#121 - Azra Raza, M.D.: Why we're losing the war on cancer

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 Dr. Azra Raza. Dr. Raza is a professor of medicine and the Director of the MDS center at Columbia University in New York. She is a practicing oncologist and a cancer researcher who has been published in over 300 peer review manuscripts. She grew up and attended medical school in Pakistan before moving to the United States for her clinical training, which we discuss briefly. She's an expert in myelodysplastic syndrome, which is a form of pre leukemia and acute myeloid leukemia, aml. She's a recipient of a number of awards, including the 2012 Hope Award in Cancer Research, which she shared with Nobel laureate Dr. Elizabeth Black Blackburn. Dr. Raza is an outspoken advocate for completely reconfiguring the current model of research in cancer, and the purpose of this discussion is really to dive into her beautiful book the First Cell, which really is a completely critical look at how medical research is using the wrong types of models. My words, not hers. The ROI on spending is completely out of line with what anybody would consider reasonable if they were to it from an objective lens. And frankly, we end with what I think is a very thoughtful discussion around what the way forward looks like, because you can easily get through this. And I always love to speak with a person a little bit before and a little bit after. And at the end she said, you know, gosh, I really, I hope we didn't get too much onto a down note. And I said, no, I don't think we did. I think that there's enough sort of hype around cancer research that it's okay to lift the sheets a little bit and show this side of things. A couple things I'd say about this episode. First of all, Azra goes out of her way both in the book and if you hear her in other interviews, to say, look this is not someone who considers herself a writer. This is a person who considers herself both a physician and a scientist. And in many ways sort of wrote this book because she just really needed to talk about this stuff. To which I would say, one, it's very beautifully written. But two, I was blown away at the literary sprinklings that made their way into this. I mean, and you have to remember we're doing this by Zoom, basically, or a comparable platform, so we can look at each other on video. And just as sure as I'm looking at another person across from me at the table, I would ask her a question and she would respond by quoting AM Emily Dickinson, and not just quote it like, I've memorized this, but quote it in the most lyrical way. So I think if you're a fan of literature, science, you have an interest in oncology, there are a lot of things you'll get out of this episode, so I'll leave it at that. And I hope that you do enjoy my conversation with Dr. Ezra Raza. Ezra, thank you so much for not just making time to be here today. But as you told me before we started setting aside a lot of time, it's an honor to sit with you. I've known a little bit about you before your book was published because one of my colleagues knew about you and said, hey, this is an amazing woman who's in the process of writing an amazing book, and you're definitely going to want to not only read it, but more importantly, I think, speak with her and be able to interview her and talk more broadly about this subject matter. And it's hard to believe that that was probably a year ago, if not more. You're an oncologist by training, and I've seen a couple of your short interviews. Though I've gone out of my way to not listen to you on previous podcasts. Who has not color how I want to talk with you. But the two times I've seen you on very short clips on YouTube, you've made it very clear that you are not a writer, which I find ironic given how well you write. So at what point did you decide that a book was an appropriate tool to communicate the amazing ideas that we're going to spend a lot of time getting into.

Thank you, Peter, for having me on your podcast. I have been an admirer of your work and of the kind of wellness philosophy that you propose you belong to. You practice, you propagate, you promote. I love it all. And the number of things you do is very admirable. So it's really a pleasure to be on your podcast. I have to tell you that Dorothy Parker once said that if one of your friends come to you and they say they want to write a book, the second biggest favor you can do them is give them a copy of the Elements of Style by Strunk and White. And of course the first favor is kill them immediately. So I knew all along that I'm never going to write a book because I'm going to. I'm a big admirer of Dorothy Parker. And then what happened, Peter, is that one of my dear friends in New York who happens to be a literary agent, and John Brockman and his wife Katinka would often talk to me and say, ezra, how about writing a book? And I would say, no, I'm not a writer. And they would say, well, you're haranguing us with the same things for 10 years. All that is wrong. You want to do something. You want to change the field, Write a book. I will get it published. And I would keep saying no until I had course as AN ONCOLOGIST Number one, after 30 years of being in the field, I had a little bit to say. But then the second thing is that I've also been a basic science researcher. I've had a very active lab all along. And my third credential is that I'm a cancer widow. So I have experienced oncology from all three perspectives. As an oncologist who sees 30 to 40 patients a week for the last 30 plus years, as a basic researcher who's had a well funded lab for 35 years, and as someone who stood on both sides of the bed at the same time of a cancer patient who was the love of my life. So even these credentials, Peter, were not sufficient to motivate me to write the book. What did it was my daughter Shahrazad's best friend since 15 years of age, not her boyfriend, her best friend who is gay. Andrew, at 22 years of age finds the feels weakness in his arm and taken to the emergency room. He's quadriplegic within hours. And he's found to have a 9 centimeter large brain tumor which was unresectable. And pathology showed that it is one of the most malignant tumors ever known to mankind. Glioblastoma multiforme. When this boy opened his eyes and he stole his diagnosis, the first thing he told his mother, Peter, was mom, don't worry, just call Ezra. She's on the cutting edge. She will cure me. So here I am. It slapped me in the face physically, that on the one hand, the ferociousness and violence of his tumor, and on the other hand, the utter helplessness of all of us, his oncologists, to do anything about it. Our complete failure in front of Andrew. How is it possible that we are so spectacularly failing a 22 year old boy? That's what forced me to write the book.

Someone once said, and I'm sure it's been paraphrased, and so I won't attribute it because I don't know where it came from. But the only reason to write a book is if you absolutely can't not write it. And it sounds like that's sort of where you were after all of the things that you've described, which is not only losing Harvey, which I think he died in 2002, is that correct?

Correct.

And then the story about Andrew, who obviously was about 60, 70 years too young to die from anything, let alone a gbm, which is a tumor, I've certainly spoken about on this podcast before, and I think we'll talk a little bit more about it. Also, the other things we're going to talk about, which are the structural failings of the system that you felt were. If I were going to sort of try to describe your book. A big part of it is the return on investment has been very poor. That's sort of one way to summarize it. There are many ways to sort of summarize it, but an overarching theme has been it hasn't been that we haven't spent a lot of money. It hasn't been that we haven't made some progress. It hasn't been for a lack of trying. But by any objective metric that we would apply to any standard of anything else, the return on that investment has been so paltry that if we are not smart enough to at least consider doing something totally different, we're completely deluded. And again, I think that's one tiny piece of it, and that's probably that burning piece that I think your agent was ultimately saying. This is either going to erode a hole through the gastric lining of your stomach or you better put it on paper.

Yes, I agree.

So let's start with oncology. What drove you to oncology? Why did you choose to become an oncologist in an era when women could have chosen far less demanding fields in medicine? Not that any field in medicine is more or less demanding, but oncology is about as demanding as it gets. What was the thinking for you?

That's an astute Observation actually, because when I was going into oncology, it was the least popular field. In fact, most people when I said I'm going into oncology, thought okay. She couldn't get into any other fellowship. That's why. Because only Indians and Pakistanis go into oncology. Who else would in their right minds would want to go except for me? It was a deliberate choice. So, Peter, I was born and raised in Pakistan. But since I was a little girl, since as far back as four years old, that is my first memory, I was very interested in the natural world around me. I would be at four years, I'd be following ants around and imagining all kinds of things. And started reading about science for as far back as I remember, really. And as I was growing up, I got more and more interested in different fields. Embryology at one point became an obsession. By the time I was 16, I had read all about evolution and evolutionary biology. I had become a big Darwinian fan. Everything I was looking at was through the prism of evolution for a long time. But then, had I grown up in a country where choices were available to me, I'm confident that I would have gone into molecular biology as a pure science or some of the one of to study one of the natural things like marine biology maybe, or probably myrmecology ants. But in Pakistan, where I grew up, there was no possibility of entering science except through medicine. So very cleverly I thought, I'm going to go join medical school. As soon as I complete, I will proceed to the west and there I will start my PhD in real scientific training. But the problem that happened with me was in third year of medical school when I saw my first patient, one look was all it took. And I realized from that moment on that all of my life would be devoted to somehow use the best that science has to offer to reduce human suffering. And I have stuck to that. The second thing that happened was, so I knew that I will do research in science, but it would be therapy driven and the patient would be front and center for me always. Second thing that happened was that I was in Karachi, Pakistan. Karachi is the largest city in the country. And people who get sick around Karachi in the suburban areas have no access really to medical care. It's a very impoverished third world country with a very overcrowded city where I grew up. So cancer patients, when they came, Peter, they would travel long distances on their donkey carts and on foot. By the time they came, they would have hugely advanced tumors that I've never seen. Since even in Pakistan we don't See them now, but back then in the early 70s, the kind of end stage malignancies sprouting through breasts or like huge lumps just breaking out of people's heads and arms and sarcomas that I saw. So it was the malevolence of the tumor, the violence of the disease on the one hand, on the other hand, the intellectual challenge of trying to figure out how this whole thing began in a single cell and how that cell goes rogue. What journeys has it undertaken to reach this level of malignancy? So it was the dual emotional as well as intellectual grip that basically caught me and at a young age. And I am confident that if I'm given 70 more lives, I will do exactly the same thing 70 more times.

Do you still remember that first patient you saw as a third year medical student? Do you remember anything about them, what condition they had, anything about them, the way they looked?

Actually. Thank you for asking. Absolutely. The patient was a young woman with acute myeloid leukemia. And she was very strange because she presented with a very large spleen as well. So we knew that she must have had a prior myeloproliferative myelodysplastic, some sort of a precursor that led up to the acute leukemia. So right there and then, I started having discussions with my teachers that how much easier it would be to study a liquid tumor because cells are already in suspension and you can go in and sample them so many times instead of trying to study a solid tumor, which is a mass that you can only remove once. Next time it appears it wouldn't even be the same tumor. And you don't have the luxury of accessing the tumor before, during, and after treatment. So that patient is etched on my brain as if it was yesterday's breakfast.

Yeah. I find that phenomenon to be interesting amongst many physicians, both oncologists and not oncologists. Steve Rosenberg, who is my mentor, talks often about a patient that changed the course of his life when he was early in his residency, a patient that had metastatic gastric cancer to the liver five years earlier was basically sent home to die. Shows up in the ER to have his gallbladder taken out. Should have been dead five years less, six months earlier. He's completely free of tumor, which ultimately, after double, triple, quadruple checking, led Steve to conclude the only way this is possible, this is back in 1968, is if his immune system eradicated that cancer. And Steve became one of the people who has pursued that to incredible ends. And though I've done nothing special, I still remember the first patient I saw in the hospital. And so though it wouldn't become the catalyst for anything particularly unique, we send first year medical students on day one into clinic. They can't do anything. They are literally there to just watch and try not to get in the way. But I selected oncology and I went to the medical oncology clinic. And I remember that very first patient on that very first day. And I still remember strange details like what the color was of the clothing of different people in the room that day. He had stage four colorectal cancer. It was my probably one of the first times I'd ever seen a CT scan and certainly seen it with such a clinical emphasis on okay, look, these are now tumors that have spread to both sides of his liver. The primary tumor was here. You can see all of these places. I would go on to become very close friends with that patient, who ultimately died two years later. His widow would come to my medical school graduation two years after that. So, yeah, there is something really special about medical education and it can totally derail the best laid plans of becoming the world's expert on ants.

Yes. And by the way, I do teach a course that is foundation of clinical medicine where first year medical students at Columbia University are exposed to mean clinic. And I'm mindful of this experience. How is this going to change the rest of their lives? The experience has to be somehow we can't take away the pain. It's like Emily Dickinson said, tell all the truth, but tell it slant. Success in circuit lies too bright for our infirm delight. The truth superb surprise as lightning to the children eased with explanation kind. The truth must dazzle gradually or every man be blind. So I'm very mindful of that. When first year students come to me.

Azra, you're the only person who's going to not just quote Emily in the midst of discussion, but do so eloquently. And to think that there was any doubt you were a writer is only comical to me. But we'll come back to that. So when you finished medical school, not only did you realize you wanted to be a clinician, but I think the hook of oncology was already well into you.

Yes, absolutely.

Now let's pivot for a moment to allow you to explain to the listener what the state of oncology looked like at that time. Specifically, when you consider what it meant to have metastatic cancer. And let's for a moment posit that we're going to talk about solid organ tumors separately from liquid tumors. If a woman had breast cancer and either at presentation or later, it had spread to her lungs, to her brain, to her bones. If a man had prostate cancer that had spread to his bones, if a person had colon cancer that had spread to their liver, what was the prognosis and how long would they be expected to survive?

I think to start with Peter, the important thing is that when I started in oncology, it was almost a stigma to have cancer. The kind of causes of cancer we were taught were basically either there's a genetic or hereditary component where you have a predisposition for high risk of some sorts of cancers, or is it some environmental exposure, some kind of toxins that you've been facing, or pathogens? Pathogens were considered a very exciting new avenue for research at the time, that maybe it's a viral disease of some sort, especially retroviruses. And clearly there was already a very strong component of association with things like smoking. So while there were these kinds of causative factors for cancer, most people who presented already had rather advanced diseases. And very little screening measures were being performed at the time. So they would come with, in pakistan, especially with the kind of textbook pictures of fund gating masses coming, breaking through, breasts in women or men suddenly showing up within with complete urinary blockage, unable to. To urinate. And we would have to do emergency kinds of things. It was just. It would be quite devastating. And of course there were people who. Women who felt a lump and came in. And so I remember how many times I was assisting in mastectomies and considered for a long time to go into sur surgical oncology because that seemed to be the cleanest treatment at the time. Cut it out. You don't have to start chasing the last cancer cell with these poisonous things we were giving. Even radiation was quite primitive at the time and quite terrible to patients. So it was all in all, it was a stigma to begin with. People didn't want to talk about it. Many people hid it. The tumors from themselves even would delude themselves into thinking that this is some kind of infection, it will go away. So most people presented with advanced cancers. The problem that I see, though, before I end this answer, is that today, in 2020, if you want to measure the success of treatment in cancer, then the thing you need to look at, Peter, is what is the age adjusted mortality of cancer today in 2020? You know what it is? It is the same as it was in 1930.

So that's interesting. I usually make the statement it's the same as 1970. I didn't realize it was still the same as you go back even further. I usually just make the point that in 50 years it hasn't changed. You're saying in 90 years it hasn't changed?

Changed, yes. I'm saying that because the 30% or 27% decline in mortality we are seeing in the last 30 years is following a 30 years increase in mortality from in cancer. You see, what happened was that with all the smoking, anyone who watches Mad Men is shocked to see it. Like my daughter saw it and she was, mommy. Is that what people used to be like everywhere? They were just smoking. Everybody was smoking. This led to such an increase in the incidence of cancer, so that the decline in mortality basically parallels the decline in smoking. That is all that has happened. Otherwise we are really at square one. And that is the embarrassment that nobody wants to recognize. In fact, somebody asked me the other day, what exactly is your point in saying? I said, look, Nietzsche's Thus Speak Zarathustra opens with this man running around with a lamp at noon in the middle of the market saying, I'm looking for God. For me it's like I'm running around looking for an adult in the room.

Yeah. So let's explain to people, let's explain some of the nuance here because most people are confused by what an extension in disease free survival means. Not that the average person knows what the difference is between a PR and a cr, but you and I both know this world well because we've been on the inside of how these clinical trials are run. So we understand that, hey, this drug got approved because X number of people met the criteria for a pr, which has a kind of a funky arbitrary definition, if you're going to be brutally honest of what a partial response is defined as. A complete response is a little easier to define. But then we don't talk about what durability means in all of these things. So I could give an entire soliloquy and lecture on this, but I'd much rather listen to you do it eloquently because the chance that you're going to quote more poetry is reasonably high. So can you explain for folks what it means to have a partial response, a complete response? And the reason I think it's important to do this is even though it sounds a little dry, you're saying things that seem completely at odds with what the propaganda machine is saying Now I know you're right because I know how the sausage is made. I've been inside the belly of the sausage. I understand how to read the literature that is actually Asking a lot for someone who maybe just wants to better understand oncology, but they haven't had the luxury of training in oncology, or even more importantly, I think, doing research in oncology. So can you go through some of the fundamentals of what these semantics are that are used, how these terms get thrown around and how ultimately it can lead to some statements like the one you just made, frankly, which is as extreme as extreme could be with respect to saying, hey, look, in 90 years, we really haven't gotten better at extending life in people with cancer once they have cancer. So let's unpack some of these definitions a bit.

I think that's a good place to start. So let me begin by a little bit of just history, because before we get into nuances, why not just talk about the very gross facts? Cancer is a very bad disease. Everybody knows it. The only good news you can give to a cancer patient is that, oh, we caught it early so we can get rid of it. So we know that cancer itself may not kill. It's the delay in treatment that really kills. So the earlier we pick it up, the better. How have we treated cancer, which has been found even in mummies? So we know cancer has existed all along, but the incidence, probably it is a disease of modernity associated with many, many of our lifestyle changes from hunter gatherer society to modern human. Nonetheless, cancer was identified in mummies and has been there all along in human history. How have we treated it? Well, the first treatment of cancer, even though it wasn't even called cancer then, was in 500 BC when the Persian queen Atossa had felt a lump in her breast. She tried to hide it by covering it with sheets and things, and eventually asked her Greek slave who took out his sword and simply slashed off her breast. She survived it. She was the wife of Darius and she survives it. And this is the first known surgery. We were slashing women's breasts in 500 BC. What is the primary treatment for breast cancer today? Same slash.

And we typically give Halstead credit for that.

So this is my point, that for 2500 years, what has exactly changed? Slight better scalpels and giving anesthesia while doing it. Okay, yes. Then second is that when you couldn't. So whatever cancer was detected early enough as a solid tumor was cut out, and the liquid tumors, you couldn't cut out, so you needed to poison them somehow. Now, how do you poison these things? There was really nothing could be done about it until in the First World War. Of course, it wasn't called the First World War because We didn't know there's going to be a second. So it was called the Great War. Part of development of weapons against each other was use of chemicals. And so when these vats of chemicals were sitting around that were dropped on humanity, people noted that one of the side effects that people died from was low blood counts. So Goodman and Gilman, two pharmacologists sitting around in Yale, decided that this could be used to treat cancer. Then these chemicals. So do you know the first three chemical weapons that were used to treat cancer? Cytoxin, chlorambucil and melphalan.

We still use at least two of those.

I gave all three with my own hands to my own husband Harvey. So we are slashing, we are poisoning the same way and then burning with radiation therapy the same way. So I wanted the audience to understand the kind of dramatic statements or melodramatic statements that I'm making are not baseless. People just have to stop deluding themselves, open their eyes and see what is in front of them. So to just finish this part with a quotation of statistics, in this day and age today, 68% of cancers that we diagnose new cases, 68% are cured. Cured with what, Peter Slash? Poison, burn, surgery, radiation and chemo. Except for a few cancers where there are targeted therapies or antibodies available, really not much has happened. The 32% who present with advanced disease that we can't use poison burn. So imagine the same treatments that were working in earlier stages are not working in later stages. This is the best proof that the only thing we can do right now is to find the cancer earlier. And even some of the therapies not working like targeted therapies may work better if we don't give them to stage four. FLT3 mutations caught early may respond much better to FLT3 inhibitors. This is the point I will keep making over and over.

I want to stop you for a second there, Ezra, because honestly, that is something that I have only in the last few years come to share your zeal for. And I can't emphasize it enough. So there was a day when I believed incorrectly, now I believe I was incorrect. That burden of tumor was not the primary determinant factor. Stage four cancer was stage four cancer, whether the burden was high or low. And it was really a property of the biology of the cancer that that was the issue. So in other words, if you took a whole bunch of women with stage one breast cancer, you took 100 women that had sub centimeter lymph node negative breast Cancer and you had a machine that could tell you which ones had the potential to go on to have metastatic cancer versus those ones that did not. And let's maybe breast cancer wasn't a great example because of the hormone complexity of it, that whether you acted then or acted later, it wasn't going to matter. Well, I no longer believe that is true for reasons I could expand upon. I want to emphasize the point you're making, which is, I mean, it's the contrapositive of your point, which is we don't really have therapy that works for systemic disease. So metastatic breast cancer, metastatic colon cancer, metastatic prostate cancer, metastatic. You fill in the blank. You are no better off today than you were 50 years ago. And that is a very sobering, if not outright depressing statistic. It's very difficult for the average person to comprehend that for all our advances, once colon cancer has gone to your liver in 2020, you are almost as hopeless as you were in 1970. And in fact you can probably put more color around it and say, well, technically Peter, you might live four and a half more months. And I don't want to discount that. I want to talk about what the cost of that is. But I mean, do you agree with. Am I also being a little too dramatic or would you agree with my assessment?

I think you're using meiosis, meaning understated. Seriously, how do you tell a 22 year old Andrew that we will add four months to your life? You should go and celebrate and proclaim from the rooftops what kind of nonsense is this? Four months of improvement in survival and that is the lucky ones who get it. You know what it is? Why people will be shocked. Why should they be shocked? They'll be shocked because they are listening. Poor things have been subjected to the ultra hype of all this self promotion of scientists and oncologists patting themselves on the back for game changers that they have. Allow me to expand on what has in my opinion, put the field back by decades. And that is the treatments that are most celebrated in cancer are treatment of chronic myeloid leukemia. This is a disease which is a disease of the myeloid cells in the bone marrow which undergoes a chronic phase where nothing much is happening except one fine day, something mutates, something happens, the disease takes off into an accelerated phase and then becomes acute leukemia. And it is universally fatal. And all of us who are older like me, have taken care of dozens of these patients who died in our own hands, young people as well as Old. Well, it turned out that chronic myeloid leukemia. Leukemia is caused by one genetic change that can be targeted with one magic bullet. And that magic bullet is Gleevac, and that was FDA approved in 2000. And now these people are being cured with one drug, and this is a fantastic success. But, Peter, the same drug doesn't work when the disease starts to accelerate. So chronic myeloid leukemia. Think of the word chronic hair. It's not really a malignancy. It's like a pre leukemia, right? Now, you caught it early that at that stage, there was only one problem, and you could fix it with one bullet. Right?

Can we put that in perspective for people? Because I want to make sure we're not. I don't want the naysayer to have too much wiggle room to say, well, you've discounted the success stories. Great. Gleevec. We're going to probably talk about some of the checkpoint inhibitors as well, which have probably been the single biggest victory in the past five years. Do we have a sense of what percentage cancer mortality has come down on the back of Gleevec? Not just from cml, but let's also look at GI Stromal tumors, which have, at least for some period of time, responded to Gleevec. Though it might not be the most durable remission ever. I mean, what type of numbers are we talking about? Has that put a 1% dent in cancer mortality in the past 20 years?

If that. It's a very rare disease.

Yeah, yeah, exactly.

Very rare. But it did prove a point, which is that targeted therapy.

Targeted therapy can work.

This is the point I'm making, that it's not even really a cancer yet in all its malignant manifestations that other cancers are. The second thing we celebrate is again, in hematologic malignancies, which is acute promyelocytic leukemia, which is cured with arsenic or with vitamin A analog vitamin A. Let's say atra. It cures acute promyelocytic leukemia, One of the deadliest. Acute leukemia. But do you know, it wasn't as if scientists sat down, studied this disease, found the lesion of retinoic acid receptor, and started to reverse it. Poor Chinese were saying for years that we are curing acute promyelocytic leukemia with vitamins. And the west didn't believe them. And finally, they sent somebody over and they saw all the patients and were convinced and came back and did a trial of ATRA here, and then were convinced and then worked backwards to find the molecular lesion. So, please, scientists, do not take Credit in front of me for acute promyelocytic leukemia. You did not work it out. You only worked it out in retrospect. So those are the two biggest advances. Now, lymphomas absolutely agree that throwing cocktails of chemotherapy together, testing this one and that one, they worked as because of the biology of the disease that was responsive to those chemotherapies. That's what I'm telling you. That some of the things that have retarded procedures, progress, in a way, is because we become convinced of a paradigm that, oh, if Hodgkin's disease can be cured with these four drugs, we just have to find the right four drugs for pancreatic cancer or ovarian cancer, and we'll fix it. And that's how we kept working, throwing crazy combinations of drugs together to follow the paradigms. The few successes that we had seen, Hodgkin's disease, a few non Hodgkin's lymphomas, or acute promyelocytic leukemia, chronic myeloid leukemia. I mean, my multiple myeloma now has been very successfully treated, but at that time it wasn't. But now it is definitely a night and day difference. But these are, again, rare types of cancers. Melanoma, dramatic differences in survival today. But again, all of these together would account for less than 10% of cancers together. Still, we have to go back to whatever we can, slash, poison and burn. And successfully we are able to do that for 68% cancers, either because their disease is responsive, like in Hodgkin's lymphoma, even if it's advanced or non Hodgkin's lymphoma or cll or because it is amenable to surgery, that's it.

So where a counter argument here is, look, this is going to be a game of inches. And the 10% that you just described, you basically gave the tour de force explanation of oncology's greatest hits in the last three decades. And again, we didn't pay a lot of spend a lot of time on it. But I think the checkpoint inhibitors also have this huge impact beyond just melanoma, because anybody who shows up with a checkpoint mutation, even if you have lynch syndrome and you go on to get pancreatic adenocarcinoma, you're probably going to respond, let's just say that adds up to 8 or 9% of the 68%. So the skeptic would say, but look, Azra, like, that's amazing progress. Give us another 40 years, give us another 30 years and cancer is eradicated. That would be the optimistic view of this. How would you counter that view?

I don't want to counter anything. I mean, that's the way the field has been. I've been hearing the same self satisfied voices saying the same thing. How wonderful they are. How they will understand every intracellular signaling pathway in the cancer cell and reverse it. How they will understand the metabolism. Don't even get me started on that. Because it's as if the last hundred years haven't existed and people haven't had any ideas until these new investigators came around on their white horses with their overconfidence and contempt for the past. Armed with new things, we are going to reverse all these. I mean, clearly, whatever advances there are. And I don't want to argue with anyone about advances. You are saying there are many. A lot of advances. Great. Do they really reflect the quarter of a trillion dollars we have invested in research? Is this all we have to show a few checkpoint inhibitors? Fine. I agree with you. Even if I agree with you. So let's just talk about immune therapy for a minute. You say checkpoint inhibitor. There are many different kinds of immune therapies. 14, 15 different kinds. The two most popular we talk about when we talk about immune therapy these days is either the cell therapies that are given where you train the lab. That is the pioneer of all of this work with cell and cytokine il therapies combined with T cells, et cetera, or the checkpoint inhibitors. Because normal cells will have signals on themselves saying eat me or don't eat me. And these can be masks and these signals are the checkpoints. And by using drugs, you can unmask the signal which has been covered up by the cancer cell. Very simple explanation for checkpoint. So the two main ideas in immunology that came along were how to target these checkpoints so that the body's own immune cells can recognize the cancer as being alien to the normal functioning of the body and must be eliminated. And the second is, can you take the body's own immune cells and engineer them in such a way that they can selectively kill cancer and car? T cells have been proclaimed once again as revolutionary. Of course, the science behind it is beautiful. It's very sophisticated. It really. It's one of those things that make you want to celebrate humanity's accomplishments. It is just a gorgeous thing. But the problem is that it has done very little for patients. Why? Because what all the oncologists talking about KTI never mention in any of their talks and by the way every morning I run every morning. And after I run, I jump on a small trampoline for 20 to 30 minutes every day because that's one way to stimulate your lymphatic system. And the trampoline is small rebounder, I should say, not a trampoline. It's one of the best exercises. You can have been doing it for 25 plus years. So during that time, I listened to YouTube lectures to all of you cancer researchers out there. Understand that there is one person who listens to your YouTube lectures every single day. And the kinds of things people confess to in public forums very different than the scientific papers they're writing. In all of those talks, I have never heard any serious scientist, oncologist, or immunologist say that their CAR T cells cannot distinguish between normal and cancer cells. They just ignore that. It's like they just don't want to acknowledge it. Why don't you say that? Basically, CAR T cells are just another form of killing machine indiscriminately. So what CAR T cells do is whatever antigen you put on it and whatever organ expresses that antigen, it will go destroy the whole organ, taking down every normal cell of that organ also. So basically, the only thing CAR T is working for right now is B cells, because you can replace B cell function after you kill every single last B cell in the body, but you can't do that to pancreatic cancer because it will kill the whole pancreas, and then you can't replace the function. But how many times have you heard people say this, Peter?

Well, I mean, do you hold out hope that some of the case studies. Because we've seen the case studies. The cholangiocarcinoma here, the pancreatic cancer there, the colon cancer, the breast cancer there, where they are able to identify the unique antigen of the cancer. And by unique, I mean distinguishing antigen of the cancer such that you can send the T cell loose and it can eradicate not the entire biliary system, but just the cancerous piece? And to be clear, I'm not speaking one way or the other, other than to sort of help me think through the. Is this a sufficient proof of principle that we believe that adaptive cell therapy, of which cars are the most far and away the most prominent, and checkpoint inhibitors are really going to be the way of the future? You didn't allude to it. You and I know this as well. As Tuesday follows Monday. There are also very nasty side effects of checkpoint inhibitors. And for every patient we see who has a response to them, some of the autoimmunity can be quite devastating. And in fact, vitiligo for a patient with melanoma might not be such a fatal form of autoimmunity. But certainly when people have life threatening enterocolitis, yes, they're cancer free, but they die from bowel disease, that follows. So certainly not to suggest these are benign. I guess the point is, do they represent a demonstrable step function forward that now puts us in a new era of okay, we've found a new beast that goes beyond surgery, radiation, and indiscriminately killing chemicals. How do we figure out how to tame this new beast? Does that resonate?

No, not particularly, because Steve Rosenberg has found this ages ago that this is the right way to go. But yes, we are making advances and I do think that all of these need to continue. I'm not saying we should stop any of this. I'm just pointing out where the field is right now. I think these are fantastic. They should continue. What needs to stop. Here's the problem. 95% of experimental agents that we bring to the bedside today, 95% in cancer, fail completely. The 5% that succeed should have failed because they are only prolonging survival for 20 to 30% of patients by a few months. And you began by asking me what is progression free survival? What is. I mean, we don't even talk about survival anymore. We just talk about progression free survival because survival has become too big of a obstacle to overcome. So as long as you don't see the tumor, but the patient dies within the same four months or five months, it doesn't matter. But you didn't see the tumor for two and a half months. That's progression free survival. So this drug should be approved and the sponsors of the drug will make billions of dollars.

Let's stop on that because it is just so darn important. Let's use a tangible example. Avastin. Okay, I don't want to put you on the spot because I don't remember the numbers of Avastin, but the only reason I bring it up is that an. Okay, do you know enough of the examples that I could use Avastin?

I mean, I don't use it myself, but I do know that it's one of the more successful.

We could pick another one that, you know, I'll explain. So Avastin was a blockbuster in the sense that it was the first of its kind and it explored a brand new idea. So Judah Folkman had a. This idea that many others followed in the footsteps of which is, look, if a tumor can't make new blood vessels, it can't get very big. Therefore, the ability to make new blood vessels must be of paramount importance to metastases. And therefore this concept of neovascularization became key. And so this was a beautiful story of science and pursuing this thesis and doing all of these experiments. And. But one step leads to another, and before you know it, you have a whole class of drugs called anti VEGF drugs, of which this drug, and I assume it was Genentech's drug, I can't even remember at this point, but I think it was Genentech that was the first in line. They have this drug, Avastin, and I believe colorectal cancer was one of the first places they looked. Again in the show notes, we'll have the story more accurately laid out. But the gist of what I remember, Ezra, is the following. You took a patient that had metastatic colorectal cancer, which again means this is a patient who had a colon cancer that has left the colon, left the lymph nodes. It is now somewhere else, usually in the liver. This is a patient who is absolutely not going to live. And if 1% of those people live five years, that would be very generous. And this is asking the question, if you use all of the standard therapies we have today, the entire cocktail of chemotherapies, and then you do the same thing, but you also use Avastin, how much do you change the median survival? Notice we don't use mean because that can be very impacted by outliers. We use median. And I believe the answer with Avastin was on the order of four months. With Avastin, which cost at the time in the neighborhood of $100,000, it was going to extend median survival for those patients by four months. And what I remember most about the discussion, Ezra, is it prompted a discussion about what is the value of a life. And different countries around the world, especially countries without private insurance, but instead those with public insurance, had to put something called a QALY at the front of that discussion. A Quality Adjusted Life Year, which says, do we believe that the cost of a life is worth x hundred thousand dollars such that a publicly funded insurance for health would be accountable to spend that money. And if you don't like that example, because I might not have the details right, that you can use a thought experiment, which is, if I told you, Azra, you have a condition that is going to allow you to die, but I could extend your life by a month and it's going to cost a billion dollars. Do we as a society think that that's a reasonable cost for society to bear on your account, despite how wonderful you are and how much amazing stuff you could do with an extra month? So it started to get into this discussion of the cost benefit analysis which gets to that return on investment. Do you want to use a better example, a more recent example than Avastin, to illustrate how relatively small changes in median survival or disease free progression, and maybe you can explain the difference between those two, because you and I will go back and forth between them. But I think the listener could be confused. And then again, just talk about the literal economics of that, because I do think people will be staggered by what the actual numbers are.

You know, John Donne said something very beautiful. So when you said give a literal example, I'm going to give a literary example. No man is an island, entire of itself, each a part of a piece of the continent, part of the main. Any man's death diminishes me. That's what you said. What is a human life worth? John Donne says, any man's death diminishes me because I am for mankind and therefore never sent to know for whom the bell tolls. It tolls for thee. Of course every human life is important. And of course every oncologist is working to try and save every human life. I'm not saying we are deliberately not doing enough. In fact, in all of my career in this country in the last 43 years, I have yet to meet an oncologist who didn't care for their patients. Never. They're all trying their hardest, but it's like trying to use a map to find your way in London, but you're using a map of Paris. It's not going to work. So how have we become so misdirected? You asked me to give a more recent example or something I'm familiar with. I started landed in this country in 1977 as a fresh medical graduate. Before my residency could start, I had six months. And I'm not someone who can sit around at home doing nothing. So I asked my sister, my older sister, who had just finished a rotation. She was a pediatric resident in Buffalo, New York. I was staying with her and she just finished her rotation at Roswell Park Cancer Institute. And I said to her that you know all the oncologists there, can you get me in there and I'll just work for six months that I have. So she went and spoke to her boss, Arnie Freeman, and he said well, if she's half as good as you, we'll take her. So I joined pediatric oncology at Roswell Park. But within a couple of months, it was very clear I couldn't handle it. I couldn't last because I was crying the whole time. I just can't handle children being sick. So my sister's friend, who happened to be my boss at the time, Judy Oakes, one day just took me by hand because I was hiding in a room crying away. I had lost a four year old that day and took me to the adult oncology unit where I met Harvey Preisler, who was later to become my husband. And Harvey was heading the leukemia program at the time at Roswell Park. And he took me on. I started working on the wards immediately. At that time, we used to have 20, 30AML patients, acute myeloid leukemia patients on the floor. And I started seeing and working completely as a fellow. I was hired as a fellow. We were using two drugs to treat AML back then in 1977, a combination of Arace and Donomycin. They were popularly known as seven and three because you give seven days of one and three days of another. By the way, Harvey and I started to use this 7 and 3 as a kind of a code word between us. We would be sitting in a meeting and Harvey would suddenly lean over and say to me, as that person is doing seven and three. And for us, that seven and three meant somebody is using seven words when three would suffice.

Another mark of a great writer.

So we were using 7, 7 and 3, 1977. Guess what we are using in 20, 27 and 3 all these years. Imagine the thousands of patients I personally have had to see and describe the same side effects and the same potential benefits they will have. Now when I started, the survival was 10%, five year survival with seven and three. Today with the same drug, it's about 26%. Why has it increased? Because the supportive care measures are better. We have better antibiotics, we can give more platelets, and red cell transfusions are easier to give. We have learned to manage better. That's it. The supportive care is better, but the backbone of treatment is the same 7 and 3. So now a company comes up with combining these two drugs, 7 and 3, in a fatty envelope. So they come up with this new drug now and it's the same 7 and 3, but it gets approved in this country and this approved form, which is I believe for a little older patients, like 60 to 75 years, if you, you have acute, myeloid leukemia. You can get this combination of seven in three which is inside this fatty capsule. Now, the regular seven in three costs $5,000.

$5,000 for how long?

For the seven days and three for the seven.

Plus the three days for one cycle.

Okay, $5,000. This fancy version seven and three costs $45,000. And do you know what is the improvement in survival under the best conditions? When they ran the study where you select patients, the eligibility criteria are so stringent. Their kidneys have to be working, their liver has to be working, their lungs have to be at capacity, etc. Etc. You know how we choose and select patients or clinical trials. They are the best of the best, right?

They have to be cherry picked. They represent the upper limit of what you expect in the real world.

Yes. And even in those cherry picked patients, the basis on which this $45,000 combination is approved is an improvement in survival by 3.7 months. That is a median improvement in survival. Which means a fraction of the patients, like maybe 30% experience 3.7 months improvement in survival. What does that mean? Median survival? So even out of those 30%, half of them didn't even experience that. But we are paying $45,000 now. If I don't prescribe that drug and continue to give seven and three, then I can go to jail because tomorrow, if the patient dies, which they eventually do because it's an older age group, then the family will sue me. Dr. Raza, this drug was available. It could have given 3.7 more months. So now the decisions that we are making as individual oncologists are not being made by us. They are made just by key opinion leaders. Or the very institutions like FDA which are supposed to protect the patients, have fallen a victim to this kind of propaganda, where under the pressure of advocacy groups who are demanding more drugs for cancer patients at any cost. Just to be able to say that we have 72 new drugs being approved this year for cancer. Look at the fantastic advances we have made. So under pressure from advocacy groups, from patients, the FDA has lowered its bar of approval, improving drugs to laughable criteria. It would be laughable if it wasn't so tragic. Here you have 3.7 month median improvement in survival for a fraction of the patients for $45,000 instead of 5,000. Are you surprised then that 42% of cancer patients who are diagnosed today will be completely financially ruined by the second year of their diagnosis? 50% of breast cancer women are being hounded by collection agencies with stage four cancer. Your friend Marty McCary has written a fabulous book. The price We Pay. People should read that book and see the obscenity we have reached. Vulgarity of it all completely. Not thinking about patients at all. Talking in terms of. Well, Azra, 3.7 months meant a lot to my patient who could go and attend his son's graduation or grandson's bar mitzvah. Yes, of course, like I said, John Donne said, every human life is important. But you asked the question earlier. At what cost do the others?

I mean, I think Marty's work does a great job of explaining this. And the only way I can sort of explain it is I think the United States has basically become the one that has to subsidize the rest of the world in terms of medical research. I mean, that's the only way I can sort of make sense of how outrageous these costs are. By the way, that's not a justification. So I could go on for days as to how frustrating it is, but it has basically become a form of subsidy. And I've been trying to get my head around what are the biggest drivers of spending in the United States, because overall, as a country, we don't get a lot in exchange for what we give. That's going to be a very polarizing comment I just made. So let me clarify it. If you take someone in the top income tax bracket in Canada, by all estimates a socialized country, you compare them to someone in the top income tax bracket in the United States, especially in a high tax state, they're paying about the same amount. The difference, however, in what they get is fundamentally quite different. In Canada, everybody gets health insurance. No ifs, ands, or buts. Everybody basically gets exceptional education at a fraction of the cost. Homelessness, mental health. A lot of these issues are just so much better. I still think I would still make the case, by the way, that the extremes of healthcare are better in the United States. I would much rather receive my medical care in the United States than in Canada. But ultimately it points to a gross inefficiency in terms of how those dollars that are collected are then turned around and spent. And I could probably point to three things that the United States is disproportionately spending money on that other countries are not spending money on. And it's those three things that are creating the biggest gap. And one of them is health care. There's simply no way to avoid it. And within the morass of health care, drugs might be one of the most egregious examples. There are others that are less sexy to point Your finger at. But as you note, I mean Marty makes a very good point that the drug story is a revolting one.

Actually after Harvey died with a five year long battle with leukemia.

You are in your early 40s at this point in time. Basically when you're widowed.

When he was died and we had it four year old daughter.

Yeah.

When he was diagnosed. So after he died, my younger sister, who's now the head of women's radiology at the Brigham, she said, well, I have to get you out of Chicago because this five years of thinking of nothing, concentrating continuously on this one thought only, which was Harvey and his illness. So we went to England because, well, London is one of my favorite cities. And I wanted to take my daughter to see Reading Jail because I'm a big Oscar Wilde fan. And we went to Reading. And the reason I'm telling you this is one of the most gorgeous ballads ever written. The Ballad of Reading Jail. The refrain is very beautiful. Yet all men kill the things they love. By each let this be heard. Some do it with a bitter look and some with a flattering word. The coward does it with a kiss, the brave man with the sword. But each man kills the thing they love. By each let this be heard. So Wilde wrote this poem when he was in this ballad when he was incarcerated in jail. And when he came out, his boyfriend, Lord Alfred Douglas asked him, what do you mean by this refrain? All men kill the things they love. What does that even mean? All men kill the things they love. And Wilde tried to just diss him and said, well, nothing, you know, it's just whatever. But Bosie, Alfred Douglas kept insisting, no, you have to tell me what this means. So you know what Wild said? He said, look, it's like this. When we meet someone or we have an idea, we make immediately an impression in our mind. We meet them the next time and they don't correspond with the impression we had. So instead of correcting our impression, we start trying to change the person. And this is how we enter this cycle of self delusion and kill the thing that we love. Why am I telling you all this is because we started with good intentions, Peter, but somehow, remember in the beginning I said, I'm looking for an adult. Why aren't we taking stock of the situation? Why is it that scientists who are going to now, let's say, attack the metabolic pathway of cancer cells to improve the efficiency of chemotherapy by simultaneously changing the dietary patterns for the patient? A very good target to think about. But before even a phase one trial has started, they are monetizing it, making companies out of it. I mean, yes, this is a capitalist system. Everything is legal, everything is allowed. But then it somehow leaves such a bad taste in my mouth all the time. All the time. It's all about. Think about it. You are never going to be able to cure an advanced cancer of the kind that Andrew had by a diet of any sort, or even by supplementing chemotherapy he's getting with a diet of any sort. All you are aiming for is improving their survival by a few months. But more important is to make companies. Why? Why have we come to this?

I mean, I think in defense of that type of idea, which I don't really know about specifically, they would probably argue changing nutrition. If a change in nutrition could have a comparable benefit to a change to the use of a drug, it's a fraction of the cost and presumably without the destruction of the quality of life. I mean, one of the things I'd like you to come back to, Azra.

Is I'm question the idea, Peter. Sorry, I'm not questioning the idea at all. I'm questioning why do you have to monetize everything? Is what I'm questioning.

Yeah, I mean, I was going to ask you the same question, which is, how do we think about the role of pharma in this entire landscape? I mean, it can't be denied, which is progress has to be funded by somebody. You have different animals. So you have public funding, which has been the majority of it through NIH via nci, which is by far the largest of the institutes within NIH and has done the lion's share of the cancer funding. So I actually did the analysis five years years ago, which means it's probably dated, but directionally correct. But if you went back to the declaration by Richard Nixon of the war on cancer, so circa 7172, more than half of the total research dollars in the world into oncology funneled through nci. Slightly over half was my recollection. Again, I could be a little wrong on that, but that's a big piece of it. Of course, pharma, as you know, has really outsourced R and D. They just don't do R and D anymore the way they used to. So they basically now acquire R and D products and so smaller and smaller companies, which means it's shifting more to venture type investing. And biotech investing is taking that early stage one, early stage two risk, at which point pharma brings in for the huge capital allocation required for late stage two and stage three approval. That gets the drug approval, which then gets to the point you raised, which is you've got these two drugs that have been off patent for. Since Moses was throwing tablets at people. What are you going to do with it? Well, you could keep selling them for $5,000 or you could repurpose them and increase by nearly 10x. And I know that it sounds egregious. I don't have an answer though, because I don't really like. This is almost to me a question of economics is the answer that all of this stuff has to be done publicly so that shareholder value is no longer the thing that's being optimized for. Because as long as these companies have to answer to shareholders, I don't think they'll ever figure out a way to put the woman with breast cancer who's going to go bankrupt ahead of their shareholder. As awful as that sounds, I think they're always going to say, I have a fiduciary responsibility to my shareholder and that is to maximize the price. And I do think the government is doing a better job at catching the most egregious examples of company that are grossly exploiting this. But in the end, is Keytruda really worth what it's being charged today? I don't know how to answer that question. I really have no clue how to answer that question. And you've more eloquently than me said every life is valuable and that includes the lives that remain. Which I think is a very important point. That's the counterpoint that's never made. It's not just the life of the individual that we're debating extending by 3.1 months at some unbelievable sum. It's the lives of everybody that remains and what it says about their Social Security security check and what it says about their schools and what it says about their health care.

Wait, I want to answer this. If you take a living frog and you throw it in boiling water, it will jump out. But if you put it in cold water and start heating it slowly, it will die in that because it has been desensitized so slowly. He began all these things with good intention. That's what I keep saying to you over and over. Some of the saddest things to me are this 95% drugs we bring to the bedside fail. Why? Because the pre testing platforms we are using are so artificial. We are taking a very complex disease like cancer and we are trying to reduce it by reductionist approaches into trying to replicate this complexity in mouse models, in tissue culture, cell lines and if those don't work, we add layers upon layers of complexity to it by genetic engineering, immune compromisation of the animal. You know, after reading my book the First Cell, a young woman wrote to me saying, Dr. Raza, I'm a PhD student, I'm working on this cell line model of breast cancer, testing drugs against it, but using a two and three dimensional in vitro system. And once this is successful, that the drugs work against the cell lines, then I will go to the mouse model. And if that works, then I have to go to human. But reading your book, I realize that it's all a waste of time. What should I do? Is this even something I should spend the next 10 years of my life doing so? But 90% of research is still funding things. Research dollars. You are talking about NCI dollars. What are they funding for God's sake? The same old, same old ancient platforms which have shown a 95% failure rate and the 5% success is ludicrous.

Secondly, before you go, can you say more about that? Actually I'm glad you brought this up because I sometimes forget that I know a lot of the things you're talking about and I take them for granted. But I think this is worth a bit of a detour if you don't mind. Explain to people what that PhD student was doing. What is a day in the life for her or what is she going to spend years doing and how does that sort of model fall short?

I think you can explain it better than me because you have spent so much time in Dr. Rosenberg's lab. But very simply stated, when we want to try and find new drugs for cancer, we can't give drugs directly to humans. So we try to first give them to something in our lab. What should that something be? Well, it started by taking patients tumor cells. But they don't last very long in our cultures in the lab. So then that becomes a problem. How should we perpetuate these cells in culture? By serendipity. Some cancer cells began to grow in the labs. And one of the first was the famous HeLa cells from a patient with cervical cancer. And these cells grew so well that they became immortalized, they self perpetuated, they can be grown from flask to flask, transferred from lab to lab. They can be put into mice and grow. And so all this reproducible system that became available is called a tissue culture cell line. And we learned with time to make more and more of these. So you make a pancreatic cancer. Now, just like the HeLa cells were cervical Cancer. You take a ovarian cancer, a pancreatic cancer, you grow them, and one of them will by chance mutate enough to become immortalized and then become the tissue culture line. Now, you can test drugs again against it. But one of the first things that I have written in my book in the first chapter, is that by using these cell lines, when it was tested to see what kind of genes are they expressing, it turns out that instead of expressing genes that were faithful to the tissue of origin from which they came, for example, an ovarian cancer cell line should be expressing genes that are expressed in ovarian cancer. Pancreatic cancer cell lines should be expressing pancreatic genes instead. It turned out that there has been a transcriptomic drift that basically all the cell lines, irrespective of their tissue of origin, express similar genes that make them survivable under adverse in vitro true conditions.

So let me explain one other thing for the listener here, which kind of ties in another theme of yours, which is because when you go back to what we learned in the Great War, killing cancer cells is easy. I've had guests on this podcast before who have eloquently stated, there's no one sitting in a home right now that doesn't already have 30 chemicals under their sink that will kill every cancer, including the most devastating cancer, like the one that killed Andrew. The challenge is killing cancer and not killing everything else. And so now, when you fast forward to what you just said, when you have immortalized in vitro cultures that have become so genetically skewed that they no longer actually represent a human cancer, you will learn a lot about what it takes to kill them and not kill them. It just won't be relevant to the species of interest, which is a human being.

This is why I read the Oscar Wilde thing to you, that all men kill the things they love. We started with a good thing when it didn't correspond to what we were hypothesizing. Instead of changing our concept, we keep tinkering with trying to change the other thing. This is exactly how you kill whatever you started out with. And you know what's worse, Peter, is that 90%. Nine zero. I want the audience to hear this clearly. 90% of the papers published in the highest profile journals of science are irreproducible.

I didn't know it was that high. It's still that high.

Up to 90% in different studies. Some show 30%, some 80%, some 90%. It is unconscionable what we are doing. Why are they not reproducible because for the same reason, one set of mice don't correspond to another set of mice in another lab. So the point I'm making is 95% of your drugs are failing until now, after quarter of a trillion dollars in research, like you said, that is between $6 billion a year right now, NCI funding and another 6 billion from philanthropic funding. Where is all this $12 billion going? And then breast cancer alone raises $6 billion in funding. And what are they doing? Studying breast cancer cell lines against drugs. And yes, it will get that young lady a PhD eventually. And then she will try to get grants. Eventually she'll get fed up and go to industry. And I must take exception with you condemning the industry. They are the easy target. Pharma companies, they are the easiest target. But the system of research and development in America is that somebody like me who is an academic researcher will write a grant to NCI. They will fund me for 250 a year, for three to five years if I'm lucky.

But let's put that in perspective. By the way, by NCI standards, that's a lot. An R01 at this point. What is an R01 down to now? Is it down to 450,000 a year for four to five years?

Yeah.

That's almost as big a grant as someone's going to get.

Yes. And with that all you can do is study one gene, one signaling pathway. But let's say I luck out and I find something which I think is looking very encouraging and is a potential target. The next step is obviously to take it to the bedside. But to do that, I have to now test this in mouse models first in two mammals in fact. And then to take it to the bedside for a phase one trial alone will cost $30 million. And by the time this drug will get approved will be two and a half billion dollars. Nobody can fund that kind of work except industry. It's a very strange kind of thing where we are strange bedfellows, academics and industry. Academics will develop the biologic insights which are needed to identify targets. But we don't have the bandwidth to take it to the patient. So industry comes in, takes that, but then they have to bring it back to academics because that's where the universities will help academically, two patients. So do you today the criterion for recruiting young faculty? The young faculty is complaining to me that Dr. Raza, all the universities where we are applying ask us for is how many clinical trials are you going to open when you come?

Yeah, look, it's a symptom of a broader issue, which is the incentives have come out of line. I don't know how to fix that, by the way, but even taking it one step further, look, just the entire system of publishing in academics has become so skewed because you took a good idea which was, wouldn't it be great if scientists would do work, would publish them in journals, would have them peer reviewed, would share knowledge broadly so that others might see it, learn from it and not make the same mistakes and build on the work of others? Right. A beautiful idea. You can't disagree with any of it. And by the way, recheck things that have been done to make sure they were done correctly, because under different conditions we want to make sure they're reproducible. Okay. Understandably, then that idea gets extended into. This should be a criteria for promotion within the academic system, which invariably turns into an entire cottage industry of garbage journals and garbage study and garbage publications which are driving up the fraction of studies which can't be reproduced. And by the way, the fraction of studies that can't even get cited. They're so insignificant. And so you sort of think, my God, if something as pure and ideal as scientific research and publishing has become so difficult to do, and I don't have a great solution for that, the process you're describing is a logarithmic order in front of that, which is taking research from the so called bench to the bedside. That's the thing that I still don't. Even after reading about this topic, and not just your book, but other books, I still don't have a great sense of what the future looks like. I don't disagree that the water is starting to get uncomfortably warm here as a little frog. And I don't disagree that we need to get out of this bath of water and into a cooler bath of water. But boy, I have to be honest with you, I'm discouraged.

No, no, don't be. I have a solution for us and a very important solution. You know, Peter de Rice is a writer who wrote a book. In 1961 he wrote a novel because his own daughter, who was 10 or 11, died of leukemia in his arms. And after a horrible battle in 1961, Peter de Reich says, so the treatment for leukemia today is a local rather than an express train. Same run, a few more stops. But that's how medicine functions. Perfecting the art of prolonging disease. This was in 1961. How is this different? The run for leukemia is still a local. What I want to say is I feel Like I'm living in a theater of the absurd. Why aren't other people seeing the spectacular failures we are dealing with? And why do we keep mollycoddling the public? Why do we keep promoting the two, three months or five months advantage in survival? Why aren't we going for bigger goals and better things? We can do it. You know how we can do it is very simple. What has worked in cancer until now? Early detection. How is it that we are living in an era of the most sophisticated technologic advances possible and yet the treatment of cancer is paleolithic? It belongs in the Stone Age, in the caves. Giving the kind of disfiguring, horrible treatments we give is like beating. Someone said this. Beating the dog with a baseball bat to get rid of its fleas. Have you ever seen somebody being treated with CAR T therapy? My God, there are whole industries sprouting up to control the side effects. Why are we even developing such terrible therapies? Yes, we should develop them, but they should be used when the tumor burden is not that high. So once again, I want to be very clear about a couple of things before I give you my solution. Number one, I'm not against animal research at all. For biology, it is very important to use the animal model. All I'm against is drug development in animals. Because what you learn in animals by using drugs is only correct for animals. It does not automatically extrapolate to humans.

So just to be clear, you're saying you would still use animals for safety, but you would disregard them for efficacy?

I would not use them for safety either. Why should it give me any level of confidence that the drug didn't kill mouse, it wouldn't kill a human? It has very little to do with each other.

We don't have to go into it now. But I guess. Do you know from sort of even back of the envelope how that would change the regulatory landscape if we now had to go to a much earlier phase one in humans, obviously probably using a milder dose escalation. Or would you be talking about doing primates instead? What is the actual model?

None of those. In fact, the FDA has a system which is called phase zero, in which you don't just bypass any Animals, you use 1-500th of the dose, starting those in humans and work your way up that.

So basically it's homeopathic all the way up.

Yeah. So that's how you do it with a phase zero trial. What I'm saying is, look, the only thing that has worked is early detection. We have great technology available. We shouldn't be talking about early detection doesn't work because mammograms have not been helpful or PSA have led to over diagnosis and men undergoing very macabre surgeries and things. No, all I'm saying is that we should definitely take advantage of the cutting edge genomics, transcriptomics, proteomics, metabolomics, the scanning and imaging devices that have been developed and use artificial intelligence to put all this together, develop 50 tests if we have to, to identify biomarkers which are based on all these things and combine them with the latest technology to try and start monitoring the human body not once a year, but continuously like a machine. And how do you do that? Well, you see this chip or you can see it, the audience cannot. It's a small chip, the M chip. You can look it up because it is FDA approved. It is based on microfluidics. You put one drop of blood here, which goes through microfluidics and interacts with the biomarker put here. The biomarker in M chip case, which is FDA approved, is psa. So men who have been diagnosed with a high PSA can use this chip. It can slide into a small device and very soon into your cell phone and give you your PSA four times a day if you want to see it. And if you're diagnosed with having a high psa, you don't have to go in and have a complete abdominal resection with the removal of every lymph node and be eviscerated. No, you follow this at home if you have to, as often as you want. I'm saying that if we develop a biomarker that is identifying the earliest footprints of a pancreatic cancer, we put that next in the next lane and for ovarian cancer in the next, or for each cancer we develop like a barcode and with one drop of blood. So Toshiba Accompanies just announced that they can detect 13 different cancers from one drop of blood in four hours for $180.

There's a company in the Bay Area that I follow very closely called Grail and they're doing something very similar at this point. They're, you know, in phase two with probably almost 30 different cancers. I agree with you completely. I mean, my view of cancer is rule number one is don't get it. I mean, that sounds glib, but I don't think enough attention is paid to the don't get it rule, which is why aren't we trying to better understand what the environmental triggers of cancer are? Because while as you point out it has always been with us. I think there is reasonable enough evidence to suggest that its incidence is higher in a modern world than in a non modern world. And therefore, what is it about a modern world? For example, what is it about our diet or about our stress or our lack of exercise that could be amplifying our risk? And if you think about it, if changing factors of our lifestyle could reduce your risk of cancer by 30 to 50%, which my reading of the literature says is absolutely the case, how could we not make that a high priority to understand? And when you pair the rule number one, don't get cancer with rule number two, very smart screening for cancer, you then get into rule number three, which is if you get cancer, treat it so early, treat it when it is basically in the millions rather than the billions of cells. And for someone who might not have the familiarity with cells, a million cancer cells is not even detectable to the naked eye. A billion is. And so there's a very big difference between when you can catch a million cancer cells versus a billion. And I agree with you, by the way, completely, that most people who are critics of early screening are unfortunately lacking the nuance to appreciate the accepted failures of things like PSA and mammography, which I won't go into here. I've covered them in great detail in some other podcasts. Two in particular, I'll just direct the listener to. I think the failures of PSA stand alone as a failure has been covered very well on the podcast with Ted Schaefer. And Ted talks very eloquently about how if you are wed to PSA using PSA volume, where you take PSA normalized to prostate volume and PSA velocity, which Ezra, you would get out of what you propose, which is the rate of change of PSA over time. So PSA is a rate of change called PSA velocity, PSA volume become much better indicators of prostate cancer risk than just psa. But also you go far beyond PSA to things like 4K and other types of tests that add more nuance to this. I think the story becomes much more clear that this type of early detection matters. And I think as it pertains to the limitations of mammography. So I would direct people to the podcast I did with Raj Atariwala where we talked about cancer screening and we actually very specifically addressed some of the limitations of the literature on these isolated techniques like mammography. So you're not going to get any disagreement out of me on both of those fronts. So I guess the Question is, do we really believe that by taking those types of steps we will reduce the need for the cancers for which we have just not had the big breakthroughs, which is basically lung, pancreas, prostate, breast, colon and gbm. Those are basically the most lethal cancers outside of gbm. It's the metastatic versions of the others. Obviously, GBM doesn't lethal the brain, it kills locally. That's got to be two thirds of cancer deaths. And you're basically saying we have to catch these things long before they're ever in a position to leave the primary organ and not try to reinvent the ankh drug discovery wheel coming up with another cocktail that's going to be as lucky as we were with Hodgkin's lymphoma. Is that. I don't want to put words in your mouth, but is that your view?

Yeah, well, sort of. But let me restate what specifically I feel, first of all, about the lifestyle you're talking about. Of course, lifestyle is. It's only common sense that if you smoke, it's not going to be good for you. Your likelihood of getting not just lung cancer but many diseases will be high. So, yes, lifestyle changes have. We have to continuously drill into our consciousness what is good for us and what is bad for us and try not to get it. The problem is that with cancer, as I began by telling you, heredity and pathogens and environmental exposure like smoking, etcetera, do account for a certain percentage, the vast majority. There is no reason why they get cancer, at least a reason that we can identify yet.

I think that's the challenge, is that with smoking, the difference between the people who smoked and the people who didn't smoke was so great that it was appreciable. But you're right, with most other environmental contributors, with maybe the only other exception being obesity, it's very difficult to tease out what else could be contributing. For example, I don't know if you're running or the trampoline is making enough of a difference because it's very difficult to study that longitudinally and prospectively. And secondly, I don't know that enough people are doing it and it would create a big enough signal that we can measure it.

Well, that's what I was going to say. We don't even know whether eggs are good or bad for you to this day. So those are the kinds of issues with lifestyle, large studies. Now, the point I'm trying to make though, is that slightly different, a lot of people smoke, not all of them get cancer. So there Are other co factors that exist. All these things have to be worked out. Haven't we been trying for a hundred years? For God's sake, don't the investigators who act like this is something they have discovered today to be looked at? No, this is what we have been trying to do forever. It's not that simple. What we are finding is that for the vast majority of cancers, There are random mutations account for it. Which means that cancer is most common with age increasing. Age, why? Because with age, many more of the cells in our body have undergone several divisions. And with each division, we pick up some DNA copying errors, two to three on an average. So by the time my cell is now from birth to like 60 years of age, Every cell has undergone multiple cycles of proliferation. Therefore, multiple gene generic mutations have collected and these are making the cell susceptible that now it's like dropping grains of sand and they will form a pile. And at one grain of sand, which is no different than millions before that had gone before, it will suddenly cause an avalanche and the pile will collapse, not because the glass grain of sand was different, but the pile had become unstable. So with age, the body becomes unstable because all the cells have these kinds of mutations. So, and not only that, metabolism can go wrong. And sometimes, as shown by whole genome sequencing of over 2000 tumors, that there are a few cancers where no mutations were found in advanced cancers. So how did that happen? Well, because sometimes it is the disturbed metabolism that then leads to production of reduced oxygen species or free radicals, for example, that go and chop up and cause mutations. And that genetic mutations are a secondary event, the primary event is a metabolic disturbance. So I mean, all this needs to be done. All this needs to be studied. And it isn't like it hasn't been studied since 1921. Poor Otto Warburg made the first observation of anaerobic metabolism. And since I was doing ketogenic type diets in the 1980s, so please don't think that any of these things are new. But the question that I am asking as someone who's been in this field for 43 years now is this. If I'm still using 7 and 3 to treat AML, and for most common cancers, we are still using slash, poison and burn, it is not for lack of resources. It is not for lack of very, very smart people, hundreds of thousands of them, who are working 16 hours a day to try and find the answer. But the answer is very complicated. It has too many aspects to it. So the only thing we should do is I am beseeching everybody in cancer related fields. Let's just spend a little more effort, a little more resources in earlier detection. Yes, keep trying to understand metabolic pathways and intracellular signaling and checkpoint and car T's and everything else. But instead of spending 5% in prevention, let's spend 50% in prevention and early detection. That is all I'm asking for. So a lot of people have asked me, Peter, because I've been completely uncompromising in my criticism, as you've heard. Now I am completely merciless. You know why? Because I have brought the patient back front and center. And everything I look at is through patients human anguish. Our problem is that 90% of our researchers never see a cancer patient because they are basic scientists and they study tumors that they grow on their own in their labs so they don't see a disease they are trying to develop treatment for. And they are using animals who don't get these diseases spontaneously. How artificial can you become, for God's sake? So my thing is, while you're doing all that, at least let's employ all of the sophisticated technology and a lot of the intellectual resources to developing biomarkers for early detection. Why not look at every compartment, whether it's blood, sweat, tears, saliva, urine, microbiome. Study everything but human. Stop studying animals, for God's sake. Study human tissue.

You're making so much sense to me that I'm struggling to come up with a counter argument to that point you're making. I mean, should 50% of our resources be. Be put into prevention and early detection rather than 4%? If that. Absolutely. Should we also shift this to study disproportionately in the study of interest? I couldn't agree with you more. You made a point a moment ago about the nature of contact. I wanted to use that as a point to come back to Omar. Why did you include contact, the story of Omar in your book? He's not unique, right? I mean, you've treated a million Omar's. What was it about him that spoke to you so much? It had to be more than just his ethnicity. But I don't know, maybe I. Maybe I shouldn't assume that.

Well, first of all, he's my best friend's son. Here is a 38 year old young man, graduate of Oxford and Columbia teaching, is finally fallen in love, calls his parents to come and get him engaged. And when they arrive, the young couple, he has a little osteogenic sarcoma. So the thing that has forced, that made me put Omar into the book is the utter helplessness of oncologists because from day one when you have not resected that solid tumor completely, you were a surgeon. You were a surgical oncologist. You are a surgeon. You know this, Peter. If you leave behind 10% of the tumor or even your microscopic pathology shows that cancer cells have entered blood vessels, as was the case with Umar, now you know that his chances of survival beyond a few couple of years at most are 0.00. What are your choices you are going to give to Umar? Either you die of cancer or you die of the treatment we are going to give you. Because the problem is if we don't give treatment, then death from cancer is horrendous in itself. It's one of the most painful deaths. So are we at least doing some palliation? And Omar's case was really. It's a good question you asked. It was emotionally soul destroying to see this young man who's already just embarking on his career finally, after years and years of hard work, has met the woman. He gets married a couple of months after the diagnosis, actually, and knowing that he's going to die. And I had to live through every single day, not just in the hospital, but also at home because we are seeing him.

And by the way, if I recall, this was only about five years after your husband died.

Yes, no longer. Harvey died in 2002. Umar dies in 2009.

Okay, okay. Sorry. But yeah.

Yes. Yeah, not that far. So I think also in the book I tried to balance it out by presenting some elderly people like Lady N, Kitty C. Are older, Harvey was older. Whereas J.C. andrew and Omar, the three are younger people, so. And different types of cancers. I also wanted to show so brain tumor, osteogenic sarcoma and a liquid tumor. Then Harvey had a lymphoma. Many people ask me because I have been so brutal in my criticism of everybody. And that's why I began telling you that please, let's not just blame pharma companies. The hospitals who are supposed to be nonprofit hospitals are making so many hundreds of millions of dollars in profits. What should they do? They have no shareholders to distribute it to. So they give large raises to their bureaucracy, the executive business people running the hospital. And then they start buying other hospitals and start investing in brick and mortar. This is what's happening. I in fact think about health care very much. I was talking to Perry Marshall the other day who was talking about higher education. That in the post Covid world one of the things that will be completely redone is higher education. Because the two variables who have Skin in the game in higher education are students and teachers. And students are embroiled in horrible loans by the time they graduate. And teachers are not even hired in permanent positions anymore. There are adjunct professors that are hired so you don't have to give them any kinds of benefits. And those two people who have skin in the game suffer, whereas universities are developing endowments in billions of dollars. These are academic institutions. But I compare that same thing to health care. The two people with skin in the game in healthcare are patients and doctors. Patients are fleeced for every last penny and doctors are overworked all the time, so we have no time to spin. And businessmen are running the whole show. So I think the system has. It's like that frog analogy over and over again. No one is going to give up what they're doing willingly at all. I believe exactly what Thomas Coon said. If you want to change the paradigm, you have to show a better one. That's it. So how do we show a better paradigm? Well, at least I'm pointing to the only successful strategy in cancer is early detection. Why not use the latest technology to go for early detection? We can financially incentivize it and with the one success, the whole field can turn around because they will see that that's where it's a better thing to invest rather than in a venture that has a 95% rate of failure. And mark my words, the coming decade of 2020-2030 will see this shift from treating the disease to trying to detect early and prevent the disease from becoming established.

I agree with you. I really do agree with you. I don't know that I can speak convincingly to the time frame, but I am actually very optimistic with the potential of liquid biopsies. And it's something we have been very eager. It's been a big part of our practice, frankly, inside of our practice. And look forward to having a more rigorous discussion about this that's dedicated on the podcast. Once some of the technologies get through certain stages of fda. Ezra, I want to close with a quick question about the loss of your husband. At any point during that ordeal when he was struggling and you were right there with him and you had this young daughter, was there any point of view that was thinking this is so unfair? The disease that you've devoted your life to, the disease that he has devoted his life to, is ultimately the disease that's going to take him, and not just take him, but take him decades too soon. Or were you able to sort of come to this place of what some Might call radical acceptance, of just saying, I accept what I can change. I have the courage to fight the things that I can, and I have the courage to know the distinction. So called serenity prayer. How did you go through that at such a young age?

It's very hard to describe what one goes through. Of course, I kicked doors all the time, and I had crossed crying fits all the time. And I remember calling my mother so often on weekends we used to talk. She was in Karachi, of course. And I would say, so many of my friends hate their husbands and they're doing fine. And look at me. I'm one who's crazy about Harvey, and he's dying in front of my eyes. I went through every human emotion that a wife would go through, especially because our daughter was so little. And Harvey is the one who actually had reached the point of acceptance. And when I would lose it, every now and then in front of him, he would very calmly tell me not to worry about it. It's just the luck of the draw as don't worry. And he would. One time he said, look, when he was diagnosed, he was initially told his diagnosis. His reaction was so quintessential Harvey, he said, well, I'm glad it's me and not you or Shahrazad. This I can handle. That I couldn't. And so when you're going through something like caring for someone who you love, but who has made you responsible for every decision as well, I'll also end by quoting my favorite Dickinson again, which is. Which is what one has to do. I had no time to hate because the grave would hinder me, and life was not so ample I could finish enmity. Nor had I time to love. But since some industry must be, this little toil of love I thought was large enough for me.

That'S a treat I don't get often. And the listeners, I think, will agree that it's not every day you tune into a podcast where you get treated to both the sort of the literary sprinklings of greatness coupled with a difficult but a very important discussion about a disease that is going to touch anybody listening to this. Because if we're fortunate enough to not be the one sort of who get it, we are going to know somebody who does. It is tragically, that ubiquitous a disease. I want to thank you for your time today, and I want to thank you for the work you've put into this and finally, your patience. It has taken far too long to get this interview on the books, and I hope that the listeners will at least agree it was worth the wait.

Well, before we end Peter, I do want to say that since 1984, as a result of my experience with a patient, I started saving samples on them. So blood and bone marrow biopsies and aspirates and two germline controls, T cells and buccal smears, seven different types of cells like CD34 separation, neutrophil separated, mononuclear cell separated, all kinds of elaborate things. And to date this tissue repository has over 60,000 samples from thousands of patients who have been serially followed for years. Some of them and not a single cell comes from a second oncologist. To this day I do all the bone marrows with my own hands. So this tissue repository, which contains samples of all sorts of following the natural history of diseases in patients as they progress from a pre leukemia to acute leukemia, is a national treasure. It's a repository which can really unravel so much and trace back to the cell of origin. The first cell find the biomarkers that are associated with pre leukemia that spiraled out of control into acute leukemia within months compared to one that took 15 years to become one. I think that I want to end by saying in a very positive way that I am extremely optimistic about the future. Even though we spent most of our time in talking about very negative and very depressing pessimistic review of what the field has been. The future looks extremely bright and I am so happy that I have collected all this tissue which can now be used in the service of our patients who went through severe pain and anguish while donating these samples. We have now the technology has developed and hopefully the resources will be there to finally study the whole whole tissue repository properly and find that first cell. Thank you so much for the time you have given me today Peter.

Well, I wish you the best as you remain in quarantine. I wish you a safe re entry in New York when the time comes.

Thank you.

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