicine training.

Talk to me about your first days as a medical oncology fellow. Now, you're basically also going through comparable stuff. Presumably you're doing rotations on GI oncology, going through the liquid cancers. I mean, you're running the gamut again, correct?

Yeah. You have a great sense of it. Yeah. The first time I left the Midwest, I went to Washington, D.C. and the National Cancer Institute. They have a very unique and fascinating program. And you get to see a lot of stuff. And it's just, as you say, one month you're with a couple of GI oncologists. You spend a few days at the nci, couple days at Georgetown, and maybe you go to Washington Hospital center, one of the other flagship hospitals in the city. One month you may go to Hopkins and do leukemia. Another month you may be at the NCI on their clinics, which are really highly specialized, often rare disease. Every patient on a clinical trial or protocol, just a different experience. And so you get a huge, I think, exposure. In oncology, you get exposure to so many different diseases, many of which, before that time, you know very little of. I think the sad reality of internal medicine training is it trains you a lot in things like cardiology and pulmonary disease. But oncology is one of the things that you don't get into that much until you commit to being an oncologist. And so the learning curve is steep. You gotta learn a lot of drugs. There are more new drugs every day, which I think we're gonna talk about. And you gotta learn a lot of new diseases and a lot of genetics and a lot of things you didn't know before. And so the learning curve is steep. But to be honest, I probably think that's one of my favorite years of training. My first year as an oncology fellow, I had a really great cohort of people training with. We always went for the drink on Friday evenings to have some camaraderie, and we had a great exposure to faculty, and we were learning 20 new things every day. I mean, I thought it was really sort of a Terrific and transformational year for me.

It's also a special place. I was at NCI in medical school and then for two years after and lived just outside of Bethesda in Silver Spring. And I still think of it as some of the fondest memories, which is a very special place. I know we're going to come back and talk about nih and I think the NIH in particular, how it funds research, is. I certainly have some issues with it and maybe we can get into that. But there's really. It's not hyperbolic to say there's no place like it on earth. And I still remember that first day I stepped foot on that campus as a third year medical student, just thinking, how can this place exist? It is so marvelous.

Yeah, it's a marvelous set of buildings there in Bethesda. This huge campus, a lot of greenery, so many different buildings. And the building that predominantly where clinical operations have is building 10, the sort of centerpiece building, this massive federal building that's just been constantly expanded over the years. So much of history occurred in that building. People pioneered the cure for Hodgkin's lymphoma, at least the chemotherapeutic cure for Hodgkin's lymphoma. People did some fundamental work on chemotherapy and breast cancer. So many great laboratory scientists come from that place. And it's a place that certainly gives you a feeling of awe and reverence when you're actually physically there. And I think many of us really are appreciative of the time we spent training there. I think it's a great experience for anyone who listens, who's a trainee, or they're thinking about going into medicine. If you can spend a year there, spend a summer there, or do a fellowship there, you'll be richer for it.

Now, coming back to oncology, I mean, I think again, maybe I'm biased because I know enough about cancer relative to other disciplines of medicine. But one of the things that strikes me as challenging about doing a fellowship in medical oncology as you did, is that there's not a lot that's consistent or similar between acute lymphocytic leukemia or lymphoblastic leukemia and breast cancer. And even though they're both quote, unquote, cancer, for all intents and purposes, they're totally different diseases. And now multiply that by all the cancers you just rattled off, right? You've got these patients with lymphomas and some of them are Hodgkin's and some of Them are not Hodgkin's. And then you've got the leukemias, and then you've got the pancreatic cancer and you've got the colon cancer and the breast cancer and the head and neck cancers. That is a lot of different diseases. How did you sort of navigate your way through that as a trainee? And then how do you decide as you're going through that what does this mean for me in my career?

I mean, I agree with your observation that cancer is a category term. It's not a single monolith. It's so many things. And even within cancers, I mean even within something as small as non small cell lung cancer, which itself is a category of lung cancer, now we have EGFR mutation driven non small cell lung cancer. We have alkary arranged non small cell lung cancer, Rett and then Ross one we have all these molecular categories, we have ras, this undruggable target. We have superimposed with that sort of the role of immunotherapy. I mean it's a lot and I guess the only way to kind of do it is just to do it piecemeal, a little bit at a time. Just reading as you go. Every night you read an article or two, you read up to date, you start there, eventually you start to dig into the references. I don't pretend to know everything about every cancer, even to this date, I don't think. You know, I once heard somebody say 1963 was the last time a scientist died who knew everything. I mean it's just impossible to know it all. You can't know all the basic science, you can't know all the clinical medicine. I pick a certain spot and I think that spot is the spot of a clinician. I mean my primary sort of interest and still to this day what I do with about half my time hour wise is see patients and think about patient care. So I start with that vantage and then I go outward from there. And so what trials do I need to know? What clinical evidence do I need to know? What heuristics do I need to know to guide patient care? How can I work on my bedside manner? And then beyond that, what policy determines these things and what basic science is relevant to that? But yeah, I don't know everything about cancer. Basic science. I don't pretend to. That's beyond what I can know. That's what most people do in oncology. They start with the patient, they work their way outward and they try to learn as much as possible. And you're always Going to be learning new things, even four or five, six years into practice, as I am now.

You've brought up bedside manner indirectly twice. So I want to touch on that. It obviously means a lot to you. You mentioned it in the first setting with respect to a mentor you had. And again, you referenced it now in a way that I think is quite interesting, which is it's an area of something you would think about improving upon, being better in. Do you get the sense a lot of doctors feel that way? And how do you specifically think about improving that? Because anybody who's done what you do understands two things that are simultaneously true, yet cut at odds. The first is the practice of medicine can be exhausting. And at times it can sort of suck the life out of the practitioner, be it the doctor, the nurse, the therapist, et cetera. But the flip side of that is again, you referenced this earlier. It's an unmistakable privilege. And that anybody gets to be that intimate with another human being at their most vulnerable time, that's something that can't really be forgotten. And therein lies this tension, at least for me, around what bedside manner means.

Yeah, I mean, I guess I can't profess to be the expert in bedside manner, but it is something that I take seriously and I'm constantly trying to do better. I'll start by saying one thing. I think there is a misconception, I think among many people outside of oncology that oncology is often doom and gloom in tough situations. And I guess I want to say that that is true. There is a fair bit of end of life in oncology. We do have to have those hard conversations, but it's not exclusively true. That's not all we do. We also have a lot of people who, who are concerned about things that frankly are not gonna be the thing that shortens their life. It's not gonna be the end of the world. We also have many patients in whom we cure and we have to follow for long term side effects. So it's really a range of medical experiences, some of which I think is that tough stuff that people focus on. I'll just tell you one anecdote, sort of what put it all in perspective for me. When I was at the nci, I worked with a really senior oncologist who had been practicing for 30 years. And we had seen a patient on several visits. And I'd followed this patient for many months with this senior oncologist. And the senior oncologist had followed this patient for, I think, over a decade. We finally reached an impasse we reached a situation where there were really no further therapeutic options. The tumors were growing uncontrolled. It was clearly going to take this man's life. And we had sort of radiographic and laboratory evidence that that was the case. We were going to go into that room, and this senior oncologist was going to have to tell this gentleman, somebody he had known for over maybe nearly a decade at that point, that there was nothing more he could do for him and that he. He was gonna pass away. To me, as a trainee, I thought that, I have no idea how this guy's gonna do this, because this is a heartbreaking conversation. My heart is broken, and I've only known this guy for a few weeks, and I'm not in his shoes. And so I go into the room, and he does what would be the stuff of legend. I mean, he's compassionate, he's caring. He's hearing the patient, he's seeing the patient. He's keeping a little bit of distance. He's giving the information he needs to give, but. But he's also giving sort of the emotional support he needs to give as well. It's very hard for me to even describe how he did it. It felt like magic to me as a trainee. And afterwards, this patient thanks him for the news and is clearly upset about it, but then hugs him and says, I just want to thank you for taking care of me for the last 10 years. I couldn't have done this without you. We come out of that room, and we're just all sort of in that shocked feeling of what we had borne witness to, which is really sort of that rare, privileged moment of being a doctor. And I remember telling this attending physician, I've seen a bunch of people do that. I don't think I've ever seen anyone do it as gracefully as you have done. That was really well done. How do you think about that? What's going through your mind? How do you approach these situations? And he looked at me and he said, I can't say that I'm good at it after doing it for 30 years, but I can say I try to be better at it each year. And I realized that that was his secret, of course, is that he had never let himself become complacent. He never let himself feel like he did a good job. He always aspired to be a little bit better at delivering that news, a little bit more in the moment than the year before. And that was why he was so good at it, is that he didn't take it for Granted, he knew how important it was and he worked on it. And I guess that's how the moment he told me that, obviously it was sort of the moment that that was how I was going to think about it forever, because he was right. And it's so easy to think as an oncologist that your decision is just prescribing the right chemotherapy drug. But so much of oncology is being the person you need to be for this person who needs you to be there for them in that moment. And I think that's in part what makes the field so rich and so interesting.

First of all, that's an absolutely beautiful story. Secondly, I find it interesting that it's hard to actually articulate the nuances of what he said while you're still able to capture the gestalt of it. And that actually echoes an experience I had also at the NCI with my mentor who I remember a very similar situation. This was a very young patient, about 27 years old, metastatic melanoma. He had progressed through at the time, the best available immunotherapy. So a couple things that stood out to me. One is when we were rounding on patients, we were never permitted to say, this patient failed such and such as, you know, in oncology, that's a very common parlance. Mr. So and so is a 27 year old male. He has failed Interleukin 2, he failed GP100 vaccine, da, da, da, da, da. No, it was never that. It was the therapy failed the patient. The patient didn't fail the therapy. So we were very clear in our words, there was no ambiguity about how we spoke about it. But when it became clear, just as you described radiographically, that there was now no option remaining for this patient and the tumors in his lungs and liver were exploding. Steve Rosenberg was my mentor. He said something to me that was, it's really easy at this point to think that because we have failed, we should be ashamed and we should run away from this patient. But he said patients who are dying need us more than patients who are living, which again, sounds kind of vague, but, but it's that ethos that gets carried into the discussion. And if you think of it that way, I think that's what actually contributed to the interaction. So your story is really a beautiful example of that. We're going to end up talking quite a bit about cancer here, not only because it's your career, but it's also potentially, maybe outside of cardiology, one of the places where we see the best of intentions gone awry with respect to how to help people. God, there's a part of me that almost wants to jump right into your hallmarks because you close your book with. And by the way, I'm in the process of sort of trying to write a book so I can appreciate the comedic relief in how the appendix or slash end of your book is. Oh, by the way, as I finish this book, I think I finally figured out a succinct way to explain this now, which I loved.

Yeah, yeah, so true.

But maybe we'll save that for a moment because I think that's a nice way to synthesize it, unless you just want to start with that. But do you want to kind of get into a little bit of the how you came to appreciate what was not working and how that sort of led you to formulate your journey through this?

Yeah, I guess I'd say I'll talk a little bit about what are the sort of structural problems in oncology. But I guess I'd say one of the sort of moments in my life that it all came into crystal clear focus was there was a year at the National Oncology Conference that there was one super transformational drug and it was the drug that made the big stage. And it was the drug everyone was celebrating. And it was a drug that prior to having this drug, the median survival with this condition was something on the order of six months. And now that we have this drug, unfortunately nobody was cured with this drug, but the median survival was extended to 11 months. And so that's something like five month improvement in average median survival that a patient would experience. And it was getting standing ovations and people were incredibly enthusiastic about it. And I just remember, I think at the time the conference was going on in Chicago and one of my high school friends was visiting, he asked me, he's like, you know, what's the big talk at that conference? And I told him about this drug survival six months and now it's gone to 11 months. And he said six months, 11 months. And he said, oh, he said, what are you talking about? He said, do better than that. That's not good. I mean, 11 months, not good enough, man. He just said it and it was just his gut reaction. He didn't go to medical school and he didn't even complete college, but he's a terrific person and. But he was just giving his sort of just raw feeling about that that wasn't good enough. You all need to aspire for more. And led to a lot of investigations where we and others have Looked at, what's the average benefit of a new cancer drug coming to market? If you look at 71 consecutively approved drugs for the solid cancers, as Foho and colleagues did in a famous paper a few years ago, the average improvement was 2.1 months. So that's the average of 71 drugs. Two months can mean a lot to somebody. I mean, those are. Those could be two months where you do a lot of important things. But two months also feels like, boy, can't we do better than that? And two months should also come with another asterisk, which is what is the cost of these medications. They now routinely run 100,000 to $200,000 per year of treatment. And you got to take it for maybe 8, 9, 10, 10 months to get the two month benefit. So you're spending nearly $100,000 of money just on the drug itself. Potentially all these other costs that come. And so many of us, myself included, started to feel like, why are we spending so much money on these drugs that appear to offer less than what we would want and hope for for our patients? Why are there so many of them coming? Why aren't there fewer but better drugs coming? What are the sort of structural problems in this space that create a glut of often me too drugs? And by that I mean there's a Coca Cola and there's a Pepsi Cola, and we're getting lots of Pepsi Colas. We're getting a lot of me too drugs. We're not getting as many drugs that are as novel, that really are transformative. And so that was kind of one of the core questions that started me on this path. And Malignant is sort of a book that summarizes sort of all the work we've done in cancer and cancer drug space and drug policy space. But it wasn't, of course, the goal when we started doing this work. We just kind of wanted to understand a bunch of things. And after a while, we understood a few things in a way, and we realized that. I realized that there's a story that could be told across all these different domains and that it makes more sense when you tell the whole story. And so that's why I decided to write that book.

So let's start with the idea of reversal. You alluded to it earlier. Let's go back and revisit that.

So that was sort of inspired by work I did as a resident. I had seen those situations that we talked about, situations where people were getting things done that appeared to run counter to the best available evidence. And With a colleague of mine, Adam Sifu, who is a professor at the University of Chicago. He was a former teacher of mine, later became a mentor of mine, and later became a friend, which is sort of how the progression of those events often is in life. We started to ask a bunch of questions about how many medical practices are adopted based on low levels of evidence. What drive their adoption? And what happens when, years later, people come along and do really carefully done, rigorous studies and find that some of them do not work as intended? And we called those practices practices that weren't just replaced by something better, but practices that truly were reversed. We found that not doing it was better, or whatever you did before was better. We called those medical reversals, and we started to kind of make lists of them, keep track of them, and try to understand how often they occur, why they occur, what the downsides of having so many reversals are. That led to the sort of. The first book that I wrote with Adam C. Foo, which is called Ending Medical Reversal, which is really about all the flip flops that happen in the doctor's office.

What are some of the examples that people might bring to mind when you think about that?

I mean, I guess a lot of them are actually from our talk and shop or sort of things that doctors do. But I'll give you a few examples. So one is hormone therapy. So there was this very provocative idea that was put out in the 1990s and supported by a couple of observational studies from the Harvard investigators. And that was the idea that women who typically have low rates of cardiovascular events when they go through menopause, they have a higher rate of cardiovascular events. Maybe estrogen was protecting them, lowering the rate of cardiovascular events. And maybe if we supplement them with estrogen after menopause, they'll have lower rates of cardiovascular events. A retrospective observational study from Harvard found that nurses who happened to take hormone therapy replacement therapy did, in fact, have lower rates of cardiovascular disease. And this led to sort of widespread promotion. There's a company called Wyeth that was really, I think, instrumental in driving prescriptions of hormone replacement therapy. There was a lot of basic science evidence that corroborated that estrogen has sort of favorable effects on vascular endothelium, et cetera, et cetera. It quickly became sort of a widely used common medication, accruing dollar amounts in the billions of dollars. And then, lo and behold, in 2001, 2002, a randomized controlled trial called Women's Health Initiative came out. But randomly assigned postmenopausal women to estrogen supplementation or not. And it found, in fact it was halted for an increase in thromboembolic and cardiovascular events. It actually did the opposite of what investigators had thought. That was sort of a seminal moment, I think for many people that maybe things that are widely done don't work as intended. I'll give you just another example. After somebody has a heart attack, if you put them on an EKG machine and watch it, you'll see there are a bunch of aberrant beats, premature ventricular contractions, PVCs. A number of really well done studies have shown that the more PVCs a patient had, the more likely they are to have sudden cardiac death. And there was a reason why that might happen, that these aberrant electrical activity of the heart could actually precipitate a re entrance circuit and precipitate actually cardiac arrest. A number of drugs were made that could suppress PVCs. They suppressed PVCs rather potently. So you could have somebody take the drug and you can watch those PVCs just drop out of the EKG tracing. And finally somebody came along and said, look, we know PVCs are bad, we know the drug suppresses PVCs, but we don't know for sure the drug lowers the risk of dying. Let's test that, let's do a randomized trial. And they did that randomized trial. It was called cast. And cardiologists were really reluctant to randomize patients because they thought it was unethical not to give the drug. And finally, through persistence, they did do the randomized study and actually found that it increased the risk of dying. And so those studies have led to the abandonment, Primarily the Class 1C agents, Flecainide and the like. And I think what the takeaway message there is that, wow, a lot of smart, well intentioned people who really have plausible pathophysiology, who have a compelling retrospective observational story, they can be wrong. And has this happened elsewhere? And so we started investigating. Now we have lists of hundreds of items. They span everything from ways in which we screen patients, ways in which we test patients, drugs we give patients, procedures we do on patients, surgeries we do on patients. It really spans the gamut. There have been these medical reversals across broad domains of medicine. They are quite common.

I'd like to come back to one of those because I do think the WHI is arguably the worst study that's ever been done. Which then brings up a broader question, which is how do we know if the patient in front of us is represented by the patient in this study, but I don't want to take us off the oncology path. Although the WHI's biggest headline, of course, was the increase in the risk of breast cancer, which of course has since been abandoned. Which actually brings up another point which is the difference between relative risk and absolute risk. So I think there's a lot of interesting stuff to talk about. So let's get back to oncology and go back to what you were just sort of outlining, as I think the broad problem statement here, which is we've got a disease that I think it's safe to say we haven't really had much success against, despite a lot of propaganda. I sort of explain it to my patients this way. I don't know if you'd agree, but I say, look, there are three broad pillars of disease, chronic disease that are going to kill us. So you've got sort of this foundation of metabolic disease. So that's everything from hyperinsulinemia to insulin resistance to fatty liver disease to type 2 diabetes. That creates the foundation upon which three other disease processes get a lot worse. Cardiovascular and cerebrovascular disease, cancer, cancer and neurodegenerative disease. There's really only one of those three pillars we've had some success against, and that's cardiovascular disease. Your probability of surviving a heart attack in 2020 is infinitely better than 1960. I mean, between advanced cardiac life support, better drugs to lower cholesterol, lower blood pressure, as you pointed out earlier, stents that actually do their job in patients who are having an MI or immediately post. And also, I think we have a greater pathophysiologic understanding of it. But if you have metastatic breast cancer in 2020 versus 1970 or 1960, if you have Alzheimer's disease in 2020 versus 1970 or 1960, you're not a hell of a lot better off. And I think that's a hard thing for people to understand, especially when you consider the resources that have been put at it. Have you got a ballpark of how much has been invested in cancer research in the last 50 years? Directionally, since the war on cancer was.

Declared, the total will easily be in the hundreds of billions of dollars. So I guess I would say, I mean, I think your assessment, although people may not like it, I think it is not inaccurate, it is accurate assessment, is that we've poured in hundreds of billions of dollars. That's probably combined with public purses and private purses and the returns on that. It's easy to sort of fixate on the few sort of Examples where we've made massive progress. But we can't forget the denominator, which is the average person walking in clinic who might not have chronic myeloid leukemia or one of the rare conditions that we've made sort of transformative leaps in. The average person, I think, is still facing a very grave prognosis, and that the progress is, as my friend said, just not good enough. You got to do better.

Yeah, it's a great story about your friend, because sometimes you just need an outsider to sort of call your bs, which is, we celebrate this drug. I remember when I was in residence, I don't remember what drug it was, but I literally remember going to Asco or something, and someone presented a drug that increased median survival by 0.7 months. 0.7 months, right. 20 days. And I remember doing the math. It was at a cost of $38,000 for the extra 20 days. And, I mean, I think people listening to this might be understandable to question, well, who are we to say what $38,000 is worth? How do you think about that question, which is the societal cost versus the individual cost? So, all things equal, let's assume there was no toxicity of the drug, or let's assume that the pain and discomfort of the drug wasn't a deciding factor. Who is to decide the cost of a life?

I guess before I dive into that answer, let me give a little bit more background that I think will even make it more sort of relevant for the listener to really get a sense of why I'm gonna answer the way I answer, which is that 0.7 months, that's not in everybody. And what do I mean by that? So the trials that we use to identify these numerical amounts that the drugs improve survival are not average Americans off the street with the cancer. They're really carefully curated populations. They're often 10 years younger than. Than average cancer patients. They don't have the same range of comorbidities. They don't have as much diabetes. They're not as overweight. They don't have cardiovascular disease. They don't have renal dysfunction. They're younger, healthier. One of my colleagues describes clinical trial patients as somebody who could run a marathon who also happens to have cancer. They're really fit individuals. And in that person, you give them a drug that may make some of them have diarrhea eight times a day or make their hands and feet ache or make them lose their hair or have bone marrow suppression or all of these things, but because they're so fit, they can tolerate that drug, and they can take that dose and they can handle those side effects. And in that person, even though they push the dose and that person can handle all that side effects, the benefit is still 0.7 months. So now imagine what happens when you give it to an older person who's frail, who can't handle the full dose because they need a dose reduction because that side effect is massively more severe in that person, or what's the benefit in that person? And I think a number of empirical studies have looked at these cancer drugs and find that the benefits in the average American are maybe even absent. I mean, I'll give you one example. There's a drug, Sorafenib, in the trial that led to its approval. This is for patients with liver cancer that can't be treated by surgery. This is liver cancer where the horse has leapt out of the barn and it cannot be cured with surgical resection or transplant. If you randomize them to sorafenib or placebo. Sugar pill, 11 months median survival with sorafenib and about 8 months with placebo, a difference of about 3 months. And this got a standing ovation at the national meeting. People really celebrated this drug. A couple of researchers looked at Medicare data sets, SEER Medicare, which is Americans over the age of 65, and they found people who took sorafenib for this disease. And they found the median survival of somebody who took Serafinib in Medicare was around four months. So in other words, in the real world, somebody taking the drug that improves survival, like lives 50% as long as the person taking sugarpill in the trial, which just shows you the grand canyon of difference between real world patients and clinical trial patients. And in the real world, they compared those people taking sorafenib who live four months to similar people who didn't take sorafenib, and they also live four months. So I think that some of the benefits of these drugs do evaporate when you give them in broad populations.

First of all, I'm really glad you brought that up. I interviewed Azra Raza a little while ago, and she made the same point. I just don't think that can be overstated. So I want to make sure that people really understand what you're getting at. When we look at nameplate clinical trials, they aren't just best case scenario by a little bit. They are best case scenario by a log order based on patient selection. And let's be clear, if you're in the business of trying to get your drug approved, it is in your Best interest to spoon feed and hand pick the absolute healthiest people on the planet in whom to test your drug. So again, the system is set up to make this happen. This isn't some grand conspiracy. It's common sense. You've spent a billion dollars generating this drug. The final hurdle for you to get this drug to market is a very large phase three trial. You're not about to blow it by screwing up the patient selection. It's no different than being a trial lawyer who spends a year preparing for a case, only to pick the wrong jury. You've got to do your job and pick the right patients. Your point is. Hey, and Azra made the same point. Look, the likelihood that the person sitting in your clinic in front of you is half as healthy as the patient, that clinical trial is very low, and therefore they're not going to be as resilient, which means, A, they probably can't tolerate the drug as well, and B, they don't have the physiologic reserve such that the delta between them and the untreated patient is likely to be far compressed.

That's right. And I think you make another terrific point, which is that we can't blame the tiger for being the tiger. The pharmaceutical company is doing what's rational. They're tasked with running a trial to test their own product. If you win, you're going to earn, on average, $12 billion in the next 14 years. If you get a P of.049, you get 12 billion. If you get a P of.051, you get, minus a few hundred million dollars, your outlay on the drug. And if you have an incentive system like that, I mean, you should not blame the industry for, I think, all of the things we see in clinical trial design, which are sort of, okay, acceptable ways to put a thumb on the scale, one of which is you carefully curate your patient population. Another is you test your new drug against, well, maybe not the drug doctors are actually using. Maybe you test it against the oldest, weakest drug in the space. Maybe for patients who take the old drug when they have progressive disease, they don't get access to the best new drugs. They get substandard care, which often happens in these registration studies. There are a number of ways that I think are within the realm of what people accept that allow for gaming of the trial. And it would be irrational not to take advantage of that because the amount of money at stake is vast. And the incentive to put a thumb on the scale when you can is great. But I think it's worth Restating, as you say, that these are drugs that we're really talking about the best case scenario. And the best case scenario is often less than desired. Should we go to the next part, which is the cost? How do you decide who pays?

Yeah. So I'll think back to probably the first time I remember thinking about this was when Gleevac was approved. Now, Gleevac was. God, I'm trying to think. I was probably in residency when gleevac was approved. 2000.

Yeah, 2001. Yeah.

Yeah. This was a big deal, because I remember in medical school, I had read Judah Folkman's book. Judah Folkman has since passed, but he was sort of a luminary oncologist, and he was basically one of the first people to propose this idea that if you cut off the blood supply to a tumor, you could stop a tumor. And again, to put this in the broader context, this was a pretty remarkable idea, because up until that point in time, you had this idea that you could cut a tumor out. If it was localized, you could give a bunch of chemicals that targeted its ability to replicate. That was sort of the gist of chemotherapy, or you could radiate the crap out of it, which also basically destroyed its ability to replicate. And some people, like Steve Rosenberg and Jim Allison, were working on these immunotherapy ideas. But Judah comes along and says, look, there's another really obvious idea here, which is any cancer cell that leaves its site of origin and goes to take up residence somewhere else, better figure out a way to get blood. And so we have these growth factors for blood. VEGF being one of them. And so this whole new thing of anti VEGF compounds comes along. And so Gleevac becomes the first drug approved for this. And if my memory serves me correctly, it was for colon cancer. Was the first indication, you probably think.

Of a bevacizumab and Avastin.

Oh, that's right. I'm sorry. Sorry, sorry, sorry, sorry. You're absolutely right. I'm thinking of Avastin. Of course, Gleevac is for GI stromal tumors. And yeah, yeah, I'm absolutely thinking of Avastin. Y. Okay. Same time period, though, avastin was about 2000, 2001, maybe 2002. And was it colon cancer for Avastin?

Yeah, it was the first one. Yeah.

And I sort of remember directionally, it being about 100,000 bucks for a year. And do you remember what the improvement in survival was with all the noted caveats that we just gave? Was it like 8 versus 12 months or something to that effect?

I think it was less than that. I think the original paper that led to approval was the Hurwitz paper. And I think it was on the order of a couple of months. But I guess I would say that if you look at Avastin across all the different cancers, I mean, you look at where it works and where it doesn't work. Where it works, we're talking about a month and a half, two months. I mean that's about the average.

The point of my very unfortunate long winded story was certain countries, and I think the UK was on the list, just said, no, we're not paying for this drug because it doesn't reach our threshold, which I think at the time was about £100,000 per quality adjusted life year per QALY. And the United States of course took a different position, which was private insurance companies will pay for this, which basically means the government and or employer will pay for this. And I remember that being the very first time that I thought about this and thought, huh, what is the implication of this? How does this work? So how do you think about that? And again, this is almost asking you to put on a policy hat on half of your head with a physician hat on the other half of your head, right?

I think you're right about one thing, which is that there are different hats. And when you're in the room, what you do might not be the same thing as what you advise a government to do. And maybe that's okay, that's the right way these things should happen. When you're in the room, you do everything you can that adds anything that the patient really wants and that the toxicity worth it to the patient. When you wear in the policy hat, you ask what's best for everybody. And I guess what I would say here is one thing that fits in this discussion and is that every dollar spent on Avastin is a dollar not spent on a lot of healthcare interventions that may have better bang for your buck. Might take all that money that we're spending on Avastin for 100 people and we might get 100,000 people to take their lisinopril or their hydrochlorothiazide, the blood pressure pills more religiously, we might get them to do something else. And the cumulative number of life years added to the world from those people doing whatever that other thing is, that may exceed the Avastin benefit by an order of magnitude. When societies pay for something, it is different than when you and I pay for something. If I take my own money and buy anything, it's really nobody else's business. And if you do whatever you want with your money, but if we all make a commitment to health care, what we're saying is we're all going to pool all this money and we're going to pool this money so that we pay for this thing that we think is a different commodity. It's something that's a human right, something that we all deserve to have. The only rational way, I think, a society to spend that money is to do what benefits most people, what brings the most good in the world. That might mean sometimes societies make, as the UK does, tough decisions. They decide, instead of 20 people getting access to some new cancer drug that doesn't cure the disease but may extend survival by a couple months, let's take all that money and let's give pregnant women access to X, Y or Z. That might improve the longevity of their children and another generation of kids in the uk. And so I think that all nations struggle with this question, which is how do we ration limited resources? In other countries, they are upfront and open about the discussion. They use things like cost effectiveness to ration products. In the us we do ration, we just ration in a way you don't see, because some people don't get anything. They don't get beneficial medicines and they don't get really marginal medicines either. They just don't have access at all. They're cut out of the system. And so we ration by discriminating against people. That's a different type of rationing. It's cruel and irrational, but it is a rationing nonetheless. I think that this is a thorny problem and no one person has the answer. And I guess I also think that people should be free to spend their own money as they so choose. I think the reality is if you had to spend your own money versus deciding whether or not to leave that money for your children or for a loved one, I think a lot of people wouldn't buy these drugs. I mean, there might be some ultra wealthy people, but I think some of us might make different choices with our own money. If you have to spend society's money, I think the obligation to really know that they work, that they actually are delivering benefit to people, I think that obligation is a bit stronger.

When you go back and think about your undergrad as a philosophy major, this is probably one of those places where you probably have an insight that someone like me doesn't have. I mean, how do you think about this? Through the lens of what philosophers would have said?

Yeah, I mean, I guess I would say I don't know if that's true, that I have an insight that you don't have. I think you have a lot of good insights. I guess I would say obviously what I'm speaking about is a type of ethic which is probably called utilitarian ethics, which is this idea of that ethical principles, when they are in conflict, they prioritize the greatest good for the greatest number over a lesser good for a lesser number. And when it comes to deciding whether or not to cover really costly cancer drugs that have small benefits and idealized settings and have question mark benefits in real world settings versus paying for other things that have more convincing evidence that they improve outcomes for a lot more people, I think a utilitarian ethic would tend to side with the latter, that you gotta pay for what benefits more people. I mean, one of the constant criticisms of the UK system is that cancer outcomes aren't as good in the UK as they are in the US. I think that fact alone has been overstated to some degree. But that's not really the question because the question is their life expectancy is better, they're spending less on healthcare, they got better life expectancy, their medical care may be better. I think if you're looking at somebody, if you're looking at the person just getting the Avastin, I think the decision is different than if you're looking at everybody. There are different conceptions of ethics and I think some people might put a value on caring for people at the end of life, irrespective of, I think, societal implications for others. And I guess I don't sort of a deontologic perspective and I guess I don't discount that at all. I mean, I think when people are question mark on Avastin for colon cancer, we're not saying don't treat a person. There's still lots of treatments you'd give, you'd give full you give the same treatment except leave out the Avastin. And the difference is probably very slight. Maybe there's no difference at all is what somebody like me might think if I haven't reviewed all the evidence.

One of the things that I just think I'll tell you a funny story and I'll come back to the thing. And I may have even mentioned this story on the podcast before, but. So I had a friend who used to live in Saudi Arabia, he's an American, lived in D.C. so during the summer he would always come back to D.C. so he would sort of spend June to September in D.C. before going back to Saudi Arabia. And I was there visiting him once, and I asked him, I said, dude, what's it like when you come back to your apartment in September? Just tell me how hot it is. Is it like, does it hit 130 degrees after you've left the apartment, sitting there all summer? He goes, no, man, it's like 70 degrees. I leave the AC on the whole summer. And I'm like, what do you mean you leave the AC on the whole summer? You have a timer set to come on an hour before you get there. He goes, no, no, no, no. When I leave, the AC is on. When I come back, the AC is on. I can't wrap my head around this. And I am like, how criminal is that? How much money are you spending? He goes, it cost me $4 a month. I'm like, how is that possible? He goes, oh, our energy is totally subsidized by the government here. We pay 19 cents a gallon for gasoline. So it's about $4 a month for me to. At the time, this was more than 10 years ago. It's about $4 a month for me to keep my apartment in Saudi Arabia, in Riyadh, at 70 degrees when it's 120 degrees outside. Now, you have to understand something. This is a totally rational human being. This is a reasonable guy who would never do this in his apartment in Washington, D.C. it just gave me a great example of how when we don't have skin in the game, we are incapable of making rational cost decisions. You know, it's like if I said to you, you can have any car you want, but you only have to pay 5% of the cost of the car. I think you're going to make a very different decision than if I say you can have any car you want, but you actually have to pay for the whole car. Now, we can lend you the money and you can do X, Y and Z. And I guess the thing I've always struggled with, I don't know how to solve the problem of healthcare cost, of which oncology is a huge driver. And we're gonna get to that shortly because I don't know how to reconcile these two points, which is, on the one hand, you cannot make rational decisions if you don't have skin in the game. And if the physician and the patient don't have skin in the game, how is a rational decision being made? But on the other hand, with the costs of these things being so prohibitive, how can people have meaningful skin in the game? So how do we reconcile these two forces?

Probably not going to have the perfect answer for that. I like what you're saying, and I like your analogy, and I want to kind of expand on it a little bit. So in your analogy, I think you're right that your friend is making the rational choice, which is it doesn't cost me much more. It's like a 50 cents. I'll just keep it cool all day. Who cares? Somebody else is paying for that. In your car analogy. Yeah. If you only pay 5% of the price of a car. Yeah, I'm going to drive McLaren.

I like your choice, by the way. Good choice.

I know McLaren.

Thank you for that.

Big fan of Top Gear and Grand Tour. But I guess I would say, but to make it really more analogous to what we're thinking about, you pay 5% for the price of the car, but you never actually get the car. And you don't get to drive the car. You just get told how good the car is. I'm telling you how good the car is. This is a great car. Don't you worry about how good the car is. You are not in a position to judge how good the car is. Having the car may change what you do. What do I mean by that? When it comes to, like, cancer drugs, in a theoretical situation, I do think people will say, if it adds anything, if there's any upside and somebody else is paying most of the cost, I'm willing to accept that. I want to try it. Let's just try. That's the mantra of oncology. But many of these drugs, that idea that it only has an upside, that is sort of a construct that's been created through a system that is not giving you the accurate information. And in fact, some of these drugs, they may actually have a net downside. How might that be? One, they don't actually improve survival. That's one, they have no survival benefit. Two, they may have an opportunity cost. That instead of being somebody who in their last few months of life is going to Tahiti or going to visit a friend, I'm somebody who is tethered to the infusion suite. And I gotta keep coming back twice weekly for four weeks. I gotta keep seeing this doctor. I gotta spend 15% of my extra life you gave me, maybe 40% of that I'm spending in your lobby. You're taking it back from me. And so it makes people make choices about what they prioritize and how they view the end of life. That may actually, I think, dissolve whatever ideal benefits that the Drugs provide. I mean, your point is well taken that there is this sort of tension between who pays for something and choices people make. And I guess the way I try to get around that is if we could just start an oncology with the choices that probably are not in your best interest, we probably would save a lot of money and people would be better off for it. And then we can go to the next level choices where there really is that trade off that you articulate so well.

What do you think are the no regret moves in oncology today?

I guess I could do it tumor by tumor, I guess. I mean, if you have localized cancer, for the most part, no regret move is to cut it out. Surgery. You guys win a lot. No regret moves.

Very little advanced in the last.

That's true.

50 years, right? I mean, where have we gotten better? Well, I think 50 years ago, Whipple procedure carried a much higher mortality than today. I think 50 years ago, women were decimated by radical mastectomies that are. I didn't do one radical mastectomy in my residency. So basically for 20 years, that's a procedure that's never been done. And today there's been a push to more and more and more localized surgeries with just as good an outcome. So that's been a huge advent. But yeah, for the most part, we figured that one out a long time ago.

Exactly right.

Let's keep doing it. Okay, next.

Okay, so next category. So let's get into. I mean, I'm going to make a nod to radiotherapy, which I think is really useful in many situations. Maybe the Michael Douglas situation. Head and neck cancer, localized, probably anything 4A or better. You know, you got a great shot of a long lasting cure with chemo, radiotherapy. Okay, so I think surgery and radiotherapy are on the table. Now. Let's talk about drugs. You got Hodgkin's lymphoma. Well, good news. We got a four drug combination that's curative. You've got testicle cancer and it's spread to your lung. Good news, we can cure 95% plus.

Of you, including those that are non seminomatous.

Now, obviously it depends on the exact subtype, and sometimes you require a combination of both chemotherapy and surgical therapy. So for instance, like teratoma or something like that. Cml. Chronic myeloid leukemia. This is the Gleevec story that I.

Think is transformative, Some will argue is not cancer. Right away the skeptic would say, is this a cancer? Right.

I mean, it's a very fair point. Which is that what is cml? It is a blood based cancer. One of the things about blood based cancers is you tend to see that a lot sooner than you see other cancers because it's easy to find, because it's in your blood. You can just draw the blood and there it is. And if you had that access to every organ in the same way, maybe you'd be finding similar malignant lesions in other organs. That's a possibility. We also know it's genomically dumb. It's driven by BCR ABL fusion, a genomic event and not a whole heck of a lot else. That's the sole driver. And if you give a drug that inhibits that fusion event, you can turn median life expectancy from three to four years to nearly normal life expectancy. In a Swedish data set, they're living almost a full life, maybe a year shy of normal life expectancy. That is a tremendous advance in medicine. So those are just a few no brainers, but there are a lot of no brainers I think that have to do with there's a benefit and the toxicity is low, or there's a benefit, a smaller benefit, but the toxicity is reversible. So you could try it and if it doesn't go well, you can stop it and you don't haven't lost too much. I think those are kind of no brainers. But some things are much more dubious, which they are caustic toxic treatments, long term toxicity, toxicities that don't get better, don't go away, that at the best don't add that much. I mean, I think there are a lot of dubious choices that people find themselves in. And I think the other thing that's hard to express is that the person in the chair, the patient, is in a very difficult position. I mean they didn't spend their lives studying cancer and studying all the data or maybe even studying how to think about cancer data. And they're in a vulnerable position, their life is on the line and that's not always a great position to make choices. And people often tend to make choices that may not be compatible with their best interest. Some people make choices that are driven by family members who believe those choices are in their best interest, but they might not be. There's a lot of social complexity here that makes it a thorny problem. But yeah, there are few no brainer decisions. There are some real advances in the last 20 years and then there's a lot of fool's gold. A lot of things people say are game changers, miracles Revolutions that are no such thing, that really don't have those substantive benefits when you look at it critically.

Give me an example of something you put in that latter category of something that's getting a ton of attention that you're not a big believer. I mean, I mean, where do the cell based therapies for immunotherapy fit in? Or something like checkpoint inhibitors like Keytruda, which, I mean, boy, when those things work, they're game changers. And when they don't work, they don't work.

Yeah, I mean, I guess I would say I have a good example that comes to mind, which I will come to. But let me just first comment about those things. I mean, I guess I would say the cell based therapies or things like CAR T or tisigenic glucil or these sort of novel cell products, they still have a lot of promise and they have definitely shown sort of great responses in some people. But the real question will be, are they so beneficial in every condition? We're trying some of those cell brace therapies in multiple myeloma and a lot of people are having remissions, but those remissions are fleeting and it looks like everyone is having relapse. That's different than what we found with lymphoma and what we found with pediatric acute lymphoblastic leukemia or all which you talked about earlier with Keytruda. We have a number of randomized controlled trials that show clear survival benefits in Keytruda in specific settings. We also have a bunch of settings that have been disappointing and we've had confirmatory randomized trials that don't show benefits. So Keytruda might be almost a case by case basis. What cancer, what patient? But let me give you a good example of a drug that I think just a classic example of really a questionable decision. I'll talk about it in one. Cancer, Pancreas cancer. So some people with pancreas cancer have a germline mutation in the BRCA gene, or brca, which is a gene that confers susceptibility to cancers, one of which is pancreas. But often breast cancer is where you most think about it. And if you have a BRCA germline mutation in pancreas cancer, they did a randomized trial where they gave people four months of the standard of careful therapy and they stopped it after a minimum of four months. You could have had a little bit more, but they stopped it after four months and randomized you to olaparib or sugar pill. And if you Take Olaparib, you have a progression free survival benefit, which I can explain what it is in a second versus sugar pill. But you don't have an overall survival benefit. You're not living any longer. And maybe it wasn't a good idea to stop Fulfirnox. I think a lot of doctors would have continued that. So the control arm shouldn't have been sugar pill. It should have been continuing the drugs that were working. This is a trial called Polo. This is a drug that has a cost of about $12,000 a month. And the reason the rhetoric and the reality are so separated is that the drugs we were using in pancreas cancer were old cytotoxic chemotherapy drugs. They were drugs that were not sexy. Didn't sound so great. And this is a new targeted drug, quote unquote targeted drug. And it's based on your genomic signature, which is unique to just your tumor. I mean, it sounds like that should be terrific. The reality is the data suggests it might not be as good as if you continued that old fashioned therapy. So that's an example where I think that hype can easily outpace benefit. And then I guess I just wanted to just explain real quick for the listener, progression free survival, which comes up just so often in cancer, it's a unique endpoint. It's really often interpreted in the lay press as the time it takes for cancer to get worse. That's not quite right. So progression free survival is the time from when a patient enrolls on a study till one of four things really happening to them. One, they could die. The first thing they could be going along, and then one day they could just die. So that's part of the endpoint. So if you die first, that's it. You have a PFS event. Fortunately, for most trials, that's not the most common thing that counts as a PFS event. The second thing that could happen is you have a new lesion. On your CAT scan, we're scanning you along and your lungs, we didn't find anything. But now there's a little ditzel there and I stick a needle in it and it's pancreas cancer. So you have progressed, you got a new lesion, that's progression. The third thing that could happen is your tumor that we measured at 1cm, it got to 1.2cm, it got 20% bigger. The moment it gets 20% bigger, 21% bigger, it's progression. When it's 19% bigger, oh, it's stable disease. That's what we call that, that's stable, but then 20%, 21%, that's progression. So it's an arbitrary cut point. Very arbitrary. And that's why it doesn't always track with how people feel. The fourth thing that could happen is your tumor got smaller before it got bigger. And if your tumor got smaller before it gets bigger, it's 20% from the smallest it ever was. So those are the four things that count as progression. Often trials are driven by the latter two events, but the tumors look 120% bigger. I like to also tell people that when you measure a tumor on a CAT scan, if you haven't done a lot of that, I'm sure you've done that. But if you haven't done a lot of that, people think it's like measuring your height. It's a lot more like measuring the width of a cloud between your fingers looking up at the sky. People have dispute about where the tumor ends and where the normal tissue begins. And that's been shown in many studies. So the reason I say all this is, let's go back to that example, that drug. This is a drug when tested against sugar pill in a setting where probably shouldn't have been tested against sugar pills, should have been tested against a real therapy. We do, the only thing it could improve was the progression free survival, which is an arbitrary line in the sand for tumor growth. That really doesn't measure people living longer or feeling better. That's why I think it's really sort of a problematic drug.

Yeah, I remember, God, how many years ago was that? Five years ago or four years ago when that came out?

This trial actually is more recent than that. It was just in the last year, but they probably started it five years ago. The enthusiasm for it was there and they started down the path.

I think I'd followed that drug maybe back at its phase two and I don't know why, for some reason I felt like that was a fool's errand, but it seems like that just sort of concludes it. So there are a couple things I want to come back to. But before we do that, I want to go back and talk through your hallmarks, because this strikes me as sort of the culmination of all the work you kind of put into this book and you sort of, you do what everybody's doing when they're writing a book, you're probably putting the finishing touches on it and you have this epiphany and you realize, well, I could sort of go and weave it into the narrative of the book, or I could very concisely, kind of lay it out here. And I think you chose the latter, which is actually quite elegant. So walk us through the notion of these hallmarks, these six hallmarks, and explain what they mean, because they're not entirely obvious just from the brief description.

Sure. Thanks for that. I guess. I think one, you're really right about how it happened, which was you write a book and people think you write the book. But of course, there's so much back and forth, and it goes on for years. And where you are emotionally and mentally when you finish the book and where you started are very different places. And often you grow a lot in the process of writing it. It changes the way you think about things. And so I start by, in this chapter by saying, here's a way I should have said things all along. I could have said things better, but at least for my case, it's better late than never. I could still toss it in the book. And I think the other thing the listeners should know is there is something called the hallmarks of cancer. These are six things proposed by Hanahan and Weinberg. There's six hallmarks of cancer, like invasion, invasion in the basement membrane, poor immune surveillance, angiogenesis. One of the ones you mentioned. These are sort of six biological hallmarks of cancer. And that is a highly influential paper. And it's been really extremely well cited and has shaped a lot of people.

Thinking it might be one of the most cited papers in oncology. Isn't it?

I think it might be. I think you're right. It might be, in fact, the most cited paper in oncology. So anyway, so like all great things, I try to steal from them. No, I try to imitate. When I finished this book, I realized that, well, you know, I'm not talking about biology. And in fact, I say many times, it's not a cancer biology book. This is a book about policy, our rules, our laws, our guidelines, and how policy can make things better. And I realized that maybe policy can be distilled like biology to six essential hallmarks, six ways in which we might make things better. And so I guess I'll take you through the six. I guess the first of the six was independence. What do I mean by this? So I guess one of the things in the book that I spend a lot of time talking about are conflicts of interest, ways in which the industry gets people who should be sort of competitors with the industry or should be stakeholders that push back on the industry. It gets them to buy into the industry's Narrative, in part because they fund those stakeholders. So talk about. Patient advocacy groups are often heavily funded by the industry. How FDA employees, who you think should be sort of separated from the industry, their most common place of employment after the FDA is the industry. And so they kind of have a unique role as regulator, but also future employee. So I call independence is we need sort of some rules in the space to, I think, minimize conflict of interest and to allow entities to be free to advocate for their constituents. Probably the biggest offender is expert oncologists like me. In my case, Unfortunately, I don't receive money from the pharmaceutical industry. However, I think that's not the case for the majority of expert oncologists. They do. And their views are often very supportive of these questionable drugs. They're almost at times, as if they're cheerleaders. And I believe that some of that is driven by those sort of financial ties. So I guess the first one is independence.

How does one do anything about that? Maybe we'll probe each one a little bit. Probably just going through them so completely. Get your point there. Look, I mean, when I was in residency, drug reps brought us lunches. Oh, yeah, right. And gave us pens. Like, you know, something as silly as that. But that's a hook.

Yeah, it's a little bit of a hook.

It's a little bit of a hook. It's who has the coolest pen? Because these weren't just generic pens. These were, like, really cool pens. Like, you wanted to be there at that lunch and get that really cool pen. It was like, I remember some of them to this day, like a pen that looked like a needle syringe. And when you clicked it, the color changed and all these other cool things. And. And look, all they wanted was five minutes of your time. And I remember by the end of residency, some of those, they were starting to take us, the senior residents, out for dinners. And I gotta be honest with you, I don't recall giving it any thought. Like, I don't recall actually feeling like I was doing something wrong. I remember being kind of annoyed that I had to listen to them talk, because at that point in my life, I feel like the only thing that mattered was getting a meal. And I was sort of like, hey, why don't you just shut up and let me eat?

Let us enjoy.

Yeah, but I honestly don't think it crossed my mind, Vinay, that this is the beginning of a very slippery slope. They're not buying me lunch, giving me pens, and eventually buying me dinner because they think I'm a nice guy. I find that a little bit disturbing, that I was too stupid to see through that. I guess I'll give myself some grace and say the sleep deprivation may have played a role in it. But have things changed in the last 20 years? I assume that pharma is not allowed in a hospital anymore.

Well, in many, but not every place. But I guess I'd say a couple things about that one. I guess I don't blame you so much. You're a resident at the time and to be honest, I actually don't what you described, although it is problematic. Those pens are collector's items, so if you have any good ones, send them my way. No, just kidding. They really were spectacular. They really were. Many people did collect them. And the next thing I would say is that there is evidence that shows even so much as a meal that is paid for by the industry is associated with a statistically significant but very small increase in prescribing patterns. So it is a strategy that pays dividends. I guess I would say that I see the problems with that and I think that they are problematic and they have largely been curtailed through a number of sort of well intentioned efforts. But one of the things I talk a little bit about in the book is that we haven't yet curtailed things on the high end. So here we spend a lot of time trying to reform on the low end the people getting the pens and the meals. There are many senior oncologists who receive over $100,000 a year in consulting payments from companies. Even more, they receive millions of dollars in research funding. We have shown in some publications that even controlling for research funding, controlling for prior publications, controlling for seniority, personal payments from the industry are associated with greater publication in the future. It's likely it's a positive feedback loop. Working with the industry helps your career, which helps you work with the industry, which helps your career. The people in those roles, the most conflicted people, people who are earning as much from the industry in their side hustle as the average household income in America. Those people, they write the guidelines and the guidelines by law in the US make Medicare pay for drugs for off label purposes. So the people who write the guideline that mandates Medicare must pay for this drug. No price negotiation. That person is being paid by the industry even for the exact same drug. And so those relationships, I think are an order of magnitude more concerning than the resident hungry resident taking a meal. In fact, I try not to talk too much about those sort of little things, but I think you're right that there is a slippery slope, and part of it is to get you accustomed to the fact that this is no big deal. So I think you're absolutely right. I guess I would say the way I would sort of structure the solution is the way I sort of structure lots of solutions, which is, I don't want to be the person setting rules and hard rules with punishments, because I don't think that that's really what gets people to change behavior. I want to create a different set of incentives that get people to maybe do something differently. And so some incentives, I think, are, we still need guidelines to help decide what to cover off label. Why don't we incentivize people who don't have conflict to join those guidelines? And, and what if we had rules and policies that favored faculty members who didn't take money from the industry to be on the guidelines? Suddenly career incentives look very different. I mean, right now, if I'm a junior faculty member and Eli Lilly offers me sort of an ad board consulting opportunity, I might jump at it. And I can still have open the opportunity of sitting on a guidelines committee. But maybe in exchange for one opportunity, I should lose the other opportunity. And if I want to keep the other opportunity, it's my choice. And the more you kind of build in those kind of structural incentives, I think people will do things that preserve different opportunities. So I think that's sort of one way you tackle the problem of conflict of interest, which is that you just sort of tinker with incentives. You create opportunities for academics to not take money and still have robust and rich careers. I think in the current system, all the opportunities are tied to taking money from the industry. And so I guess how can I blame anybody? Just like I don't blame the industry for putting a thumb on the scale, I guess I don't really blame the faculty members for doing it.

Is there evidence that physicians are, for the most part, honestly disclosing these things? I mean, I know there was a very famous case at Memorial Sloan Kettering where there was a huge blow up over this. So if a system like the one you described were in place, do we believe that we could believe people?

Yeah, that's a great point. I mean, I guess I would say that most of the available evidence suggests that disclosure is incomplete and often inaccurate. Some of the available evidence suggests that people don't even believe that they have the conflict. And so some of it is an honest error that they don't even see that they're being conflicted. They may have Forgotten. You cite a really sort of high profile example of Jose Baselga, who had found to omit conflicts in dozens and dozens of articles and conflicts that were really pertinent to what he was talking about. And he ultimately was pushed out of his role at Memorial Sloan Kettering, which is a form of punishment. But very shortly, he became vice president of AstraZeneca, a job that probably pays him several times as much money as he was making earlier. So I hope someday somebody punishes me in the same way and pushes me out of my job, but then pays me a whole lot more money to do something in the same space. I want to be punished like that. But, I mean, I think that speaks to the fact that we don't really take disclosure seriously. I guess the other thing I would say about disclosure is disclosure has been one of the methods that we have confronted conflict of interest with. But I'm not exactly sure it makes the world better. There's some psychology evidence, some business evidence that suggests that once people disclose, there may be actually greater trust placed in the discloser. And it doesn't actually correct. I think the bias, it just leads the patient to have more trust in their doctor, having seen the doctor disclosed. So I think maybe divestment is a better way. Maybe sort of different rules and incentives for people is a better way to kind of separate these things. I think that these conflicts are problematic in one respect that I'll kind of flesh out a little bit. So in cancer medicine, so often you got a drug that costs $100,000 a year, and it changes something like how big the tumor is on a CAT scan. With all the problems of measurement, we don't know if you live longer, we don't know if you live better. And you got to take the drug. Who decides whether or not we should recommend that routinely or not? That guideline decision is of huge importance. It will shape how many, many people practice. And I want people to make that decision who are oncologists, who have experience, who may know a lot about how to read studies and interpret data, but who don't have any financial relationships with the company that makes that product. I think that leads to just sort of a cleaner decision making process. And it's the same kind of way we set up a courtroom. Can you imagine a courtroom where the prosecutor and the defendant are both being paid by the defendant? I mean, I think many of us would say that's not really a balanced courtroom. And yet in medicine, we do have many imbalanced courtrooms where almost everybody in the Courtroom is getting money from the company. And so I guess I'm just suggesting that we don't take away the industry's incentive, we keep the profit. Of course, I think it does drive innovation, but we remove it from the people that supposed to provide opposition force and try to preserve a healthy sort of dynamic there.

What is the opposition to your idea which is so obvious it's painful to listen to you articulate it?

The opposition is probably principally that the people who are best in the position to fix the situation are the ones who are personally getting the most money. I mean, I guess I'd say that our professional societies are driven by the industry payments. The professional societies, senior leadership at universities and academic medical centers are often on the boards of directors of companies. They're the ones getting the biggest payments. The most senior and famous oncologists are the ones getting the most money. And so I think it's hard in any system where the people you need on your side to change the system, the people with the power are the ones benefiting most from the system. Doctors are smart people. We can all come up with reasons why what we're doing is not bad. And in fact probably I believe this might be true for everybody. We all believe we're all ethical actors. I mean, I don't think anyone thinks that they are an unethical person. They just feel that they're a product of their circumstances. And so I think the real way to fix this problem is somebody external to the medical profession has to come in and do it. I don't think it's ever going to happen from self policing because the people who are in power are the ones who are getting the most payments. And it's very likely the case that there's a reason why they're the ones getting the most payments is because the industry knows that that's what it takes to keep the system going.

All right, so the second hallmark.

Okay, second hallmark.

Evidence.

Yeah.

What does that mean?

Evidence is, as I describe it, as measure what matters and do it fairly. There are a lot of technical things that I won't get into for this podcast that I talk about in the book. But I guess basically evidence is the following, that when we give cancer drugs we care about two things. People living longer or living better, increased survival or health related quality of life. We have a system where two thirds of cancer drugs that are being approved one third I know they shrink tumors more than 30% in a fraction of people. The other third I know they delay tumor growth by 20% and then the other third, I know you live longer, live better. That to me is a strange reorientation of you're spending so much money on costly drugs, only one third do you measure what actually matters to people. The other two thirds, you're measuring tumor size on CAT scans. And I'll say one more thing that I think is interesting here, which is we use this cutoff of tumor shrinkage of 30%. In writing this book, I spent a lot of time trying to get the bottom of why it is this 30%. And I found out it goes back to a 1976 paper where this Mayo Clinic doctor got a bunch of marbles and he put them on a dining table and he rolled out foam rubber and he got 16 oncologists to come to his house with calipers and measure the marbles. And he asked at what size difference can two doctors reliably tell the marble has gotten bigger or gotten smaller? And the answer was certain cut point. And that cut point is the same cut point we use today. We use a cut point to measure tumor shrinkage as a response or not response. Because a bunch of Men in 1976 measuring marbles through foam rubber, which was how we measured tumors in the day before imaging, that's what they could tell apart. So these cutoffs that we have sort of confused as measures of efficacy were really just sort of operational measures to sort of get, get some inter rater reliability, get us to agree. And so the moment you start to know that, you realize, like, why am I putting so much stock in drugs with a 10%, 20% response rate? I really don't know if the patient lives longer, lives better. And this cutoff is really arbitrary. So that's what I mean by evidence. Let's measure more. Not always, but more. What matters? Living longer, living better.

And what would be the implications of that? I mean, it basically would imply that two thirds of the treatments out there go in the waste bin.

At least they won't be approved at the same moment in time. So what might happen is that if you really created a policy where generally the industry is obliged to show survival or quality of life benefit, a lot of things are going to change in the industry. So one thing is they're going to run more trials in patients who have relapsed cancer than trials in patients with low risk early stage cancer. They're going to go into the last line setting because that's where the event rate is highest. They're going to be more selective, I think, about drugs that they deploy. They're not going to deploy drugs that may change tumor scans. They're really going to try to think about drugs that improve survival or quality of life. So they might be more picky in which drugs they advance in the process. I think it changes a number of things in the drug development pipeline, and I guess I kind of talk about that in the book. But to your point, which is, does it actually change the number of drugs that come to market? I guess I would say that of those two thirds that just changed tumors on scans, maybe some of them actually do help you live longer and live better. Those are still gonna come to the market, but the ones that don't are gonna fall short and they're not gonna come to the market. So we'll have probably fewer drugs come to market, but the drugs we have will probably be better drugs. My friend who posed that dilemma to me many years ago, he'll probably be more satisfied.

All right, what's the third hallmark?

Yeah, the third hallmark is something that we've talked a lot about on this podcast. It's called relevance. And it basically means that we should do more studies in people that look like average Americans. And I think we kind of talked about how we're studying populations that don't reflect what average people have and experience. Why don't we just study average people and let's find out if the drugs work as we prescribe them.

And again, that'll have the same effect, which is it's effectively going to reduce the success rates, probably due to both decreased tolerability and actual poorer response.

Yes, I think that that's the case. Yeah.

Okay, the next one is near and dear to my heart.

Affordability.

Tell us about that. How do we fix that issue?

That's a thorny problem. We've written a number of review articles that have looked at so many different solutions. I mean, I can't even get into all the solutions just to put them in a few buckets. They're solutions that rely on existing legal structures to make progress here. They're solutions that require novel legal structures. One solution, I think maybe one of the clearest solutions here is that in the US we have a system that anytime a cancer drug is approved, Medicare, which is perhaps the single largest payer in this country, Medicare, has to pay for the drug, and they can't negotiate the price. Not only that, they have to pay for any drug recommended at a level 2A or higher by a number of guidelines, like this National Comprehensive Cancer Network, which has got a lot of people writing the guidelines who are funded by the industry. So I think one way we could kind of make some headway in the affordability is to give Medicare the ability to decline to pay for drugs. Many years ago, a couple of states went to Seema Verma and colleagues at HHS and they said, well, let us at least experiment. You know, states are the laboratory of experiment. Let us say Massachusetts doesn't have to cover all these drugs for Medicaid. But they were denied the ability to experiment at a state level. I think we should encourage state level experimentation in how to bring down drug prices. And there are a number of other things that are really sort of technical solutions. But I guess what I think is important here is just the recognition that a drug that you cannot actually get in the hands of somebody is no better than no drug at all. And, and we have affordability crisis in this country, but globally we have a huge affordability crisis. These drugs for the most part are out of reach of billions and billions of people in this world. And so it's one thing to live in 2020 when you have access to the greatest medicines. It's really sad, I think, when there are some drugs that are transformative and the best centers globally just really do not have access. And in the book, I give example of trastuzumab, a drug developed in the late 1990s for a certain type of breast cancer. That is really a terrific drug. But in a study that came out of India just five years ago, only one in a hundred people who could have gotten that drug, got that drug. And this is at a referral center in sort of one of the biggest cities in the country at a really sort of premier center. And it's still so difficult out of reach of so many people globally. I think that's a real tragedy.

Do we have a sense of on average how much more drug cost in the United States than say in Europe or Asia?

Yeah, I mean, I guess. I mean, a couple figures are of course, of the pharmaceutical space. About 50% of spending in the US comes from the US even though we count for maybe 4% of the world's population.

And how much of that do we know if it's volume versus price? Like obviously there's an accessibility issue which says in the United States you're going to, on a per capita basis, more people are going to receive the drug as well. It just seems like as a casual observer of oncology, that basically the United States kind of has a sort of tacit quid pro quo with pharma, which is, here's the deal do the lion's share of the R and D inside the United States, let us have first access to the drugs, we're going to subsidize the cost for the rest of the world. Directionally. That seems to me what's happening. Is that about accurate?

That is a fair summary of the lay of the land. I guess I say a couple things. I mean, one of the points you made earlier was what about the price versus volume? I mean, I think one helpful comparison would be like two nations with comparable gdp, US And Norway, and we pay roughly double what Norway pays for cancer drugs. The other thing I would say about subsidization is I think people like me who are reformers, I guess the real question I have in my mind is why do we subsidize marginal drugs the same way we subsidize transformative drugs? I think that's the. The kind of crux of the space. You named a couple of drugs. Avastin. This is a drug that has multiple approvals in many different tumor types, doesn't cure a single person. Median survival about one to two months. A tremendous price. Global lifetime earnings of that drug are close to $100 billion. I mean, that is a massive global lifetime earnings drug. You get another drug, Gleevec. It doesn't cure everybody, but for the cancers, it works in. It works rather dramatically. Massive transformational benefit mass, and I don't know off the top of my head, lifetime earnings, but it's still in the several billions and billions of dollars. And then you get drugs that are really marginal, toxic drugs that don't do that much and still can accrue billions of dollars. I guess what I wanna say is that one of the ways in which I think we can correct the market here is if we just incentivize the drugs we want, which are drugs that have bigger benefits, more substantive benefits. And if we didn't pay so much for those, drugs that really don't add a lot, don't cure people, and just prolong survival very modestly in very select cohorts. So I guess I'm not opposed to paying for things that really do work. I guess I'm opposed to paying for things that we don't know, work that have a lot of uncertainty, or that we know don't work. I think that's more what my criticism is.

Yeah, and it's funny, I find myself struggling with this one a lot because on the one hand, I really do agree that pharma needs to be incentivized to innovate. And the cost of innovation is staggering. Now that said, I also think pharma grossly overstates the risk they're taking. I mean, they've basically outsourced research to biotech. So if you really want to think about it, drug discovery is now a venture capital problem, which means it's a private citizen funded risk. So private citizens and pensions basically fund VCs that take the risk to take biotech from Ind to phase one to phase two. Pharma then says, okay, this is de risked enough. I'll come in and on my balance sheet I can do phase three. So their success rate has gone way up. That seems to be a pretty efficient model, I guess. I think pharma's basically decided we don't want to own all of those risks. We don't want to own technical and market risk all the way through. But the flip side of that is do we really want cms? And you'll have to forgive my skepticism, but I don't know that I trust CMS to be the one negotiating price because what's the knockoff effect of that going to be in terms of incentivizing pharma? Even though I agree CMS shouldn't have to pay sticker price. Like, I guess this is why I'm so glad I don't do what you do. Because these are some of the hardest decisions one has to think through. If you're trying to do this through the lens of what is a policy, what is a logical and, and reasonable and fair policy around the incentives. It seems obscene that CMS doesn't have the ability to negotiate. But at the same time, I don't know that I want anybody in the US government making a decision when it comes to healthcare because I just, I've stopped trusting these entities. Just using Congress as an example, right? I mean we've got what, 550, 600 people make up the US Congress. Like two of these people have a degree in science.

Oh yes, it's tragic.

They're just not a group of people I want ever making scientific decisions.

Same for the Supreme Court.

Yeah, yeah, yeah, exactly. So how do we think about balancing that? Is your solution of let the states do it better where there's less collateral damage. But I can also think of ways that that goes sideways also.

Yeah, I mean, I guess I would say that. I mean one thing to acknowledge is that no one has solved the problem, so the problem remains unsolved. I guess the next thing I would say along these lines is that having a cms, the Way we have a cms, it is a certain type of incentive. It's a very interesting incentive. The incentive is basically we will pay for any drug that gets FDA approval whatever you charge. So companies will always keep cranking it up as much as they can. And some of the things about how they crank it up, they'll crank it up in lockstep. So they'll all move together upward. They won't go too much, nobody will be an outlier because then you're going to be on 60 Minutes and that's no good for your brand. So you want to go up together slowly, but you can keep cranking it up. You can do it 9% year over year over year over year. And when the frog doesn't jump out of the pot, when the water boils slowly, so that's one, two, then the next thing they build into CMS is once the drug is approved for one use, we're going to let CMS pay for the drug for any other use if these expert doctors believe it should be used in that way. And we're going to detail those expert doctors and give them a lot of money and make them come on our side and they're going to see things from our point of view. So we're going to get all that market share that way too. And sometimes that market share can be even more lucrative than the initial approval market share. So I guess what I think this creates in the system is an incentive, a powerful incentive that the hurdle for a drug is drug approval. You can charge whatever you want. You really don't have to look too deep into like what it costs you to make the drug or what the benefit of the drug is. You can charge what you want as long as you're not too much of an outlier, you're not going to stick out too much. We had that drug, the Car T cells, they cost 300,000, $400,000. But then they'll rationalize and say, well, it's a one time dose, you know, it's not every month after month. And those other drugs, they cost $200,000 a year anyway. Well, of course that's how you got us to where we are. So I guess what I would say about CMS negotiating is, I guess I think I want to say that not negotiating is a decision of sorts. It's a decision to, to just really put a lot of incentive here without any sort of care as to what you're incentivizing. You're incentivizing an approval. The next piece of that puzzle is, well, how are they approving drugs? And I think many of us who look at the FDA approval process will see that the bar for approval is getting lower and lower. You used to be able to trip on it, now I think you can probably go right over it. But it's getting lower and lower. I mean the number of patients for approval not having a control arm. There's a drug which I always forget the name, it's a drug that lowers the rate of a blood protein. But almost everybody who takes the drug suffers ocular impairment and some people suffer severe ocular impairment. So there's a lot of blindness going on or pre blindness like conditions. But I don't know if people live longer. I don't know if they live better. I know they have to see the ophthalmologist a lot. That adds more healthcare costs, costs a ton. Why is this approved? I mean, why can't we wait for a little bit better data? So I think that's part of the puzzle. I think that among the many ideas out there, one idea is sort of the value based pricing model which a number of sort of commenters have kind of developed, which is this idea that we should pay more for drugs that provide us more value, that have more incremental survival benefits than drugs that are more modest or mediocre. And I think if there's some way in the system to build in greater incentive for the drugs we want, well then that would be good. It would have a lot of good secondary effects. But I agree with you that all policy, it's so hard because there's always unintended consequences and people will always sort of find paths of least resistance you couldn't foresee. The reason I do like state level expansions, state level initiatives is that to some degree good policy is experimentation. You experiment, you see what happens. You course correct, you run experiments in parallel, you see what works, you adopt that broadly, I think you do need experimentation in the policy space and in medicine we've suffered because we have not done enough of it in the long run.

Now if CMS makes up, I don't know, I have no idea what it is today, but let's just say it's 25 to 35% of the payer in the world in the United states, right? So 25 to 35% of all insurance is CMS. What about the private payers? Why have they not banded together and say, well, there's no law that's preventing us from negotiating with these clowns. We're going to do it now. I know that part of it, of course, is that the majority of their business is probably aso, so they're not on the hook for risk. They don't care. I mean they're basically administering a service and it's the employer that's doing so. Is that why is it just there's no one big enough to negotiate? Clearly CMS is bigger than any one entity.

Yeah, I think there's probably couple reasons why we haven't seen more activity from private payers. One is that if they don't cover what CMS covers, I think they will look bad and they can easily be on the nightly news where you'll find a cancer patient who's angry that they didn't get some drug or the other. And that's not good for your brand, that's not good for your reputation. And there have been some high profile situations in the last 30 years where people went on the news and I think insurers, they may not want to take that risk. And the next thing is some of these drugs may cost a lot, but the budgetary impact might be a little bit lower to the insurer because it's a small population. So in those cases it might be cheaper for them just to pay for the drug than it is to deal with the pushback from not paying for it. I think the worst thing is that the insurers may have a different incentive altogether. What do I mean? One of the provisions of the Affordable Care act was to cap the amount of profit that could come off revenue through an insurance company and 20% profit on revenue, the medical loss ratio, the MLR, the moment that that is inserted into a system, it's a really unique incentive. The industry, the insurance industry, now they're being told that no matter what, you can never earn more than 20% profit on revenue. That's the most profit you can earn. That's a law. So if I tell you you're really hungry and you can only eat 20% of the pizza, what size pizza should I order? The answer is going to be extra large. So what I think has happened in the insurance industry is that although we hear a lot about insurers who have pre authorization requests and all these things that are a pain in the ass for doctors and doctors hate. Although we hear a lot about insurers pushing back on this or that, I think they do that for a couple of reasons. One, that the insurer's incentive is to make sure year to year variability of costs is predictable and that they can model that out and make sure their premiums go where they need them to go to ensure their profit revenues. They're really nervous about year to year variability and that's why hep C drugs come along and they can blow the whole model because the population is massive. But I think the insurers in the long run, keeping costs down, I think that they may not have enough skin in the game. They don't have enough skin in the game to keep costs down. So they really don't care. And so I think the narrative is of course that insurers are the downward force, but I don't think they're the downward force that we think they are.

I agree with you and I think it's the employer that has the most skin in the game. But the problem is they're so disaggregated and so spread out that they can't speak in a unified way and they can't fight in a unified way. But if you were to look at the sort of. This is a loose way to think about it, but let's just call it a handful of buckets of insured Medicare Medicaid private insurance that is administered only through the insurance company. So the ASO employer based versus the insurer based private insurer, I think the biggest one has to be the employer. And even if it's not, it's the one that would have the most sway. But yeah, it's like how does this company of 300 people band together with this company of a thousand people and that company, which again I think speaks to the pain of all of this.

One last thought on this space is there's also tragedy, the commons problem. Many years ago when autologous stem cell transplant for breast cancer gained popularity, there are a couple of insurers that did pay for some of the clinical trials that ultimately debunked that procedure. But now one of the risks is let's say there's some new drug out there and a lot of people say like this is not, doesn't work so well. This trial is really contrived. An insurer could come along and they could do the right study. They could really test how it works in a different population. They could fund such a study. The moment they fund that study, that information is generated. Well, all their competitors will get access to that information. So there's a bit of, bit of that challenge as well. But yeah, I mean, I think you're asking terrific questions about this space.

So let's get back to hallmarks. Number five is possibility. What does that mean?

I guess I call it the preclinical pipeline must be expanded possibility. So I guess I would say we spent a lot of time talking about drug development from the point of view of the fledgling biotech to the pharmaceutical industry. One of the things that's a part of drug development that gets forgotten about a little bit is the role of the nih, of course, in funding basic science. And the nih, to some degree, does shoulder some risk in this space. They fund a lot of sort of science for science sake, identifying novel targets that are ultimately, some of which are clinically exploited. I guess I would say that although it feels like we spend a lot of money on the NIH, $30 billion or so per year, I think it's not nearly enough that science is like the greatest thing that people have ever done. And if I were in charge of anything, I would crank up the funding for science because I think science is possibility. And that's what I mean by this possibility. We need to increase the funding for science. We should increase it slowly and steadily. I think there are problems that happen when you give a lot more money to people who are not used to getting that. I think there's a lot more waste. But if you slowly grow something, we need to kind of separate science funding from political cycles. It shouldn't be that just because the red team or the blue team is in power, that science funding is on the chopping block or getting more. We need some sort of stability for science funding. Science needs slow, steady growth. And then the last thing I kind of talk a lot about, and this is, how do you give out the money? It's fascinating to me. We've been giving out billions of dollars in research funding. We've never really studied how do you give out the money? If you look at the way the money is given, it's really kind of lopsided. There are a few people who get a lot of funding. Their labs are flush with money. Some of their labs are so big, one wonders if the boss ever meets all the people who work in the lab. There are hundreds of people working the lab. They're really like financial operations run by a financial manager who's the boss, and then some scientists underneath it. And there are a lot of people on the other end of the spectrum whose labs struggle to get money, even basic funding. And so I guess in this kind of section of the book, I kind of explore, are there ways we can kind of bring some experiments to giving out money, do some small, simple, randomized, controlled trial studies, follow people and look to see measures of equity of who gets the money, measures of research satisfaction, burnout, measures of how translation occurs, some kind of controlled studies in grant giving. And then the last thing I just say is blue sky science. So there's this branch of science typically called blue sky science, where it's just science for science sake. You don't come to me and say, I want to do this experiment because I'm going to cure melanoma. You come to me and you say, I just want to know how the cell does this. I just want to know why does it do it, why does this happen? And that type of science, that type of inquiry that we all have, as I think kids and high school kids, that inquiry is really, really difficult when you are an academic doctor because the there's not a lot of money unless you make promises, I'm going to cure this disease, I'm going to cure that. If you want, say, I just want to understand how this works. It's really hard to get funding, and I think it should be the other way around. Some of the greatest advances in science were people who pursued things purely because that interested them. And the finding and the translation was serendipitous. And so I think that's what I mean by possibility.

I couldn't agree with you more on this. I have many friends who sit on study sections in nih, which means they're basically the people that watch how NIH gives money. And their biggest complaint is, look, we are really not permitted to take big risks here. I mean, we are very incremental in how we fund because we are on a funding cycle. They cannot fund pie in the sky, blue sky. Really, really fundamental, basic questions. Because when I go back to Congress in two years and say, I need this much money, the answer better be because I did X, Y and Z with this. And, you know, I've seen some of this firsthand and again, I understand it. I mean, we don't want resources to be wasted. So it almost suggests you want to have two arms. That would be my take. You want to have two funding arms, you want to have the translational funding arm. That is meant to be incremental, that is meant to look at basic science and ask, is this ready to go to the next step? Is this ready to be taken to a clinical pathway? If so, are you leaping too much? Are you not leaping enough? And then I think you have to have a totally separate group that is responsible for funding a totally different type of science, which is all about basic inquiry and the advancement of natural Knowledge, regardless of where it takes us. Because as you pointed out in the book, actually there are lots of examples of some of the most exciting discoveries in the history of the last 400 years, which is effectively the era of modern science that came from nothing other than pure inquiry.

I think that's well said. It's a very thoughtful way to look at the problem. One of the people that you cited, Jim Allison, whose work ultimately led to that blockbuster class of drugs, an immunotherapy. Dr. It wasn't that long ago when, when people, I remember people made jokes that that line of inquiry was foolish and misguided and that was never going to succeed. Lo and behold, it turned out to be sort of a Nobel prize winning discovery. So I think you're right. Yeah, that's the right way to think about it.

So the final hallmark is agenda. What do you mean by that?

Agenda is something that there have been a number of researchers, including people who work with me and myself, who have gotten interested in the last couple years, which is what happens when you take a 30,000 foot view of cancer and look at the clinical trial's agenda. And it's very interesting that some spaces in cancer medicine you got the same drug or similar drugs, 20 such drugs, Coke, Pepsi and 18 other Cokes and Pepsis, and people are running redundant and duplicative trials. They're all testing them in the same tumors, in the same setting, with the same old controls sometimes. They're running many different clinical trials with drugs that have low promise. And one of the observations that we make is, well, boy, by chance alone, aren't some of these trials gonna be positive? I mean, we're not using a very stringent nominal cutoff for significance. We're using a P of 0.05. Usually some are gonna be positive by chance alone. How do you account for that? How do you account for this duplication? Who's keeping track?

It's like you need a Bonferroni correction factor for the number of trials as opposed to the number of looks, right?

Absolutely. In fact, we did a paper where we corrected one with a Bonferroni. We got a lot of pushback from those peer reviewers.

It's a totally novel application of how you would use a Bonferroni correction factor.

But you instantly see what I'm getting at, which is that within a study, if you do a lot of comparisons, you take into account the number of comparisons to some degree, we can debate what statistical procedure to use, but we do take into account that we're looking at this data many times, so we could fool ourselves. But when you're running many, many studies, shouldn't you also do the same? It's philosophical question. It's not really a statistical question. And the answer, I believe, is yes. So that's what we talk about in this section in agenda. We talk about what does it mean to take that into account. And also we forget sometimes that the most critical resource in cancer medicine are the patients themselves. They're a scarce resource. In some tumor types, there are now more trials ongoing than there are even people with that condition, which may sound ridiculous, but it's because everybody chases the ball. Somebody recently told me this great story about, it's like 3 year olds and 5 year olds playing soccer. They all run after the ball, nobody plays positions. And that's what happens sometimes with the pharmaceutical industry. They're all running after the ball. They're all running duplicative trials. There are not enough patients with this condition anymore. We're depleting that resource and what do we have to show for it and how do we interpret those studies? So I think that's what we talk about, which is that somebody has to think about the big picture. At least we have to look at it and we recognize what the agenda look like across the entire field.

So coming back to oncology, is there a role anywhere for tumor genome sequencing? There are many companies that do this commercially. If there's one email or call I hate getting, and unfortunately I get it every two weeks. It's the friend of the friend or the friend of the family, the patient's cousin, whatever, that has just been diagnosed with essentially an uncurable cancer. They're basically saying, peter, what advice do you have? And it's always heartbreaking because I don't have any. Any. It's by definition, if I'm getting that call, it's because their oncologist has already said there is nothing to do here. These calls go in many different ways. I just had one a week ago. They were asking about some supplement. And generally when I get asked, when I go down the path of, well, this person has this hyperbaric oxygen protocol with this supplement, protocol with this, this thing and the other, you know, the first thing I like to inquire about is the cost. My view on this, which may differ from yours, is first, we don't want to increase the harm of this person. I don't think there's anything wrong with hope. I think there's a lot of things we don't know if they work or don't work, but I'm certainly pretty squirrely when someone's offering a panacea treatment for $20,000 of vitamin C, rubbing garlic on your testicles or whatever the concoction is. So we go down that whole path which is, is there anything out there that's in the quote unquote holistic world that that's going to work. Another thing that tends to come up is is there a role for tumor genome sequencing? And I've certainly had within my own family and that of friends sent people to foundation medicine. Truthfully, I haven't really had anything come out of it. That's been a game changer. Probably the only time in my life with this experience that I've gotten kind of lucky was a friend that had pancreatic cancer. This was several years ago, but he had Lynch. And I had just remembered reading a paper about how patients with lynch were more likely to have checkpoint mutations. This was prior to the approval of Keytruda, but it was in trials. And so we were able to get him into a trial of Keytruda and he turned out to be a remarkable responder. And to this day he went from unresectable to cancer free, which he remains about a decade later, or nearly a decade later, long winded. Preamble. Talk to me about your view on tumor sequencing, off label drug use, targeting therapies, that sort of thing.

Just to allude to the other part of what you were saying that I thought was really right, which is I think we probably share the same philosophy, which is that often people come to me and they talk about some alternative or complementary approach that they want to bring into their care. And my view is probably maybe not dissimilar from yours, which is as long as it's not too costly, as long as it doesn't have an opportunity cost, interfere with what we're wanting to do. It's not a hill I want to die on because I think people should be allowed to pursue those things. And I do think that one of the problems I get a little irritated by is there are people who want to die on that hill and really draw a line in the sand. And I think you can poison a relationship with somebody and it's not worth it. I mean, at the end of the day, if it doesn't cost too much, it's not really too harmful and somebody really is motivated to do it and it's not going to interfere with what you want to do. Have at it.

And just the humility of like, what do we know? We have to be clear here, like we don't know a lot of stuff.

Right.

And by the way, it's not like we have a track record that says we're winners. Right?

Right. I mean, I think that all goes into it. And that's also why I think that's all a part of it. Yeah, right. And then to come to your NGS question, I guess I would say next generation sequencing, tumor genomics. I guess right off the bat there are definitely some people who definitely need to be tested for some mutations. So let's just talk about the ones that definitely need to happen.

You mentioned lung cancer. It's a no brainer.

Right lung cancer. There are at least six or seven mutations that we now have FDA approved therapies for. Definitely there are different ways you could test for the same mutations, but that's another thing to keep in mind. But you need to know about egfr, you need to know about alk, particularly if the person is a younger person, non smoker melanoma, you need to know about BRAF colon cancer, you need to know about MSI high status. So there's a number of things. We have approved drugs and we published some papers. There's maybe 20 or 30 things and a good oncologist usually knows the mutations for the tumor. The next thing is now we do have an approval for microsatellite instability high, which is probably like your patient with the lynch syndrome, pancreas cancer. No matter what tumor type, you know, that's something that we have an approved drug, very reasonable to test for. Then I think the next way that NGS can be used is exactly as you used it. I'm a huge supporter of which is that you're using NGS to pair your patient with a clinical trial. I think that's a perfectly acceptable way to use NGS to run a broad NGS panel. And if you find a trial that fits, have edit. The next part about it I think is tricky, which is that the part that I think that I kind of have the most friction with some of my colleagues is after having done all these things, you've looked at mutations, we have approved drugs, you've tried to find somebody trial. Sometimes you do NGS on a patient and there is a mutation that is seductive. It looks like you have a drug for it, there's no trial available and you also have a standard drug that we normally give. And in these situations it is so seductive to believe that because we found the mutation and the target, it's better to use the targeted drug than that. Older drug that may have a longer track record. And I think that's where people get into a bit of trouble, that sometimes you actually end up eroding outcomes, not enhancing outcomes. You actually make worse choices in those cases. Because the truth is that some genomic mutations are mutations that are fueling the tumor, and that if you fix those mutations, you would improve the outcomes. But some mutations are the product of a genome that is undergoing massive instability and damage. Some of these tumors, when you look at the sequence, it's like a dinner plate that's been dropped on the floor and it's in shards. It's broken all over the place. You may find that for one of those two shards, you can put a little piece of tape on it. But are you really going to help the whole person? And there are some studies that show sometimes if you take biopsies from a bunch of different sites and you sequence them, you don't even have the same mutations in different sites. And one study shows that if you sequence this part of the body, different.

Parts of the tumor.

Yeah, the tumor has spread to, let's say, the lung and the liver. If you looked at the liver, you might give drug A. If you looked at the lung, you might give drug B. That's not a very precise therapy. And then the other thing that's a complexity is some researchers have sent the exact same tumor to a couple of different companies, and they haven't always gotten the same result. That also makes one a little concerned. So I guess I would say approved drugs, the sort of very common mutations all good doctors are going to test for. To pair somebody with a trial, as you did your friend, that's really terrific. I think, particularly people who suffer from rarer tumor types at younger ages, they should also keep an eye out for fusion events. Those are really important to know about. They're often. There are a lot of researchers who are interested in studying that. There's some trials at Sloan Kettering. The place, I think maybe you don't always have to do it is for somebody who is not doing well and they have progressed through many lines of therapy and they have a tumor that we just don't have a lot of mutations that we know a lot about. I mean, I don't think it's obligatory. And if you do find something, I think sometimes you got to be careful that you don't just gravitate to what is a key and a lock, what sounds like a key and a lock, but it may be sort of taking you away from something that has a Better track record.

That has to be literally one of the most elegant and brief descriptions of the pros and cons of that type of approach. So I'm glad I asked that question, because I could have spent two hours and said less. Are you bullish or bearish on liquid biopsies? You indirectly alluded to it, which is, look, with leukemia, we're basically doing a liquid biopsy, correct? So now the question is, when we, a year from now, presumably have at least phase 2 data on liquid biopsies for solid organ tumors and lymphomas, are you optimistic, and how do you see that changing the way we practice?

Potentially, I guess I'd say the interesting thing about leukemia is it was very likely one of the first things we studied, in part because we can access it so frequently and so readily, and we can actually track its volume in an era where the doctors had to measure marbles through foam rubber with their calipers. And so that's why leukemia has always sort of been a couple steps ahead of everything else about liquid biopsies, I guess I would say that, you know, we do have a number of appropriate approved liquid biopsy tests, and they're certainly going to have a role anytime. We've already conceded that there are some mutations that are very important in certain tumors, and we have drugs for those mutations. If you can find out that mutational information without having to stick a needle in someone, everyone is going to be grateful for that. I guess the questions that are always going to be kind of. And they vary probably test by test, mutation by mutation. Is, is the test sensitive enough? In this case, if you find you don't have the mutation on the liquid test, are you still going to want to go get tumor tissue or. Or do you need to get tumor tissue for another reason to figure out the subtype? And in that case, you might as well. You already have the information you need. The real role for liquid biopsy might be the serial nature of it. You can track something over time, see how it's doing over time, and that might be the real boon. But I guess I would say, am I bullish about it? I'd say yes. I mean, I'm not known for being a bullish person, but I guess I would say that's something that I would definitely study more and do sort of really good clinical trials at the end of the day to see what the role can be. But, yeah, they're already in our clinics. We use them.

Yeah, you've talked about this indirectly, that. I mean, look, you're naturally a skeptic. You're naturally critical. Those are very valuable tools. They've served you well and more importantly, they've served many people well. Meaning your skepticism and your critical thought has sort of made medicine better. How do we, or maybe I'll ask it more directly, how do you navigate that balance? There are some people that are skeptical for the sake of being skeptical. They're always the contrarian. No matter what the answer is, they're always going to take the opposite side of that. How do you sort of police is the wrong word. But how do you navigate that internally?

I guess I would say, I mean there is an example of something where I was not on the side I'm usually on and people gave me a hard time about which was the dexamethasone in Covid the recovery study, very recently. So I mean, let me just put it in the context. One of the things that happens a lot in medicine these days is medicine by press release, which is one day Eli Lilly announces top line results are positive for this trial and this drug improved outcomes in these people. And this is the hazard ratio 0.7. But how long did they live? Did it have side effects? None of that's in the press release. You know, it's just sort of a fragment of information. And I think they put that out primarily for the shareholders and for their information. And some doctors may act upon that. I mean that might be something that people find enough to act upon. And I'm always a big critic of that and say, let's wait for the paper, let's wait for more information. Recently there was a recovery trial out of the UK and they say that dexamethasone for people who are hospitalized requiring O2 with SATs less than 94 people who are mechanically ventilated, that they benefit from dexamethasone, all cause mortality benefit. Whereas people who are hospitalized did not require supplemental O2. They actually, maybe they didn't benefit, they were harmed. And there's a significant interaction coefficient. They put out that press release and I went online and I looked and I'm like, oh boy. You can read their protocol. Their protocol was published a month ago. It's available, it's 35 pages. You can read it and you can read the statistical analysis plan that's also out there. It tells you exactly what they were gonna do, what the pre specified endpoints are. And we're in the midst of a pandemic where people have been trying things left, right and center, throwing the kitchen sink at people with COVID and so I said, the evidence is good enough. We gotta do this right now. We got the press release. We got, you know, I like to say, a press release and a protocol that's like a driver's license and a Social Security card and a paper that's like a passport. Do I have to show you my passport? I can show you the other two. It's another form of identification. Okay. So anyway, so I say this, and I got a lot of heat from the usual critical club because they said, well, we gotta wait for the paper. And I say there's such a thing as too much skepticism. And that's what I think is a good example. I guess I would say that probably the greatest way in which I can't even claim that I'm on the set point on the thermostat, but I can't say. The only way to kind of keep this in balance is between skepticism, that's so bad that it's paralyzing, you can't do anything, and blind acceptance, that's so bad that you are cheerleader for everything. The way to keep that in balance is I find going into the clinic because no matter how skeptical you are about drugs, you have to have those conversations with real people. And there's some people who are going to be taking drugs that you're skeptical of. And maybe I should just make a point about what I think my clinical philosophy is. Some people sometimes ask me, it's not the doctor's role to determine what treatment is right for someone. It's really the doctor's role in my mind to. To empower the patient with what I know about the drug, what's been shown, what hasn't been shown, what the benefit might be, what are the uncertainties, what are the known toxicities and risks? And then to walk them through how they would decide, is it worth it to them to take those risks? And different people will choose differently. Some people will choose differently than what I would choose for myself. Some people will choose differently than the next person with the same information. I think those are all okay. The more you practice medicine, the more you realize that this is. It's an art. You're never going to have perfect information. You're going to have to make decisions today with less than perfect information. And I think that's a way that one keeps skepticism in check.

I actually think this is one of the biggest challenges in this art science of medicine. This is very different from experimental physics, where we could all hang around a particle collider and debate the experimental results all day long and red team, blue team them. I mean, it is really different. And I struggle with this so much. And I think you said it exactly correctly with respect to that thermostat is if you're too much of a skeptic, you're not doing anything, you're going to sit on your hands forever. And there's a cost of doing nothing. And that should never be forgotten. And if you blindly accept everything, you are almost unquestionably subjecting patients to unnecessary treatments. I feel lucky, right, Because I have two full time colleagues in my practice and then two part time colleagues. So there's a group of five of us basically can argue with each other all day, but we never lose sight of the fact that it's not an intellectual pursuit. At the end, a decision needs to be made. Even if that decision is to do nothing, that's still a decision. And I love that. I actually find that to be some of the most enjoyable stuff we do is just the debate.

That's another nice thing that you brought out, which is that's another way to keep skepticism in check is you go to a tumor board or you go to a multidisciplinary meeting, or you sit around the table with a few of your colleagues and you present some cases and you hear what other people have to say. At the end of the day, something's got to be done. They're either going to do it or they're not going to do it. And sometimes it is important to know that people do things differently than we might do it. And I think it keeps us in sort of a balance.

This was a fascinating discussion. God, there's a lot of other things that we could talk about here, but I also am wary of the fact that in a Covid environment, people have less and less time for podcasts. So the longer this podcast goes on, the lower the probability people are going to listen to it. And I want to make sure people hear this one. So I wish you the best as you continue with your move into San Francisco. I'm sure we will speak again.

Thanks so much, Peter. Thanks for having me. It's a terrific discussion and great to chat with you on these topics.

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