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

00:00:00.000 Hey everyone, welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:15.480 my website and my weekly newsletter all focus on the goal of translating the science of longevity

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00:00:37.320 the end of this episode, I'll explain what those benefits are. Or if you want to learn more now,

00:00:41.720 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay, here's

00:00:48.080 today's episode. My guest this week is Dr. Azra Raza. Dr. Raza is a professor of medicine and the

00:00:56.600 director of the MDS Center at Columbia University in New York. She is a practicing oncologist and

00:01:02.540 a cancer researcher who has been published in over 300 peer review manuscripts. She grew up and

00:01:07.900 attended medical school in Pakistan before moving to the United States for her clinical training,

00:01:11.500 which we discuss briefly. She's an expert in myelodysplastic syndrome, which is a form of

00:01:16.740 pre-leukemia and acute myeloid leukemia, AML. She's a recipient of a number of awards, including the 2012

00:01:24.420 Hope Award in cancer research, which she shared with Nobel laureate, Dr. Elizabeth Blackburn. Dr.

00:01:30.360 Raza is an outspoken advocate for completely reconfiguring the current model of research in

00:01:36.320 cancer. And the purpose of this discussion is really to dive into her beautiful book, The First

00:01:42.360 Cell, which really is a completely critical look at how medical research is using the wrong types of

00:01:52.140 models. My words, not hers. The ROI on spending is completely out of line with what anybody would

00:01:59.340 consider reasonable if they were to consider it from an objective lens. And frankly, we end with

00:02:04.520 what I think is a very thoughtful discussion around what the way forward looks like, because you could

00:02:09.300 easily get through this. And I always love to speak with a person a little bit before and a little

00:02:12.240 bit after. And at the end, she said, you know, gosh, I really, I hope we didn't get too much onto a

00:02:15.940 down note. And I said, no, I don't think we did. I think that there's enough sort of hype around

00:02:20.600 cancer research that it's okay to lift the sheets a little bit and show this side of things.

00:02:25.060 A couple of things I'd say about this episode. First of all, Azra goes out of her way, both in

00:02:28.840 the book and if you hear her in other interviews to say, look, this is not someone who considers

00:02:32.760 herself a writer. This is a person who considers herself both a physician and a scientist. And in

00:02:37.560 many ways sort of wrote this book because she just really needed to talk about this stuff.

00:02:41.000 To which I would say, one, it's very beautifully written, but two, I was blown away at the

00:02:45.780 literary sprinklings that made their way into this. I mean, and you have to remember, we're doing this

00:02:51.400 by Zoom basically, or a comparable platform. So we can look at each other on video. And just as sure

00:02:57.880 as I'm looking at another person across from the table, I would ask her a question and she would

00:03:01.800 respond by quoting Emily Dickinson. And not just quote it like I've memorized this, but quote it in

00:03:07.660 the most lyrical way. So I think if you're a fan of literature, science, you have an interest in

00:03:13.380 oncology. There are a lot of things you'll get out of this episode. So I'll leave it at that.

00:03:18.080 And I hope that you do enjoy my conversation with Dr. Azra Raza.

00:03:27.360 Azra, thank you so much for not just making time to be here today, but as you told me before we

00:03:33.500 started setting aside a lot of time, it's an honor to sit with you. I've known a little bit about you

00:03:39.380 before your book was published because one of my colleagues knew about you and said, hey,

00:03:45.320 this is an amazing woman who's in the process of writing an amazing book. And you're definitely

00:03:50.360 going to want to not only read it, but more importantly, I think, speak with her and be

00:03:55.000 able to interview her and talk more broadly about this subject matter. And it's hard to believe that

00:03:59.060 that was probably a year ago, if not more. You're an oncologist by training. And I've seen a couple of

00:04:06.540 your short interviews, though I've gone out of my way to not listen to you on previous podcasts,

00:04:10.960 who is not color how I want to talk with you. But the two times I've seen you on very short clips on

00:04:16.980 YouTube, you've made it very clear that you are not a writer, which I find ironic given how well you

00:04:22.820 write. So at what point did you decide that a book was an appropriate tool to communicate the amazing

00:04:34.180 ideas that we're going to spend a lot of time getting into?

00:04:38.020 Thank you, Peter, for having me on your podcast. I have been an admirer of your work and of the kind

00:04:46.740 of wellness philosophy that you propose, you belong to, you practice, you propagate, you promote. I love

00:04:56.020 it all. And the number of things you do is very admirable. So it's really a pleasure to be on your

00:05:02.620 podcast. I have to tell you that Dorothy Parker once said that if one of your friends come to you,

00:05:10.200 and they say they want to write a book, the second biggest favor you can do them is give them a copy

00:05:17.220 of the Elements of Style by Strunk and White. And of course, the first favor is kill them immediately. 1.00

00:05:23.400 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 0.99

00:05:32.600 Dorothy Parker. And then what happened, Peter, is that one of my dear friends in New York who happens

00:05:38.520 to be a literary agent, John Brockman, and his wife Katinka would often talk to me and say,

00:05:46.020 Ezra, how about writing a book? And I would say, no, I'm not a writer. And they would say, well,

00:05:49.880 you're haranguing us with the same things for 10 years. All that is wrong. You want to do something,

00:05:55.820 you want to change the field, write a book. I will get it published. And I would keep saying, no,

00:06:02.080 until I had a course as an oncologist, number one, after 30 years of being in the field,

00:06:10.740 I had a little bit to say. But then the second thing is that I've also been a basic science

00:06:17.140 researcher. I've had a very active lab all along. And my third credential is that I'm a cancer

00:06:23.020 widow. So I have experienced oncology from all three perspectives. As an oncologist who sees 30

00:06:32.800 to 40 patients a week for the last 30 plus years, as a basic researcher who's had a well-funded lab for

00:06:41.320 35 years. And as someone who stood on both sides of the bed at the same time of a cancer patient,

00:06:48.260 who was the love of my life. So even these credentials, Peter, were not sufficient to motivate

00:06:56.980 me to write the book. What did it was my daughter Shahrazad's best friend since 15 years of age,

00:07:03.580 not her boyfriend, her best friend, who's gay, Andrew, at 22 years of age, finds the field's weakness 0.85

00:07:12.360 in his arm and taken to the emergency room. He's quadriplegic within hours, and he's found to have a

00:07:18.060 nine centimeter large brain tumor, which was unresectable. And pathology showed that it is

00:07:25.400 one of the most malignant tumors ever known to mankind, glioblastoma multiforme.

00:07:31.360 When this boy opened his eyes, and he stole his diagnosis, the first thing he told his mother,

00:07:38.160 Peter, was, Mom, don't worry, just call Asra. She's on the cutting edge, she will cure me.

00:07:44.740 So here I am, it slapped me in the face physically, that on the one hand, the ferociousness and violence

00:07:53.820 of his tumor. And on the other hand, the utter helplessness of all of us, his oncologists,

00:08:02.460 to do anything about it. Our complete failure in front of Andrew. How is it possible that we are

00:08:10.020 so spectacularly failing a 22-year-old boy? That's what forced me to write the book.

00:08:16.900 Someone once said, and I'm sure it's been paraphrased, and so I won't attribute it because

00:08:21.540 I don't know where it came from, but the only reason to write a book is if you absolutely can't

00:08:27.200 not write it. And it sounds like that's sort of where you were after all of the things that you've

00:08:33.160 described, which is not only losing Harvey, which I think he died in 2002. Is that correct?

00:08:39.400 Correct. And then the story about Andrew, who obviously was about 60, 70 years too young to

00:08:46.480 die from anything, let alone a GBM, which is a tumor I've certainly spoken about on this podcast

00:08:52.620 before, and I think we'll talk a little bit more about it. Also, the other things we're going to

00:08:56.580 talk about, which are the sort of the structural failings of the system that you felt were, if I

00:09:01.280 were going to sort of try to describe your book, a big part of it is the return on investment has been

00:09:07.480 very poor. That's sort of one way to summarize it. There are many ways to sort of summarize it,

00:09:12.440 but an overarching theme has been, it hasn't been that we haven't spent a lot of money.

00:09:17.140 It hasn't been that we haven't made some progress. It hasn't been for a lack of trying, but by any

00:09:24.260 objective metric that we would apply to any standard of anything else, the return on that investment has

00:09:32.280 been so paltry that if we are not smart enough to at least consider doing something totally different,

00:09:39.560 we're completely diluted. And again, I think that's one tiny piece of it. And that's probably

00:09:44.440 that burning piece that I think your agent was ultimately saying, this is either going to erode

00:09:49.440 a hole through your, the gastric lining of your stomach, or you better put it on paper.

00:09:54.240 Yes, I agree.

00:09:55.280 So let's start with oncology. What drove you to oncology? Why did you choose to become an

00:10:01.440 oncologist in an era when women could have chosen far less demanding fields in medicine? Not that

00:10:09.080 any field in medicine is more or less demanding, but oncology is about as demanding as it gets.

00:10:14.300 What was the thinking for you? That's an astute observation actually, because

00:10:19.020 when I was going into oncology, it was the least popular field. In fact, most people, when I said

00:10:27.700 I'm going into oncology thought, okay, she couldn't get into any other fellowship. That's why, because

00:10:32.380 only Indians and Pakistanis go into oncology. Who else would in their right minds would want to go? 1.00

00:10:38.280 Except for me, it was a deliberate choice. So Peter, I was born and raised in Pakistan.

00:10:43.640 But since I was a little girl, since as far back as four years old, that is my first memory,

00:10:50.720 I was very interested in the natural world around me. I would be at four years, I'd be following ants

00:10:56.260 around and imagining all kinds of things and started reading about science for as far back as I remember

00:11:04.180 really. And as I was growing up, I got more and more interested in different fields. Embryology at one

00:11:09.900 point became an obsession. By the time I was 16, I had read all about evolution and evolutionary biology.

00:11:17.040 I had become a big Darwinian fan. Everything I was looking at was through the prism of evolution for

00:11:23.880 a long time. But then had I grown up in a country where choices were available to me, I'm confident that

00:11:31.560 I would have gone into molecular biology as a pure science or some of the one to study one of the

00:11:38.820 natural things like marine biology, maybe or probably myrmecology. And but in Pakistan, where I grew up,

00:11:47.480 there was no possibility of entering science except through medicine. So very cleverly, I thought I'm

00:11:54.740 going to go join medical school, as soon as I complete, I will proceed to the West. And there I

00:12:01.640 will start my PhD and real scientific training. But the problem that happened with me was in third year

00:12:07.760 of medical school, when I saw my first patient, one look was all it took. And I realized from that moment

00:12:15.820 on that all of my life would be devoted to somehow use the best that science has to offer to reduce

00:12:25.540 human suffering. And I have stuck to that. The second thing that happened was so I knew that I will do

00:12:33.320 research in science, but it would be therapy driven and the patient would be front and center for me

00:12:38.820 always. Second thing that happened was that I was in Karachi, Pakistan. Karachi is the largest city in

00:12:46.320 the country. And people who get sick around Karachi in the suburban areas have no access really to

00:12:54.560 medical care. It's a very impoverished third world country with a very overcrowded city where I grew up.

00:13:00.960 So cancer patients, when they came, Peter, they would travel long distances on their donkey carts and

00:13:08.000 on foot. By the time they came, they would have hugely advanced tumors that I've never seen since.

00:13:16.280 Even in Pakistan, we don't see them now. But back then in the early 70s, the kind of end stage

00:13:22.940 malignancies sprouting through breasts or like huge lumps just breaking out of people's heads and

00:13:30.240 arms and sarcomas that I saw. So it was the malevolence of the tumor, the violence of the

00:13:37.940 disease on the one hand, on the other hand, the intellectual challenge of trying to figure out

00:13:43.580 how this whole thing began in a single cell and how that cell goes rogue. What journeys has it

00:13:51.260 undertaken to reach this level of malignancy? So it was the dual emotional as well as intellectual

00:14:00.500 grip that basically caught me and at a young age. And I'm confident that if I'm given 70 more lives,

00:14:09.780 I will do exactly the same thing 70 more times. Do you still remember that first patient you saw

00:14:17.500 as a third year medical student? Do you remember what anything about them, what condition they had,

00:14:22.440 anything about them, the way they looked? Actually, thank you for asking. Absolutely.

00:14:27.560 The patient was a young woman with acute myeloid leukemia. And she was very strange because she

00:14:35.280 presented with a very large spleen as well. So we knew that she must have had a prior myeloproliferative,

00:14:41.840 myelodysplastic, some sort of a precursor that led up to the acute leukemia. So right there and then

00:14:49.340 I started having discussions with my teachers that how much easier it would be to study liquid tumor

00:14:57.200 because cells are already in suspension. And you can go in and sample them so many times instead of

00:15:02.720 trying to study a solid tumor, which is a mass that you can only remove once. Next time it appears,

00:15:09.660 it wouldn't even be the same tumor. And you don't have the luxury of accessing the tumor before,

00:15:15.840 during and after treatment. So that patient is etched on my brain as if it was yesterday's breakfast.

00:15:22.320 Yeah. I find that phenomenon to be interesting amongst many physicians, both oncologists and

00:15:28.820 not oncologists. Steve Rosenberg, who is my mentor, talks often about a patient that changed the course

00:15:35.820 of his life when he was early in his residency. A patient that had metastatic gastric cancer to the

00:15:42.040 liver five years earlier, was basically sent home to die, shows up in the ER to have his gallbladder taken

00:15:47.900 out, should have been dead five years less, six months earlier. He's completely free of tumor,

00:15:53.960 which ultimately after double, triple, quadruple checking led Steve to conclude the only way this

00:15:59.180 is possible, this is back in 1968, is if his immune system eradicated that cancer. And Steve became one

00:16:06.000 of the people who has pursued that to incredible ends. And though I've done nothing special, I still

00:16:11.840 remember the first patient I saw in the hospital. And so though it wouldn't become the catalyst for

00:16:17.060 anything particularly unique, we send first-year medical students on day one into clinic. They

00:16:23.640 can't do anything. They are literally there to just watch and try not to get in the way. But I selected

00:16:29.660 oncology and I went to the medical oncology clinic and I remember that very first patient on that very

00:16:34.780 first day. And I still remember strange details like what the color was of the clothing of different

00:16:41.380 people in the room that day. He had stage four colorectal cancer. That was probably one of the

00:16:48.060 first times I'd ever seen a CT scan and certainly seen it with such a clinical emphasis on, okay,

00:16:53.540 look, these are now tumors that have spread to both sides of his liver. The primary tumor was here. You

00:16:59.120 can see all of these places. I would go on to become very close friends with that patient who ultimately

00:17:03.960 died two years later. His widow would come to my medical school graduation two years after that.

00:17:10.480 So yeah, there is something really special about medical education and it can totally

00:17:15.240 derail the best laid plans of becoming the world's expert on ants.

00:17:21.380 Yes. And by the way, I do teach a course that is Foundation of Clinical Medicine where

00:17:27.020 first-year medical students at Columbia University are exposed to being in clinic. And I'm mindful of this

00:17:33.400 experience. How is this going to change the rest of their lives? The experience has to be

00:17:39.560 somehow we can't take away the pain. It's like Emily Dickinson said, tell all the truth, but tell it slant. 0.99

00:17:49.740 Success in circuit lies. Too bright for our infirm delight, the truth's superb surprise.

00:17:57.740 As lightning to the children eased with explanation kind, the truth must dazzle gradually or every man

00:18:09.060 be blind. So I'm very mindful of that when first-year students come to me.

00:18:16.220 Azra, you're the only person who's going to not just quote Emily in the midst of discussion,

00:18:23.600 but do so eloquently. And to think that there was any doubt you were a writer is only comical to me,

00:18:30.640 but we'll come back to that. So when you finished medical school, not only did you realize you wanted

00:18:35.680 to be a clinician, but I think the hook of oncology was already well into you.

00:18:40.240 Yes, absolutely. Now let's pivot for a moment to allow you to explain to the listener what the

00:18:49.440 state of oncology looked like at that time, specifically when you consider what it meant

00:18:57.560 to have metastatic cancer. And let's for a moment posit that we're going to talk about solid organ

00:19:03.380 tumors separately from liquid tumors. If a woman had breast cancer and either at presentation or later,

00:19:12.080 it had spread to her lungs, to her brain, to her bones. If a man had prostate cancer that had spread

00:19:18.100 to his bones, if a person had colon cancer that had spread to their liver, what was the prognosis and

00:19:24.060 how long would they be expected to survive? I think to start with, Peter, the important thing is that

00:19:31.060 when I started in oncology, it was almost a stigma to have cancer. The kind of causes of cancer we were

00:19:40.560 taught were basically either there's a genetic or hereditary component where you have a predisposition

00:19:46.340 for high risk of some sorts of cancers, or is it some environmental exposure, some kind of toxins

00:19:53.660 that you've been facing that you've been facing, or pathogens. Pathogens were considered a very exciting

00:20:00.520 new avenue for research at the time, that maybe it's a viral disease of some sort, especially

00:20:08.060 retroviruses. And clearly, there was already a very strong component of association with things like

00:20:16.480 smoking. So while there were these kinds of causative factors for cancer, most people who presented

00:20:25.360 already had rather advanced diseases, and very little screening measures were being performed at the

00:20:33.820 time. So they would come with, in Pakistan especially, with the kind of textbook pictures of

00:20:42.700 fungating masses coming, breaking through breasts in women, or men suddenly showing up within with

00:20:51.640 complete urinary blockage, unable to urinate, and we would have to do emergency kinds of things.

00:20:59.720 It was just, it would be quite devastating. And of course, there were people who, women who felt a lump and

00:21:07.020 came in. And so I remember how many times I was assisting in mastectomies and considered for a long time to go

00:21:14.420 into surgical oncology, because that seemed to be the cleanest treatment at the time. Cut it out, you don't

00:21:21.980 have to start chasing the last cancer cell with these poisonous things we were giving. Even radiation was 0.80

00:21:29.340 quite primitive at the time and quite terrible to patients. So it was all in all, it was a stigma to

00:21:36.860 begin with. People didn't want to talk about it. Many people hid it. The tumors from themselves even

00:21:42.860 would delude themselves into thinking that this is some kind of an infection, it will go away. So most

00:21:48.860 people presented with advanced cancers. The problem that I see though, before I end this answer, is that

00:21:56.940 today, in 2020, if you want to measure the success of treatment in cancer, then the thing you need to

00:22:07.080 look at, Peter, is what is the age-adjusted mortality of cancer today? In 2020, you know what it is? It is

00:22:17.260 the same as it was in 1930. So that's interesting. I usually make the statement, it's the same as 1970.

00:22:24.660 I didn't realize it was still the same as now. You go back even further. I usually just make the point

00:22:30.920 that in 50 years, it hasn't changed. You're saying in 90 years, it hasn't changed.

00:22:36.380 Yes. I'm saying that because the 30% or 27% decline in mortality we are seeing in the last 30 years

00:22:44.800 is following a 30 years increase in mortality in cancer. You see, what happened was that with all

00:22:52.360 the smoking, anyone who watches Mad Men is shocked to see it, like my daughter saw it and she was,

00:22:58.380 mommy, is that what people used to be? Like everywhere, they were just smoking. Everybody

00:23:03.460 was smoking. This led to such an increase in the incidence of cancer, so that the decline in mortality

00:23:12.520 basically parallels the decline in smoking. That is all that has happened. Otherwise,

00:23:18.560 we are really at square one. And that is the embarrassment that nobody wants to recognize.

00:23:27.040 In fact, somebody asked me the other day, what exactly is your point in saying, I said, look,

00:23:33.040 Nietzsche's Thus Spake Zarathustra opens with this man running around with a lamp at noon in the middle

00:23:40.900 of the market saying, I'm looking for God. For me, it's like I'm running around looking for an adult

00:23:47.360 in the room.

00:23:48.820 Yeah. So let's explain to people, let's explain some of the nuance here because most people are

00:23:54.580 confused by what an extension in disease-free survival means. Not that the average person knows

00:24:01.980 what the difference is between a PR and a CR, but you and I both know this world well because we've been

00:24:07.460 on the inside of how these clinical trials are run. So we understand that, hey, this drug got

00:24:13.240 approved because X number of people met the criteria for a PR, which has a kind of a funky arbitrary

00:24:19.920 definition, if you're going to be brutally honest, of what a partial response is defined as. A complete

00:24:25.260 response is a little easier to define. But then we don't talk about what durability means in all of

00:24:30.240 these things. So I could give an entire soliloquy and lecture on this, but I'd much rather listen to

00:24:35.640 you do it eloquently because the chance that you're going to quote more poetry is reasonably high.

00:24:40.260 So can you explain for folks what it means to have a partial response, a complete response?

00:24:46.800 And the reason I think it's important to do this, even though it sounds a little dry,

00:24:51.540 you're saying things that seem completely at odds with what the propaganda machine is saying.

00:24:57.420 Now, I know you're right because I know how the sausage is made. I've been inside the belly of the

00:25:04.160 sausage. I understand how to read the literature. That is actually asking a lot for someone who

00:25:10.840 maybe just wants to better understand oncology, but they haven't had the luxury of training in

00:25:16.180 oncology or even more importantly, I think doing research in oncology. So can you go through some

00:25:22.120 of the fundamentals of what these semantics are that are used, how these terms get thrown around

00:25:27.480 and how ultimately it can lead to some statements like the one you just made, frankly, which is as

00:25:33.840 extreme as extreme could be with respect to saying, hey, look, in 90 years, we really haven't gotten

00:25:40.660 better at extending life in people with cancer once they have cancer. So let's unpack some of these

00:25:47.320 definitions a bit. I think that's a good place to start. So let me begin by a little bit of just

00:25:54.700 history, because before we get into nuances, why not just talk about the very gross facts?

00:26:01.700 Cancer is a very bad disease. Everybody knows it. The only good news you can give to a cancer patient

00:26:07.500 is that, oh, we caught it early so we can get rid of it. So we know that cancer itself may not kill.

00:26:14.960 It's the delay in treatment that really kills. So the earlier we pick it up, the better. How have we

00:26:21.120 treated cancer which has been found even in mummies? So we know cancer has existed all along. But the

00:26:28.280 incidence, probably it is a disease of modernity associated with many, many of our lifestyle

00:26:34.760 changes from hunter-gatherer society to modern human. Nonetheless, cancer was identified in mummies

00:26:42.740 and has been there all along in human history. How have we treated it? Well, the first treatment of

00:26:50.200 cancer, even though it wasn't even called cancer then, was in 500 BC when the Persian queen Atossa

00:26:57.160 had felt a lump in her breast. She tried to hide it by covering it with sheets and things and eventually

00:27:04.580 asked her Greek slave who took out his sword and simply slashed off her breast. She survived it.

00:27:11.640 She was the wife of Darius and she survives it. And this is the first known surgery. We were slashing 0.63

00:27:20.760 women's breasts in 500 BC. What is the primary treatment for breast cancer today? Same slashing. 0.99

00:27:29.280 And we typically give Halstead credit for that.

00:27:31.600 So this is my point that for 2,500 years, what has exactly changed? Slight better scallopels and

00:27:39.620 giving anesthesia while doing it? Okay, yes. Then second is that when you couldn't, so whatever

00:27:47.220 cancer was detected early enough as a solid tumor was cut out and the liquid tumors you couldn't cut

00:27:54.260 out. So you needed to poison them somehow. Now, how do you poison these things? There was really

00:28:00.800 nothing could be done about it until in the First World War. Of course, it wasn't called the First

00:28:07.320 World War because we didn't know there's going to be a second. So it was called the Great War. 0.62

00:28:12.620 Part of development of weapons against each other was use of chemicals. And so when these vats of

00:28:19.280 chemicals were sitting around that were dropped on humanity, people noted that one of the side effects

00:28:26.740 that people died from was low blood counts. So Goodman and Gilman, two pharmacologists sitting

00:28:34.220 around in Yale, decided that this could be used to treat cancer then, these chemicals. So do you know

00:28:40.880 the first three chemical weapons that were used to treat cancer? Cytoxan, Chlorambucil, and Melphalan.

00:28:48.260 We still use at least two of those.

00:28:50.420 I gave all three with my own hands to my own husband, Harvey. So we are slashing, we are poisoning

00:28:58.720 the same way, and then burning with radiation therapy the same way. So I wanted the audience

00:29:06.040 to understand the kind of dramatic statements or melodramatic statements that I'm making are

00:29:14.160 not baseless. People just have to stop deluding themselves, open their eyes and see what is in

00:29:22.320 front of them. So to just finish this part with a quotation of statistics. In this day and age today,

00:29:32.220 68% of cancers that we diagnose, new cases, 68% are cured. Cured with what, Peter? Slash poison burn,

00:29:43.440 surgery, surgery, radiation, and chemo. Except for a few cancers where there are targeted therapies or

00:29:52.400 antibodies available, really not much has happened. The 32% who present with advanced disease that we

00:30:02.400 can't use slash poison burn. So imagine the same treatments that were working in earlier stages

00:30:08.720 are not working in later stages. This is the best proof that the only thing we can do right now is

00:30:15.620 to find the cancer earlier. And even some of the therapies not working, like targeted therapies,

00:30:21.740 may work better if we don't give them to stage 4. FLT3 mutations caught early may respond much better to

00:30:29.940 FLT3 inhibitors. This is the point I will keep making over and over.

00:30:35.900 I want to stop you for a second there, Ezra, because honestly, that is something that I have

00:30:43.040 only in the last few years come to share your zeal for, and I can't emphasize it enough. So there was

00:30:50.900 a day when I believed, incorrectly now, I believe that I was incorrect, that burden of tumor was not

00:30:58.580 the primary determinant factor. Stage 4 cancer was stage 4 cancer, whether the burden was high or low.

00:31:04.580 And it was really a property of the biology of the cancer that was the issue. So in other words,

00:31:09.800 if you took a whole bunch of women with stage 1 breast cancer, you took 100 women that had sub

00:31:16.400 centimeter lymph node negative breast cancer, and you had a machine that could tell you which ones

00:31:24.100 had the potential to go on to have metastatic cancer versus those ones that did not. And let's,

00:31:30.400 maybe breast cancer wasn't a great example because of the hormone complexity of it. 1.00

00:31:34.580 That whether you acted then or acted later, it wasn't going to matter. Well, I no longer believe

00:31:40.460 that is true for reasons I could expand upon. I want to emphasize the point you're making,

00:31:46.000 which is, I mean, it's the contrapositive of your point, which is, we don't really have therapy that

00:31:51.620 works for systemic disease. So metastatic breast cancer, metastatic colon cancer, metastatic prostate

00:31:58.600 cancer, metastatic, you fill in the blank, you are no better off today than you were 50 years ago.

00:32:06.300 And that is a very sobering, if not outright depressing statistic. It's very difficult for the

00:32:15.400 average person to comprehend that for all our advances, once colon cancer has gone to your liver

00:32:22.140 in 2020, you are almost as hopeless as you were in 1970. And in fact, you can probably put more color

00:32:29.660 around it and say, well, technically, Peter, you might live four and a half more months. And I don't

00:32:34.600 want to discount that. I want to talk about what the cost of that is. But I mean, do you agree with,

00:32:39.160 am I also being a little too dramatic? Or would you agree with my assessment?

00:32:43.320 I think you're using meiosis, meaning understated.

00:32:49.000 Seriously, how do you tell a 22 year old, Andrew, that we will add four months to your life,

00:32:56.100 you should go and celebrate and proclaim from the rooftops? What kind of nonsense is this?

00:33:01.820 Four months of improvement in survival. And that is the lucky ones who get it. You know what it is,

00:33:08.000 why people will be shocked. Why should they be shocked? They'll be shocked because they are

00:33:13.100 listening. Poor things have been subjected to the ultra hype of all this self-promotion of scientists

00:33:20.820 and oncologists patting themselves on the back for game changers that they have. Allow me to expand on

00:33:28.900 what has, in my opinion, put the field back by decades. And that is the treatments that are

00:33:37.320 most celebrated in cancer are treatment of chronic myeloid leukemia. This is a disease which is a

00:33:46.680 disease of the myeloid cells in the bone marrow, which undergoes a chronic phase where nothing much

00:33:53.020 is happening, except one fine day, something mutates, something happens, the disease takes off

00:33:58.480 into an accelerated phase and then becomes acute leukemia. And it is universally fatal.

00:34:04.000 And all of us who are older, like me, have taken care of dozens of these patients who died in our

00:34:10.960 own hands, young people, as well as old. Well, it turned out that chronic myeloid leukemia is caused by

00:34:19.760 one genetic change that can be targeted with one magic bullet. And that magic bullet is Gleevec.

00:34:26.700 And that was FDA approved in 2000. And now these people are being cured with one drug. And this is

00:34:33.660 a fantastic success. But Peter, the same drug doesn't work when the disease starts to accelerate.

00:34:41.460 So chronic myeloid leukemia, think of the word chronic here. It's not really a malignancy. It's like a

00:34:49.340 pre-leukemia right now. You caught it early. At that stage, there was only one problem and you

00:34:57.440 could fix it with one bullet, right? Can we put that in perspective for people? Because I want to

00:35:02.720 make sure we're not, I don't want the naysayer to have too much wiggle room to say, well, you've 0.98

00:35:08.260 discounted the success stories, Gleevec. We're going to probably talk about some of the checkpoint

00:35:13.980 inhibitors as well, which have probably been the single biggest victory in the past five years.

00:35:19.180 Do we have a sense of what percentage cancer mortality has come down on the back of Gleevec,

00:35:25.300 not just from CML, but let's also look at GI stromal tumors, which have at least for some period

00:35:30.900 of time responded to Gleevec, though it might not be the most durable remission ever. I mean,

00:35:36.000 what type of numbers are we talking about? Has that put a 1% dent in cancer mortality in the past 20 years?

00:35:41.860 If that. It's a very rare disease.

00:35:44.660 Yeah, yeah, exactly.

00:35:46.040 Very rare, but it did prove a point, which is that targeted therapy can work.

00:35:52.420 This is the point I'm making, that it's not even really a cancer yet in all its malignant

00:35:57.700 manifestations that other cancers are. The second thing we celebrate is again in hematologic

00:36:04.540 malignancies, which is acute promyelocytic leukemia, which is cured with arsenic or with vitamin

00:36:11.740 A analog, vitamin A, let's say ATRA. It cures acute promyelocytic leukemia, one of the deadliest

00:36:19.000 acute leukemia. But do you know, it wasn't as if scientists sat down, studied this disease,

00:36:25.360 found the lesion of retinoic acid receptor and started to reverse it. Poor Chinese were saying

00:36:31.420 for years that we are curing acute promyelocytic leukemia with vitamins and the West didn't believe

00:36:38.740 them. And finally, they sent somebody over and they saw all the patients and were convinced and

00:36:46.040 came back and did a trial of ATRA here and then were convinced and then worked backwards to find

00:36:52.600 the molecular lesion. So please, scientists do not take credit in front of me for acute

00:36:59.500 promyelocytic leukemia. You did not work it out. You only worked it out in retrospect.

00:37:04.320 So those are the two biggest advances. Now, lymphomas absolutely agree that throwing cocktails

00:37:12.160 of chemotherapy together, testing this one and that one, they worked as because of the biology

00:37:17.820 of the disease that was responsive to those chemotherapies. That's what I'm telling you,

00:37:22.560 that some of the things that have retarded progress in a way is because we become convinced 0.95

00:37:28.620 of a paradigm that, oh, if Hodgkin's disease can be cured with these four drugs, we just have to find

00:37:35.400 the right four drugs for pancreatic cancer or ovarian cancer and we'll fix it. And that's how we kept

00:37:41.360 working, throwing crazy combinations of drugs together to follow the paradigms. The few successes

00:37:49.060 that we had seen, Hodgkin's disease, a few non-Hodgkin's lymphomas or acute promyelocytic

00:37:55.960 leukemia, chronic myeloid leukemia, I mean, my multiple myeloma now has been very successfully

00:38:02.600 treated, but at that time it wasn't. But now it is definitely a night and day difference.

00:38:10.020 But these are again, rare types of cancers, melanoma, dramatic differences in survival today.

00:38:17.960 But again, all of these together would account for less than 10% of cancers together. Still,

00:38:26.120 we have to go back to whatever we can slash poison and burn. And successfully, we are able to do that

00:38:33.500 for 68% cancers, either because their disease is responsive, like in Hodgkin's lymphoma, even if

00:38:40.100 it's advanced or non-Hodgkin's lymphoma or CLL, or because it is amenable to surgery. That's it.

00:38:49.300 So where a counter argument here is, look, this is going to be a game of inches. And the 10% 0.76

00:38:57.440 that you just described, you basically gave the tour de force explanation of oncology's greatest hits

00:39:03.540 in the last three decades. And again, we didn't pay a lot of, spend a lot of time on it, but I think

00:39:08.960 the checkpoint inhibitors also have this huge impact beyond just melanoma, because anybody who

00:39:14.420 shows up with a checkpoint mutation, even if you have Lynch syndrome and you go on to get pancreatic

00:39:20.080 adenocarcinoma, you're probably going to respond. Let's just say that adds up to eight or 9% of the 68%.

00:39:26.860 So the skeptic would say, but look, Azra, like that's amazing progress. Give us another 40 years,

00:39:34.640 give us another 30 years, and cancer is eradicated. That would be the optimistic view of this.

00:39:41.480 How would you counter that view? I don't want to counter anything. I mean,

00:39:47.500 that's the way the field has been. I've been hearing the same self-satisfied voices saying the same thing,

00:39:54.380 how wonderful they are, how they will understand every intracellular signaling pathway in the cancer cell

00:40:02.100 and reverse it, how they will understand the metabolism. Don't even get me started on that,

00:40:07.360 because it's as if the last hundred years haven't existed, and people haven't had any ideas until these

00:40:14.080 new investigators came around to, on their white horses, with their overconfidence and contempt for

00:40:20.460 the past, armed with new things. We are going to reverse all these. I mean, clearly, whatever advances

00:40:28.800 there are, and I don't want to argue with anyone about advances, you are saying there are a lot of

00:40:34.480 advances, great. Do they really reflect the quarter of a trillion dollars we have invested in research?

00:40:42.620 Is this all we have to show? A few checkpoint inhibitors? Fine, I agree with you, even if I agree with you.

00:40:48.580 So, let's just talk about immune therapy for a minute. You say checkpoint inhibitors. There are

00:40:54.600 many different kinds of immune therapies, 14, 15 different kinds. The two most popular we talk

00:41:00.980 about when we talk about immune therapy these days is either the cell therapies that are given,

00:41:08.120 where you train the lab that is the pioneer of all of this, work with cell and cytokine,

00:41:14.720 IL therapies combined with T cells, etc., or the checkpoint inhibitors, because normal cells will

00:41:22.560 have signals on themselves saying, eat me or don't eat me, and these can be masked, and these signals

00:41:28.220 are the checkpoints. And by using drugs, you can unmask the signal, which has been covered up by the

00:41:36.740 cancer cell. Very simple explanation for checkpoint. So, the two main ideas in immunology that came along

00:41:44.000 were how to target these checkpoints so that the body's own immune cells can recognize the cancer as

00:41:52.140 being alien to the normal functioning of the body and must be eliminated. And the second is,

00:42:00.000 can you take the body's own immune cells and engineer them in such a way that they can selectively kill

00:42:09.600 cancer? And CAR T cells have been proclaimed once again as revolutionary. Of course, the science behind

00:42:19.660 it is beautiful. It's very sophisticated. It really, it's one of those things that make you want to

00:42:27.920 celebrate humanity's accomplishments. It is just a gorgeous thing. But the problem is that it has done

00:42:35.240 very little for patients. Why? Because what all the oncologists talking about CAR T never mention in

00:42:44.260 any of their talks. And by the way, every morning, I run every morning. And after I run, I jump on a

00:42:51.800 small trampoline for 20 to 30 minutes every day. Because that's one way to stimulate your lymphatic

00:42:58.460 system. And the trampoline is small rebounder, I should say, not a trampoline. It's one of the best

00:43:04.220 exercises you can. I've been doing it for 25 plus years. So during that time, I listened to YouTube

00:43:11.380 lectures. To all of you cancer researchers out there, understand that there is one person who

00:43:18.080 listens to your YouTube lectures every single day. And the kinds of things people confess to in public

00:43:25.440 forums, very different than the scientific papers they're writing. In all of those talks, I have never

00:43:32.900 heard any serious scientist, oncologist or immunologists say that their CAR T cells cannot

00:43:41.980 distinguish between normal and cancer cells. They just ignore that. It's like they just don't want to

00:43:49.780 acknowledge it. Why don't you say that basically CAR T cells are just another form of killing machine

00:43:57.760 indiscriminately. So what CAR T cells do is whatever antigen you put on it, and whatever organ expresses

00:44:05.700 that antigen, it will go destroy the whole organ, taking down every normal cell of that organ also.

00:44:14.380 So basically, the only thing CAR T is working for right now is B cells, because you can replace B cell

00:44:20.900 function. After you kill every single last B cell in the body, but you can't do that to pancreatic

00:44:27.300 cancer, because it will kill the whole pancreas. And then you can't replace the function. But how many

00:44:33.460 times have you heard people say this, Peter? Well, I mean, do you hold out hope that some of the case

00:44:40.140 studies, because we've seen the case studies, the cholangiocarcinoma here, the pancreatic cancer there,

00:44:44.960 the colon cancer, the breast cancer there, where they are able to identify the unique antigen

00:44:50.420 of the cancer. And by unique, I mean distinguishing antigen of the cancer, such that you can send the

00:44:56.760 T cell loose, and it can eradicate not the entire biliary system, but just the cancerous piece.

00:45:03.620 And to be clear, I'm not speaking one way or the other, other than to sort of help me think through

00:45:09.820 the, is this a sufficient proof of principle that we believe that adaptive cell therapy,

00:45:17.280 of which CARs are the most far and away the most prominent, and checkpoint inhibitors are really

00:45:22.440 going to be the way of the future. You didn't allude to it. You and I know this as well as Tuesday

00:45:26.580 follows Monday. There are also very nasty side effects of checkpoint inhibitors. And for every

00:45:32.080 patient we see who has a response to them, some of the autoimmunity can be quite devastating.

00:45:37.240 And in fact, vitiligo for a patient with melanoma might not be such a fatal form of autoimmunity,

00:45:43.500 but certainly when people have life-threatening enterocolitis, yes, they're cancer-free, but they

00:45:50.040 die from bowel disease that follows. So certainly not to suggest these are benign. I guess the point is,

00:45:55.880 do they represent a demonstrable step function forward that now puts us in a new era of, okay,

00:46:03.500 we've found a new beast that goes beyond surgery, radiation, and indiscriminately killing chemicals.

00:46:10.980 How do we figure out how to tame this new beast? Does that resonate?

00:46:15.480 No, not particularly because Steve Rosenberg has found this ages ago that this is the right way to

00:46:21.260 go. But yes, we are making advances. And I do think that all of these need to continue. I'm not saying we

00:46:28.620 should stop any of this. I'm just pointing out where the field is right now. I think these are

00:46:33.740 fantastic. They should continue what needs to stop. Here's the problem. 95% of experimental agents that

00:46:42.980 we bring to the bedside today, 95% in cancer fail completely. The 5% that succeed should have failed

00:46:52.680 because they are only prolonging survival for 20 to 30% of patients by a few months. And you began by

00:47:04.900 asking me, what is progression-free survival? I mean, we don't even talk about survival anymore.

00:47:12.000 We just talk about progression-free survival because survival has become too big of an obstacle

00:47:19.100 to overcome. So as long as you don't see the tumor, but the patient dies within the same four months or

00:47:25.680 five months, it doesn't matter. But you didn't see the tumor for two and a half months, that's

00:47:30.260 progression-free survival. So this drug should be approved and the sponsors of the drug will make

00:47:35.920 billions of dollars. Let's stop on that because it is just so darn important. Let's use a tangible

00:47:43.080 example. Avastin. Okay. I don't want to put you on the spot because I don't remember the numbers of

00:47:49.460 Avastin, but the only reason I bring it up, is that an okay? Do you know enough of the examples that I

00:47:53.100 could use Avastin? I mean, I don't use it myself, but I do know that it's one of the more successful

00:47:59.380 We could pick another one that you know. I'll explain. So Avastin was a blockbuster in the sense

00:48:04.560 that it was the first of its kind and it explored a brand new idea. So Judah Folkman had this idea that

00:48:10.680 many others followed in the footsteps of, which is, look, if a tumor can't make new blood vessels,

00:48:16.440 it can't get very big. Therefore, the ability to make new blood vessels must be of paramount

00:48:22.600 importance to metastases. And therefore this concept of neovascularization became key.

00:48:30.000 And so this was a beautiful story of science and pursuing this thesis and doing all of these

00:48:35.100 experiments. And one step leads to another. And before you know it, you have a whole class of drugs

00:48:39.700 called anti-VEGF drugs, of which this drug, and I assume it was Genentech's drug. I can't even

00:48:46.740 remember at this point, but I think it was Genentech that was the first in line. They have this drug,

00:48:51.880 Avastin, and I believe colorectal cancer was one of the first places they looked. Again,

00:48:57.900 in the show notes, we'll have the story more accurately laid out. But the gist of what I remember,

00:49:03.460 Azra, is the following. You took a patient that had metastatic colorectal cancer, which again,

00:49:09.700 means this is a patient who had a colon cancer that has left the colon, left the lymph nodes. It is

00:49:15.680 now somewhere else, usually in the liver. This is a patient who is absolutely not going to live.

00:49:22.500 And if 1% of those people live five years, that would be very generous. And this is asking the

00:49:27.840 question, if you use all of the standard therapies we have today, the entire cocktail of chemotherapies,

00:49:34.500 and then you do the same thing, but you also use Avastin, how much do you change the median

00:49:41.060 survival? Notice we don't use mean, because that can be very impacted by outliers. We use median.

00:49:48.760 And I believe the answer with Avastin was on the order of four months. With Avastin, which cost at the

00:49:55.580 time in the neighborhood of $100,000, it was going to extend median survival for those patients by four

00:50:03.200 months. And what I remember most about the discussion, Ezra, is it prompted a discussion

00:50:09.800 about what is the value of a life. And different countries around the world, especially countries

00:50:16.260 without private insurance, but instead those with public insurance, had to put something called a

00:50:21.880 quali at the front of that discussion, a quality adjusted life year, which says, do we believe

00:50:28.800 that the cost of a life is worth X hundred thousand dollars such that a publicly funded

00:50:35.700 insurance for health would be accountable to spend that money? And if you don't like that example,

00:50:41.160 because I might not have the details right, that you can use a thought experiment, which is if I told

00:50:46.600 you, Ezra, you have a condition that is going to allow you to die, but I could extend your life by a

00:50:52.280 month and it's going to cost a billion dollars. Do we as a society think that that's a reasonable cost

00:50:59.060 for society to bear on your account, despite how wonderful you are and how much amazing stuff you

00:51:05.000 could do with an extra month? So it started to get into this discussion of the cost benefit analysis,

00:51:11.940 which gets to that return on investment. Do you want to use a better example, a more recent example

00:51:16.880 than Avastin, to illustrate how relatively small changes in median survival or disease-free

00:51:25.760 progression? And maybe you can explain the difference between those two, because you and I will go back

00:51:30.120 and forth between them, but I think the listener could be confused. And then again, just talk about

00:51:34.500 the literal economics of that, because I do think people will be staggered by what the actual numbers

00:51:41.560 are. You know, John Donne said something very beautiful. So when you said give a literal example,

00:51:48.580 I'm going to give a literary example. No man is an island entire of itself, each a part of a piece of

00:52:00.520 the continent, part of the main. Any man's death diminishes me. That's what you said. What is a human life

00:52:09.520 worth? John Donne says, any man's death diminishes me because I am for mankind and therefore never

00:52:20.300 sent to know for whom the bell tolls. It tolls for thee. Of course, every human life is important. And

00:52:28.520 of course, every oncologist is working to try and save every human life. I'm not saying we are deliberately

00:52:36.000 not doing enough. In fact, in all of my career in this country, in the last 43 years, I have yet to

00:52:43.640 meet an oncologist who didn't care for their patients. Never. They're all trying their hardest.

00:52:50.740 But it's like trying to use a map to find your way in London, but you're using a map of Paris.

00:52:57.980 It's not going to work. So how have we become so misdirected? You asked me to give a more recent

00:53:07.060 example or something I'm familiar with. I started, landed in this country in 1977 as a fresh medical

00:53:15.000 graduate. Before my residency could start, I had six months and I'm not someone who can sit around at

00:53:22.680 home doing nothing. So I asked my sister, my older sister who had just finished a rotation. She was

00:53:31.220 a pediatric resident in Buffalo, New York. I was staying with her and she just finished a rotation

00:53:37.360 at Roswell Park Cancer Institute. And I said to her that, you know, all the oncologists there,

00:53:44.100 can you get me in there and I'll just work for six months that I have. So she went and spoke to her

00:53:50.240 boss, Arnie Freeman. And he said, well, if she's half as good as you, we'll take her. So I joined

00:53:56.780 pediatric oncology at Roswell Park. But within a couple of months, it was very clear I couldn't handle

00:54:02.860 it. I couldn't last because I was crying the whole time. I just can't handle children being sick.

00:54:09.440 So my sister's friend, who happened to be my boss at the time, Judy Oakes, one day just took me by

00:54:15.740 hand because I was hiding in a room crying away. I had lost a four-year-old that day and took me to

00:54:21.660 the adult oncology unit where I met Harvey Prysler, who was later to become my husband. And Harvey was

00:54:29.600 heading the leukemia program at the time at Roswell Park. And he took me on. I started working on the

00:54:36.920 wards immediately. At that time, we used to have 20, 30 AML patients, acute myeloid leukemia patients

00:54:45.540 on the floor. And I started seeing and working completely as a fellow. I was hired as a fellow.

00:54:52.200 We were using two drugs to treat AML back then in 1977, a combination of aracy and donomycin.

00:55:01.840 They were popularly known as seven and three because you give seven days of one and three

00:55:07.820 days of another. By the way, Harvey and I started to use this seven and three as a kind of a code

00:55:15.000 word between us. We would be sitting in a meeting and Harvey would suddenly leave no one and say to

00:55:20.240 me, as that person is doing seven and three. And for us, that seven and three meant somebody is

00:55:25.880 using seven words when three would suffice. Another mark of a great writer.

00:55:33.100 So we were using seven and three in 1977. Guess what we are using in 2020? Seven and three.

00:55:41.440 All these years, imagine the thousands of patients I personally have had to see and describe the same

00:55:53.720 side effects and the same potential benefits they will have. Now, when I started, the survival was

00:56:03.120 10% five-year survival with seven and three. Today with the same drug, it's about 26%. Why has it

00:56:10.200 increased? Because the supportive care measures are better. We have better antibiotics. We can give

00:56:17.040 more platelets and red cell transfusions are easier to give. We have learned to manage better.

00:56:23.720 That's it. The supportive care is better. But the backbone of treatment is the same seven and three.

00:56:29.660 So now a company comes up with combining these two drugs, seven and three, in a fatty envelope.

00:56:39.140 So they come up with this new drug now, and it's the same seven and three. But it gets approved in this

00:56:47.140 country. And this approved form, which is, I believe, for a little older patients, like 60 to

00:56:53.440 75 years, if you have acute myeloid leukemia, you can get this combination of seven and three,

00:57:00.120 which is inside this fatty capsule. Now, the regular seven and three costs $5,000.

00:57:07.920 $5,000 for how long?

00:57:10.100 For the seven days and three days.

00:57:11.500 For the seven plus the three days for one cycle. Okay.

00:57:14.000 $5,000. This fancy version, seven and three costs $45,000. And do you know what is the

00:57:22.980 improvement in survival? Under the best conditions when they ran the study where you select patients,

00:57:32.340 the eligibility criteria are so stringent. Their kidneys have to be working, their liver has to be

00:57:39.960 working, their lungs have to be at capacity, et cetera, et cetera. You know how we choose and

00:57:45.760 select patients for clinical trials. They are the best of the best.

00:57:50.140 Right. They have to be cherry-picked. They represent the upper limit of what you expect in the real world.

00:57:55.100 Yes. And even in those cherry-picked patients, the basis on which this $45,000 combination is approved

00:58:04.320 is an improvement in survival by 3.7 months. That is a median improvement in survival,

00:58:11.200 which means a fraction of the patients, like maybe 30%, experienced 3.7 months improvement

00:58:19.260 in survival. What does that mean? Median survival. So even out of those 30%,

00:58:24.120 half of them didn't even experience that, but we are paying $45,000. Now, if I don't prescribe

00:58:32.440 that drug and continue to give 7 in 3, then I can go to jail. Because tomorrow, if the patient dies,

00:58:41.820 which they eventually do because it's an older age group, then the family will sue me. Dr. Raza,

00:58:48.580 this drug was available. It could have given 3.7 more months. So now the decisions that we are making

00:58:54.980 as individual oncologists are not being made by us, they are made just by key opinion leaders or

00:59:02.940 the very institutions like FDA, which are supposed to protect the patients, have fallen a victim to

00:59:11.420 this kind of propaganda where under the pressure of advocacy groups who are demanding more drugs

00:59:18.920 for cancer patients at any cost. Just to be able to say that we have 72 new drugs being approved this

00:59:27.340 year for cancer. Look at the fantastic advances we have made. So under pressure from advocacy groups,

00:59:35.840 from patients, the FDA has lowered its bar of approving drugs to laughable criteria. It would be

00:59:43.960 laughable if it wasn't so tragic. Here you have 3.7 month median improvement in survival for a fraction

00:59:52.440 of the patients for $45,000 instead of $5,000. Are you surprised then that 42% of cancer patients

01:00:02.680 who are diagnosed today will be completely financially ruined by the second year of their diagnosis?

01:00:10.220 50% of breast cancer. 50% of breast cancer women are being hounded by collection agencies with stage 4

01:00:17.440 cancer. Your friend Marty McCary has written a fabulous book, The Price We Pay. People should read

01:00:24.920 that book and see the obscenity we have reached. The vulgarity of it all, completely not thinking about

01:00:34.100 patients at all. Talking in terms of, well, Azra, 3.7 months meant a lot to my patient who could go and

01:00:41.460 attend his son's graduation or grandson's bar mitzvah. Yes, of course, like I said, John Dunn said,

01:00:48.600 every human life is important. But you asked the question earlier, at what cost to the others?

01:00:55.240 I mean, I think Marty's work does a great job of explaining this. And the only way I can sort of

01:01:01.360 explain it is, I think the United States has basically become the one that has to subsidize

01:01:07.940 the rest of the world in terms of medical research. I mean, that's the only way I can sort of make sense

01:01:13.380 of how outrageous these costs are. By the way, that's not a justification. So I could go on for

01:01:19.100 days as to how frustrating it is. But it has basically become a form of subsidy. And I've been

01:01:24.860 trying to get my head around what are the biggest drivers of spending in the United States. Because

01:01:31.580 overall, as a country, we don't get a lot in exchange for what we give. That's going to be a

01:01:38.700 very polarizing comment I just made. So let me clarify it. If you take someone in the top income

01:01:44.400 tax bracket in Canada, by all estimates, a socialized country, and you compare them to someone

01:01:51.280 in the top income tax bracket in the United States, especially in a high tax state, they're paying

01:01:55.860 about the same amount. The difference, however, in what they get is fundamentally quite different.

01:02:01.220 In Canada, everybody gets health insurance, no ifs, ands, or buts. Everybody basically gets

01:02:05.980 exceptional education at a fraction of the cost, homelessness, mental health. A lot of these issues

01:02:11.680 are just so much better. I still think, I would still make the case, by the way, that the extremes of

01:02:16.860 healthcare are better in the United States. I would much rather receive my medical care in the

01:02:21.260 United States than in Canada. But ultimately, it points to a gross inefficiency in terms of how

01:02:26.440 those dollars that are collected are then turned around and spent. And I could probably point to

01:02:31.140 three things that the United States is disproportionately spending money on that other countries are not

01:02:37.180 spending money on. And it's those three things that are creating the biggest gap. And one of them

01:02:42.380 is healthcare. There's simply no way to avoid it. And within the morass of healthcare, drugs might be one of

01:02:49.780 the most egregious examples. There are others that are less sexy to point your finger at. But as you

01:02:55.780 note, I mean, Marty makes a very good point that the drug story is a revolting one, actually.

01:03:01.460 After Harvey died with a five-year-long battle with leukemia.

01:03:07.160 You are in your early 40s at this point in time, basically, when you're widowed?

01:03:11.260 When he was diagnosed, yes. And we had a four-year-old daughter when he was diagnosed. So after he died,

01:03:18.720 my younger sister, who's now the head of women's radiology at the Brigham, she said,

01:03:23.700 well, I have to get you out of Chicago because this five years of thinking of nothing, concentrating

01:03:30.740 continuously on this one thought only, which was Harvey and his illness.

01:03:37.640 So we went to England because, well, London is one of my favorite cities. And I wanted to take my

01:03:46.620 daughter to see Reading Jail because I'm a big Oscar Wilde fan. And we went to Reading. And

01:03:54.760 the reason I'm telling you this is one of the most gorgeous ballads ever written, the Ballad of Reading

01:04:01.640 Jail. The refrain is very beautiful. Yet all men kill the things they love. By each, let this be heard.

01:04:12.220 Some do it with a bitter look and some with a flattering word.

01:04:19.840 The coward does it with a kiss, the brave man with the sword. But each man kills the thing they love.

01:04:27.600 By each, let this be heard. So Wilde wrote this poem when he was in this ballad, when he was

01:04:35.880 incarcerated in jail. And when he came out, his boyfriend, Lord Alfred Douglas asked him,

01:04:42.060 what do you mean by this refrain, all men kill the things they love? What does that even mean,

01:04:47.020 all men kill the things they love? And Wilde tried to just diss him and said, well, nothing,

01:04:51.860 you know, it's just whatever. But Bosie, Alfred Douglas kept insisting, no, you have to tell me

01:04:58.440 what this means. So you know what Wilde said? He said, look, it's like this. When we meet someone

01:05:04.580 or we have an idea, we make immediately an impression in our mind. We meet them the next time

01:05:12.660 and they don't correspond with the impression we had. So instead of correcting our impression,

01:05:20.480 we start trying to change the person. And this is how we enter the cycle of self-delusion and kill

01:05:27.760 the thing that we love. Why am I telling you all this is because we started with good intentions,

01:05:36.780 Peter. But somehow, remember in the beginning, I said, I'm looking for an adult. Why?

01:05:42.660 Why aren't we taking stock of the situation? Why is it that scientists who are going to now,

01:05:50.620 let's say, attack the metabolic pathway of cancer cells to improve the efficiency of chemotherapy

01:05:59.000 by simultaneously changing the dietary patterns for the patient? A very good target to think about.

01:06:10.220 But before even a phase one trial has started, they are monetizing it, making companies out of it.

01:06:18.020 I mean, yes, this is a capitalist system. Everything is legal. Everything is allowed. But then

01:06:23.140 it somehow leaves such a bad taste in my mouth all the time. All the time. It's all about,

01:06:31.180 think about it. You are never going to be able to cure an advanced cancer of the kind that Andrew had

01:06:40.260 by a diet of any sort, or even by supplementing chemotherapy he's getting with a diet of any

01:06:46.740 sort. All you are aiming for is improving their survival by a few months. But more important is to

01:06:54.700 make companies. Why? Why have they come to this?

01:06:59.300 I mean, I think in defense of that type of idea, which I don't really know about specifically,

01:07:04.720 they would probably argue changing nutrition. If a change in nutrition could have a comparable

01:07:11.360 benefit to a change to the use of a drug, it's a fraction of the cost, and presumably without the

01:07:17.440 destruction of the quality of life. I mean, one of the things I'd like you to come back to, Azra, 1.00

01:07:21.240 is... I didn't question the idea, Peter. Sorry, I'm not questioning the idea at all.

01:07:26.620 I'm questioning why do you have to monetize everything, is what I'm questioning.

01:07:31.160 Yeah. I mean, I was going to ask you the same question, which is how do we think about the role

01:07:41.460 of pharma in this entire landscape? I mean, it can't be denied, which is progress has to be funded

01:07:49.740 by somebody. You have different animals. So you have public funding, which has been the majority of

01:07:56.160 it through NIH via NCI, which is by far the largest of the institutes within NIH, and has done the

01:08:03.320 lion's share of the cancer funding. So I actually did the analysis five years ago, which means it's

01:08:09.220 probably dated, but directionally correct. But if you went back to the declaration by Richard Nixon

01:08:15.980 of the war on cancer, so circa 71, 72, more than half of the total research dollars in the world

01:08:24.880 into oncology funneled through NCI. Slightly over half was my recollection. Again, I could be a little

01:08:31.120 wrong on that, but that's a big piece of it. Of course, pharma, as you know, has really outsourced

01:08:37.980 R&D. They just don't do R&D anymore the way they used to. So they basically now acquire R&D'd products.

01:08:47.080 And so smaller and smaller companies, which means it's shifting more to venture type investing and

01:08:52.920 biotech investing is taking that early stage one, early stage two risk, at which point pharma brings

01:08:59.640 in for the huge capital allocation required for late stage two and stage three approval that gets

01:09:07.520 the drug approval, which then gets to the point you raised, which is you've got these two drugs that

01:09:13.320 have been off patent for since Moses was throwing tablets at people. What are you going to do with it?

01:09:18.480 Well, you could keep selling them for $5,000 or you could repurpose them and increase by nearly 10x.

01:09:26.220 And I know that it sounds egregious. I don't have an answer though, because I don't really,

01:09:32.260 like this is almost to me a question of economics is the answer that all of this stuff has to be done

01:09:36.440 publicly so that shareholder value is no longer the thing that's being optimized for. Because as long

01:09:44.220 as these companies have to answer to shareholders, I don't think they'll ever figure out a way to put

01:09:50.720 the woman with breast cancer who's going to go bankrupt ahead of their shareholder. As awful 1.00

01:09:55.940 as that sounds, I think they're always going to say, I have a fiduciary responsibility to my

01:10:00.800 shareholder and that is to maximize the price. And I do think the government is doing a better job

01:10:06.300 at catching the most egregious examples of company that are grossly exploiting this.

01:10:10.980 But in the end, is Keytruda really worth what it's being charged today? I don't know how to

01:10:18.420 answer that question. I really have no clue how to answer that question. And you've more eloquently

01:10:23.720 than me said, every life is valuable and that includes the lives that remain, which I think is

01:10:30.140 a very important point. That's the counterpoint that's never made. It's not just the life of the

01:10:34.800 individual that we're debating extending by 3.1 months at some unbelievable sum. It's the lives

01:10:41.940 of everybody that remains and what it says about their social security check and what it says about

01:10:47.620 their schools and what it says about their healthcare. Wait, I want to answer this. If you

01:10:53.500 take a living frog and you throw it in boiling water, it will jump out. But if you put it in cold

01:11:00.820 water and start heating it slowly, it will die in that because it has been desensitized so slowly.

01:11:08.940 We began all these things with good intensity. That's what I keep saying to you over and over.

01:11:15.360 Some of the saddest things to me are this. 95% drugs we bring to the website fail. Why? Because

01:11:22.820 the pre-testing platforms we are using are so artificial. We are taking a very complex disease

01:11:30.960 like cancer and we are trying to reduce it by reductionist approaches into trying to replicate

01:11:38.620 this complexity in mouse models, in tissue culture, cell lines. And if those don't work,

01:11:45.220 we add layers upon layers of complexity to it by generic engineering, immune compromisation of the

01:11:53.340 animal. You know, after reading my book, The First Cell, a young woman wrote to me saying,

01:12:00.780 Dr. Raza, I'm a PhD student. I'm working on this cell line model of breast cancer, testing drugs against

01:12:10.280 it, but using a two and three dimensional in vitro system. And once this is successful,

01:12:19.220 that the drugs work against the cell lines, then I will go to the mouse model. And if that works,

01:12:25.580 then I have to go to human. But reading your book, I realized that it's all a waste of time. What should

01:12:30.620 I do? Is this even something I should spend the next 10 years of my life doing? So, but 90% of

01:12:40.200 research is still funding things, research dollars. You are talking about NCI dollars. What are the

01:12:45.560 funding for God's sake? The same old, same old ancient platforms which have shown a 95% failure

01:12:53.280 rate and the 5% success is ludicrous. Secondly, before you go, can you say more about that? Actually,

01:13:00.760 I'm glad you brought this up because I sometimes forget that I know a lot of the things you're

01:13:05.360 talking about and I take them for granted, but I think this is worth a bit of a detour if you don't

01:13:09.740 mind. Explain to people what that PhD student was doing. What is a day in the life for her or what is

01:13:17.100 she going to spend years doing? And how does that sort of model fall short? I think you can explain

01:13:24.820 it better than me because you have spent so much time in Dr. Rosenberg's lab, but very simply stated

01:13:30.820 when we want to try and find new drugs for cancer. We can't give drugs directly to humans. So we try to

01:13:38.040 first give them to something in our lab. What should that something be? Well, it started by taking

01:13:44.760 patients' tumor cells, but they don't last very long in our cultures, in the lab. So then that becomes a

01:13:51.680 problem. How should we perpetuate these cells in culture? By serendipity, some cancer cells began

01:14:00.080 to grow in the labs. And one of the first was the famous Hela cells from a patient with cervical cancer.

01:14:08.700 And these cells grew so well that they became immortalized. They self-perpetuated. They can be

01:14:15.080 grown from flask to flask, transferred from lab to lab. They can be put into mice and grow.

01:14:21.680 And so all this reproducible system that became available is called a tissue culture cell line.

01:14:28.960 And we learned with time to make more and more of these. So you make a pancreatic cancer now,

01:14:35.280 just like the Hela cells with cervical cancer. You take an ovarian cancer, a pancreatic cancer,

01:14:40.740 you grow them, and one of them will by chance mutate enough to become immortalized and then become

01:14:47.560 a tissue culture line. Now you can test drugs against it. But one of the first things that

01:14:53.600 I have written in my book in the first chapter is that by using these cell lines, when it was tested

01:15:01.760 to see what kind of genes are they expressing, it turns out that instead of expressing genes that were

01:15:09.620 faithful to the tissue of origin from which they came, for example, an ovarian cancer cell line

01:15:16.180 should be expressing genes that are expressed in ovarian cancer. Pancreatic cancer cell lines should

01:15:22.540 be expressing pancreatic genes. Instead, it turned out that there has been a transcriptomic drift

01:15:30.260 that basically all the cell lines, irrespective of their tissue of origin, express similar genes that

01:15:39.460 make them survivable under adverse in vitro conditions.

01:15:44.820 So let me explain one other thing for the listener here, which kind of ties in another

01:15:49.480 theme of yours, which is, because when you go back to what we learned in the Great War,

01:15:55.180 killing cancer cells is easy. I've had guests on this podcast before who have eloquently stated,

01:16:00.820 there's no one sitting in a home right now that doesn't already have 30 chemicals under their sink

01:16:05.780 that will kill every cancer, including the most devastating cancer like the one that killed

01:16:12.640 Andrew. The challenge is killing cancer and not killing everything else. And so now when you fast

01:16:20.040 forward to what you just said, when you have immortalized in vitro cultures that have become so

01:16:28.020 genetically skewed that they no longer actually represent a human cancer, you will learn a lot

01:16:36.540 about what it takes to kill them and not kill them. It just won't be relevant to the species of

01:16:42.680 interest, which is a human being. This is why I read the Oscar Wilde thing to you, that all men kill

01:16:49.560 the things they love. We started with a good thing. When it didn't correspond to what we were

01:16:55.360 hypothesizing, instead of changing our concept, we keep tinkering with trying to change the other

01:17:01.960 thing. This is exactly how you kill whatever you started out with. And you know what's worse, Peter,

01:17:10.180 is that 90%, 9-0, I want the audience to hear this clearly, 90% of the papers published in the highest

01:17:21.560 profile journals of science are irreproducible. I didn't know it was that high. It's still that

01:17:28.900 high. Up to 90%. Different studies, some show 30%, some 80%, some 90%. It is unconscionable what we are

01:17:39.920 doing. Why are they not reproducible? Because for the same reason, one set of mice don't correspond to

01:17:47.060 another set of mice in another lab. So the point I'm making is 95% of your drugs are failing until

01:17:54.700 now, after quarter of a trillion dollars in research, like you said, that is between $6 billion a year

01:18:03.140 right now, NCI funding, and another $6 billion from philanthropic funding. Where is all this $12 billion

01:18:10.400 going? And then breast cancer alone raises $6 billion in funding. And what are they doing?

01:18:17.320 Studying breast cancer cell lines against drugs. Yes, it will get that young lady a PhD eventually, 1.00

01:18:25.040 and then she will try to get grants. Eventually, she'll get fed up and go to industry. And I must

01:18:31.180 take exception with you condemning the industry. They are the easy target, pharma companies.

01:18:36.760 They are the easiest target. But the system of research and development in America is that

01:18:44.460 somebody like me, who is an academic researcher, will write a grant to NCI. They will fund me for

01:18:51.480 $250,000 a year for three to five years if I'm lucky. But let's put that in perspective, by the way.

01:18:59.620 By NCI standards, that's a lot. An RO1 at this point, what is an RO1 down to now? Is it down to

01:19:06.520 $450,000 a year for four to five years? Yeah.

01:19:10.360 That's almost as big a grant as someone's going to get.

01:19:13.460 Yes. And with that, all you can do is study one gene, one signaling pathway. But let's say

01:19:19.340 I luck out and I find something which I think is looking very encouraging and is a potential target.

01:19:26.580 The next step is obviously to take it to the bedside. But to do that, I have to now test this

01:19:32.160 in mouse models first, in two mammals, in fact, and then to take it to the bedside for a phase

01:19:38.360 one trial alone will cost $30 million. And by the time this drug will get approved, it will be $2.5

01:19:44.980 billion. Nobody can fund that kind of work except industry. It's a very strange kind of thing where

01:19:52.360 we are strange bedfellows, academics and industry. Academics will develop the biologic insights which

01:19:59.300 are needed to identify targets, but we don't have the bandwidth to take it to the patient. So industry

01:20:05.100 comes in, takes that, but then they have to bring it back to academics because that's where the

01:20:10.420 universities will help a co-patient. So do you today, the criterion for recruiting young faculty,

01:20:19.780 the young faculty is complaining to me that Dr. Raza, all the universities where we are applying,

01:20:26.240 ask us for it, how many clinical trials are you going to open when you come?

01:20:31.500 Yeah, look, it's a symptom of a broader issue, which is the incentives have come out of line.

01:20:38.240 I don't know how to fix that, by the way, but even taking it one step further, look,

01:20:42.380 just the entire system of publishing in academics has become so skewed because you took a good idea,

01:20:50.140 which was, wouldn't it be great if scientists would do work, would publish them in journals,

01:20:55.720 would have them peer reviewed, would share knowledge broadly so that others might see it,

01:21:00.800 learn from it and not make the same mistakes and build on the work of others, right? A beautiful

01:21:05.420 idea. You can't disagree with any of it. And by the way, recheck things that have been done to make

01:21:10.840 sure they were done correctly because under different conditions, we want to make sure they're

01:21:14.100 reproducible. Okay. Understandably then that idea gets extended into, this should be a criteria for

01:21:20.780 promotion within the academic system, which invariably turns into an entire cottage industry

01:21:27.500 of garbage journals and garbage study and garbage publications, which are driving up the fraction of

01:21:35.620 studies, which can't be reproduced. And by the way, the fraction of studies that can't even get cited, 0.87

01:21:41.680 they're so insignificant. And so you sort of think, my God, if something as pure and ideal as scientific

01:21:50.420 research and publishing has become so difficult to do, and I don't have a great solution for that.

01:21:58.420 The process you're describing is a logarithmic order in front of that, which is taking research

01:22:06.200 from the so-called bench to the bedside. That's the thing that I still don't, even after reading

01:22:13.940 about this topic and not just your book, but other books, I still don't have a great sense of what the

01:22:21.000 future looks like. I don't disagree that the water is starting to get uncomfortably warm here as a

01:22:26.180 little frog. And I don't disagree that we need to get out of this bath of water and into a cooler bath

01:22:32.540 of water. But boy, I have to be honest with you, I'm discouraged. No, no, don't be. I have a

01:22:38.420 solution for us and a very important solution. You know, Peter DeRice is a writer who wrote a book in

01:22:45.800 1961. He wrote a novel because his own daughter, who was 10 or 11, died of leukemia in his arms and

01:22:55.080 after a horrible battle. In 1961, Peter, DeRice says, so the treatment for leukemia today

01:23:05.940 is a local rather than an express train. Same run, a few more stops. But that's how medicine functions,

01:23:16.940 perfecting the art of prolonging disease. This was in 1961. How is this different? The run for

01:23:27.760 leukemia is still a local. What I want to say is I feel like I'm living in a theater of the absurd.

01:23:36.020 Why aren't other people seeing the spectacular failures we are dealing with? And why do we keep

01:23:43.720 mollycoddling the public? Why do we keep promoting the two, three months or five months advantage in

01:23:51.440 survival? Why aren't we going for bigger goals and better things? We can do it. You know how we can do

01:24:00.200 it is very simple. What has worked in cancer until now? Early detection. How is it that we are living

01:24:08.700 in an era of the most sophisticated technologic advances possible? And yet the treatment of cancer

01:24:17.720 is paleolithic. It belongs in the Stone Age in the caves. Giving the kind of disfiguring, horrible

01:24:27.440 treatments we give is like beating, someone said this, beating the dog with a baseball bat to get rid of

01:24:34.980 its fleas. Have you ever seen somebody being treated with CAR-T therapy? My God, there are whole industries

01:24:41.560 sprouting up to control the side effects. Why are we even developing such terrible therapies? Yes, we

01:24:49.960 should develop them, but they should be used when the tumor burden is not that high. So once again, I want

01:24:56.220 to be very clear about a couple of things before I give you my solution. Number one, I'm not against

01:25:02.900 animal research at all. For biology, it is very important to use the animal model. All I'm against

01:25:11.960 is drug development in animals because what you learn in animals by using drugs is only correct for

01:25:20.440 animals. It does not automatically extrapolate to humans. So just to be clear, you're saying you would

01:25:28.080 still use animals for safety, but you would disregard them for efficacy? I would not use them

01:25:34.300 for safety either. Why should it give me any level of confidence that the drug didn't kill mouse, it

01:25:40.200 wouldn't kill a human? It is very little to do with each other. We don't have to go into it now, but I

01:25:46.080 guess, do you know from sort of even back of the envelope how that would change the regulatory landscape

01:25:52.260 if we now had to go to a much earlier phase one in humans? Obviously, probably using a milder dose

01:25:59.280 escalation, or would you be talking about doing primates instead? What is the actual model?

01:26:05.040 None of those. In fact, the FDA has a system which is called phase zero, in which you don't just bypass

01:26:13.360 any animals, you use one five hundredth of the dose, starting dose in humans, and work your way up

01:26:21.280 that. So basically, it's homeopathic all the way up. Yeah. So that's how you do it with a phase zero

01:26:27.680 trial. What I'm saying is, look, the only thing that has worked is early detection. We have great

01:26:33.720 technology available. We shouldn't be talking about early detection doesn't work because mammograms have

01:26:39.720 not been helpful or PSA have led to overdiagnosis and men undergoing very macabre surgeries and things.

01:26:47.180 No, all I'm saying is that we should definitely take advantage of the cutting edge genomics, transcriptomics,

01:26:55.700 proteomics, metabolomics, the scanning and imaging devices that have been developed and use artificial

01:27:02.400 intelligence to put all this together. Develop 50 tests if we have to, to identify biomarkers,

01:27:09.120 which are based on all these things and combine them with the latest technology to try and start

01:27:17.660 monitoring the human body, not once a year, but continuously like a machine. And how do you do that?

01:27:24.940 Well, you see this chip. You can see it. The audience cannot. It's a small chip, the M chip. You can look it up

01:27:31.960 because it is FDA approved. It is based on microfluidics. You put one drop of blood here,

01:27:37.620 which goes through microfluidics and interacts with the biomarker put here. The biomarker in M chip's

01:27:44.300 case, which is FDA approved is PSA. So men who have been diagnosed with a high PSA can use this chip.

01:27:52.960 It can slide into a small device and very soon into your cell phone and give you your PSA four times a

01:27:58.960 day if you want to see it. And if you're diagnosed with having a high PSA, you don't have to go in

01:28:04.640 and have a complete abdominal resection with the removal of every lymph node and be eviscerated. No,

01:28:13.180 you follow this at home if you have to as often as you want. I'm saying that if we develop a biomarker

01:28:20.680 that is identifying the earliest footprints of a pancreatic cancer, we put that next in the next lane.

01:28:27.620 And for ovarian cancer in the next door, for each cancer, we develop like a barcode

01:28:33.300 and with one drop of blood. So Toshiba, a company just announced that they can detect 13 different

01:28:41.300 cancers from one drop of blood in four hours for $180. There's a company in the Bay Area that I

01:28:48.660 follow very closely called Grail, and they're doing something very similar. At this point,

01:28:54.100 they're, you know, in phase two with probably almost 30 different cancers. I agree with you

01:29:00.880 completely. I mean, my view of cancer is rule number one is don't get it. I mean, that sounds

01:29:06.480 glib, but I don't think enough attention is paid to the don't get it rule, which is why aren't we

01:29:12.060 trying to better understand what the environmental triggers of cancer are? Because while, as you point

01:29:18.080 out, it has always been with us, I think there is reasonable enough evidence to suggest that its

01:29:23.900 incidence is higher in a modern world than in a non-modern world. And therefore, what is it about

01:29:29.840 a modern world? For example, what is it about our diet or about our stress or our lack of exercise

01:29:35.840 that could be amplifying our risk? And if you think about it, if changing factors of our lifestyle

01:29:42.420 could reduce your risk of cancer by 30 to 50%, which my reading of the literature says is absolutely

01:29:50.240 the case, how could we not make that a high priority to understand? And when you pair the

01:29:58.000 rule number one, don't get cancer, with rule number two, very smart screening for cancer, you then get

01:30:06.200 into rule number three, which is if you get cancer, treat it so early, treat it when it is basically

01:30:13.060 in the millions rather than the billions of cells. And for someone who might not have the familiarity

01:30:19.240 with cells, a million cancer cells is not even detectable to the naked eye. A billion is. And so

01:30:26.000 there's a very big difference between when you can catch a million cancer cells versus a billion.

01:30:31.220 And I agree with you, by the way, completely that most people who are critics of early

01:30:35.980 screening are unfortunately lacking the nuance to appreciate the accepted failures of things like

01:30:44.900 PSA and mammography, which I won't go into here. I've covered them in great detail in some other

01:30:50.620 podcasts too. In particular, I'll just direct the listener to, I think the failures of PSA stand alone

01:30:57.040 as a failure has been covered very well in the podcast with Ted Schaefer. And Ted talks very eloquently

01:31:03.580 about how if you are wed to PSA using PSA volume, where you take PSA normalized to prostate volume and

01:31:10.860 PSA velocity, which Ezra, you would get out of what you propose, which is the rate of change of PSA over

01:31:18.160 time. So PSA has a rate of change called PSA velocity, PSA volume become much better indicators

01:31:25.040 of prostate cancer risk than just PSA. But also you go far beyond PSA to things like 4K and other types

01:31:32.660 tests that add more nuance to this. I think the story becomes much more clear that this type of

01:31:38.940 early detection matters. And I think as it pertains to the limitations of mammography, I would direct

01:31:45.000 people to the podcast I did with Raj Atariwala, where we talked about cancer screening. And we actually

01:31:53.300 very specifically addressed some of the limitations of the literature on these isolated techniques like

01:31:59.420 mammography. So you're not going to get any disagreement out of me on both of those fronts.

01:32:05.040 So I guess the question is, do we really believe that by taking those types of steps, we will reduce

01:32:14.340 the need for the cancers for which we have just not had the big breakthroughs, which is basically

01:32:22.160 lung, pancreas, prostate, breast, colon, and GBM. Those are basically the most lethal cancers.

01:32:31.720 Outside of GBM, it's the metastatic versions of the others. Obviously GBM doesn't leave the brain,

01:32:36.580 it kills locally. That's got to be two thirds of cancer deaths. And you're basically saying,

01:32:43.860 we have to catch these things long before they're ever in a position to leave the primary organ and not

01:32:49.280 try to reinvent the onc drug discovery wheel coming up with another cocktail that's going to be as

01:32:57.860 lucky as we were with Hodgkin's lymphoma. Is that, I don't want to put words in your mouth, but is that

01:33:02.480 your view? Yeah. Well, sort of, but let me restate what specifically I feel. First of all, about the

01:33:11.220 lifestyle you're talking about. Of course, lifestyle is, it's only common sense that if you smoke,

01:33:16.920 it's not going to be good for you, your likelihood of getting not just lung cancer, but many diseases

01:33:23.180 will be high. So yes, lifestyle changes have, we have to continuously drill into our consciousness,

01:33:31.400 what is good for us and what is bad for us and try not to get it. The problem is that with cancer,

01:33:37.780 as I began by telling you, heredity and pathogens and environmental exposure like smoking, etc.,

01:33:45.320 do account for a certain percentage, the vast majority, there is no reason why they get cancer.

01:33:51.420 We, at least a reason that we can identify yet. I think that's the challenge is that with smoking,

01:33:57.960 the difference between the people who smoked and the people who didn't smoke was so great that it was

01:34:04.420 appreciable. But you're right with most other environmental contributors, with maybe the only

01:34:11.020 other exception being obesity, it's very difficult to tease out what else could be contributing. For

01:34:18.340 example, I don't know if you're running or the trampoline is making enough of a difference

01:34:25.280 because it's very difficult to study that longitudinally and prospectively. And secondly,

01:34:31.240 I don't know that enough people are doing it and it would create a big enough signal that we can

01:34:35.920 measure it. Well, that's what I was going to say. We don't even know whether eggs are good or bad for

01:34:41.480 you to this day. So those are the kinds of issues with lifestyle large studies. Now, the point I'm trying

01:34:47.740 to make, though, is slightly different. A lot of people smoke. Not all of them get cancer. So there are

01:34:54.020 other co-factors that exist. All these things have to be worked out. Haven't we been trying for a hundred

01:34:59.740 years? For God's sake, don't. The investigators who act like this is something they have discovered

01:35:05.300 today to be looked at. No, this is what we have been trying to do forever. It's not that simple.

01:35:12.220 What we are finding is that for the vast majority of cancers, their random mutations account for it,

01:35:19.260 which means that cancer is most common with age, increasing age. Why? Because with age, many more of

01:35:27.140 the cells in our body have undergone several divisions. And with each division, we pick up

01:35:32.860 some DNA copying errors, two to three on an average. So by the time our cell is now from birth to like

01:35:40.440 60 years of age, every cell has undergone multiple cycles of proliferation. Therefore, multiple gene

01:35:47.560 genetic mutations have collected. And these are making the cell susceptible that now it's like dropping

01:35:55.000 grains of sand and they will form a pile. And at one grain of sand, which is no different than millions

01:36:01.760 before that had gone before, it will suddenly cause an avalanche and the pile will collapse.

01:36:08.180 Not because the last grain of sand was different, but the pile had become unstable. So with age,

01:36:14.180 the body becomes unstable because all the cells have these kinds of mutations. So, and not only that,

01:36:20.260 metabolism can go wrong. And sometimes as shown by whole genome sequencing of over 2000 tumors,

01:36:27.180 that there are a few cancers where no mutations were found in advanced cancers. So how did that

01:36:33.600 happen? Well, because sometimes it is the disturbed metabolism that then leads to production of reduced

01:36:42.580 oxygen species or free radicals, for example, that go and chop up and cause mutations and that genetic

01:36:48.740 mutations are a secondary event. The primary event is a metabolic disturbance. So, I mean, all this needs

01:36:55.180 to be done, all this needs to be studied. And it isn't like it hasn't been studied. Since 1921,

01:37:02.080 poor Otto Warburg made the first observation of anaerobic metabolism. And since I was doing ketogenic

01:37:09.160 type diets in the 1980s. So please don't think that any of these things are new. But the question that I am

01:37:18.000 asking as someone who's been in this field for 43 years now is this, if I'm still using seven and three

01:37:26.300 to treat AML and for most common cancers, we are still using slash poison and burn. It is not for lack

01:37:34.040 of resources. It is not for lack of very, very smart people, hundreds of thousands of them who are

01:37:40.640 working 16 hours a day to try and find the answer. But the answer is very complicated. It has too many aspects

01:37:48.980 to it. So the only thing we should do is I am beseeching to everybody in cancer related fields, let's just spend

01:37:59.000 a little more effort, a little more resources in earlier detection. Yes, keep trying to understand metabolic

01:38:06.440 pathways and intracellular signaling and checkpoints and CAR T's and everything else. But instead of

01:38:13.200 spending 5% in prevention, let's spend 50% in prevention and early detection. That is all I'm

01:38:20.600 asking for. So a lot of people have asked me, Peter, because I've been completely uncompromising in

01:38:28.360 my criticism, as you've heard now, I am completely merciless. You know why? Because I have brought the

01:38:35.160 patient back front and center and everything I look at is through patients' human anguish.

01:38:42.160 Our problem is that 90% of our researchers never see a cancer patient because they are basic scientists

01:38:48.840 and they study tumors that they grow on their own in their labs. So they don't see a disease they are

01:38:56.460 trying to develop treatment for and they are using animals who don't get these diseases spontaneously.

01:39:02.960 How artificial can you become, for God's sake? So my thing is, while you're doing all that,

01:39:10.520 at least let's employ all of the sophisticated technology and a lot of the intellectual resources

01:39:16.480 to developing biomarkers for early detection. Why not look at every compartment, whether it's blood,

01:39:24.460 sweat, tears, saliva, urine, microbiome, study everything but human. Stop studying animals,

01:39:31.840 for God's sake. Study new issue. You're making so much sense to me that I'm struggling to come up

01:39:37.300 with a counter-argument to that point you're making. I mean, should 50% of our resources be put

01:39:43.840 into prevention and early detection rather than 4% if that? Absolutely. Should we also shift this to

01:39:53.360 study disproportionately in the study of interest? I couldn't agree with you more.

01:39:58.040 You made a point a moment ago about the nature of contact. I wanted to use that as a point to come

01:40:06.460 back to Omar. Why did you include the story of Omar in your book? He's not unique, right? I mean,

01:40:13.120 you've treated a million Omars. What was it about him that spoke to you so much? It had to be more than 0.85

01:40:19.660 just his ethnicity, but I don't know. Maybe I shouldn't assume that.

01:40:23.400 Well, first of all, he's my best friend's son. Here is a 38-year-old young man, a graduate of

01:40:32.180 Oxford and Columbia. His teaching has finally fallen in love, calls his parents to come and get him

01:40:39.820 engaged. And when they arrive, the young couple, he has a little osteogenic sarcoma. So the thing that

01:40:47.920 has forced that made me put Omar into the book is the utter helplessness of oncologists because from

01:40:56.240 day one, when you have not resected that solid tumor completely, you were a surgeon, you were a

01:41:03.720 surgical oncologist, you are a surgeon. You know this, Peter. If you leave behind 10% of the tumor or

01:41:11.240 even your microscopic pathology shows that cancer cells have entered blood vessels, as was the case

01:41:18.500 with Omar. Now you know that his chances of survival beyond a few couple of years at most are 0.00.

01:41:27.200 What are your choices you are going to give to Omar? Either you die of cancer or you die of the

01:41:32.840 treatment we are going to give you. Because the problem is if we don't give treatment, then death

01:41:38.440 from cancer is horrendous in itself. It's one of the most painful deaths. So are we at least doing

01:41:45.900 some palliation? And Omar's case was really huge. It's a good question you asked. It was emotionally

01:41:54.200 soul destroying to see this young man who's already just embarking on his career. Finally, after years

01:42:01.960 and years of hard work, has met the woman, he gets married a couple of months after the diagnosis

01:42:08.260 actually, and knowing that he's going to die. And I had to live through every single day, not just in

01:42:16.600 the hospital, but also at home because we are seeing him. And by the way, if I recall, this was only

01:42:23.000 about five years after your husband died, yes? No longer. Harvey died in 2002. Omar dies in 2009.

01:42:30.240 Okay. Okay. Sorry. But yeah. Yes. Yeah. Not that far. So I think also in the book, I tried to balance

01:42:37.420 it out by presenting some elderly people like Lady N, Kitty C are older. Harvey was older, whereas JC, 0.92

01:42:46.100 Andrew and Omar, the three are younger people. So, and different types of cancers I also wanted to show.

01:42:52.280 So brain tumor, osteogenic sarcoma and a liquid tumor. Then Harvey had a lymphoma.

01:42:58.020 Many people ask me because I have been so brutal in my criticism of everybody. And that's why I began

01:43:06.440 telling you that, please, let's not just blame pharma companies. The hospitals who are supposed to be

01:43:12.020 non-profit hospitals are making so many hundreds of millions of dollars in profits. What should they do?

01:43:17.860 They have no shareholders to distribute it to. So they give large raises to their bureaucracy,

01:43:24.880 the executive business people running the hospital, and then they start buying other hospitals and start

01:43:31.600 investing in brick and mortar. This is what's happening. I, in fact, think about healthcare very much.

01:43:38.360 I was talking to Perry Marshall the other day, who was talking about higher education, that in the

01:43:43.760 post-COVID world, one of the things that will be completely redone is higher education, because the

01:43:50.120 two variables who have skin in the game in higher education are students and teachers. And students

01:43:57.280 are embroiled in horrible loans by the time they graduate. And teachers are not even hired in permanent

01:44:04.220 positions anymore. There are adjunct professors that are hired. So you don't have to give them any kinds

01:44:09.820 of benefits. And those two people who have skin in the game suffer, whereas universities are

01:44:15.720 developing endowments in billions of dollars. These are academic institutions. But I compare that

01:44:21.740 same thing to healthcare. The two people with skin in the game in healthcare are patients and doctors.

01:44:27.400 Patients are fleeced for every last penny, and doctors are overworked all the time. So we have no time

01:44:33.860 to spend. And businessmen are running the whole show. So I think the system has, it's like that frog

01:44:40.260 analogy over and over again. No one is going to give up what they're doing willingly at all. I believe

01:44:46.800 exactly what Thomas Kuhn said. If you want to change the paradigm, you have to show a better one. That's it.

01:44:53.120 So how do we show a better paradigm? Well, at least I'm pointing to the only successful strategy in

01:44:59.560 cancer is early detection. Why not use the latest technology to go for early detection?

01:45:06.140 We can financially incentivize it. And with the one success, the whole field can turn around because

01:45:12.320 they will see that that's where it's a better thing to invest rather than in a venture that has a 95%

01:45:19.820 rate of failure. And mark my words, the coming decade of 2020 to 2030, we'll see this shift from treating

01:45:28.420 the disease to trying to detect early and prevent the disease from becoming established.

01:45:35.500 I agree with you. I really do agree with you. I don't know that I can speak convincingly to the

01:45:41.400 timeframe, but I am actually very optimistic with the potential of liquid biopsies. And it's something

01:45:48.000 we have been very eager. It's been a big part of our practice, frankly, inside of our practice.

01:45:54.740 And I look forward to having a more rigorous discussion about this that's dedicated on the

01:45:59.880 podcast. Once some of the technologies get through certain stages of FDA.

01:46:03.900 Ezra, I want to close with a question about the loss of your husband. At any point during that ordeal,

01:46:11.200 when he was struggling and you were right there with him and you had this young daughter,

01:46:17.480 was there any point of view that was thinking, this is so unfair,

01:46:21.280 the disease that you've devoted your life to, the disease that he has devoted his life to is

01:46:27.280 ultimately the disease that's going to take him and not just take him, but take him decades too soon.

01:46:33.160 Or were you able to sort of come to this place of what some might call radical acceptance of just

01:46:38.600 saying, I accept what I can change. I have the courage to fight the things that I can. And I have

01:46:45.100 the courage to know the distinction, the so-called serenity prayer. How did you go through that at such

01:46:50.140 a young age? It's very hard to describe what one goes through. Of course, I kick doors all the time

01:46:58.800 and I had crying fits all the time. And I remember calling my mother so often on weekends we used to

01:47:05.540 talk. She was in Karachi, of course. And I would say so many of my friends hate their husbands

01:47:10.180 and they're doing fine. And look at me. I'm one who's crazy about Harvey and he's dying in front of

01:47:17.620 my eyes. I went through every human emotion that a wife would go through, especially because our

01:47:24.280 daughter was so little. And Harvey is the one who actually had reached the point of acceptance. And

01:47:30.220 when I would lose it every now and then in front of him, he would very calmly tell me not to worry

01:47:35.620 about it. It's just the luck of the draw as don't worry. And he would one time he said, look, when he

01:47:42.040 was diagnosed, he was initially told his diagnosis. His reaction was so quintessential Harvey. He said,

01:47:50.680 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

01:47:59.400 going through something like caring for someone who you love, but who has made you responsible for

01:48:07.580 every decision as well, I'll also end by quoting my favorite Dickinson again, which is what one has

01:48:16.080 to do. I had no time to hate because the grave would hinder me. And life was not so ample I could

01:48:27.980 finish enmity. Nor had I time to love. But since some industry must be, this little toil of love I

01:48:41.480 thought was large enough for me.

01:48:48.000 That's a treat I don't get often. And the listeners, I think, will agree that it's not every day you tune

01:48:53.040 into a podcast where you get treated to both the sort of the literary sprinklings of greatness coupled

01:49:00.220 with a, you know, a difficult but a very important discussion about a disease that is going to touch

01:49:05.840 anybody listening to this. Because if we're fortunate enough to not be the ones who get it, we are going

01:49:11.780 to know somebody who does. It is tragically that ubiquitous a disease. I want to thank you for your time

01:49:18.840 today. And I want to thank you for the work you've put into this. And finally, your patience. It has

01:49:25.940 taken far too long to get this interview on the books. And I hope that the listeners will at least

01:49:32.800 agree it was worth the wait. Well, before we end, Peter, I do want to say that since 1984, as a result of

01:49:40.720 my experience with a patient, I started saving samples on them. So blood and bone marrow biopsies

01:49:49.840 and aspirates and two germline controls, T cells and buccal smears, seven different types of cells like

01:49:57.900 CD34 separation, neutrophil separated, mononuclear cell separated, all kinds of elaborate things.

01:50:04.640 And today, this tissue repository has over 60,000 samples from thousands of patients who have been

01:50:12.360 serially followed for years, some of them. And not a single cell comes from a second oncologist.

01:50:21.440 To this day, I do all the bone marrows with my own hands. So this tissue repository, which contains

01:50:28.360 samples of all sorts, following the natural history of diseases in patients as they progress from a pre-

01:50:36.640 leukemia to acute leukemia, is a national treasure. It's a repository which can really unravel so much and

01:50:46.560 trace back to the cell of origin, the first cell, find the biomarkers that are associated with a pre-

01:50:55.360 leukemia that spiraled out of control into acute leukemia within months compared to one that took

01:51:01.780 15 years to become one. I think that I want to end by saying in a very positive way that I am

01:51:11.480 extremely optimistic about the future, even though we spent most of our time in talking about very

01:51:17.980 negative and very depressing, pessimistic review of what the field has been.

01:51:23.700 The future looks extremely bright and I am so happy that I have collected all this tissue,

01:51:31.120 which can now be used in the service of our patients who went through severe pain and anguish

01:51:38.020 while donating these samples. We have now, the technology has developed and hopefully the resources

01:51:45.020 will be there to finally study the whole tissue repository properly and find that first cell.

01:51:51.920 Thank you so much for the time you have given me today, Peter.

01:51:55.880 I wish you the best as you remain in quarantine. I wish you a safe re-entry in New York when the time

01:52:01.720 comes. Thank you.

01:52:03.380 Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper

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The Peter Attia Drive - July 27, 2020

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

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