Cancer Stories: The Art of Oncology

Dr. Hayes interviews Dr. Bruce Chabner on his experience with cancer drug discovery and development, phase I trials and pharmacology. Dr. Daniel F. Hayes is the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center. Dr. Hayes' research interests are in the field of experimental therapeutics and cancer biomarkers, especially in breast cancer. He has served as chair of the SWOG Breast Cancer Translational Medicine Committee, and he was an inaugural member and chaired the American Society of Clinical Oncology (ASCO) Tumor Marker Guidelines Committee. Dr. Hayes served on the ASCO Board of Directors, and served a 3 year term as President of ASCO from 2016-2018. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Welcome to JCO's Cancer Stories, The Art of Oncology, brought to you by the ASCO podcast network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the role of cancer care. You can find all of the shows, including this one, at podcast.ASCO.org. Today my guest on this podcast is Dr. Bruce Chabner. Dr. Chabner's is widely considered one, or frankly if not the father, of our understanding of the pharmacology principles of anti-neoplastic drugs. And probably more importantly, the translation of these principles to the intelligent application of the agents we use in clinic every day. Among the many accomplishments that Dr. Chabner has had working with his mentor, Dr. Joseph Bertino at Yale, who developed the concept of high dose methotrexate leucovorin rescue, that was completely based on their preclinical understandings of the mechanism of action, and more importantly, resistance to this agent. Dr. Chabner was also instrumental in the development of paclitaxel when he was at the National Cancer Institute, and he was intimately involved in many of the early studies that led to better understanding of AIDS and the ways to treat it. Dr. Chabner was raised in Shelbyville, Illinois, and I'm going to digress for a moment, because I've always had a very special soft spot in my own heart for Bruce Chabner. A, because of his science, but more importantly, because I was raised in Shelbyville, Indiana. Both of these towns were named after Colonel Isaac Shelby, who was a hero in both the Revolutionary War and the War of 1812. By the way, Dr. Chabner, I know you were a big student of history when you were in college, so I thought you'd like this. Dr. Shelby became the first and then the fifth governor of Kentucky, and as a citizen he was a land surveyor. There were actually nine counties and 11 cities and towns spread around the Eastern and Midwest regions that are named after Colonel Shelby. And I don't know about you, Bruce, but I had this drilled into my brain in eighth grade history class. I had to learn all about Colonel Shelby. Anyway, so he and I are brothers in Shelbyville. Dr. Chabner received his undergraduate degree of Yale, where again, he spent a lot of his time in the history department but also in the biology department. And then he got his medical degree at Harvard, where he stayed to complete his residency in internal medicine at the Peter Bent Brigham Hospital before it became the Brigham Women's Hospital. In 1967, Dr. Chabner became a clinical associate in medical oncology at the National Cancer Institute, where he was, in succession, a senior investigator in the laboratory of clinical pharmacology, chief of the clinical branch of the clinical oncology program, associate director of the clinical oncology program, and then he succeeded Dr. Ben [? Stabida, ?] someone I have previously interviewed for this series, as director of the division of cancer therapy. In 1995, after 25 years at the NCI, he moved to Boston as the chief of the division of hematology oncology and the clinical director of the Massachusetts General Hospital Center, where he is now the clinical director emeritus. Dr. Chabner has authored, I counted, over 500 peer reviewed papers. I think even more than that. By the way, his first was in 1969, a case report of shaking chills related to occult lymphoma, authored with Drs. DeVita and the [INAUDIBLE] of the [INAUDIBLE] syndrome. Bruce, that really shows how old you are. He's been the editor of all five editions of the Principles and Practice of Cancer Chemotherapy and Biologic Response Modifiers, which I consider the bible of cancer pharmacology. And I'm looking at my fifth edition on my bookshelf right now. He's trained too many Fellows for me to name, but numerous of them have gone on to be cancer center directors, chiefs of division, department chairs, and other leaders of oncology in the world. He's won way too many awards me to go through, but he received a Karnofsky award from ASCO, and he served on the ASCO board of directors. Dr. Chabner, welcome to our program. Nice, that's a lot of history. It speaks to my name. Well, that's the problem of interviewing all of you folks. It takes a long time to get through all the things you've done. It's a good problem to have, though. First, I want to start out, I understand you carry the flag rank of rear admiral. And I want to know, have you ever even been on a ship? And more importantly, did you and Dr. Shelby actually serve together in the Revolutionary War? I couldn't figure that out. You know, I never bumped into him when I was on the battleship Shelbyville, but who knows. He seemed to be what I call a name dropper. He left his name on so many different things, and I think there's a Shelby County, Tennessee, which is Memphis. Plus I think the smallest thing that he ever created was Shelbyville, Illinois, which was even smaller than your hometown. Yep, that's true. All right, that's the last joke I'm going to tell in this interview, but I like that connection. Anyway, so how did a guy from Shelbyville, Illinois get to Yale and then Harvard and NCI? And more importantly, what made you decide to be an oncologist? I know your father was a general practitioner, but at that time the field barely existed. What was your motivation? Well, OK, I'll tell you a bit of a story. My mother came from Chicago and she had a brother who was pretty smart. And he went to Harvard. And he used to come down to Shelbyville because he liked the pies that she made. And we were 200 miles south, so it was a trip for a pie, but anyway we used to play chess together. And when he was a college student and I was like in fourth grade, I beat him in chess and he said, Jesus, you ought to go to an Ivy League school. So that put the idea in my mind. And then my parents were not really happy with that. They wanted me to go to Washington University or University of Illinois, but I wanted to get away from home. It was a little bit confining to be around my parents for the rest of my life. So I applied to Yale, Harvard, and Princeton, and the deal was I could go to school if I got a scholarship. So I got a scholarship to Yale, so I went there. I was happy with that choice. I really-- it was sort of, you know, life changing, actually. Stayed on the east coast. But I still have many good friends from my Shelbyville days. We all get together once a year to play golf and poker and tell life stories. So I have to interject. My father told me I could go to any college in the United States as long as the tuition was the same as in-state tuition of Indiana University, which at the time was $400 a year. So I ended up going to Indiana University. So how did you-- That was such a great deal. Yeah, that was my-- How did you get into oncology? Well, when I was at the Brigham, I got interested in cancer. There was not much going on there, but one of my residents was a guy named Jack [? Moxley, ?] who had been a part of the initial study with DeVita and others, George [? Kinellas, ?] of the mop treatment for Hodgkin's disease. And I got really interested in that. And actually during my internship my sister got an immediate stromal tumor during her pregnancy, and it turned out to be a thymoma. But cancer really intrigued me at that point. And we all had to apply for positions at NIH as a way to get out of the draft, and I wanted to do research, so that really appealed to me. And I actually applied for cardiology and cancer, and I was interviewed by Gene Brown for cardiology, and he didn't seem very impressed. But the cancer people did like me, particularly George and Vince, who had come back there. And they were young and energetic and they had interesting ideas about combination therapy, so I ended up in oncology. Yeah, I talked with some of the other people I've interviewed about the so-called era of the yellow berets and how that really transformed medicine, in my opinion. Because so many smart people went to the NIH to stay out of Vietnam. It's probably the only good thing that came out the Vietnamese war, as far as I can see, and especially the NCI. So when you went to the NCI, [? Harlan ?] and Frye and [? Freirach, ?] I believe, were gone. So you've already started to say, it sounds like Dr. DeVita and Dr. [? Kinellas ?] were the movers and shakers at the time. Is that fair, or? Yeah, well they were really young. I mean, it was like working for, you know, contemporaries. There were no old people there. And Frye and [? Freirach ?] weren't that old at that time. They were in their 40s with Vince and George, who were in their mid 30s. And I was 28 years old, I guess, when I went down there. I loved it. We had laboratory opportunities, we had patients, we had people that believed that they could change the way cancer was treated. George and Vince, particularly Vince, were so energetic and so committed to the idea of changing therapy, and particularly combination therapy. And then the other thing that made it such a great experience were the colleagues that I had in my first group of clinical Fellows. Bob Young was part of it, and I became very close friends with Bob Young. And in the same group, David Livingston was my next door neighbor, and we had interned together and been arrested together. So we had just constant stimulation from a lot of different people, all of them energetic and interested in research. Who else was in your class besides Dr. Livingston and Young, then? Phil Shine, who made a name for himself in toxicology and then in industry. And let's see-- He was director at the cancer center at Georgetown for a while. Georgetown, right. Subsequently, there was just a long list of wonderful Fellows. When I came back, I actually spent two years at Yale between my NCI time and then coming back to NCI. And I had a wonderful time with Joe Bertino. He was, I think, very important to me, because he was really a great scientist. And I learned a lot about biochemistry enzyme purification and working in the lab. And so when I came back to NCI I had sort of converted to being an anti-folate person from being interested in alkylating agents. And so I was always interested, I guess, in anti-metabolites. But that was a great anti-folate experience with Joe, high dose methotrexate. It was really his idea, not mine. But the thing I worked on was the clinical pharmacology and trying to figure out why it was so toxic to kidneys. So we actually did some really interesting experiments. We gave high dose methotrexate to monkeys, and then when they died, we took the kidneys out and looked at them. And we were doing it because we thought we would see interesting pathology. What we saw were a bunch of yellow gravel in their tubules. And it turned out it was methotrexate, and it became obvious what was happening. The drug was precipitating in the acid urine environment. But that was sort of the beginning of the methotrexate studies. And personally, I don't think we teach pharmacology very well anymore. What made you want to go to high dose methotrexate? Well, interestingly, I was particularly interested in-- Joe was trying head and neck cancer. There was almost simultaneously an article from Frye and Isaac [? Jurassi ?] about adjuvant therapy of osteogenic sarcoma. And there were several interesting things about that. One is that it turned out that 12 patients weren't all patients with osteogenic sarcoma. But prognosis of those patients wasn't apparently obvious. But there seemed to be some success with it, and there was a lot of toxicity that they didn't really know how to deal with. And so I started doing pharmacokinetic monitoring in patients that we had that were on the treatment. And then when they went into renal failure, they just didn't clear the drug. The drug was hanging around for many days and they were getting this horrible toxicity. So we got into this business of why the renal toxicity and the need for hydration and alkylization, particularly. And so first of all, I have to tell you I blamed you for much of my first year as a Fellow, because we had to draw the blood. So there were no study coordinators. Dr. Frye would just run around at all times of day and night drawing blood on patients for getting high dose methotrexate. And I still mumble under my breath when I hear your name. Well, you don't have to do all of that now, but you know, in those days we were trying to get a more complete profile, so we did. There was a woman there at the Farber that was doing similar work. I can't remember her name. Sue Pittman I think, right? Yeah, Sue Pittman. That's right, that's right, that's right. But that was certainly the introduction to the anti-folate. And then I got into a very interesting area of polyglutamation and how it changed the potency of the drug and led to retention, and it was an important determinant of response. That was quite an interesting area of research. Were you the first to report amplification of DHFR? No, that happened in 1978. I was working on MTX at the time and we had noticed that you could select highly resistant cells in culture. But then we were interested in knowing why, and Joe and Joe Bertino had described the fact that increased dihydrofolate reductase activity was found in this circumstance. But the actual demonstration of amplification in mammalian cells was done by Bob [? Shimke ?] when Joe was on a sabbatical with him. And they had a medical student working in the lab on that on that paper, and that was Dan [? Haber ?] actually. Who came back to-- Who is now the cancer center director [INAUDIBLE], right? Yeah, he wrote a key paper. So we had, at the time when that came out, we got interested in that. And we stuck radiolabeled methotrexate in the culture with some tumor cells and found these odd migrating entities that turned out to be polyglutamate. So that led to the whole issue of what were polyglutamates and how did they change the biochemistry? And that was quite interesting, and then actually at the same time we saw a patient. It was a young man who came to NIH with non-Hodgkin's lymphoma and was treated with high dose methotrexate. I can't remember. I think he had CNS involvement or something like this. We found evidence of gene amplification in this patient. So it was actually the first demonstration that gene amplification occurs in people on the drug. There are a lot of interesting things that were happening at that time. How was translational medicine before it was called translational medicine? That was the nice part of NIH, you know? The emphasis was on the labs working with the clinics, and particularly with physician scientists. So, you know, we were one of the few places where our Fellows were expected to work in labs in their second and third years, and they did, and we had a wonderful group of Fellows that came through. The first guy that worked on polyglutamation of MTX was Rich [? Shilske. ?] Who is now the chief medical officer of ASCO, and many, many other accomplishments after that. Right. But many-- Actually, I'd like to change gears for a minute, because I know you had a lot to do with the development of paclitaxel. And I always found that story interesting that, you know, it was in the bark of the Japanese yew tree, which had to do with ultimate supplies. But also the first phase one trials, which some of that was done at the Dana Farber when I was there. Can you just walk through the history of paclitaxel? I think our listeners would love to hear this. Well, it was an accident of history. Believe me. The thing started in 1964, when a group at the research triangle, a chemist, isolated this compound from the yew tree. And they didn't actually know what it was, but it was cytotoxic. And it was an anti-mitotic, and it took him seven years to figure out the structure. So finally in 1971 a guy named Ronnie from that group published the structure. It was a ridiculously complicated structure, And nobody could synthesize it, at least at that point. It hung around in the lab and nobody was interested in developing it, because it was such an odd molecule. It was insoluble. Nobody can put it in solution. So it really wasn't an attractive pharmaceutical. And the thing that happened was, in 1978 or 1979, we had a very hot drug that was called maitansine. And we were very eager to put this into the clinic. And it was an anti-mitotic also, and very, very potent drug. And so Dr. DeVita asked me to personally shepherd this thing and he told me that he didn't want it to fail. And so I put it into patients and it was terrible. And I kept telling him, this is not going to work. He said, it's got to work. He was pretty persistent. Well, it didn't, and he was very disappointed. So was I. And the fact is, we had nothing else to put in the clinic at that time except for paclitaxel. So we said, oh, well, we'll try it. And we put it in a lipid emulsion. It was like putting it in engine oil or something, but it went into the clinic in several places. Peter [? Wernick ?] did it. Einstein. I guess you guys did it at the Farber. And it was causing all sorts of hypersensitivity responses. It looked impossible. And it took about, I don't know, four or five years to get it into a regimen that was tolerable. And there had been responses. The first response was in melanoma, so we were all excited about that. That was the usual circumstance in those days that, when you took a drug into the clinic, melanoma would be the first response. And no one else from melanoma. Everywhere was-- and so but then Peter began noticing responses in ovarian cancer. And a regimen was worked out with antihistamines so it was reasonably tolerable. And finally in 1991, which was eight years after it went into the clinic, we finally decided, well, it was time to license it to industry. There was no patent, but we did it under a co-operative research and development agreement. And the only company that was interested in the US was Bristol-Myers. Everybody else said, this is ridiculous. Nobody wants this drug. And it was too hard to make it. You had to make it from the bark of plants and it was insoluble and it caused hypersensitivity. So they took it. And about a month afterward there was a report from M.D. Anderson saying that it was active in breast cancer. And at that point it just took off like a rocket. And, you know, tried in all sorts of different diseases. Was active in lung and bladder and-- I can't remember all the other things. Head and neck. Anyway, it became the first billion dollar drug in the cancer drug industry. And I think, you know, there are two things that really set off industry to be interested in cancer. One was that, the fact that you could actually make money on it. And the second was the notion of targeted therapies, which was growing at that time. So to my knowledge, this is the only time somebody at the NCI had to work with the US Forest Service and the Bureau of Land Management regarding a new drug. Can you tell that story? Well, yes. The only place where you get the raw material for the drug was from the US Forest Service. And so Texas plants were being sort of cut and burned because they were considered scrub and not worth anything as lumber. So they were cooperating. And finally when we licensed it, Senator Ron Wyden, who's still in the Senate from Oregon, got interested in this whole thing. He said, why isn't the government making money on this license? Why did you license it to Bristol-Myers and you didn't you didn't ask for anything back? And we said, well, you know, that's not the function of NIH. We didn't have a patent. I guess we could have asked for a slice of the pie, but we didn't because no one else wanted it. We really were trying to give it away. And he was giving us a really hard time at this hearing. And then the key thing that happened was a woman who was a forest ranger with ovarian cancer, we found this woman, and she testified to how much good it did for her. And that sort of stopped all the fuss about the license. And we actually, it was the first drug where as part of the licensing agreement we had the chance to fix the price or agree to the price that Bristol-Myers fixed. And the government never has done that since that time. Of course, this was a circumstance where we sort of owned the information, so they had to listen to it. But they set the price at $2,000 a course. And we consider that pretty high, but it was sort of equivalent to what other drugs were costing at the time, so we let that go by. But ever since then, the price of drugs has just escalated remarkably. I hope there are some young people listening, because this story, in my opinion, the story of trastuzumab again, I think people think that these things just happen because the system makes them. And my experience is they happen because the drug or the treatment gets a hero, gets a champion. Ultimately the science has to prove it works, but I'm sure lots of people wanted to walk from Taxol. You know, everybody thought it was a dog. Because it was, you know, caused hypersensitivity, it wasn't all that active in the initial testing, and it was really hard to make the stuff. Well, the same thing is true with platinum I did my residency at UT Southwestern with Donald Sullivan, who's the chair of medicine. He was a renal guy, and a patient with metastatic-- and I had gone to Indiana. So Dr. [? Einhardt ?] taught me how to give it. So I had a patient come in with widespread testicular cancer, I wanted to give him cisplatin, and Dr. Sullivan wouldn't let me do it because it would hurt his kidneys. I said, Dr. Sullivan, he's going to die if we don't do this. And he said, he'll die anyway. And so I did it behind Dr. Sullivan's back and I got a complete response. Fortunately in those days the residents didn't have a lot of oversight so I could do what I wanted to do. There were a lot of people that thought these drugs should be shut down, and it took the courage that you guys had back at the NCI and other places to push them out. Don Sullivan was very anti cancer chemotherapy for the rest of his life. And it was odd for me, because I actually had a relative who was on his faculty and I went down there a couple times to talk. And I always felt very uncomfortable telling him that we were accomplishing something. Because his concept of success in science was getting an RO1 in your lab. Yeah. He finally came to terms because [? Shelfke, ?] myself, Fred [? Lemaitre, ?] and a number of us went into oncology and had been reasonably successful. And I think he decided that it was worthwhile after all. But it wasn't easy for him. We lost him a year ago. I still miss him. Yeah, he was an amazing guy, but he really did have a hard time believing in cancer. So the other question, I wanted to change gears a little bit, because I know just about the time you became the director of the DCT was when the AIDS epidemic was exploding in the early 1980s. That must have been a very confusing situation about who should be in charge of this at the NIH, which institute, and how you approach it. Can you give us some background on that? Again, it was really a crazy time. Because I remember one of the first patients that was identified as having AIDS was a person admitted to the immunology branch at the NCI. Not the medicine branch or the clinical branches. It was a patient who had disseminated tuberculosis and it had no CD4 cells. And, you know, everybody said, oh my god, what is this? This is really a weird, weird circumstance. And then other people began reporting this from San Francisco and New York. So we actually, DCT, the reason we got involved was because of Bob Gallo. Bob Gallo had discovered the HTLV1 virus, which was causing this lymphoma in T cells. And we suspected that this might be a syndrome caused by a T cell virus. So in 1981, really quite early, we convened I think the first meeting about the biology of what was called HTLV2, I think, at the time, or three. I can't remember which one it was. But at any rate, there were a cadre of people at NIH that felt that it was caused by inhaling gases or, I don't know, their various weird theories about it. But this theory that made sense to us was that it was caused by a virus. So Sam [? Brodeur ?] was collecting samples from patients and brought them over to Gallo's lab. And of course Gallo mixed those samples with the French sample and found virus and then made a test kit for the virus, which was really a key event in beginning to control the epidemic. And because of all that work going on at NCI at the time, we were asked-- we had the only drug development system at NIH. We were asked to, well, look, can you set up a drug development system for this? And Sam [? Brodeur ?] set up assays in infected T cells and showed that certain nucleocyte analogs could stop the virus from replicating. The first one was ADT. And his first study was, I think, was 16 patients with AIDS in which he showed that the T cell counts recovered and people didn't die. And from that point on, we were getting significant funding for doing research on treatment development. And it was it was done in conjunction with NIAID and Tony Fauci. What Tony did is he delegated a fellow to work with us and sort of be the liaison. And the first fellow that did that was Margaret Hamburger, who became [INAUDIBLE] FDA subsequently. And, you know, subsequently, four other people from our division-- well, actually one from NGH, became directors of FDA. Ned Sharpless most recently, and then Steve Hahn, who was a Fellow in the medical oncology group at NCI. Yeah, he's just been named. It was, you know, an unusual breeding ground for people interested in therapeutics. That's interesting. You know, I was a third year resident at UT Southwestern. I was at the VA in March and a young man was admitted to our service. He had been a Vietnam veteran and he had red splotches all over him, so I called a dermatologist who biopsied it. And I got a page from the pathologist and I called him back and he said, you have mislabeled the samples. And I said, what do you mean? He said, well, this says it's a 37-year-old man. This is something I've never seen before, but I looked it up and it's called Kaposi sarcoma, and that only happens in old men or people from Africa. And I said, I don't think we mislabeled things. And I think he was probably the first man in Dallas to be diagnosed with this. Because just as the MWR and the new journal paper came out a few months after that. So again, for the young folks listening to this, and we've already hit this a couple of times, it's one or two patients that pique your interest that often change the world in terms of, gee, I wonder why that happened. Yeah, absolutely. I mean, you know, a lot of this is an outcome of the fact that you have research people as physicians who are working with patients, and then they ask questions. Yeah. One of the things I've carried forward, Dr. Frye used to always say, think like a scientist. Think like a doctor. And ask yourself, so what? And I know you do that, because again, you've already told us today and I've seen you do that in other places. You know, so what? Why did this happen to this patient? Why did that happen, yeah. What in my lab actually will change that? And you guys did that in spades, I think, 40, 50 years ago. It's pretty amazing. Yeah. Well, I [INAUDIBLE]. [INAUDIBLE]. Go ahead. Go ahead. No, it's really happening a lot now, you know, in terms of recognizing subsets of diseases. We used to think that non-small cell lung cancer was just one disease. Now it's 20 diseases. It's amazing, you know? It's amazing, you know, as science progresses, you begin to understand the complexity of cancer. And then therapies become meaningful. Yes, I agree. It's so nice. And so I wish, you know, we were curing people. But we are making a difference, and least we're understanding it a little. I agree. Anyone who has not heard or read Bruce Johnston's ASCO presidential address should do so. Because he did point out exactly what you just said. He had a pie chart, and 10 years ago the entire pie chart was chemotherapy for metastatic non-small cell lung cancer with little or no success. And now the pie chart is well over half the patients getting some kind of targeted or immunotherapy. Yeah, it's pretty amazing. It is quite [INAUDIBLE] for young people that are listening to this, is that there are enormous opportunities for doing even better than we did. So we just made a start in this whole thing. OK. With that inspiring message, which I'm glad you said it, we've run out of time. Actually we come at the end of our time. But Dr. Chabner, I want to thank you on behalf of all of us who trained after you, who've learned so much from what you've done, and more importantly, the patients who have benefited from the stuff that you've contributed to the field. It's pretty remarkable and inspiring. I don't use that word too often, but it is. So thank you, and thank you for taking time today. I hope folks listen to this and say, I'm going to go back and make a difference here. Thank you, Dan. I have enjoyed it. It's been a wonderful time in this career. Yeah. Well, my pleasure. Until next time, thank you for listening to this JCO's Cancer Story, the Art of Oncology Podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories, The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.ASCO.org.

In the poem, Housekeeping, by David Harris, a patient struggles with what it means to be saved. Read by Seema Yasmin. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Welcome to JCO's Cancer Stories, The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org. Housekeeping by David Harris. I've been clearing out my closets so that my husband won't have to afterward. She wiped her eyes on her hospital gown. I imagined her at home, pulling out hangers and holding up clothes to her wasted body, choosing what to save and what to throw away. And by save, I mean leave behind for her husband afterward. Me imagining her imagining him, pulling out hangers, loosely dangling clothes, a Christmas sweater, the jeans he liked, a scarf, a blouse. Him wondering what he is supposed to do with a pink blouse. Should he throw it away or bury it in some unsorted pile, half forgotten, or save it, leaving it hanging in the closet of their bedroom? I am talking to her about CPR now. About what we can save and what we can't. And by save, I mean prolong. And she turns to me and asks what she is supposed to do with the word terminal. Afterward, after latex gloves are peeled off hands, after the bag is found and zipped around her quiet body, after all the things I said or didn't say, this is what we save. Her hospital gown, unbuttoned, washed clean, folded onto itself, with thousands of other gowns. With me today is Dr. David Harris, a palliative care physician at Cleveland Clinic. Dave, welcome to our podcast. Thank you, Lidia. I'm grateful to be here. It's great to have you. You're the author of a poem that we recently published called Housekeeping. Before we start to talk about your poem, tell me a little bit about what you enjoy reading and perhaps what's on your nightstand right now. Sure. I've been reading some nonfiction work on behavioral economics by Predictably Irrational or Thinking Fast and Slow by Daniel Kahneman. But I should also probably talk about poetry that I like reading, since the poem in JCO was published. Two of my favorite poets, and if you read my poem and you want to find more like it, would be Mary Oliver and Marie Howe. And if you're looking for a place to start with those poets, you could look for What The Living Do by Marie Howe or The Fourth Sign of the Zodiac by Mary Oliver. So training does one need to have to read and appreciate poetry? Oh, that's a great question. I think when I was in high school, I kind of got scared away from poetry because it felt like something that I really didn't understand and that you had to have a lot of training to read and appreciate. But I don't think it necessarily has to be that way. I find poetry really nice because it's short, and if you find authors that keep their poetry accessible, you can just read it and spend a moment appreciating it, and go on with your day. So I'd say you don't really need a lot of training other than just being a human being and bringing to the poem the experiences that you've had in your life. I love that. And with that, let's talk a little bit about the poem that you wrote and that I've had an opportunity to read and love it, and that is Housekeeping. There's a line here that drew me right in, and that is the line, a very simple line, me imagining her imagining him. It seemed to me that that's almost the perfect definition of empathy. Is that what you had in mind? The ability to connect and just imagine what it's like to be somebody else, to see the world through the mindset of another person? Yeah. Thank you, Lidia. That's exactly what I was going for. I mean, I think that this poem is mostly in the speaker's imagination. The inspiration for the poetry was the quote at the beginning of the poem, which was told to me by a patient. I'd been cleaning out my closets so that my husband won't have to afterward. And I think we've all had patients tell us something, and after we leave the room, we just pause and say, like, wow, I can't believe that that conversation just happened. And, you know, what a strange, and meaningful, and powerful thing that patient said to me. So that was the inspiration for the poem. And then for the rest of the poem, I was just sort of imagining different scenes or different thoughts that were inspired by that line. So in the poem, you talked about having the difficult conversation with a patient, and you state this in the present tense. I am talking to her about CPR now. And then you bring us also to the world of the very practical task of having this conversation and imagining a time when the patient is no longer present, her death. And then you have this parallel process where you describe all the tasks, the very practical housekeeping tasks, of what happens after death. The sorting of possessions and the dispatching of the body. Tell us a little bit more about how you thought about putting these two things together, and so compactly and beautifully. Oh, thank you, Lidia. Yeah. I think as I was writing the poem, I began to think more and more about those material pieces of our lives, that they're of special significance when we're thinking about end of life. And that came from the patient who was going through her closets and holding out clothes and thinking, you know, am I going to wear this before I die or can I throw this away, and thinking about how much clothing means to people. And then I thought about the hospital gowns and how much of a contrast that is, how impersonal that is compared to what people wear in their day to day lives. That sort of focus on these material possessions and these tasks that can be kind of mundane at times came out as I was writing the poem. And there is this parallel, also, about what we do as physicians when we are looking after patients who are so ill. There are some very practical things, but then there are conversations that have to do with the ultimate abstraction, which is imagining not being here. I think the title grounds us in the same way that some of these tasks, perhaps, ground us in our day to day world. I also thought that it was very interesting that you used the word afterwards twice, including leading with it in the last stanza. And I imagine that, perhaps, as you were thinking of a title, another title could have been Afterward. Yeah. So does that capture some of your process? Yeah. Afterwards was a rough draft title. You guessed it. Because I think that so much of the poem is about thinking of the future or we're thinking about what's going to happen next. I think I chose Housekeeping instead because one of the things that I really am interested in in art and in talking with patients is the importance of daily lives, or the importance of these kind of mundane tasks that we all go through. And how, for people who have cancer and are struggling to maintain quality of life, sometimes doing the laundry or cooking suddenly becomes really meaningful and important to them, or maybe even housekeeping becomes meaningful and important to them. So that title felt like there were more layers to it, which is why I chose it. You know, as I was reading this, and I read that you were imagining your patient imagining her husband's grief and her husband's reaction to her passing, I was imagining what you, as the clinician in this situation, were imagining and feeling. It was very impactful to me. And there's something about how simple the lines are and the language is that really drew me in. Tell me a little bit more about your feeling and what this kind of an encounter with a patient does to you as palliative care physician. Thank you for asking me that, Lidia. You know, this meant a lot to me. And after I left the room after having this conversation with the patient, I was struck by how profound that moment was and how meaningful having those conversations with patients is for me. And part of the purpose of writing this poem and publishing it is to share that experience. I think most of us in oncology and palliative care go into the field because we look for moments like this and we appreciate moments like this. But also, day to day life can kind of make us blind to these things with all the paperwork we have to do and all of the red tape. And when I talk to physicians who are feeling burned out, I notice that they don't really bring up moments like this anymore, and I feel like they're not noticing them the way they used to. So noticing moments like this and appreciating them helps me from being burned out, and I'm hoping that people will read this poem and sort of be able to be resensitized to those moments in their practice. That's a lovely thought. I also would add that one of the themes that we find in the submissions we receive to Art of Oncology is this very sincere desire to honor a patient. And I read that also in your line. Yeah. I mean, this patient has passed away, but they've made such an impact on me, and it feels like I need to do something to remember them. That's part of what made me write this piece as well. Well, thank you for sharing all of that with us. And I hope our readers go back and read your beautiful poem, Housekeeping, over and over. Let me finish by just asking you a little about the process of writing. You-- are you a repetitive writer? Do you have time set aside to write, or do you write when you're inspired or when it calls you? That's a great question. And I feel like people who have previously been on your podcast have said something similar. But for me, I have these moments, and it feels like there's something in me that has to come out. It feels like I already know there's a poem there, and I just have to start writing it. So usually, that's how things begin. If I'm not feeling burned out and I'm in a place where I can notice those feelings, and then I start writing. And then once I've begun writing, I notice different ideas that I want to develop in the piece. These are things that you picked up on, sort of this interest in the mundane, daily tasks of life, or another thing that I wanted to develop in this piece was the idea of saving, and what does it mean to save something. And then, you know, I just kind of keep writing and trying to figure that stuff out until it feels like the poem is done. Well, thank you so much, Dave. I loved Housekeeping, and I hope you keep writing. So this ends our podcast. Please join me again for more of about cancer stories. Until next time, thank you for listening to this JCO's Cancer Stories, The Art of Oncology Podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories, The Art of Oncology Podcast is just one of ASCO's many podcasts. You can find all of the shows at podcast.asco.org.

Dr Hayes interviews Dr. Lawrence Einhorn and patient, John Cleland, on the cure for testicular cancer. Dr. Daniel F. Hayes is the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center. Dr. Hayes' research interests are in the field of experimental therapeutics and cancer biomarkers, especially in breast cancer. He has served as chair of the SWOG Breast Cancer Translational Medicine Committee, and he was an inaugural member and chaired the American Society of Clinical Oncology (ASCO) Tumor Marker Guidelines Committee. Dr. Hayes served on the ASCO Board of Directors, and served a 3 year term as President of ASCO from 2016-2018. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Welcome to JCO's "Cancer Stories, The Art of Oncology," brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the role of cancer care. You can find all of the shows, including this one, at podcast.asco.org. Welcome to the "Cancer Stories." I'm Dr. Daniel Hayes. I'm a medical oncologist and a translational researcher at the University of Michigan Rogel Cancer Center. And I've also been privileged to be the past president of ASCO. I'll be your host for a series of podcast interviews with the founders of our field, have been, and will continue to be over the next several months. In this series of podcasts, I'm hoping to bring the appreciation of the courage and the vision and the really scientific background among the leaders who founded our field of clinical cancer care over the last 70 years. I hope that by understanding the background of how we got to what we now consider normal in oncology. We can all work together towards a better future for our patients and their families during and after cancer treatment. Today, my guests our Dr. Larry Einhorn, who first demonstrated the cure of testicular cancer with cisplatin. And we have a special guest, Mr. John Cleland, who as far as I know was the first man to be cured of this cancer with cisplatin in the world. Dr. Einhorn is currently the Distinguished Professor of Medicine on the faculty of the section of hematology oncology at Indiana University School of Medicine. Mr. Cleland is now retired after a distinguished career as a high school teacher in track and field coach in Indiana. This interview is really particularly poignant for me. I knew John Cleland socially before I had ever heard of Larry Einhorn because our respective wives worked together while I was in med school as I began my clinical training. I then had the enormous privilege of being assigned to the oncology ward at the University Hospital for one of my rotations in internal medicine during my third year of medical school in 1977. And Dr. Einhorn was the attending. And frankly, for me, the rest is history. I had no chance. I had to become an oncologist. Dr. Einhorn received his undergraduate degree at Indiana University, went to medical school at the University of Iowa. He then returned to Indiana for his residency and fellowship. But he spent an oncology fellowship year at MD Anderson, Houston. After that you then returned back to IU in 1973 and has remained there ever since. He has won nearly every award and honor available in clinical research. And I'm not going to try to name them all, but most importantly, like me, as many people in this podcast series, he has served as president of ASCO, in his case, in the year 2000 and 2001. Dr. Einhorn and John, welcome to our program. Thank you. Thank you. Thank you. Dr. Einhorn, I'll start with you. Obviously, your greatest contribution is the cure for testicular cancer, which is pretty good. Can you kind of walk us through the history? How did you get involved with cisplatin? How did you derive the three drug regimen? What were the early obstacles? Especially with your returning back to Indiana. Can you kind of just walk us through that history? Certainly. So as you mentioned, I did a one-year fellowship in oncology at M.D. Anderson before returning to the faculty in 1973 and Indiana University. And in that time period, which was 46 years ago, the thought was that you might be able to cure adult leukemia like was cured with childhood leukemia from the wonderful studies from St. Jude's and that the studies that were ongoing in lymphomas and other hematological malignancies were very promising. But it was felt that you really don't want to do too much toxicity in a solid tumor, where you're getting a one log kill before you get progressive disease. And there was a clear pervasive atmosphere of pessimism of what can be done with solid tumors in general. So when I joined the faculty in 1973, I was the only oncologist. We had two hematologists that were there in our small faculty, which went from 2 to 3. And I wanted to be involved with both liquid tumors as well as solid tumors. But I wanted to be involved with solid tumors that were chemo sensitive. And even back in the early 1970s, testicular cancer was responsive to older drugs like actin or myosin-D and later with a two-drug combination of vinblastine plus bleomycin. And there were a small number of not just remissions but cures, and that was one of the few solid tumors that actually had a modest cure rate back at that time. And then the platinum story came around. And this is a podcast of itself with the wonderful work of a biophysicist at Michigan State, Dr. Barnett Rosenberg, who first discovered that platinum could be the first heavy metal ever to be looked at as antineoplastic agent. And when platinum entered first in human clinical trials in 1972 and 1973, it was [? selfed ?] at an NCI-sponsored phase I working group that I attended that this drug was producing minimal benefit and tremendous toxicity, especially horrendous nausea and vomiting. And the drug was pretty close to being discarded as a interesting novel mechanism of action, but not a drug that really had much of a future. But what changed the history of platinum and changed the history of testis cancer was the fact that among the phase I patients were treated with platinum, which included melanoma, lung cancer, colon cancer, breast cancer, the usual type of patients that enter phase I studies back in those older days were 11 patients that had testicular cancer who had failed actin or myosin D, failed vinblastine, plus bleomycin, and so they received single agent platinum. And when we, even today-- Actually, where were those studies done? That was done at Roswell Park actually, phase I study. And Roswell Park-- and this was an era, by the way, that there were only four NCI cancer centers in the United States, Roswell Park, M.D. Anderson, Memorial Sloan Kettering, and, of course, the NCI. So Roswell Park did a broad-based phase I study. Jim Holland was there at that time. He has unfortunately subsequently passed away. He was one of the real pioneers and also a past ASCO president. So among the patients in that phase I study were 11 patients with testes cancer. And there were three complete remissions and two partial remissions. And even in 2019, if we saw that with the phase 1 novel agent, there would be a tremendous amount of enthusiasm generated. We also looked at some of the preclinical work with platinum. And it is a drug that can cause testicular atrophy. In my youthful ignorance, I didn't realize that there are many drugs that cause testicular atrophy. So with that as a background, in 1974-- and I was on the faculty for one year at that time-- we wrote a protocol to simply add platinum, a novel experimental drug, and added it to the established two-drug regimen that I learned about when I was at M.D. Anderson, namely vinblastine and bleomycin. And the principles of combination chemotherapy aren't complicated. We want each drug to have single agent activity, different mechanism of cytotoxicity, different toxicity, and platinum as a non-mild suppressive drug, which can be given in full dosage, with vinblastine as a mild suppressive drug, and evidence of synergy. And one of the unique characteristics of platinum is it is synergistic across a panoply of cytolytic agents. So we started to study in the late summer of 1974 as a phase II study. And so we treated 47 patients when we first presented this data at the American Urological Association, later at ASCO. And I would be the first to admit that I was as startled as anyone that we were able to literally have a one logarithmic increase in the cure rate, because most progress in oncology is going from a 5% to a 10% to a 15% long-term survival rate. But all of a sudden with this three-drug combination, 60% of these patients were not only complete remission, but durable complete remission and cures. There was a lot of toxicity with platinum. And over the years, we learned, as science tends to learn, when a drug is active to mitigate the side effects as far as nephrotoxicity and nausea and vomiting. And we made modifications to the treatment regimens as the years went by, as you know, with changing the dosages have vinblastine, lowering the duration of maintenance therapy, and eliminating maintenance therapy, reducing the number of courses of platinum, substituting etoposide for vinblastine to where it's now the standard, bleomycin, etoposide, platinum, or BET. And I will make a final comment, in my long career, that this was a very exciting time in 1974. There were several chemotherapy drugs that were experimental drugs, such as doxorubicin and even a nitrosourea the first drugs to have penetration into the blood brain barrier. But the era of chemotherapy is gone and appropriately so. And science and medicine has moved forward. And now, we look at molecular targeted agents and immune checkpoint inhibitors and immunooncology. And that's what is exciting, so much more exciting about the field in 2019 than it was in 1974. But nevertheless, platinum has had legs. In 2019, it is still first line therapy in 12 different types of malignancies. Of course, testis cancer being the poster child for curable cancer. And I often mention that just as platinum has cured thousands, tens of thousands, hundreds of thousands of young men with cancer, testicular cancer saved platinum, because if it weren't for those early studies showing activity of platinum, I think I can say without fear of contradiction that the drug wouldn't be around right now because of this tremendous toxicity in the early phase I studies. Yeah, Larry, let me ask about that, because in the early 1970s when-- I wasn't around, but you didn't have antiemetics. You didn't have drug fractures. You didn't really understand the renal toxicity. Just briefly, how did you get around those? How do you get people-- I'm going to ask John the same question in a minute. What were you thinking, John? John is the recipient of our ignorance in that era. So taking it one item at a time. Platinum is a heavy metal. And we were somewhat slow in realizing that other heavy metals, like mercury, can cause acute tubular necrosis. And so when patients were getting platinum, as is true in those days, they would often just get IV pushed platinum. And so we learned that in order to prevent acute tubular necrosis, we needed to make sure that patients were well hydrated with IV saline solution before they start chemotherapy. We then give the intravenous platinum and then follow that with intravenous saline hydration, so that the drug doesn't accumulate in the proximal tubules, and we force a diuresis. And we never needed mannitol. And some people back then, in fact, perhaps even now, are doing the silly thing of mannitol diuresis, which is totally unnecessary. And so back in the early days before we had antiemetics, everyone had to be treated as an inpatient because we had to give 24-hour continuous hydration because of the [INAUDIBLE] from severe nausea, vomiting, and dehydration that would happen. Of course, today, it's all done as an outpatient with three or four hours of hydration. As far as nausea and vomiting is concerned, one of our first studies we published in The New Journal of Medicine was a cannabinoid derivative from Eli Lilly, called nabilone. And so nabilone, didn't produce a marijuana-type of high. It didn't cause euphoria. It caused some dysphoria and had a variety of side effects. But it lowered the incidence of nausea and vomiting. But what revolutionized chemotherapy induced nausea and vomiting, and ASCO recognizes this as one of the five leading advances in the past 50 years, was the discovery of the first 5-HT3 receptor antagonists. And this was a rational, selective pharmaceutical development. And this truly changed the face of how we give chemotherapy with drugs like platinum. Instead of having an average of 10 to 12 emetic episodes on day 1 of platinum, today with appropriate anti-emetics, the median number of emetic episodes is zero. People still get nausea. People still get occasional vomiting. But everything is done as an outpatient now. And it's done as an outpatient because of the discovery by others of what is the mechanism with platinum, which is not a gastrointestinal mechanism, but affects the emetic center in the medulla oblongata and the chemo receptor trigger zone and finding that patients get drugs like platinum, they get high level of 5-HT3. And developing a selective 5-HT3 receptor antagonist change the field completely. And, of course, now we also [? weigh ?] a methasone and neurokinin-1 antagonist, aprepitant or fosaprepitant. And we also have olanzapine as far as the nausea issue. And olanzapine is probably the best drug for nausea. So patients today have no concept of what patients like John went through when we had no knowledge about any of this whatsoever. And we were looking at things kind of naively by 2019 standards. I don't think I'm making this up. I recall as a medical student walking down the inpatient at University Hospital and thinking this smells just like my fraternity house. Without the fun involved. Yeah. And I got a kick now out of the so-called medical marijuana. But didn't you talk the administration into looking the other way for a while so that these guys could do that? Sort of. What had happened with nabilone, it had to be under lock and key, as if it were gold at Fort Knox. When we had an audit by the FDA and we had-- I don't know how many, I think 60 or 70 patients on nabilone, you know, we had to make sure we had every consent form and every safety guarded and everything. You know, here, we're using these incredibly toxic chemotherapy drugs and there was no regulation at all. And here we're using a pill to lessen nausea and vomiting, and it was just the hoops you had jump through were tremendous. When did you start realizing you had something big. Was it, you know, after two, three patients, or later-- Well, again, when you're young and dumb, it's easy, because you treat someone like John and you get the first chest X-ray three weeks later and things are gone and with pulmonary metastases. And you naively think, not only this cool, but, gee, that's great, it's not going to come back again. But we know even 40 years later that most epithelial malignancies that we get nice remissions with, the disease does come back again. So we had initial enthusiasm that platinum vinblastine myosin was a very active, but very toxic regimen. And we had the hope that this might be durable remission. And, Dan, I actually first presented data with testes scores, not at ASCO, but with the Annual American Urological Association meeting, and that was 99% urologists there. And so we had 20 patients that we had treated. And then that following year, I submitted an abstract to ASCO. And back then, it wasn't done online. We would send a paper abstract with a self-addressed postcard that they would send back to us whether it was accepted or not. And so when I sent in the abstract, I get the postcard back saying it was accepted as a plenary session paper. And I had no idea what plenary session even meant. It's true. And we get this postcard back in January for this June meeting. And all of a sudden my naivete went away, and I thought what, if I make a fool of myself? And I had this initial abstract with these complete remissions, and by the time June rolls around every one of them would have relapsed, which I was starting to learn happens in other tumors like small cell lung cancer, that are chemo sensitive disease. But fortunately, the time of presentation everyone was still disease free. And, of course, everyone for the most part remain disease free. So we had the first glimpse of activity with the first few patients. But it really wasn't until patients were out at a year that we really had the realization that these were not temporary remissions, but these were durable. And as it turned out, permanent remissions and cures. I wasn't there, but I understand that after you recorded that it looked like you had change the ratio of [? puranoctur ?] from 10%, 90% to 90%, 10%, that people in the audience, you had a standing ovation at the end of your presentation. Yeah, it was very heartwarming. It's literally the walk on the moon type of things is the things that you do once in your career, you know, that you never forget about. I had the opportunity to do that and not one of those four NCI cancer centers, but little Indiana University with our faculty of three. And we had one oncology nurse at that time, Becky Furness. We had no data managers. We had no compliance office or anything else. And we were giving [INAUDIBLE] back in the 1970s. I'd like now to turn briefly to your relationship with John Cleland. John, can you give us a brief history of your cancer treatment before you and Dr. Einhorn decided to go with the cisplatin. I was a student Purdue University, the fall of 1973, when I discovered I had a lump on the my left testicle. And I went to a local urologist. And he examined me on a Tuesday afternoon, in the middle of November, and told me he wanted me at the hospital the following morning. And the following day after that, they performed surgery. And I was diagnosed with testicular cancer. That was November 15, 1973. On the 29th of November then, I had a retroperitoneal node dissection. That was at the UI Cancer Center by Dr. John Donohue. And then on December 3, 1973, on a Monday morning, Larry Einhorn walked into my hospital room. And that was my first introduction to Dr. Einhorn. He talked to me a little bit and said we were going to put me on a 5-day course of a drug called mithramycin. We took mithramycin for five days. And then a couple of days after that, I was released from the hospital. So that was in the 1st of December of 1973. The middle of February of '74, I returned to IU Med Center just for a routine checkup. And I was diagnosed there again with testicular cancer had returned. And Dr. Einhorn began putting me on a three-drug regimen-- adriamycin, bleomycin, and [INAUDIBLE]. And I was on that until about July of '74. Then I was on actin myosin-D for a couple of months. And then we ultimately started in on the cisplatin in early October of '74. You have to tell us the story that you actually had to tell Dr. Einhorn about cisplatin because of a radio show you listened to. Well, by the middle of the summer, I had been pretty beat up, after all the chemotherapy and the nausea and everything. And I didn't really have a job-- or I couldn't do a job or anything. So most of the time, I just lay on the couch in our apartment and listened to the radio or watch TV. And one day-- I really like Paul Harvey-- and he came on the radio every day at noon there in Lafayette, Indiana. And one day he begins talking about researchers at Michigan State University. have maybe come up with the cure for cancer. So I begin listening much closer. And they talked about this chemotherapy called cisplatin. So I just made a mental note to myself, well, the next time I go see Dr. Einhorn, I'm going to ask him about this. Well, a couple of weeks later, I'm down at IU. And he's palpating me and listening to my chest and all this type of thing, you know. And I began asking him about that. And he said, John, just don't get too excited about that. We've heard of these cancer cures before. Probably nothing important has happened here. Don't worry about it, you know. And then two or three months later, I'm taking it. So that was my introduction, Dan, to cisplatin. Well, I can't to you-- Some of those Purdue graduates are pretty smart every now and then. We get lucky, like a blind squirrel. I just say, I can't tell you how many-- probably 100, 200 patients will told me things like this. And I've said exactly what Dr. Einhorn said to them, yeah, yeah, yeah. I wonder how many cures I've missed. OK, and the second story I want you tell us, John, is about your readmission to the hospital after your first cycle of chemotherapy. Yeah, I started this platinum October 7, 1974. I had five doses in the hospital. And then I was released. That was on October 7. October 20 rolls around, which was a Sunday, and I was violently ill. I had a fever of over 104, almost 104 and 1/2. And I was just completely almost derelict. My wife and a couple of friends, we contact Becky first, us my oncology nurse. And I guess she called Dr. Einhorn. And he said, well, come on down and check in through the emergency room at IU. And so that's what we did. We got there late at night, 9:30, 10:00 at night, something like that. And they always-- if I went to the emergency room, they always took a chest X-ray, which they did. And then in the hospital overnight and middle of the next morning, I see Dr. Einhorn and Becky getting off the elevator. My room was kind of in a corner. I could see part of the lobby out there and the elevator and the nurses station. And I could see them kind of go past the nurses station. And I could just tell that something was up. Somebody had good, let's put it that way, just by their body language, and the way they looked at each other and talked and walked. And they kept coming closer and closer and closer to my room. And finally, they walked in. And Dr. Einhorn says, John, your chest X-rays are clear. That's really good news. And, you know, I kind of interpreted that as, hey, I'm cure, you know. And ultimately, I guess I was, because from that chest X-ray the night before, my chest film was-- the weak before, my chest film was just riddled like Swiss cheese. And then the film was totally clear. You probably don't know this, but I've seen your chest x-rays, which is probably illegal now. Probably did a lot of illegal things back then. And, you know, that's when the scales fell from my eyes and I said, I'm going to be an oncologist. This is unbelievable. But, you know, I think to emphasize, it wasn't clear you were going to survive that weekend. To survive, you would be cured. But that goes back to how toxic this drug was at the start. Right. Right. It was not a lot of fun. I know that. Yeah. Well, I want to get back, Larry, to you for a moment, because there were two people in your life who were really essential to this story. One, of course, was Dr. Donohue, with whom you have published the, I think, seminal and classic paper in the annals of internal medicine. You want to say a few words about John. And the other is I'd love you to talk a little bit about Steve Williams. Steve was a fellow when I was a med student that I used to tease-- I mean, he's the only guy I ever knew who went from being a fellow to cancer center director I think in one year. I'm making that but-- he kept saying, you know, I might as well put me on faculty because he doesn't have any other fellows. Sure. So when I joined the faculty in 1973, in July of 1973, as I mentioned, I was the first oncologists. There were two hematologists there. And John Donohue is a true gentleman, one of the world leaders in urological oncology and the urological transplant with kidney transplant and many other fields. His ability to surgically cure patients with extensive retroperitoneal disease was known worldwide. And because of who John was and the fact that there were very few oncologists in the state of Indiana treating solid tumors, when he would see patients who would relapse after a retroperitoneal lymph node dissection, he would give chemotherapy himself, usually with actin myosin-D, which, by the way, causes almost as much nausea and vomiting as platinum did. And when I first got there, I knew John by reputation, but not by his interpersonal relationships with others. And with some fear and trepidation, I walked into his office because I told him I wanted to start looking at clinical trials in testes cancer. And I thought we might have a turf battle because he was treating patients with chemotherapy himself. And he just welcomed me with open arms. And he was so enthusiastic about finally having a partner and someone to collaborate with. And we had a wonderful, 30-plus years of collaboration with many important discoveries that John made equally, as I did. And, unfortunately, after John retired, he subsequently died when he was in Florida. And it's a similar sad story with Steve Williams. So Steve Williams was in my third fellowship class, which means we had one fellow a year. He was great, very humble, from Bedford, Indiana. And father was a newspaper reporter from the small town newspaper. And Steve was the eternal optimist. And to show you what an eternal optimist he was, when the Indianapolis Colts would those 14 games in a row, he always knew they going to win the next game, you know. And that's Steve. And John Cleland talking about Paul Harvey, Steve would have believed that platinum was going to be the cure too, you know. He was just a very positive person. And Steve was very gifted. He has a great relationship with patients. And there's not a person, a doctor, nurse, or patient, who has ever said anything unkind about Steve. He's one of the kindest people that we ever had the privilege of knowing. And Steve was very much involved with our testicular cancer research studies and many other pivotal studies as well. We decided to be a NCI cancer center, which is an enormous amount of work. And by then, we had about 10 faculty members in hematology, oncology. And no one wanted to do it. And so we went up to poor Steve and said, boy, Steve, this would be a great career move for you-- without telling him how much work is involved. We are cancer center today because Steve Williams made us a cancer center and everything that goes along with that. And before leaving, and fortunately, we're talking about John being cured with fourth line therapy with platinum combination chemotherapy, whereas if John had had that disease diagnosed a year earlier, quite honestly, John, you wouldn't be alive right now. And it's sort of the opposite for Steve Williams. He eventually developed metastatic melanoma before any of the marvels with immunotherapy or even the BRAF inhibitors were around. And he eventually died from these diseases that he fought so hard to palliate and prolong survival and cure with metastatic melanoma. And now there's a 30% cure rate-- 30%, 5-year survival and continuous 5-year survival with single agent PD-L1 inhibitors. And I want to make a final comment about John. And if this were 2019, rather than 1974, and you're looking at a patient who has been through mitramycin, which is used by me as adjuvant therapy briefly for adenocarcinoma, which is what John had, and then going through actin myosin-D and all the toxicity with that drug and then gone through a adriamycin combination chemotherapy, and looking at fourth line therapy. So when we started platinum combination chemotherapy, and John his fourth line therapy, yes, his chest X-ray looked like Swiss cheese, as he mentioned, but he was pretty much asymptomatic. And the courage and fortitude that it takes to go through treatment like this, because we knew what the side effects were with platinum. It had been around for about eight months, and we knew about all the horrendous side effects of the drug. We had no idea whether this would produce as fourth line therapy any prolongation of survival or any meaningful quality of life. And to go through this therapy without any idea whether it's going to help you, but to do it with truly altruistic motives and knowing that maybe this will help other patients in the future is really noble and admirable. And this is why John over the decades has been such a role model for clinical trials and for the cancer patient population. And I want to follow up. John, briefly, tell us about your history since then-- your family, your athletics, your career. I think it's inspirational, frankly. Well, I worked for the animal science industry for five years following my cure. And I decided finally I needed to give something back a little more to society than what I was actually doing. So I knew I wasn't smart enough to be a medical doctor. Male nursing wasn't exactly in vogue at that time, which might have been honestly a pretty good job for me. So I thought, well, I could be a teacher. I can teach life sciences. So background is pretty much life sciences in agriculture. So I did. I turned to teaching and teaching biology for 31 years and did a lot of coaching of track and cross country. And my wife and I have three kids. I married my college sweetheart even before I had testicular cancer. And, you know, I owe her just about everything in life. She hung in there with me when times were really dark. And I say we got three kids. And I've had great job and great career and friends. I want to emphasize you've had three children since your treatment. I also want to emphasize I know you've run one or two marathons since your treatment. Actually, Dan, I ran four marathons. So you ran four marathons since your treatment. Four full marathons, yes, sir. And I believe that your baseline creatinine is something like twice normal. And, Larry, you probably know this better than I do. But, again you've been inspirational to all of us. Well, thank you. Thank you, Dan. I'll tell you this. Every day I live is a blessing. I should have probably died 44, 45 years ago. I could drop dead at the end of this telephone conversation and have no regrets in life whatsoever. Well, John, you keep thinking that maybe one day you'll live long enough to see Purdue win the NCAA, but I wouldn't count on it. I was going to make a point, it must pain him truly to thank two guys from Indiana and also be appreciative of Michigan State, you know, for a guy from Purdue that must really be painful. Well, yeah, you know, testicular cure is basically Big 10 centered with Michigan State coming up with this cisplatin and Dr. Einhorn being on the IU you faculty. But it took a Purdue Boilermaker to be tough enough to handle all that to begin with, you know. That's true. OK, we're running out of time. I need to bring this to an end. I want to thank both of you again, both of you're inspirational, John for all the things we've talked about and Dr. Einhorn for so many of us who've gone into the field that we've trained and even the ones we've never touched directly, you touched hundreds of thousands of oncologists around the world indirectly. So thanks for all your contributions and what you've done. And thank you both for being on this podcast. I hope it opens up more inspiration for other young investigators and other young oncologists who don't really realize how we got where we are. So with that, we'll end this. And thanks a lot. And hope you have a nice weekend. OK, thanks, everyone. Have a good rest of the week. Bye, bye. Until next time, thank you for listening to this JCO's "Cancer Stories, The Art of Oncology" podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's "Cancer Stories, The Art of Oncology" podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.asco.org

In Chopin's Rubato in Cancer Care, by Rajiv Agarwal, an oncologist finds appreciation on how music can inspire his care for patients with cancer. Read by JoBeth Williams. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Welcome to JCO's Cancer Stories, The Art of Oncology, brought to you by the ASCO podcast network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org. Chopin's Rubato in Cancer Care. Years ago, my art was different. I mastered how to read and interpret the language of music. I spent over two decades learning from mentors, Bach, Mozart, Haydn, Chopin, Beethoven, Brahms, and Rachmaninoff. I adapted to each of their styles, forcing my fingers to move in unfamiliar ways until muscle memory took over, changing the pressure by which I applied my fingers to piano keys to produce different textures of sound. Now, as a oncologist and palliative care specialist, I have come to appreciate how my musical background has inspired how I care for patients with cancer. The notes, the rhythm, the beat, the freezing, the harmonies, the softness and loudness, the intentional silence, and the underlying musical theory and history that grounds it all. These are analogous to the scientific principles I practice and uphold in medicine today. But as in music, the art and the artistry of medicine are found in the performance. Below is my sonata. Exposition. I was approximately seven years old when I first met Frederic Chopin. From the start, I understood Chopin's science. I listened to him, I heard what he said with his notes, and heard why he chose to say it in that manner. Chopin tested me and I responded. Not always with perfection, but always with sincerity, emotion, and resolve. Even so, I never really understood his art. I saw his notes on the page and relayed synaptic signals to my fingers to produce the corresponding sounds with accuracy and precision, but this was not enough. As I was playing one of Chopin's nocturnes, which I practiced for months, my piano teacher stood up in the middle of her living room and raised her hand signaling me to stop. What could I have done differently? I had perfected those notes, perfected his rhythm. I thought I had reproduced his results. She sat down on the piano bench in my place. She did not play, she performed. She started similarly to establish the foundation of the song, and then she did something different. Her right hand was not completely in sync with her left. She deliberately played faster then intentionally slowed down. She stole time from certain notes and added the time back in others, temporarily changing the structure and timing of musical phrases without losing its integrity. She shaped a new interpretation that was uniquely hers, nuanced and free but without completely abandoning Chopin's scientific arrangement. In essence, she deviated with reason. This experiment spanned a total of a few seconds, and the result was beautiful. My rendition was mechanical. Hers was expressing and living. She explained to me that this was Rubato. In that moment, I discovered that art, or at least my interpretation of it, was an expression of individuality and a result of innovating within a theoretical framework. With Rubato, the musician discovers rhythmic subtleties to produce a novel and meaningful interpretation of a melodic phrase. And perhaps most importantly, the musician cannot be radical, lavish, or wander too far. He or she has always pulled back with an understood force to the fundamentals of musical theory and the notated language. To distort or deviate too much would be destructive. A musician must always remember and respect the scientific background upon which art is produced. Development. More recently, I have realized that Rubato exists within the practice and performance of medicine. As I learn medical science and the historical evidence that guides decision making, I marveled at how seasoned physicians knew when and the degree to which to adjust and innovate in clinical practice. For me, this became most evident in my observations and experience while caring for patients with cancer. I completed my training in both oncology and palliative medicine with Chopin's music playing in the background. The interplay between the scientific knowledge and artistic freedom in oncology is fascinating and is perhaps that which brings verve to the care that we provide. We practice clinical oncology with rigor and technique, using an algorithmic logic that is rooted in a growing field of scientific evidence. These are the notes on the page. As oncologists, we understand why we recommend standard treatment regimens because this is the science that we honor and apply. In addition, we contribute to our science and advance our discipline through research. We test and combine pharmacological instruments to compose new and sophisticated regimens with the goal of improving the lives and outcomes for our patients, potentially reaching a larger audience. Yet, not every clinical presentation or situation is the same. At times, we are asked to improvise and think beyond the written notes and beyond our comfort zone, acknowledging that our understanding of what to do is limited to an extent. We often extrapolate with nuance and stretch what is known to fulfill the unique needs of each patient. And above all, in our assessment and treatment planning, we incorporate who the patient is as a person. In doing so, we fine tune our approach and add artistic style. The final product is a performance of evidence-based notes that is deeply personal and powerful and one that cannot be simply replicated. It is in the performance that we apply our clinical judgment. We personalize cancer care, and ultimately, we build a meaningful relationship with each of our patients. I witnessed my mentors in oncology practice their art with ease. They use their experience to manage patients both within and outside of guidelines, using individualized rationale and intention. They made modifications to treatment on the basis of a patient's comorbidities, preferences, and life outside of cancer. They were experts in knowing when not to take treatment breaks, when and when not to consider local regional approaches. When and when not to advocate for investigational agents, and when and when not to expand beyond the available data, all done to carefully tailor treatment and provide individualized care. They acknowledged their variations in management and never lost sight of the theory that grounded all aspects of their clinical decisions. Drugs were not offered if there was neither a molecular nor clinical rationale to do so. They made decisions with controlled instinct, yet never broke the fundamental pillars of our science. They performed. In palliative medicine, the conversation is the song. As palliative care specialists, we rehearse communication techniques to create a therapeutic alliance and partner with patients facing serious illnesses. We are taught how to structure a conversation and are often reminded why language and discourse matter. We use mnemonics, validated questions, and logical transitions to effectively communicate in the clinical encounter. We cover a range of topics from addressing symptoms to eliciting the values, goals, and preferences of patients and their loved ones. We value the science and mechanics of our song. But what continues to amaze me is when adjustments have to be made in this process in spite of the guiding principles that have been so well studied. A subtle change in communication occurs, and in just seconds, the clinical encounter can be transformed. I listen to how my mentors in palliative care performed their art. They shifted and directed the conversation to match the needs of the patient, and the flow of conversations unfolding to create new meaning and understanding for both parties involved. I observed how some patients preferred not to discuss their code status or divulge what mattered most to them on their first visit with a palliative care specialist. When this happened, my mentors paused. They remained fully present. They avoided rushing into the next notes when the timing was not right. This was the artistic rest needed in the music to give our patients time to reflect on what was previously said and played. It became clear to me as we learned difficult conversations that I had to expect and encourage variation within the structure of the clinical encounter. Conversations could not be robotic or purely technical. I found art in the performance of palliative care when we led conversations freely and did so out of instinct, while always remembering the core principles of empathic communication. I discovered that the science of palliative care and communication was not neglected if questions remained unanswered and that intentional silence during family meetings often created a powerful space that could unite everyone, patients, family members, nurses, oncologist, and palliative care specialists. My palliative care mentors taught me to be meticulous, yet flexible. We stole time from certain topics only to invest time in others, tailoring discussions to meet the individual needs of each patient. Through our artistry, we listened and our patients felt heard. Recapitulation. The musical already mastered years ago has informed the art of oncology and palliative medicine that I perform today. Chopin's Rubato has changed how I listen, how I make medical decisions, and how I converse. It has helped me understand that the art of caring for a patient with cancer hinges on the regard for the science of oncology and palliative medicine, while also recognizing the value of innovation and making subtle adjustments when needed. Finding freedom within the structure of oncology and palliative medicine can be beautiful and rewarding. Displaying too much freedom, however, can be dangerous and unsettling. Like a musician, a physician must always remember and respect the scientific background upon which art is produced. Both in music and in medicine, Rubato comes with practice and experience. I am and always will be refining my art. Today, when I sit on my piano bench after a day in the clinic treating patients with cancers, I thank all of my musical and medical mentors for sharing with me their expertise and inviting me to their performances, and most of all, I thank Chopin. [MUSIC PLAYING] Welcome to Cancer Stories, The Art of Oncology Podcast. I'm Lidia Schapira, your host of its program, and with me today is Dr. Rajiv Agarwal. He's an assistant professor of medicine in the division of Hematology and Oncology at Vanderilt-Ingram Cancer Center. Welcome, Rajiv. Thank you so much for having me. It is a pleasure. Rajiv is the author of "Chopin's Rubato in Cancer Care", an essay that was just published in Art of Oncology and JCO. Tell us a little bit about your career as a physician, musician, and how this art of performance informs your practice? Sure. I was introduced to music really early on and really it became my first love playing when I was three, and my piano teachers really pushed me in a way that, I think, really informed how I practice medicine now. Over the course of medical training, I've had less opportunities to perform in public spaces, but I've been able to transition some of the skills that were in the music to my performance as a physician, and I think that's really what this piece is about is how to find meaning and reflection and nuance in the art of oncology and medicine as a whole. And one of the aspects of the piece that sounds so interesting I'm sure will resonate with readers is that you talk about communication as the tool for palliative care physicians and perhaps even oncologists, and you talk about the delivery as a performance. Tell us a little bit about how you think about the delivery, the communication, as performance. Yeah, that's a fantastic question. So I trained in both oncology and in palliative medicine, and in my palliative medicine training, I really witnessed and heard, which I think is the key point of my training is I heard experts in the field communicate. And I think when you approach a conversation with a patient or with any person, you are aware of what you want to say, but you also reflect and adapt the conversation based off of what is heard, and I found in my experience listening to people have these conversations, which are very sensitive and pertinent conversations that it didn't always follow a formula. There was a structure to the conversation. We could address symptoms physical symptoms, emotional symptoms, it then could segway into discussing illness understanding, and then it could segway into discussing goals and preferences and values, but it didn't always have to follow in that exact structure. Sometimes the conversations would adapt, and that's the part that I found to be the most artistic, and frankly, the most musical. Tell me a little bit more about some listening aspect of these conversations. In just a few minutes we've spoken together, you've used the word heard and listened. How does your training as a musician perhaps inform your ability to listen to patients? So I think what Rubato really embodies as a musician, and it's how do you listen in between the notes? You can move from one note to the next, which is written on a page of a musical score. But it's almost the instant pause or the instant rest in between notes. How do you move from one note to the next, and when you fully listen to that change in a musical piece, I think that's where you can find a lot of meaning. And similarly, in a conversation what I found to be the most important is how do people use words and then connect those words and have a pause, or where do they pause in their conversation? I think you can gain a lot from, not only what is said, but how it is said. And that, I think, as a palliative care physician, has really helped me with my musical background, because if a patient may say something, they may say it in a different tone or they may have different pauses between the words they're using and their language, and that can directly impact how I would respond or whether it's needed to continue that direction of the conversation and do we need to make a shift. That I think it's a skill set that has really been, in a way, impacted by my musical background. I found this so fascinating, and boy, your patients are lucky to have you. Rubato really means the stolen, so what your piece is about and your reflections are about is the reminder that sometimes we need to borrow a little time or speed it up or slow it down, and you need to have a mastery over the music and we feel it in order to know when to do these things, and this is what you tell us you've learned from your role models. Can you tell our listeners a little bit more about this idea of the rhythm of conversations and the flow of a dialogue between physician and patient? The way I think about Rubato is, on a musical piece, you can look at the musical notes, and if one were to just play those notes as written with the exact time and exact rhythm of those notes and rests, it would be almost too perfunctory, too mechanical. And so what Rubato does is allow the performer to look at those notes, and the key point is that you can't sway away too far because it destroys the integrity of the key, but you're able to really interpret those notes in a meaningful way. And I think in a conversation between patients and physician, it's almost the exact same thing. You can walk into a clinic or walk into a hospital room and have a conversation with the patient, and we know what we need to discuss that physicians. Sometimes the topics can be can vary from addressing symptoms to very serious conversations about where people are, what their values are, and how they're processing their illness in the context of their lives. And when you're able to kind of listen to the rhythm of the conversation, and if that means taking a pause, allowing there to be a breath space in the conversation where you normally would not have done so and just allowing patients to speak, that really I think can guide a conversation in a more meaningful manner. Another way to think about it is even if we do all of that, sometimes conversations don't happen the way that we intend for them to happen. And I've found that it's best to kind of reflect on those conversations and think why was that the case. Sometimes it's not the context of what is being-- content of what is being said, but it's more of whether patients feel as though they are being heard, and I think hearing patients in that rhythmic manner can really have a profound impact. That's beautifully stated. And music is so much about feelings, although you're remind us that there's also a science to it and a structure to it and an order that needs to be respected in order for it to be beautiful and to be played as it was written and intended by the composer. Tell me a little bit more about how you practice and how you teach your fellows now some of some of these incredibly wise things that you've just shared with me. I think one thing that I tried to really uphold in my practice is to always remember the science, because I think the evidence is really what guides us in our field. And so we have to honor and respect that, and that means not doing something too outside of the box. You have to be able to understand where the evidence lies and the treatments of certain cancers, where the evidence lies in the ability to have a conversation or how to impact advanced care planning. I think that is really key because it lays the foundation, but what goes beyond that step, then is where to add the nuance. How do you add your individual flair to practicing medicine without really swinging too far away from the theory and the science that we have to uphold. Sometimes, it is important to really just stick by the science, and that should always be the very first step, but we have more cases than not, where we have to think outside of the box. And in doing that process, I felt that transitioning or seeing medicine through the lens of Rubato has allowed me to understand the limits of swaying away from science and swaying away from the fear and evidence that we have, because one cannot truly try to create something novel without evidence. That's not what a musical piece is intended to do, which is to have notes on a page and then for you to improvise completely. There's still a force that's pulling us back towards the evidence and science, and so that's really what I always try to teach fellows, residents, med students, and even myself constantly is that we have to always remember what are the notes on the page. That's, again, beautifully stated, and music provides so many metaphors for medicine, doesn't it? Do you ever talk with your patients about music? Have you bonded with a particular patient to also share a love of music and performance? I've had a few patients. When I talk with patients, I always ask, what matters to you in life and what are some of your hobbies and what are some of your goals, and usually, when I ask, then I'm able to get to know patients of people, and some of the patients have told me in the past that they were pianist themselves or they have a deep love for classical music, and in that, we're able to share stories, and I think that's very human is to be able to bond with someone, irrespective of their illness or where they are in life through a sharing of a story or a connection. And so in those conversations with the few patients that do have that same reflection of music, it's nice. It's comforting, I think, both for the patient and for myself to be able to share that human bond in a way. Sure. There have been so many programs around the country that try to bring physicians to the arts. Literary arts, visual arts, and certainly music. Have you participated in any or do you have any preferred programs that you've been exposed to? Yeah, so when I was in college, actually, I used to volunteer for an organization called Musicians on Call, and it allowed musicians to locally, nationally, to perform for hospitals and other clinic settings, and so that was something that was very unique for me at the time. And throughout medical training, I've adapted and I've performed a few places for patients where I can. At Vanderbilt, I do know that there is a group of physicians and nurses and health professionals that get together, and I am-- after writing this piece, actually, I was invited because I'm still relatively new to Vanderbilt at this moment, and I was invited to be part of this group, so I'm looking forward to more opportunities at my institution. Well, Rajiv, thank you for a lovely conversation and for sending your work to JCO. A beautiful reflection of the art of performance, the art of oncology and all of the enormous gifts that music can bring to our lives and to our work in the service of patients. So thank you very much, and I hope you send us another essay sometime. Thank you so much, Dr. Schapira. It was an honor to be able to have this conversation with you today. Great. So I look forward to sharing more conversations with you about the art of oncology. Until next time. Thank you for listening to this JCO's Cancer Stories, The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you are there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories, The Art of Oncology podcast is just one of ASCOs many podcasts. You can find all of the shows at podcast.asco.org.

Dr. Hayes interviews Dr. Trevor Powles his involvement with translational medicine in the UK and early bisphosphonate. Dr. Daniel F. Hayes is the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center. Dr. Hayes' research interests are in the field of experimental therapeutics and cancer biomarkers, especially in breast cancer. He has served as chair of the SWOG Breast Cancer Translational Medicine Committee, and he was an inaugural member and chaired the American Society of Clinical Oncology (ASCO) Tumor Marker Guidelines Committee. Dr. Hayes served on the ASCO Board of Directors, and served a 3 year term as President of ASCO from 2016-2018. Conflict of Interest: Dr. Powles has not reported any conflicts of interest to ASCO. TRANSCRIPT The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Welcome to JCO's Cancer Stories-- The Art of Oncology brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the role of cancer care. You can find all the shows, including this one, at podcast.asco.org. Welcome to Cancer Stories. I'm Dr. Daniel Hayes. I'm a medical oncologist, and I'm a translational researcher at the University of Michigan Rogel Cancer Center in Ann Arbor. And I'm also the past president of the American Society of Clinical Oncology. Today I am privileged to be your host for a series of podcast interviews with the founders of our field-- today in particular Dr. Trevor Powles. Over the last 40 years, I've been fortunate to have been trained, mentored, and inspired by many of these pioneers. It's my hope that through these conversations all of us can be equally inspired by gaining an appreciation of the courage, the vision, and frankly the scientific understanding that these men and women who established the field of clinical cancer care over the last seven decades. By understanding how we got to the present and what we now consider, quote, "normal," end of quote. I hate using quotes, but in oncology I think we can also imagine our work together towards a better future for our patients and their families during and after cancer treatment. As I've noted today, I'm really honored to have as my guest on this podcast Professor Trevor Powles. He's really generally considered one of the true pioneers in breast oncology. Dr. Powles was raised in London, where he went to medical school. He trained in medicine and surgery at St. Bartholomew's Hospital and associated affiliates, graduating from medical school in 1964. He went on to obtain a PhD at the Institute of Cancer Research. He directed his thesis towards hypoglycemia and bone metastasis. Following his PhD, he then completed specialist training in medical oncology at the Royal Marsden and further pursued training in endocrinology with Professor Philip Bundy, [? who was ?] then Chief of endocrinology at Yale before moving to the UK. Dr. Powles remained at the Royal Marsden hospital during the bulk of his distinguished medical career, first as head of the Marsden breast cancer unit, and ultimately is the founding chairman of the Committee for Clinical Research for the entire Royal Marsden. After he retired-- which again requires [INAUDIBLE]-- at the age of 65, Doctor Powles has served on staff at the Cancer Center at London Parkside. Dr. Powles has authored hundreds of peer reviewed papers. He's mentor of many of the leaders in breast college around the world, which we will discuss in a second. And he's really won too many awards and honors from me to list here, but they include the coveted William McGuire Award presented annually at the San Antonio Breast Cancer Symposium-- and by the way, so have two of his mentees, Professors Mitch Dowsett and Ian Smith. And he's also won the Nancy Brinker Award. Many of you know Miss Brinker founded the Komen for the Cure Foundation. And perhaps what is perplexing to those of us in the colonies, in 2002 he and his twin brother Ray were named Commanders of the Most Excellent Order of the British Empire, or CBE for short-- which of course is one of the highest honors one can obtain in the UK-- for their work in breast in Trevor's case, and haematologic cancers in Ray's case. Trevor, I know that a lot of your work also was done with a variety of other contributors, including Dr. John Kanis, Dr. Eugene McCloskey, and of course Sandy Patterson [? period. ?] You've always been quite generous in pointing out that they had a lot to do with your own contributions, and we appreciate that as well. Dr. Powles, welcome to our program. Thank you very much, and thank you for those kind words. Yeah. Actually, I interviewed someone a few weeks ago, and he said, "Geez, that sounded like my mother wrote that." [LAUGHTER] I have a number of questions for you, and I want to start out-- your research and your background was really in endocrinology of the 1960s. And that was a particularly exciting time for endocrinology with the discovery of the hormones not more than 20 years before that, and then the increasing knowledge of understanding of [? the ?] peptides steroid hormone receptors. What made you veer off from that field into oncology in general and breast cancer specifically? When I was working at the Hammersmith Hospital doing my endocrinology [INAUDIBLE] endocrinology there. And one of the conditions we would be looking at would be hypercalcemia with hyperparathyroidism. And hypercalcemia was occurring very commonly in the breast cancer patients in the oncology and the radiotherapy department. [? And ?] to begin with, we thought this would just be another paraendocrine-type syndrome, and that was the thing that really fired my interest. From there, I then wanted to do my PhD to look more into what was causing the hypercalcemia with breast cancer, and that started the whole path of finding out about bone metastases, what they were doing, how they were causing the hypercalcemia, and the path just continued and continued. Most of your work-- I'm going to get to some of the other things you've done-- has been endocrine therapy, endocrine processes, and the bone metastasis, which is really endocrinology. In the United States about that time, most of the excitement in the 60s was around chemotherapy. Was it difficult for you to stick with the endocrine approach? No, it wasn't really. When I first started, all of in the endocrine treatment was ablative treatment. And I knew that from when I was doing my endocrinology is that the hypophysectomy, adrenalectomy, oophorectomy, those were the early days for chemotherapy at using combination chemotherapy and metastatic disease. [INAUDIBLE] and endocrine therapies were far better treatments from the chemotherapy. And although I was doing chemotherapy because we started with single agents then combination treatments-- and there was a lot of chemotherapy going on at that time at the milestone for haematological cancers, lymphoma, teratomas, et cetera-- I was able to do that, but I really focused on the endocrine side. And coming back to the hypercalcemia, the one thing that really impressed me was when I was originally doing my endocrinology was that rapid response you could get to the hypercalcemia by ablative endocrine therapy for oophorectomy, or adrenalectomy, or hypophysectomy. And that was really the thing that started all of the research I did in bone. It started on my PhD with in vitro work. We set up bone assays, I went to Cambridge to [INAUDIBLE] very famous scientist Cambridge to teach us how to do the bone assays for in vitro bone assays. We also set up the animal model with breast cancer. We were able to show that breast cancers could cause bone breakdown and osteolysis in vitro. We could find that we could block that by using drugs like aspirin, and that got us very interested in cross [? demandings. ?] We could then go into the animal experiments. And when we had a rat model using breast cancer that we knew from our assays caused bone breakdown in vitro, and when we did that in the animals by injecting into the aorta we could get bone metastases [? and ?] soft tissue tumor. When we gave aspirin, we could completely prevent the bone metastases-- quite dramatic experiments. And that was what really fired me into getting into the oncology, getting into the endocrine treatment in oncology because of my background in endocrinology. And that has stayed ever since. So what was the timing there? This is the late 60s? My PhD was 1970 to '73. I was at the Hammersmith from '67 to '69, and then I went to [? Barts ?] to endocrinology, and then I came back and then with Bondy in the Marsden, and then I got on the staff of the Marsden as a senior lecturer in 1975. So what you just described to me sounds like translational science. That word wasn't coined until probably 20 years later. Was it unique where you were to be taking things from the lab straight out to the clinic? And where there obstacles to doing that? No, there weren't. The thing that was good about that was we were doing the laboratory work based on what we'd seen, what I'd seen in the endocrinology with the hypercalcemia and the bone metastases, and responding to endocrine therapy. I then was in the PhD, doing the PhD, and then I was able to translate that into the clinic once I then became a consultant. So the main work I was doing when I was first a consultant, the research work, was actually looking at hypercalcemia bone metastases in patients. We had a surprise because when we took the aspirin into patients, we could see no effect at all even though we'd had very dramatic effects in vitro and in vivo. And it was only when the bisphosphonates came through that we were able to then use those, because at this stage we knew it was working on osteoclasts. And it was only when we started to get the bisphosphonates that we really got into the dimension of first of all, being able to treat the hypercalcemia, then being able to switch off the bone metastases, bone pain, and bone fractures with bisphosphonates. And then take it into the adjuvant, I was then able to take it into the adjuvant scene and set up the first adjuvant bisphosphonate trial. So I'd gone right from in vitro, I continued the path right the way through to clinical work. And then what happened was that if we did the bisphosphonate trial and we got the result of just like that had happened in the rats-- it stopped the development of bone metastases and it stopped the hypercalcemia in the rats, but didn't affect the soft tissue. So in the humans, we had exactly the same result where we were able to reduce bone metastases, not have an impact on soft tissue or other disease, and improve mortality. And so we've gone right the way through. It's a story that's extraordinary from my point of view, because I was able to follow the whole path all the way through. And you're absolutely right. That is a really good example of translational research where you hang in there until you get the answer. What's the history behind transferring the bisphosphonates from prevention of osteoporosis in cancer? Now they're widely used as well as denosumab. In fact, it's malpractice not to use them in a patient with bone metastasis. How did you make that leap where you're standing next to somebody who was treating osteoporosis, and you said, "I wonder if that should work?" And how did you get hold of the drug? There's got to be a history behind it. Well, we were looking. We were looking for [? anti-osteodiscitis ?] agents [INAUDIBLE] the aspirin didn't work but [INAUDIBLE] worked so we knew for no reasons at all that it would prevent, stop hypercalcemia. And so we were going down that path, and two really important people in the way the path was going. One was Herbie Fleisch, and Herbie Fleisch [? had ?] suddenly produced bisphosphonates. It was a terrific story if anybody was interested in bone, because it was an agent that clearly was working on osteoclasts, and that was the target we were after. We knew at that stage that the cancer cells had to activate osteoclasts in order to cause the bone breakdown and develop in bone. And the second person who was key was Craig Mundie, who again I met. And I went over to the Boston Dental Hospital several times, and I met Craig and the others there, and that was linking up with being able to see the story that they were developing where tumor cells were activating osteoclasts that were then causing bone breakdown that was then producing growth factors to activate the cancer. So it became a really preferential site for bone metastases to develop because of the interaction between the cancer cells and the osteoclasts. So then there's Herbie Fleisch in Switzerland. I had a few skis with him. He was a very good skiier. But the spin off was that bisphosphonates were going to be the thing that we really [INAUDIBLE] to be looking at. And then we tried four different bisphosphonates. Five foot was a guy in Amsterdam who had APD that was actually the forerunner for [INAUDIBLE]. And the one that worked best for us was clodronate, which we got originally from Finland. And we set up the bone trials. We had to go through three stages. We had to-- first of all, before we could use adjuvant, we had to show that it worked in metastatic bone disease. And it did. It reduced what's called skeletal related events-- that's fracture, hypercalcemia, pain-- requirements of radiotherapy. We then did a trial for phase 3 trial of using clodronate for patients who had metastatic disease but who didn't have bone metastases. And we could reduce the risk of them getting bone metastases. And then we had the justification for doing the-- So let me interrupt you for a minute. Now you're about 1983 or '4 I think when that was probably? Is that right? It was-- yes, it would be. With the adjuvant trial, we would have started in '86. I think. That's the window of time. And then in that trial, we didn't get the results from that until I think it was 1997 when we did the first analysis, and that we were able to then show in that randomized-- it was placebo controlled as well-- we were able to show a reduction in bone metastases and improved survival. And then we did a subsequent analysis in 2006. So we've got longer term data. Back then where other bisphosphonate trials were going on, adjuvant bisphosphonate trails going on, and then we had the meta analysis in 2015, Oxford meta analysis, which I was involved with Rob Coleman. And we did the analysis there, which confirmed that we could reduce bone metastases and improve survival with adjuvant bisphosphonates. So the story that starts from a test tube, so to speak. Oh, there's one other very interesting experiment we [INAUDIBLE] that's never been repeated. Right at the beginning, we were able to show that doing co-cultures-- you're reminding me of things now-- doing co-cultures of the bone assay with human breast tumors I'd get from the Marsden while I was at the institute. We'd have fresh human tumors, and we would do a co-culture and some of them could cause the complete breakdown of the bone assay, and others would not have osteoporosis. And we did a follow up of those patients-- it was only about 30 patients, I think-- and we did a follow up of those patients, and those who had the most bone breakdown in vitro [? with ?] [? those ?] patients who were then going to get the bone metastases. That was a real incentive to show that link that we were getting. So we knew something was going on there. And that experiment was going on in 1971. And in 2015 with the meta analysis of bone mets and mortality. So that's a long story. That's the story. Let me say that this entire story reiterates the phrase that, "On the shoulders of giants we all stand." You look at the number of people you've laid out who led to this story, which is still ongoing. It's actually fascinating. I want to return just a minute to your work with endocrine therapy of breast cancer and your work with tamoxifen. But first of all, a lot of young people listen to this. 'Cause I came in the field just as surgical ablation of many of the origins of estrogen was going away. Can you talk about what it was like to take care of the patients who were having hypophysectomies and adrenalectomies and oopherectomies? I recall thinking, "I'm an endocrinologist here. I'm not a medical oncologist," as a first year fellow taking care of Addison's disease and other things. There are two things about ablative endocrine therapy. The first was that the responses could be very dramatic, and it was quite a high response rate. There was something [INAUDIBLE]-- don't forget we weren't basing it on ER. ER came later, and then [INAUDIBLE]. Even not based on ER, we were getting 30% to 40% response rates, particularly in bone. The second thing is the management of the patients. The hypophysectomies were relatively easy, because I'd already got experience of patients who got pituitary failure from my endocrinology, and that's much it easier to manage. But the adrenalectomies are much more difficult because you can get very acute glucocorticoid symptoms if you're not getting cortisol, whereas in hypophysectomies it's a relatively slow process. And they were much more difficult to look after. But the thing that was important about it was the fact that although we were doing it, these patients were getting hypercalcemia [INAUDIBLE]. You could have a patient who was hypercalcemia, you do ablative surgery, within 48 hours the calcium is back to normal. In fact, it will go hypoglycemic sometimes on bone hungry [INAUDIBLE] thing. And from a clinical point of view, it was some of the best responses we ever saw even up to this time. Now one of the things that came out of that was that we had one patient-- I can say a name because he's long since dead and [INAUDIBLE] anyway-- her name was Mrs. Pottinger. It's engraved in my mind forever. And she had bone metastases, and she was not particularly well and also had some heart problem. And she was due to have adrenalectomy, and she wasn't well enough for adrenalectomy. And so what I did is I'd used [INAUDIBLE] when I was at the Hammersmith as part of treating Cushing's disease. And so I'd already knew about medical treatment for-- so I then decided that we would do-- and I think it must have been the first patient. I had to get permission from [INAUDIBLE], and I still got the letter I wrote to the medical director of [INAUDIBLE] then saying could we use [INAUDIBLE]. So what we do is the basis was in order to get her well enough to have her adrenalectomy, and she did exactly the same as she would have done if we'd done adrenalectomy. Within 24 to 48 hours, she's getting better, the pain's going, the calcium's down. So she then refused to have an adrenalectomy. There's no way she is going to have it. She said, "No I'll continue with the [INAUDIBLE]." And she continued on [INAUDIBLE] for over a year before she died. And that started a whole new thing. [? Ian ?] [? Smith ?] was my registrar at the time. And so we decided we'd do a phase 2 trial. We did a Phase 2 trial of [INAUDIBLE] on the understanding we were doing a medical adrenalectomy. And that started the whole story that we were doing using [INAUDIBLE], because a [INAUDIBLE] came over, I had various other people come, and what we found was the story was. It wasn't the medical adrenalectomy by blocking postmenopausal estrogen. And then we went down the pathway of doing various, about three or four different aromatase inhibitors with Mitch doing all of endocrinology. It's a wonderful time. We had Adrian Harris, Charlie [INAUDIBLE]-- [COUGHING]. [INAUDIBLE]. [INTERPOSING VOICES] That's a parade of stars. Were you talking across the Atlantic a lot during that time with Dick [? Stanton, ?] and Angela Brody, and the other two who were also-- Yes. Angela Brody was the one who got us a source for [INAUDIBLE]. That was the phase 2. Charlie led on that on the phase 2. That was Angela getting us to do that and linked him with Mitch. And Dick Stanton, yes it was a lot of collaborative work with Donald MacDonald. And a lot of the endocrinologists I knew. So that was how that whole story rolled. That's an amazing library. Let me take you back now to your childhood. I know you and your identical twin, Ray-- by the way for the listeners, if you Google either Trevor or Ray Powles, you'll see pictures of the two of them standing together. And I challenge you to tell who's who. [LAUGHTER] Anyway-- Well I could. I could tell the difference. Yeah I know you can tell the difference. I know that you were both young boys in London during World War II. Tell me about the experience then, and how your mother moved you. Obviously, we were very young. My father was in the Navy abroad, so my mother was alone and was looking after my older brother David, who was four or five years older than us. And I can remember the bombing. I can remember quite a lot about it, surprisingly. We were evacuated up into the north of England 1943, 1944, something like that. And we were there for I think something like six months. And it was an incredible story. I went back to see-- I hadn't been back-- I went back to see-- I was up in the north of England, and I suddenly thought I'll go over. We were at a place called Stockton. And so I was five when we left-- four, four years old when we left. And I had no idea. I knew it was Stockton, and I knew the name of the house was the Priory, and I had a faint recollection of the door. And then I went up to Stockton, and I found the house we were in. And I knocked on the door, and it was a major-- a colonel-- Colonel Brown and his sister who lived there. And the sister was still alive, and she must have been about 90. [INAUDIBLE]. And she looked at me and she said, "You're one of the twins." [LAUGHTER] So we had a chat. [INTERPOSING VOICES] At the time, did you think of this as being frightening, or was it just a great adventure for a young boy? Yeah, I wasn't unaware of danger. My house was bombed down the road flattened and presumably a lot of people died, but I was unaware of danger as such. We had a shelter-- it's something called a [INAUDIBLE] shelter, I think it was called-- that was half buried with corrugated iron as the top thing. And if the siren went, I can remember that we would have to go out and get into the shelter. And we could hear the V-1s very, very-- I can still remember. You can hear the V-1s coming over. It made a hum-- [HUMMING] --like that. And it's gradually getting louder and louder, and then it would stop, and then it would just fall out of the sky at an angle. It would go down at about 45 degrees. So if you could hear the [? stop ?] overhead, you weren't going to be hit. But if you could hear the [? stop ?] coming towards you, there was a chance you were going to get hit. I can remember that. Everybody was sitting listening to where these bombs were cutting out their engine. So that's one of the things I can remember. And I can remember the V-2. It was a huge bang if one went off. I know that you and Ray both also developed tuberculosis as young boys. What was the background behind that, and how were you treated? Yeah, Ray-- we'd just finished school. And we weren't sure what we were going to do, and Ray had developed [INAUDIBLE], which again didn't mean anything to me. He coughed up a couple of times or [INAUDIBLE] of blood. And the next thing he's carted off and he's got tuberculosis, and he's been taken down to a sanatorium down near the Thames out along the marshes sort of thing. And he's there for six months. And during that six months, I can't see him and everything, and I thought, "Well, you know I'd like to do medicine. I think this is rather a good thing." So what I did, I then applied for medical school and got a place. And then Ray gets better, and he then applies to medical school, and he gets a place as well. The dean said to Ray when he saw it, he said, "Haven't we seen you here before?" And Ray said, "No, it's my twin brother." And he then says, "Did we accept him?" And Ray said, "Yes." And then he said, "Pity." [LAUGHTER] And it was the end of the interview. The next thing, he's in as well. [LAUGHTER] And then I get TB, because it's about an 80% chance you get it if an identical twin's had it. And I was in the hospital for three months. So we were both back a year. I would have been a year ahead of Ray, but in fact then suddenly we're both back a year. And it was quite an interesting year for me, because I only had one subject to do. So I was able to do some reading, things like Darwin and that sort of stuff. And then we just carried on. And you were treated with streptomycin in those days? [INAUDIBLE]. You had 50 grams of strep. Yeah, yeah. Sounds like you used that as a springboard to change the practice of medicine. So in every cloud there's a silver lining. The one thing I want to bring up-- I remember several years ago at one of the San Antonio meetings, and you and Dr. [? Bernie ?] Fisher were the bait. And he did all but call for you to be arrested and locked up because your study was negative, and of course the [? PL1 ?] one was positive. And you very graciously responded to that, "You know, Dr. Fisher, I didn't start this trial up to be negative." [LAUGHTER] That was a great response. My goodness did I not admire him. The reason I did the trial is-- again, this is a funny story. I did a lot of horse riding, as you know. And what I did is after the 1985 first meta analysis, Oxford meta analysis, that was the first one to show that chemotherapy worked for the [INAUDIBLE] and other trials that chemotherapies show the reduction. And it showed that tamoxifen worked. That was the first meeting where I was really convinced that both those were positive effects. Up till then, it was one trial and you couldn't be sure if it was going to be reproduced all the like. And that was the 1985 meta analysis meeting in Oxford. And then I came back home, and I got on my horse, and I rode for a week. I took the horse down to the South Downs. The South Downs is a long, expansive country, and it took me five days, I think it was, of riding to get across from one side to the other where I'd stop in a pub. I had to go down the week before and plan out exactly what I was going to do. So I've got five days on a horseback thinking, and that was where I thought, "Well, where do we go from here?" You might say, well, let's do bigger and better chemo or the like, right? And you might say endocrine therapy, let's do more tamoxifen, or different doses, or [INAUDIBLE] down those paths. So I said, "But if you really want to do something different, the two things you could do would be for chemotherapy is why not give it before surgery?" That was the time when I really thought neoadjuvant chemotherapy was where we ought to be going, because then we could see that they're responding or not et cetera. But tamoxifen, if it weren't for adjuvant therapy, then it should work for prevention. We had a clinic at the Marsden that I took over because somebody was leaving-- which was a family history clinic, and they all had very strong family histories three or four relatives, et cetera, et cetera. And I took over this clinic, and I thought to myself we could do a prevention trial here with tamoxifen. We'll do a pilot. What happened at the Marsden they just had a ethics committee set up, one of the first in the world. This is in 1985. And it had never met, it had only passed the trials to be done. And so the first meeting of the ethics committee at the Marsden was to discuss the prevention, because it was such a awful thing to do. Do you know what I mean? And but after two or three goes, I got it through the ethics committee mainly because a colleague of mine who was the head of medicine then was Tim McIlwain. He pushed it through because he said "Look, it makes so much sense." And we did a [INAUDIBLE] and we had an agreement that we could do 250 patients randomized, then go to 500. And then we had a national meeting to discuss setting up the national program. And so it was a feasibility trial actually looking to see what the toxicity was or whether it was acceptable to do it. And we had such a spin off from that, because tamoxifen at that stage was supposed to be a pure anti estrogen. And we were screening all the tissues, we were doing bones that [INAUDIBLE] from the clotting factors. Everything. Cholesterol. We were doing, measuring everything in pre and post menopausal women. And everywhere we looked, tamoxifen wasn't acting as an anti estrogen. It was acting as an estrogen effect, so much so that at the Think Tank-- I presented it at the Think Tank, and I said, "Look these aren't [INAUDIBLE] tamoxifen and anti estrogen at all." And I thought Mark, dear old Mark Lippert, was going to have an epilepsy, which 'cause it's correct because it is an anti estrogen breast cancer effect. But that was the first time. So then in the paper I wrote, I called it a selective anti estrogen. But I didn't coin [INAUDIBLE], but I did coin the expression, the first published thing of a selective anti estrogen. I remember that paper. [INAUDIBLE]. I remember that. So I want to finish up with just-- Let me just finish up one thing. Can I just finish up one thing? [INTERPOSING VOICES] Because it links into [INAUDIBLE]. So after Think Tank presented it possibly as an estrogen. And what was happening is we've got a bell shaped curve that was very narrow. So we were on the estrogen side as opposed to the anti estrogen side, right? And that was what was happening in the normal tissues. So I had a slides that said, "Tamoxifen is not an anti estrogen." You probably remember if you were there. You were there. We go out on the boat, and we get stranded out of the boat in the mist-- the one you've mentioned about where you and I and Mark, et cetera-- when we're approaching the time after about four hours when we're thinking about meeting our maker, Mark says to me, "I've really got to have a word with you about this anti estrogen." Well one other thing-- and this is going to be more my talking than yours. I really just touched on the surface of your contributions to the field, but I think probably the greatest is your mentoring history. And you've already hit on a few of these, but I travel extensively and I'm struck by the number of times I've been in some remote area-- or at least remote to me-- and corner of the world, and somebody-- it's usually my host-- volunteers that he or she trained at the Royal Marsden with Trevor Powles. And I think it's one of the things you should be most proud of all the many things you've done. And I want to know that you set up a system that was opening and inviting and also somehow funded to support people to come from all over the world. What made you do that? How did you do that in the first place? It's hard to do. Certain people came to me, which was very nice. We did have funds. I would be able to get funding even at that stage. There are many more hurdles for getting funding now than there were then. And the other thing about it was the fact that I find that people-- many times we've [INAUDIBLE] [? mentioning ?] things-- but one of the things I really did [? let ?] is let people have the run of doing things as opposed to me doing it maybe with the assistant. And that was very rewarding for me in terms of results and [INAUDIBLE], 'cause people were very motivated to do it, people like you, and Charlie, and the others. So in some senses, I think it was the fact I was looking for the results we wanted to get rather than anything else. That's probably the basis of it, and therefore people came who ere good. And I'm very lucky I had very, very good people come. So just to go through the list briefly-- Ian Smith, Mitch Dowsett, Troy [? Kohns, ?] Adrian Harris, Paul Goss, who am I leaving out? Anyway, it's a who's who of breast cancer, especially endocrinology and breast cancer. And they all came out of your brilliance. So we owe you not just for what you've done, but who you've trained to do even more. Very kind of you to say that, but in fact they get the credit because if you look through my publication lists you can see. Actually, I left out Steven Johnston, of course, who is-- Steve. Yeah, Steve. Yeah. OK, we've run out of time. I very much appreciate the fact that you've taken time to come on and do that for us. I'm sure our listeners will be thrilled by the stories you've told-- at least I always am-- and it's great to hear most of them again. And I hope sometime we can even do this again. So thank you for all you've done, thank you for all the people you've trained, and thank you for taking time to do this today. Well, thank you so much for asking me. Until next time, thank you for listening to this JCO's Cancer Story-- The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories-- The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.asco.org.

Dr. Hayes interviews Dr. Bloomfield on her role as one of the first physician-scientists to investigate treatment for acute myeloid leukemia (AML). Dr. Daniel F. Hayes is the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center. Dr. Hayes' research interests are in the field of experimental therapeutics and cancer biomarkers, especially in breast cancer. He has served as chair of the SWOG Breast Cancer Translational Medicine Committee, and he was an inaugural member and chaired the American Society of Clinical Oncology (ASCO) Tumor Marker Guidelines Committee. Dr. Hayes served on the ASCO Board of Directors, and served a 3 year term as President of ASCO from 2016-2018. TRANSCRIPT The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] Welcome to JCO's Cancer Stories-- The art of Oncology brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the role of cancer care. You can find all of the shows, including this one, at podcast.asco.org. [MUSIC PLAYING] Welcome to today's version of the ASCO Cancer Stories podcast. Today, my guest on the podcast is Dr. Clara Bloomfield. Dr. Bloomfield was instrumental in the early studies investigating the biology of leukemias and lymphomas, and also the interaction between various molecular markers and treatment. She founded the Correlative Science Committee of The Cancer and Leukemia Group B, which is now designated the Alliance in the 1980s. And I believe that was probably the first such committee in the cooperative groups, and she chaired it for at least 25 years. Her work resulted in numerous groundbreaking insights that led to changes in practice. Personally, and having worked with her for several of those years in CALGB, I really consider her one of the first investigators to perform what we now blithely called, quote, "translational," end of quote, science in cancer. Dr. Bloomfield was born in New York City, but her father, who was an expert in labor and industrial relations, moved the family to Washington, DC during World War II. And after the war, he then took a position at the University of Illinois, leading Dr. Bloomfield to have a nearly lifelong association with the Midwest. She attended undergraduate school at the University of Wisconsin, but then graduated from San Diego State College during a brief foray to the West Coast. She returned to the Midwest to attend medical school at the University of Chicago, and then completed her internal medicine residency and her medical oncology fellowship at the University of Minnesota, where she stayed on faculty until 1989. She then became chair of the Department of Medicine at Roswell Park Cancer Institute in Buffalo for the next eight years, and then moved to the Ohio State University, where she accepted the position as director of the comprehensive and now designated the James Cancer Center. She's remained at OSU and is currently a distinguished university professor and the William G. Pace II professor of cancer research and a senior advisor at the OSU James Cancer Center. Dr. Bloomfield has authored hundreds of peer-reviewed papers. She is an elected member of the National Academy of Medicine and the National Academy of Sciences. She's, frankly, won just too many awards that I can name here. But importantly, she served on the ASCO board of directors, and in 2009, she gave the David A. Karnofsky Memorial Lecture, the highest honor our society can bestow. Clara, welcome to our program. Thank you. You know, I have a lot of questions for you, many of which I thought about that I should have asked you 30 years ago or so when we first started working together in CALGB. But I think the biggest one is, how did you get interested in leukemia in the first place? Were any particular personal insights that resulted in the basis of your career? Or was it just happenstance? I think it happened because in grade school, I had a number of classmates who developed leukemia. And they were sent to the National Cancer Institute because people in those days didn't treat leukemia. And they returned with steroid-bloated faces and soon died. And I thought, well, wouldn't it be cool to develop medicine that could save kids from dying? I'd already decided to become a doctor, so seeing the real-life effects of cancer helped shape my early desire to become an oncologist. So that must have been about the same time, a little bit after, that Drs. Frei, and Freireich, and Holland started combination therapy for leukemia. They must have had a big impact on your career then. I don't remember. [? No, ?] I'm kidding. Actually, the other question-- I know that you spent some time at Stanford and ran into Henry Kaplan. And there was a cute anecdote, I think, about how you presented with his backing at one of the conferences. Can you tell us a little bit about Dr. Kaplan and your work with him? Sure. During my junior and senior years in medical school, I did a sub-internship at the University of California at San Francisco. And I saw a patient with Hodgkin's disease who was not being treated with curative intent. And I said to the attending, you're not giving this patient modern therapy. And the attending replied, well, if you're so smart, we'll have you do grand rounds on how to treat Hodgkin's disease. Remember, I was a medical student. So I called Professor Henry Kaplan at Stanford for advice. And he was great, and he said, well, they never want me to come. I'd be happy to come and help you give grand rounds. So to the surprise of my attending and awe as a medical student, I conducted grand rounds at the University of California at San Francisco with Professor Kaplan. That must have been a big surprise. Yes, I think it was. Actually, one of my interviews has been with Saul Rosenberg, and he also had some great stories about Dr. Kaplan when they first started giving chemotherapy at Stanford. And Kaplan was apparently quite supportive of doing this. So-- Yes, he was. --I never got to meet him. Yeah. Another question, again, about the time you entered the field, I referred to what I consider the big three, Frei, Freireich, and Holland, but their therapy was really pretty empiric for leukemia. It was just hoping that giving more drugs would be better than one drug. But you really got us into genetics. What made you do that? I mean, what made you think that we could treat people, really, with precision medicine better than we did in those days? Well, my second research project I had as a fellow, which was presented at ACR in May of 1972 and published in April of 1973, involved daunorubicin-prednisone therapy for AML. And in that, the question was raised in patients without Auer rods, the question were these of CML in blast crisis was raised, so chromosome studies were done. And this got me started studying cytogenetics in leukemia, and subsequently molecular genetics. And also, you asked if I had a role model, and the answer is no. I did not have a role model. I know that very early on in your career, you published a very controversial paper suggesting that the Philadelphia chromosome could be found in acute lymphocytic leukemia, which at the time, I think, was probably heresy, since it had been associated with CML. I understand that you interacted with Avery Sandberg, the [? tube ?] giant. I remember hearing about Avery Sandberg when I was a freshman in college in genetics, and he supported you. What was the background behind that? At the 1975 ASH meeting, I presented an abstract, I gave a talk on the Philadelphia chromosome-- on Philadelphia chromosome positive acute leukemia. And after that talk, many prominent cytogeneticists raised questions about the validity of my findings. However, Avery Sandberg, while surprised by the findings, said, she may be right. Sometimes these youngsters get things that we've missed. And did you walk out beating your chest? That must have been quite a moment. I was happy that he-- I was happy that he supported me. Well, I want to go on to some of your other work, but I'm going to tell you that in our fellows clinical conference here a couple of weeks ago, which I attend every week, one of the fellows started talking about FLT3 leukemia. But his comment was leukemia is described as the most genomically defined cancer. And I didn't bring it up at that meeting, but I thought, you owe Clara Bloomfield for that statement. You should be really proud of your work. I almost picked up the phone to call you to tell you that our fellows don't know that you did the work. They should, and that's why we're doing these podcasts. So the only thing-- I know you challenged dogma was the treatment of older patients with leukemia. And as you and I both get older, I think it becomes more near and dear to our heart. Can you give some insight into that? I mean, my impression, when I was a fellow, was we just kind of said, oh, you're over 60, it's not worth treating you. But I think you really challenged that and changed that dogma. So ASH [INAUDIBLE] the third paper I published and project that I started on when I started as a fellow, because I was asked to do this by one of my attendings, was to look at treating older patients with acute leukemia. In the early 1970s, which we're talking about, it was considered that standard intensive treatment of patients with acute leukemia over the age of 40 or 50 years of age was malpractice or at least wrong. So when I was asked to look at this, we had a few patients over the age of 60 with AML treated with what was then standard intensive chemotherapy. So I compared the outcome of patients aged 21 to 40, 41 to 60, and 61 to 86 years. And what I found was that patients aged 41 to 60 and greater than 60 responded equally well. As a result, we said that patients over 60 should be treated. This meant that what we did was told major researchers in leukemia that they were wrong. This caused quite a stir, as you might imagine. And interestingly, within the next five to 10 years, they all came back to me and said they had been wrong. In that regard, I watched you in CALGB. I was on the solid tumor side, obviously, but you were really a pioneer in organizing and conducting translational research and correlative research in leukemia in the cooperative groups. When you started, I don't think there was any of that, was there? Were there a lot of obstacles to doing that? I think everybody just takes it for granted now, especially with so-called precision medicine. But what did you have to do to get that started at CALGB? From 1982 on, I was chair of the Correlative Science Committee in Cancer and Leukemia Group B. In 1984, I actually started to have NIH grant to support correlative science in the CALGB cooperative group. In 1984, we already had a trial in Cancer and Leukemia Group B to do cytogenetics in acute leukemia. I mean, a lot of this work was based on my work in cytogenetics. And while there may have been clinicians who were opposed, I had the support of important people like Professor Janet Rowley and the cytogeneticists at the CALGB institutions. And there really were not significant obstacles that I can remember. Of course, if there were people who tried to block me, I probably didn't care and worked around them. I'm sure that's true. I am too. This is part of what-- when you're one of the few women, as I was when I started in the field, I mean, I suppose I was always getting blocked about things, I just don't think much about it. I didn't then and I don't now. That segues into my final question, actually. And these days, more than half of our medical students are women. More than half of our residents are women at the University of Michigan. More than half of our fellows in hem-onc are women. Increasingly, the faculty is there. But when you started, you were really a pioneer, I think, in introducing women into clinical and laboratory research in oncology and academic medical leadership. And I just want to list the things, because I don't think you will, that I think you've done. First, I understand you were the first woman chief resident at the University of Minnesota, the first woman full professor in medicine at the University of Minnesota, one of the first women chairs of medicine in the United States when you were at Roswell Park, the third woman to be director of an NCI-designated Cancer Center. And frankly, as I was preparing this, I was on an airplane and I was watching A Matter of Sex about Ruth Bader Ginsburg, and I thought, this is a really familiar story. Do you have any war stories that you thought were particularly telling when you began? And especially, for example, I know you have a story about what the dean told you when you were considering becoming an academic professor. Do you have anything to inspire the people listening to this podcast? I'm sure there were some probably pretty aggressive war stories that I don't remember. And as I said, I don't tend to think about what happened in the past since I'm trying to keep up with the present. But I guess there are a couple of stories. Unbelievably, when I was a medical student, I always sat in the front row in class because that was the only way I could see the slides. And the dean, medical school dean, called me into his office and said it was not ladylike to sit in the front row. And I told him-- it's unbelievable really-- I told him that when he became a lady, he could tell me how to act like one, and walked out on him. But the more important story, I suppose-- that I can remember-- is that when I was appointed an associate professor, which occurred three years after I became an assistant professor, so the head of medicine called me in and said, congratulations, Clara. This is a great accomplishment. He went on to say, however, that since your husband is on the faculty and gets a good salary, we are not going to increase your salary. So when I came home, I told my husband, where upon he called the dean, who called the University president, who said, you be sure she gets the same salary or higher than the highest one you've ever given a new associate professor in medicine. Thus, my pay issue was immediately resolved. It's hard to believe that's a true story, except I saw similar things myself as I was going up, and they were getting corrected, at least. Well, anyway, we're running out of time. And I just want to thank you for all the things you've done, the contributions you've made to the field. Your legacy is incredible, in my opinion. And I think people will long remember what Clara Bloomfield has done in terms of changing how we treat leukemia, changing the treatment of leukemia into groups of patients who traditionally weren't treated, like older folks, and probably the pioneering work you did in bringing women into science and medicine, especially in oncology. So thanks for taking time to speak with me today. And I think people are going to be really thrilled to listen to your story as they drive to work and say, wow, I didn't realize that that's what it was like back in the old days. So thanks so much. And I think, especially, our young and translational scientists, particularly women, and also, most importantly, our patients deserve to give you credit for all of the things you've done and [? thanks ?] you've done. Until next time, thank you for listening to this JCO's Cancer Stories-- The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories-- The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.asco.org. [MUSIC PLAYING]

Dr. Hayes interviews Dr. Lippman discuss on being one of the first translational scientists in solid tumors. Dr. Daniel F. Hayes is the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center. Dr. Hayes' research interests are in the field of experimental therapeutics and cancer biomarkers, especially in breast cancer. He has served as chair of the SWOG Breast Cancer Translational Medicine Committee, and he was an inaugural member and chaired the American Society of Clinical Oncology (ASCO) Tumor Marker Guidelines Committee. Dr. Hayes served on the ASCO Board of Directors, and served a 3 year term as President of ASCO from 2016-2018. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Welcome to JCO's Cancer Stories, The Art of Oncology brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the role of cancer care. You can find all of these shows, including this one, at podcast.asco.org. Welcome to Cancer Stories. I'm Dr. Daniel Hayes. I'm a medical oncologist and a translational researcher at the University of Michigan Rogel Cancer Center. I'm also the past president of ASCO. I'm really privileged to be your host for a series of podcast interviews with the founders of our field. In this series of podcasts, I'm hoping I'll bring appreciation of the courage, the vision, and the scientific background among the leaders who founded our field of cancer clinical care over the last 70 years. I think that by understanding the background of how we got to what we now consider normal in oncology, we can work together towards a better future for our patients and their families during and after cancer treatment. Today, I am privileged to have as my guest on this podcast Dr. Marc Lippman. Dr. Lippman was really instrumental in the early studies of the role of the S receptor in breast cancer. And personally, I consider him with his former colleague Dr. William McGuire the first investigators to perform what we now call, quote, "translational," end of quote, science in solid tumors. Dr. Lippman was raised in Brooklyn. He received his undergraduate degree at Cornell where, by the way, he played on the varsity tennis team. And then he got his medical degree at Yale. He did his residency at Johns Hopkins and returned to Yale for a fellowship in endocrinology. Somewhat surprisingly, to me at least, he served a year from 1970 to '71 as a clinical associate in the leukemia service at the National Cancer Institute while simultaneously working in the laboratory of biochemistry with Brad Thompson, with whom he published extensively. Dr. Lippman has authored nearly 500 peer-reviewed papers. He co-edits Diseases of the Breast, which is considered the Bible of breast cancer with Dr. Jay Harris and Monica Morrow and Kent Osborne. And fundamentally, he has mentored the leaders of breast cancer in the world, in my opinion. Welcome to our program. Hello. I have a number of questions I'd like to ask you. First of all, clearly, you took a really unusual path to being a cancer doctor. To my knowledge, you actually never formally trained in oncology. Can you tell our audience how you went from being an endocrinology Fellow to being an oncologist? I think it's worth it, from my vantage point, to give a little background about me. I came from very, very intellectually rich family. And there was never any question that I was going to do some kind of science. I was certain that that's where I was headed. And when I was in medical school, I think it's important that while everybody was doing research at the school like Yale, a lot of medicine as we now think of it as evidence-based was completely mysterious. In those days, when I was starting medical school, really, I think the only fully scientific field was infectious disease because we had Cox postulates. And we knew what drugs killed what bugs. And we knew what bugs caused what diseases, for the most part. And that was wonderful. But endocrinology, at that time, was completely functional assays. It was completely not scientific. You looked to see if the rabbit ovulated or something like that for a bio assays. And Nobel Prize winning research was done, which developed the radio immuno and the radio receptor assay. And that completely transformed endocrinology over night. And within about one year, virtually every endocrine disease, the pathophysiology of Addison's, thyroid disease, you name it was worked out based on being able to measure minuscule amounts of hormones. And to me, this was fabulous. I was going to be an endocrinologist. I had no doubt about it. This was real science. And I could get into it. When I was in medical school, you had to do a thesis. And for reasons that I'm not even sure of now, I can recall, I got involved with a guy who was a hematologist. But he did work on leukemia. And I enjoyed that work greatly. It was very interesting. And right about then, you may recall, there was a minor episode going on called Vietnam. And many physicians or people who were about to become physicians, myself included, weren't very anxious to go to Vietnam. And one of the main alternative routes was to become an officer in the public health service at the NIH and to do your military service at the NIH. And that seemed like exactly what I wanted to do. It was a very unusual process. People at the NIH picked you for their own personal lab. And because I had been working in this hematology lab, a scientist, an administrator actually at the NCI invited me to join his lab, Saul Perry. And I took him up on that because that seemed like my only alternative. But after I finished my internship and residency and showed up at the NIH, because I was part of Saul Perry's group which was the leukemia service, I had to spend a year on the wards taking care of extremely sick people, most of whom died during that year. But because of my love of endocrinology, I kept studying all kinds of stuff around endocrinology, took the molecular endocrinology courses. And then I met this wonderful mentor, Brad Thompson. And my first project with him actually was an attempt to combine leukemia and endocrinology. And I started measuring glucocorticoid receptors in leukemia. And that's, frankly, some of the best work I ever did. We showed that they existed, that they were receptors, and that they predicted response. I mean, we did in leukemia what people were doing in breast cancer, and I thought that was pretty interesting. And there was always this tension in my mind between the science of endocrinology and the almost complete lack thereof, at that time, in oncology. And I thought that I might try to think about putting them together. But I needed to do formal endocrine training. So after I finished my clinical year at the NIH and my two years in the laboratory with Brad Thompson, I went back to Yale to do endocrinology. And I thought that's where I would complete my career. After I'd been there about a year, Paul Carbone called me up and said, would I like to come back to the NCI and join the breast cancer service? And I have to tell you candidly, I had never treated a case in breast cancer in my life when I went to join the breast cancer program at the NCI. And I completely learned everything I learned about breast cancer absolutely on the fly. So what made Dr. Carbone call you to do breast cancer? Well, I'm not absolutely certain. I had done well at the NCI. I'd been very interested in a lot of things. And I'm not certain I can remember anymore. I don't remember why Paul called me, but he did. And at that time, I had been looking at several endocrine jobs at a variety of institutions, including University of Chicago. And I was thinking I'd just spend my life as an endocrinologist. But I thought this was such a great opportunity to pursue my research that I decided to take my chances. I was extremely full of myself in those days. And I didn't see the problem that I had never treated breast cancer. I know it sounds dumb to say it. But I actually said, well, OK, I'll figure this out. How hard can it be? And I guess I didn't find it all that hard. And at that time, because I had already gotten into what I would refer to as molecular endocrinology, half of which was steroid-hormone action, I was highly familiar with the work of Elwood Jensen, who was the real pioneer at that time, one of two actually. So naturally, it made sense to me to take the work I'd already done in glucocorticoid receptors and try to make models in tissue culture for how breast cancer responded to hormones, the kind of thing you would never suggest that a newly minted faculty member try a completely insane project, which I was extremely fortunate that it succeeded. You refer to Elwood Jensen. Tell us more about Dr. Jensen and what he did that got you where you were. Well, Elwood was a tremendous scientist and basically a chemist. And people don't understand how technology sometimes makes a field possible. And just as I mentioned before, radio immuno and radio receptor assay made the entire field of endocrinology and now so many other subspecialties of medicine possible as you measure pulmonary and GI and cardiac hormones, in the same exact sense, what Elwood succeeded in making was radiolabeled steroids. And you can't do receptor assays unless you have high specific activity compounds. We don't use radio isotopes touch so much anymore, and people don't appreciate that. But there was absolutely no way to measure the binding in picomolar and centimolar ranges without high specific activity steroids. And Elwood was able to manufacture created hexestrol, which is a similar compound to estradiol. And with that, he was able to basically separate bounds from free hormone and prove the existence of receptors. It was extremely important studies that he did at the time. And it opened up the entire field of hormone dependency in breast cancer, which, up until that time, had been based entirely on clinical criteria for response. And furthermore, what occurred almost simultaneously with that was finally the invention of some serious drugs that could interfere with hormone action, most notably tamoxifen but several others that were synthesized at the time. And so rather than just having to oblate organs or use very toxic super pharmacological doses of steroids to treat patients with breast cancer, there was now a readily obtainable and usable oral therapy. And so there was a tremendous need to figure out how and why it worked. And a lot of people got into that field relatively rapidly. Bill McGuire being among them. James [? Whitless ?] being among them, myself for sure. And all of us felt that this was an extremely important aspect. There was the clinical aspect, which became clear in the early '70s that there was, as you would expect, a very, very nice correlation between the presence of receptors and response. And that led up to the entire opening of this field of now that you could measure these receptors of how they worked, where they bound, what they did, what genes they induced. And so that became a lifetime exercise for many. My impression is that before about 1970, endocrine therapy, which dated back the 1890s, was mostly done by the surgeons. Did you have to muscle your way into that field? Or were they openly agreeable that some guy who had never even did oncology would start treating breast cancer patients? Well, I think that what was going on then, in England, there was a much greater delay in medical oncology as a field. And these patients were still treated by surgeons and radiation oncologists. I don't think there was any parallel issue in the United States. There were some very wonderful pioneering surgeons, but they didn't, I think, pretend to fundamentally want to get into molecular endocrinology. I don't recall that as being an area of conflict in terms of doing these kinds of studies. And of course, in this country, we were unbelievably blessed by the extraordinary, absolutely extraordinary pioneering and organizational skills of Bernie Fisher, tremendous scientist, in his own right, a tremendous surgeon, but, even more importantly, the ability to really form the most effective, ragtag, co-operative group the NSABP, which was able, from its very inception, to do some of the most groundbreaking studies not just around hormone therapy, which they certainly did, but obviously as we all know about, differences in surgical care. And so-- You eluded to Dr. Carbone. My impression is the NCI, mostly, in those days, was all about leukemia and lymphoma, the so-called gang of five, MOPP and CHOP and Doctors Frei and [INAUDIBLE]. Who was behind you to move out and start taking care of patients with cancer in a more scientific basis? Was it just Carbone or were there other people at the NCI who [INTERPOSING VOICES] Well, shortly after I got, there Paul left. He went to Wisconsin. And Doug Tormey, who had been nominally head of the breast group, departed. And so I was suddenly given an empty stage and said, well, why don't you do it? So within two years, I was running a program in which, the previous year, I hadn't even treated a patient. It was extraordinary. But right about that-- I was-- that's a very good question and a slightly personal one. About 30. About 30, 31. Yeah. Most 30-year-olds now are just starting their residency or their fellowship. Right. And it is unfortunate that people with the most energy and most intelligence get increasingly pushed downstream. I mean, the age of first RO1s in this country is horrible, as we all know. And that's a major other problem that people need to address. But at that time, as you may recall, several groups were developing the first multi drug combinations for breast cancers. CMF, or as Johnny [INAUDIBLE] used to refer to it as CMF, and of course other variations with the MD Anderson regimens of so-called FAC chemotherapy, F-A-C, and other regimens that included vinca and prednisone. And so for the first time, reasonably active regimens were available for metastatic disease. Where in the past, it had only been a handful of single agents, vinca, methotrexate, 5-FU. And at the same time, I think there were the extraordinary, a little bit later, the extraordinary first data that adjuvant therapy was successful. I mean, the studies done by the NSABP initially was single agents and then the CMF studies from Milan were extraordinary. I mean, breast cancer was and remains the most tractable of the solid tumors with the possible exception of testicular that we've treated in this country or anywhere. Tell us about your lab work and how you established what you did, and then really interested in how you looked at what you were doing in the lab and said, jeez, this relates to my clinical work. Well, thank you. As I said, when I had been working at Yale before I came back to the NCI. And at that point, at Yale, I was trying to develop models of gluconeogenesis in liver cells. It had nothing to do with cancer. And so I arrived at the NCI, recruited by Paul, offered some laboratory space, and said, go to it. And I literally, literally scratched my head and said, well, what am I going to do now? And because I hadn't had a previous thing I was just going to expand on. And because another great miracle that had been growing from very late '50s to the mid '60s was cell culture. I don't think people can now imagine how pioneering the results were to grow cancer cells and to get them to reflect, in any sense, the phenotype of human malignancy. I mean, now we take it for granted. But these were pioneers trying to figure out how to grow cells, Harry Eagle and Hamm and Dulbecco, and all of these other wonderful people. So anyway, it seemed to me, wouldn't it be great, since someone had described a cell line that had estrogen receptor, I said to myself, what would be more straightforward than to figure out how you could manipulate these breast cancer cells with hormone therapies and figure out the mechanisms by using cell culture as a model for steroid hormone action? So I set about doing that. And after about six months, I succeeded. And that was the good news. And ironically, the better news was that nobody else could reproduce it, including Dale McGuire. And lots of people said this was, frankly, garbage, that I was making it up. And so when eventually-- no. It was very upsetting. I don't think many people when they first start off and they have their first big set of papers, and I published this stuff in Nature and serious journals. And all of a sudden, everybody says, it's not true. I remember giving a lecture at Harvard. And somebody at the end at the questions said, we just can't reproduce this data. We don't think you're telling the truth. I mean, how often you want to have that happen in your career? And as I said, what turned out to be very fortuitous was that we were right. And so eventually, that made things even easier for me in terms of my career. There's no question about that. And a lot of people wanted to go to the NIH. I think it's now with so many wonderful-- what are there more than three dozen comprehensive cancer centers? But the United States in those days, there were just a handful. And most of them were doing leukemia and lymphoma, like Stanford, which certainly had almost no breast cancer program at the time. And so people who wanted to work in breast cancer came to work with me. And lots of people wanted to get a BTA degree, Been to America. So I was fortunate to have some very outstanding people from Europe and Asia come to participate in my work. And there was still the tail end of Vietnam. So some of the very best and brightest, if I could misuse that expression, people like Neil Rosen and Ed Gellman and Doug Yee and George Wilding, people who all became cancer center directors were people that I was very fortunate to have work with me. And I was pleasured to deal with them. When did you say you were doing the lab models of cell lines and discovering how ER mediated the effects of estrogen? When did you start saying, let's take this over to the clinic? I mean, what was the first thing you did that you translated into the clinic? Well, the first translational study I did when I was a fellow when I tried to do correlations of response to glucocorticoids in leukemic patients and ALL and AML. So I mean, I was used to going back and forth that kind of way. And we did a series of drug trials in breast cancer patients. I was seeing patients. I haven't spoken much about it. But I don't know how to say that any other way whether it sounds modest or not. I simply love being a physician. I found that the main appeal of oncology was dealing with people at times of enormous obvious stress and disturbance in their lives. And I found that that brought out some of my best skill sets. And so I was anxious. I was always involved with patients like that. One of the main trials that we got involved with involved Allen Lichter because Allen and I were endlessly discussing what was the right therapy for localized breast cancer. You may recall that Sam Hellman, the joint center, refused to be part of clinical trials looking at lumpectomy and radiation, as he was convinced, turns out correctly, that that was equivalent to doing mastectomy. And we felt, Allen and I, I think somewhat maybe arrogantly again, that we could do a single institution trial for lumpectomy versus radiation. And we did. We ran a randomized trial of about 350 women at the NCI, a prospective randomized trial of lumpectomy and radiation versus chemotherapy. And of course, all of these patients became fodder for advanced disease trials and everything else we were doing. And those are some of the happiest days of my life working with Alan side by side in what may have been the first multidisciplinary clinic in breast cancer. If I may, I'm going to interject. Allen Lichter, who started the department of radiation oncology at the University of Michigan, where I'm sitting right now, was my dean when I arrived here, became ASCO president at one point, and then was the ASCO CEO for years. Since this is an ASCO publication, if you will, I'd give him credit for all of that. And well he deserves it. Well he deserves it. Yeah. I can't agree more with that. That's for sure. The other thing I've heard you-- by the way, I've always wondered. How did you get 350 patients onto that trial at the NCI, since you've tended not to see walk in the door kind of breast cancer patients, right? So how did you? Well, the NCI remember, everybody was treated free. So fortunately or unfortunately, given American medical economics, people who had a diagnosis would come to see us because they had no other option. We would pay all their travel and everything else. So we treated patients. And I have to tell you, up until last year when she died, I still had patients from that study who had followed me around the country to be treated. That's a great story. It's true. It's absolutely true. So the other thing I've heard you talk about, and I think people should-- given the proliferation of medical journals now, there's one on every corner, I've heard you talk about the fact that you really have a hard time finding places to present your endocrine results, that the Endocrine Society didn't care about cancer. And AACR didn't care about endocrinology. ASCO didn't really exist almost in those days. Give us some stories about that. Well, that's completely true. It's completely true. There was always a session in the Endocrine Society called cancer and hormones, which was late on Friday afternoon. And everybody had gone home. And AACR had the same thing. Because at that time, there just wasn't an obvious niche for cancer. What began to make it more popular to both societies were when things like, quote, "growth factors," close quote, became more in evidence. And they clearly played a role in cancer. But clinical trials and clinical experience had no role in the Endocrine Society. And basically studies in molecular oncology just didn't seem all that attractive to AACR. It wasn't like you couldn't talk about it. It just wasn't front and center what people were interested in. Everything goes through vogues periods. We're now going through an immunooncology voguish period. And I'm not trying to suggest that that's not extremely important and going to have endless value for people. But now, if you're doing almost anything else, you can't even write a protocol. It's true. It's true in some ways. I was trained. [INAUDIBLE], who's an endocrinologist, was at the Dana Farber and told me that cancer is just endocrinology gone wild. In fact, I believe, in many respects, that's what precision medicine is all about is that we begun to take what you guys did 50 years ago and said, let's do it for all the diseases other than immunology, which is a different issue. I agree with you. I think that that's a good point. I think that one of the fundamental differences between normal and cancer, however, is genomic elasticity. If you had psoriasis, and I put you on methotrexate. Then 10 years later, I doubled the dose, it would kill you. Because you never amplify the target gene, dihydrofolate reductase. And you remain sensitive throughout your entire life. Whereas doing that with a leukemic cell, in a couple of months, you'd be completely resistant. And that is, in my mind, one of the shortcomings of so-called precision medicine in which you're trying to match a pathway, an oncogene, to a specific therapy. In that, oftentimes, these studies are in end stage patients with multiple resistant clones now has become endlessly clear from single cell sequencing studies. And I think that there is, I think, personally, slightly less to most efforts in precision medicine than most people think. And I believe that it's amusing that precision medicine has come to include immunooncology, which has little, in my mind, to do with the initial way in which precision medicine was touted, which is find the oncogene. And we will give you the drug. And I think, by and large, that, except for some incredible successes like Gleevec for CML, hasn't really panned out. Personally, I think what we're going to do is head back to what doctors Hall and Frei and [INAUDIBLE] taught us, which is that resistance is a heterogeneous issue, and we need to combine drugs. We just need to do it more thoughtfully than perhaps we've been doing in the past. Couldn't agree more. I want to change the paths for just a moment. To my knowledge, you are one of the few and maybe you were the first oncologist who's been both a cancer center director at Georgetown's Lombardi Cancer Center but also a chair of medicine. You've been at two major academic centers, here at the University of Michigan and University of Miami. Why do you think there have been so few oncologists who have been chiefs of medicine, chairs of medicine? Well, your personal favorite institution, UT Southwestern, would be an example as well of a chair of medicine who's an oncologist. Right. But no particular reason comes to mind. I think that the skill sets and interests of a chair of medicine, at least as it used to be, up until maybe about 10 years ago, were someone who actually wanted to, A, have somewhat less of a research footprint, which would discourage some people, and something less of the same focus on curing a specific disease, which would certainly describe a cancer center director. And I think that exactly explains some of my clinical interest in becoming a chair of medicine at Michigan. I went there, there are always push and pull reasons. The push reasons were that Georgetown was economically a disaster. And they had sold both the hospital and the clinical practice to a large non-profit community-based hospital. And I thought that would be, more or less, the end of the cancer center as I knew it in. And unfortunately, that prediction turned out to be, in many ways, correct. So there was push issues. I just didn't want to officiate over the deconstruction of the cancer center that I had helped to build. And in addition, I felt clinically, I was raised in the era of great chairs of medicine. I was raised in the era of Don Seldon and Dan Foster and A. Magee Harvey, and people who knew everything and would teach at the bedside and knew everything about disease. And frankly, I felt that breast cancer clinically, not emotionally and not from a research point of view, but clinically is relatively straightforward and not that complicated. And I wouldn't say I was bored. But I was looking for a new challenge. And I thought the notion of really trying to bring other areas to bear in terms of my research would be fun. And so I was thrilled to be chair of medicine. But I don't think that's necessarily the career path that many oncologists or any other subspecialist would want. Which did you enjoy most, being cancer center director or being chair of medicine? Unquestionably, being cancer center director here at Georgetown. It was the thrill of a lifetime. When I came here, there were three people in the division of hematology, oncology. Two of them immediately left. And by the time I moved to Michigan, the Department of Oncology that I had created had more faculty than all of the basic science departments at Georgetown combined and more research money than all of the basic science departments at Georgetown combined. It was tremendously happy, very successful. And I felt we were doing really wonderful things. It was just a fantastic time, just like that, which is one of the reasons why I've come back. And I was going to say, although Georgetown did fall on hard times. My opinion is grown back into a major institution. And I'm sure they're happy to have you back. So we're running out of time. I really just touched the surface of many of your contributions. In addition to your scientific contributions, you really touched on it. You've been one of the most prolific mentors in our field in my opinion. I looked over your CV. I count at least six cancer center directors. I think five, four PIs and probably hundreds of others who are proud to have been under your watchful training eye, by the way, including myself, in our careers. So of all the things you've done, your science, your administration, your mentoring, we've touched on all three of those. How do you want people to remember Mark Lippman when it's all said and done? So there's a wonderful joke about that. These three guys are standing around saying what would they like to hear said around their coffin when they're dead. And one guy was a teacher, and he says, you know, I'd like them to remember what a wonderful teacher I was, how I helped people. And another guy's a physician, and I'd like to hear if I'm lying in my coffin, them say, what a wonderful physician. He did everything for his patients. The third guy says, what I'd like to hear is, look, he's moving. So it's hard to-- right. I am certain that the place that I feel most happy, it's not even a close call, is the ability to have played an important role in helping people's careers succeed. I mean, I'm something of a tough guy. But I have been, I feel, very willing to see people grow up and leave the nest and keep them nurtured and look after them for many additional years in their career and enjoy those relationships. It's incredibly enriching. Well, I also have to say there are hundreds of thousands, if not millions of women who have benefited from the contributions you and your colleagues made 50 years ago at the NCI and since then. I've tried to make it clear through all these podcasts how much we owe all of you for what you've done and where we are now. And the reason we're doing this is so people don't forget about those things as we move into medical economics and some of the other things that I think are less fun. So it's time to conclude here. I want to thank you for taking your time. And again, thank you for all you've done for the field, for those of us who've trained with you, and again, mostly for our patients. And I hope you've enjoyed this conversation as much as I have. Very much, Dan. Thanks for including me in this podcast. Until next time, thank you for listening to this JCO's Cancer Stories, The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or a review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe, so you never miss an episode. JCO's Cancer Stories, The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.asco.org.

A doctor finds compromise with a patient for one last gamble. TRANSCRIPT The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] Welcome to JCO's Cancer Stories-- The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org. "The Gambler," Katherine E. Reeder-Hayes. "All he wanted was to go to Vegas. I knew Josh only at the end of his life, far into his story, after an old man's cancer had already wreaked havoc on his young body. At the age of 29 years, he lay in an intensive care unit bed, tethered to the wall and to his many medical providers by high flow oxygen tubing and intermittent and continuous positive airway pressure to deliver as much oxygen as possible to his disease swamped lungs. His outpatient oncologist told me that like many adolescent and young adult patients with cancer, his attitude toward cancer treatment had been somewhat cavalier. He missed some appointments, declared he needed a day off on his birthday, and so on. But lately, he had been doing his best to make it to the clinic, and his oncologists had already tried two successive lines of therapy for his metastatic esophageal cancer. On his admission, scans showed striking progression of his disease in a short period of time. My oncology consult team was called in to assist with goals of care. One of our first orders of business was to deal with the question of his code status. As usual, I started the conversation by sharing what I had observed on his scans. My concern that his cancer was now at a point where more chemotherapy would not change its course, and my expectation that his lungs would soon become unable to take in enough oxygen, even with maximum external support. I explained that if our other best efforts failed, the only way to deliver more oxygen would be to intubate him and use a ventilator. This conversation is usually somewhat of an art form, a gradual process that can evolve over days as I answer questions, elicit the patient's goals and values, offer emotional support, and give the patient time to think. But in this case, my powers of persuasion had barely gotten warmed up when the patient interrupted me with a stern look. Doc, if you put me on a ventilator, am I going to die on a ventilator? I paused. This seemed to be a direct question that required a direct answer. Yes, Josh. I believe that you will. OK, there is no way that I'm going to die on a ventilator. Do not put me on one. A couple of days into his hospital stay, as we toyed with antibiotics and tried to optimize anything fixable that might affect his breathing, while discussing whether getting him even as far as an inpatient hospice unit was feasible, we got a call from the ICU team that the patient wanted to leave. At first it seemed ludicrous. I quizzed the unfortunate fellow leading our team. Leave? He's on 80 liters per minute. What do they mean leave? Did they make him mad or something? We sped to the bedside. The ensuing conversations were lengthy and many. Patient and palliative care team, patient and ICU team, patient and family, patient and oncology team. The upshot was pretty simple. Josh's big wish had been to go on a trip with his father. His dad had supported him a lot through his illness, and they had grown closer than before. The initial plan was to visit Las Vegas. However, flying was now out of the question. Instead, they had planned a weekend trip to Nashville to stay at a fancy hotel and visit the honky tonks. The trip was supposed to have taken place the week that Josh was hospitalized. After mulling it over, he had cooked up what he saw as a compromise. He would leave the hospital and drive to a casino town approximately three hours away for one last great weekend. He informed me that he had won $1,500 betting on basketball from his hospital bed to fund the trip. And a GoFundMe page was apparently doing well. This influx of cash, in his opinion, erased the major barrier to the feasibility of his weekend plans. As far as I could discern, there was no plan for Monday. I'd taken care of many patients near their end of life who decided to take gambles, wise and unwise, but I had never been faced with one who wanted to gamble in the literal sense. We discussed the many potential downsides to his plan. The amount of oxygen we could deliver through a portable tank was vastly less than his current need, meaning that he would rapidly become hypoxic. He might die in the car. He might feel so bad by the time he arrived that he would not be able to enjoy it anyway. The resort was at a higher altitude, and I had little idea whether that change would worsen his oxygenation. He might collapse in a public place, alarming strangers and traumatizing his family members. He might die alone in a hotel room. I couldn't guarantee that paramedics would honor a "do not resuscitate" form stapled to the shirt of a young, healthy looking man. I couldn't even guarantee that we had a stapler on the unit. Hospice does not, I am almost certain, serve casinos. I called a psychologist who had worked with Josh regularly in the past, hoping for some backup from someone who had an established rapport with him. I resorted to some dramatically nonmedical language in my attempts to describe the patient's state of mind. He basically has a mental image that he wants to go over the cliff, like the last scene of Thelma and Louise. But this isn't a movie. Patients with cancer don't die by driving off a cliff. He's going to scare some hotel manager out of their wits. He doesn't even have a plan for what to do if he makes it back. The kindly psychologist agreed to evaluate the patient, although it is possible he may have been evaluating the oncologist as well. I began my conversations with Josh assuming that either he had not thought of these things or that he was in denial about the severity of his illness. Thinking back to our ventilator talk, however, I gradually realized that he was not, generally speaking, that sort of patient. I began slowly to wrap my head around the fact that this patient was not afraid, at least not of the things that I feared on his behalf. It was not that he didn't believe the scenarios I presented. To him, dying on the floor of a casino after a great night out was not the worst possible scenario. Dying in a cage in our ICU, the last days of his life orchestrated by others and mimicking the death of a man three times his age, waiting around in the least fun place on earth for his time to die, that was what scared him. The things that I would want for myself at the end of life-- quiet and calmness, being surrounded by loved ones, help to ease my physical symptoms-- were not things that would comfort him. I was not going to make him a middle-aged man in the course of three days in the ICU. And quite quickly, I began to like him for it. One has to admire the spirit of someone who can hold out against such a large team of experts telling him how he ought to die. Slowly, with almost audible creaks from our collective old age, the team turned its focus to making the most of Josh's plan. An oxygen tank and wheelchair were procured. Several copies of a large yellow form with a "do not resuscitate" order were signed. The palliative care team provided oral morphine for air hunger. The primary oncologist and nurse urged Josh and his family to contact them immediately if he made it home so that they could mobilize hospice to keep him from returning to the hospital. We all wished him good luck. As I pressed the button to leave the ICU on the last day of Josh's stay, a thought occurred to me. I turned and walked back into the room. Hey, Josh, there is one more thing I want to ask you. His face took on a good humored but slightly exasperated look, the look of the teenage boy bracing himself to endure one more well-intended mom lecture. Doubtless he thought I'd come up with one more excellent reason why he should not carry out his plan. Yeah, he said. Well, I sometimes write stories about my patients. Usually I write about people I've taken care of who taught me something important or made me think about things in a different way. And I think that one day I might want to write about you. Would that be OK with you? He straightened up in the bed, pushing his hands under himself in the effort to be more upright. Yeah, I'd like that. But just one thing, you have to use my real name. No pseudonyms. And so I'm telling Josh's story, the story of a patient who is young enough and reckless enough to tell us all exactly how he wanted to live the rest of his life, even when his plans did not fit into his medical team's boxes. Josh made it to the casino. He sent our fellow picture of himself surrounded by what seemed to be groupies. I'm told that he won $1,100 and bought his father a ridiculously large television. He lived for six days, long enough to return home and die comfortably with hospice care. Somewhere I sense he's laughing at me. To the end, his gambles paid off. For our patients at the end of life, how often do we try to assign them a pseudonym, one that fits neatly into our medical boxes? And do we know how to listen when they ask us to acknowledge their real identities and to help them conclude their lives in the way that fits them, not in the way that would fit us? Perhaps we too can stand to take some risks. I am grateful that I got in one last gamble with Josh. That, believe me, is his real name." [MUSIC PLAYING] With me today is Dr. Katherine Reeder-Hayes, who is an assistant professor of medicine at the University of North Carolina, and the author of "The gambler published online July 30th of 2019. Welcome Katherine. Thank you. Thanks for asking me. You are most welcome. You are a masterful storyteller. "The Gambler" is such an incredible story of a young man with cancer who is so determined to live the end of his life the way he wants to, on his terms. And he sounds like he taught you a powerful lesson. Tell us a little bit about Josh. Sure. So I think Josh was challenging to me as a clinician for a reason that I think many of us identify with. I didn't know him very long. And sometimes I think, as impatient physicians, we are faced with situations where something dramatic is happening in a patient's life, and we are the provider who circumstantially needs to stand with them at that time. But we really don't know them. And we really don't have a relationship or a prior knowledge of them to draw from. And so I really felt like I spent the first few days that I was caring for Josh really just trying to figure out who he was. And particularly, as a younger patient, I think most of us as oncologists care for midlife and elderly patients a lot. And our skill sets at caring for younger patients, particularly those of us who care for solid tumors, are maybe not as honed, or not as sharp, or it's been a little bit longer time since we were in that person's shoes. So just by virtue of the fact that he was young and he was male, he wasn't a patient that I could necessarily put myself in his shoes or claim to be knowing where he stood, just from a demographic standpoint. But I think it's always easier in these difficult situations when they can be diffused with humor. And Josh was a very funny person. And so I think that was something that he and I had in common immediately. And I think that that initially helped to lighten a little bit what was otherwise, obviously, a very dark situation. One of the points you make in the essay is that Josh taught you to listen more deeply. And one of the themes in the essay, and one that you just alluded to, is the fact that his youth made him so special. Can you tell us a little bit more about what you learned about listening deeply and attentively to young patients who are faced with a horrible cancer and nearing the end of their lives? Sure. So I think as a 40-something myself, I hate to think that I am set in my ways, because I think of being set in my ways as something that describes an older person. But I think as physicians, we get set in our ways pretty quickly. There is a culture to our hospitals. There's a culture to the way that we take care of patients. There's a power dynamic where the physician or the provider in the hospital setting is the one in charge and the patient is the one taking advice. And I think one of the things that was good and challenging about Josh is that he didn't really sign up for that. So he didn't want to do things the way things are usually done in the hospital. And a patient who reacts like that, I think if we're at our best, makes us go back and question, well, why do we do this this way? Why do we have this rule? Why do we usually try to discharge the patient to hospice? Well, why couldn't he leave the hospital hypoxic? What would be so-- what would be bad about that, right? And thinking through not only what we usually do, but what could we do? And so I think that was one of the things that I enjoyed about taking care of Josh was that he pushed me to think about not only the way we usually do things, but the way that things could be done. And I think that had something to do with his youth and just how flexible his mind was as a 20-something. So let's go back to this theme of the power dynamic here that you just talked about and that also is clearly developed in your essay. You describe finding Josh sort of tethered to a wall. And then you describe to Josh what end of life looks like in a hospital and in intensive care settings and so on. And he basically rebels and begins to work on this power dynamic by saying, absolutely not. I will have none of this. What did it take for you, as the team leader and as the professional who did not have a long standing relationship with Josh, to absorb all this? And how did you respond? What did it do to you? So I think patients have two things on their side, or at least Josh had two things on his side in this power dynamic that were powerful. I think one of them is that the patient always has the power to refuse, right? So sometimes that's the only power patients have left to exercise is their autonomy, their ability to tell the team no, this is my body, and I'm not going to do that. And I think that's something that Josh was exercising to feel like he was regaining some control of the situation. And for patients in extreme situations like this, they also have the power to command attention as a dying person. I think as a society and as providers, we have some respect for the immense value of those last days of life. And so I think sometimes we're more prone to listen to a patient and to their wishes and preferences when they have that persuasive argument, that these are not just any five or 10 days of my life. These are the five or 10 days of my life. And so I think those were the things that Josh had on his side, at a point where perhaps we weren't on the same side-- although I like to think we ended up on the same side-- that were persuasive to me and to other people that we needed to think more carefully about how he wanted to do things. And whether the requests he was making really, really weren't feasible or whether we did just hadn't thought creatively enough about them. I think Josh was lucky that you were the attending, because sometimes what I've seen colleagues do is actually sort of get-- bear down on their position. And sometimes this could even rise to a confrontation. And it seems you absorbed the message, empathized with Josh, and then worked with him to help him get his way. Is that a correct understanding of what happened? I hope so. I hope that that's what I did. I think I was lucky in my team. And I say that to say, first of all, that I was paired with a fellow who was a very warm person, a person who is extroverted and just enjoys getting to know people. And she was, of course, younger and more of Josh's contemporary. And I think they had a good rapport. And so that kept the tone of the team's interactions with him more friendly and warm and collegial, as opposed to I think sometimes these things can get confrontational. Although I think we should always strive to not have them be confrontational. I think the fact that Josh was just a very likable person also helped. He was putting forth his requests in a forceful way, but he wasn't angry. He wasn't mean. He wasn't abusive to anyone who was taking care of him, even though he really had every right to be. And so I think his own attitude and personality made it easier for things not become confrontational. And then in the background, there was Josh's primary oncologist. And she was the person that I phoned up and said, oh, you have to let me get to know this person better. You have to tell me some background. Is he crazy? Has he been a rational decision maker in the past? Fill me in. And she was very supportive of us trying to do, to the extent that we could, what Josh wanted. And even to accept the responsibility for if he left the hospital and traveled and then found that he urgently needed to be plugged into hospice. When he made it back to his home, if he did, that she was willing to take on the downstream consequences after he left the hospital if he needed further care. As opposed to pushing me to definitively solve the problem in the hospital as though he were a problem. So I think I was fortunate in the whole team that was around me and was connected to him as well. So here's this young man who says to you, there is no way I'm going to die on a ventilator, and I want to gamble. And there he goes to gamble. So we have the two levels of gamble-- the gamble that this is going to work out and this young man who was in the hospital on 80 liters of oxygen is going to be able to take the trip, and then the literal gamble. So my question to you, and something I'm sure you've thought about is, what if his gamble had not paid off? What if he had had a horrible death someplace outside of the hospital or in the casino? How did you think about that? So I think I certainly did think about that. And I have had other patients who made decisions at the end of life that wouldn't have been my decisions, and that I was sad about. And it hasn't always worked out. And they have had deaths that I thought incorporated more suffering, either for themselves or for loved ones, than I was wishing for them. And I think although we were able to rejoice for Josh and be so happy for him that his gamble did work out for him, and that was certainly a happy ending to this story, we didn't know that at the time we were making the decisions. And so I think that is the hard part of truly letting patients have autonomy, is that we may be able to see a future, maybe not the definite future, but a future that isn't a happy ending. And that to truly respect people's choices means being able to let them go anyway, certainly with informed consent and with making sure that they understand your concerns. But I think that's part of listening to patients is that when we get answers we don't want to hear, if we're confident that the patient has listened to us and understands our side or our concerns about them, then we have to give them that same respect in return when they're telling us, yes, I've heard you. Yes, I understand your points. But that's not-- that's not me. That's not my decision. That's not what I want to do. And I think it's hard. It continues to be hard. Let me go back to this idea of Josh-- Josh's youth influencing this whole process. And in what ways do you think that being very young shaped these findings and these conversations? And how would you react to a middle-aged Josh? So I think being young made Josh courageous in a way that perhaps he wouldn't have been if he was middle-aged, in a few ways. I think even for a person who is physically very ill and has plenty of evidence that they have advanced disease, I think it is very difficult for a 20-year-old to truly imagine themselves dying. And that's appropriate in most circumstances to feel a little bit immortal when you're in your 20s. I think that can be a bad thing if it causes people to be in denial. But I think it also imparts a kind of bravery. I think the choice that Josh made was a courageous choice. I think also by being young, many times that's the time in our life when we don't have as many ties to people who are dependent on us, right? And part of what enabled Josh to make the choice he did, he did have some family members and he had some concern for them and their concerns and emotions, but he didn't have a spouse whom he had a commitment to and had to think about their feelings. He didn't have children who needed to be considered, whose mental health needed to be considered, their ability to say goodbye in a certain way or to witness or not witness certain things. So I think that gave him a freedom. So I think a middle-aged person might have different ties, different concerns, and also different kinds of fears about the end of their life. So those might make the story play out differently. But I've certainly had middle-aged patients who also didn't want some of the things that we would imagine they wanted at the end of life. And that's OK too. That's a deep reflection, and I thank you for that. How long ago did you look after Josh? I believe we're coming up on a year. And how long did it take you to process through it and turn it into this beautiful essay that's full of humor and respect and love for Josh, by the way? Thank you. I would say it happens in stages. I think anytime I lose a patient in a particularly memorable or emotional or even traumatic way, there are stages. In the immediate term, I think probably the most therapeutic thing for me almost always is talking to colleagues. And in this case, I think there was some joy and humor in the reflections with colleagues about taking care of him and about the things about him that had really stood out. I think that's one stage. Because being a writer, I often will put something on paper about an experience with a patient that's been particularly meaningful pretty quickly, I mean within weeks perhaps, but it's not usually a finished something. I kind of jot down what really struck me, or perhaps the outline of something, or a message that I got out of that situation. And then I sort of tuck it away and then go back to it later. And I think that's sort of the process I went through with this story over the course of a few months. That's incredibly helpful. Thank you for that. My final question is about your fellow. Was your fellow OK with how the story unfolded? I think she is. And I don't think she would mind my saying her story and his story intersected in an interesting way in that, at the same time that we were doing this end patient consultation together, she was making some hard decisions about changes in her career planning, and in the direction that some people were pushing her to go. And that she had been encouraged to develop her career and her future plans in a certain direction, and she was coming to feel that that wasn't the right direction for her. And really needed to pull the trigger on just saying that out loud and making some changes in her plans for training so that she could get back to a place where she really felt like she was doing something that was right for her. And so in a way, I think Josh was an inspiration in that sense to do something that is hard and may feel scary, but that ultimately is going to be true to who you are. So it was, I think, a good thing for us to all work through together in that sense. Well, thank you, Katherine. It's always a pleasure to read your work and a real pleasure to have a chance to have this conversation. Well, thank you so much. I really appreciate being invited. Thank you. You're very welcome. Until next time, thank you for listening to this JCO's Cancer Stories-- The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories-- The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all of the shows at podcast.asco.org. [MUSIC PLAYING]

Dr. Hayes interviews Dr. DeVita about his role as Director of NCI and his time with CHOP and MOPP. Dr. Daniel F. Hayes is the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center. Dr. Hayes' research interests are in the field of experimental therapeutics and cancer biomarkers, especially in breast cancer. He has served as chair of the SWOG Breast Cancer Translational Medicine Committee, and he was an inaugural member and chaired the American Society of Clinical Oncology (ASCO) Tumor Marker Guidelines Committee. Dr. Hayes served on the ASCO Board of Directors, and served a 3 year term as President of ASCO from 2016-2018. TRANSCRIPT [MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] Welcome to JCO's Cancer Stories, The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the role of cancer care. You can find all of the shows, including this one, at podcast.asco.org. Welcome to Cancer Stories. I'm Dr. Daniel Hayes. I'm a medical oncologist and a translational researcher at the University of Michigan Rogel Cancer Center. And I'm the past president of ASCO. I'm really privileged to be your host for a series of podcast interviews with the founders of our field. In this series of podcasts, I hope to bring appreciation of the courage and the vision and most importantly the scientific background among the leaders who founded our field of clinical cancer care over the last 70 years. I hope by understanding the background of how we got to what we now considered normal in oncology, we can all work together towards a better future for our patients and their families during and after cancer treatment. Today, my guest on this podcast is Dr. Vincent T. DeVita, best known as Vince. Dr. DeVita is generally considered one of the so-called Gang of Five, including Doctors Canellos, Young, Chabner, and Schein, who I've been trying to get on for this podcast in the future, all at the NCI, and who brought many of the concepts we now accept as standard into the clinic in the 1960s and '70s. Dr. DeVita is currently a Professor of Medicine and Epidemiology and Public Health at the Yale School of Medicine. I think it's also fair to say, Dr. DeVita was instrumental in the passage of the 1971 National Cancer Act. And I want to hear more about that as we get into this. He was director of the NCI and the National Cancer Program from 1980 to 1988 and then moved to Memorial Sloan Kettering Cancer Center as Physician in Chief and subsequently became the Director of the Yale Cancer Center in 1993. Among his many honors-- and I don't have time to go through them all-- but he has served as President of the American Cancer Society. And I think most dear to me, he was President of ASCO in 1977 and 1978. Dr. DeVita, welcome to our program. Nice to be here, Dan. I've done a little background. I know you grew up in the Bronx. And I know you went to William and Mary for undergrad and George Washington Medical School. And I also read what I didn't know, which is that you did your internship and residency at the University of Michigan. We're recording this just before the NCAA basketball tourney. And I have to say, go blue. We're all excited here in Ann Arbor about our basketball team. [LAUGHTER] What I'm really interested in is, were your parents physicians? Or what made you choose medicine out of the Bronx? Well, no, my father was a banker. And my mother was an interior decorator. So it was kind of a funny mix. But I think it's kind of peculiar. I was growing up, and my mother-- I tell this story in my book. My mother was kind of frightened by the fact that I really, as a seven- or eight-year-old kid, really thought the guy who delivered the ice-- in those days, we had ice boxes-- was terrific. And I wanted to be like Nunzi the iceman. And she panicked and said, no, no. You're going to be a doctor. And every time someone asked me what I was going to be, I just said I was going to be a doctor. And when I went to school, I decided I'd be a doctor. It was sort of Mama driving me in that direction. So you had a choice of being an iceman or a doctor [LAUGHS]. Right. I like-- I mean, biology was always a favorite subject of mine. So it was a good fit. And tell me about how you ended up going to the NIH and choosing oncology. Was that serendipitous? I talked to Bob Young the other day. And he said, fundamentally, he hadn't planned to be an oncologist and got to the NIH and liked it. Was that your role, or did you know you wanted to do cancer from the start? No, I was going to be a cardiologist. In fact, when I was a first-year resident, I did cardiac catheterizations and was a co-author on a paper that for a long time was well-cited in the field. So I applied to both the Heart and Lung Institute and the Cancer Institute. And those are very competitive positions. And I had an interview with Robert Berliner, which didn't go well [LAUGHS]. So I didn't get invited to the Heart Institute. And I went to the Cancer Institute. And when I walked in, Dr. David Rall was the chief of the pharmacology branch. And I asked him if I could work on the pharmacology of digoxin. And he, wise person that he was, said, sure. Go ahead if that's what you want to do. And I was surrounded by people who were working on anti-cancer drugs. And I actually became fascinated with them. And it was only a few months, because I was also on the wards at the time, that I said, oncology is the way to go. It was an exciting new field. It was kind of a funny field in those days. But I found it exciting, so I switched. So just to give you a plug here, I think many of us know that you wrote a book, The Death of Cancer, published a couple of years ago, co-written with your daughter Elizabeth by the way. But in it, you described a number of things. And one of those that I loved were your stories about Gordon Zubrod. And I trained with Dr. Frei at the Dana-Farber. He always had great things to say about Dr. Zubrod. And I wonder if you could tell the folks listening in who he was-- I think most people don't even know that-- and the impact he had on our field. Yeah, I used to call him the great umbrella. The field was very controversial at the time. And so the people who were doing things like saying, I'm going to try to cure this cancer-- leukemia in Frei's case and Hodgkin's in our case-- were considered just a little bit this side of insane. He was somebody who was distinguished. Now, Frei had-- Zubrod had been at St. Louis as a professor and also at Johns Hopkins. And he was a very distinguished-looking man and a very polite, careful man. And so he used to provide sort of the umbrella for all of us, so that [INAUDIBLE] he'd take the heat. And we could go on and do our work. So he was-- he did enormous number of things. I mean, the whole clinical trial structure was established by Gordon Zubrod. The phase I, II, III trials was all done in a paper by Gordon Zubrod in the late 1950s. So I think he was just a guy who had foresight and was a great leader. I ultimately took his job. He got tired of bucking the bureaucracy and retired and went to Florida as the director of their cancer center there. So I got to know him pretty well. And like Frei, I have great admiration with him. I mean, it's interesting how we take phase I, II, and III for granted. And when he came in, and not too long before you came in, those things weren't-- nobody really knew how to do this stuff. Doctors Frei and Freireich were already at the NCI when you got there, correct? Yes, indeed. Yeah, they were. Yeah. And so they must have been inspirational. They were, and especially Freireich. Freireich was always on the wards. And Tom didn't come over to the wards very much. He was sort of the direct-- he was chief of medicine. And Freireich was the chief of the leukemia service. So we saw Freireich all the time. Tom came over once in a while. And Jay was a super doctor. And it was very hard to stay ahead of him. You'd get an x-ray on a patient. And he'd call you up 20 minutes later and tell you what it was. He was already down looking at it. So you had to stay on your toes with Jay. And of course he was, as everybody knows-- Jay-- he was a bold guy, who-- I mean, he looked like he could walk through a wall. So he frightened a lot of people. But he was an inspiration. So I'm always grateful for what Jay Freireich taught me. There's a great story in your book, that Dr. Frei has told me as well, about the first platelet transfusion at the NCI. Can you elaborate on that? I think most folks don't know about that story. Platelet transfusion was, again, one of those radical departures. But Freireich reasoned that we were losing more people from bleeding than we were from leukemia. So he worked out a way of plasma pheresing people and collecting platelets. And we didn't have a lot of the expertise we have now. And they came in quart bags. I mean, they were plasma bags that were huge. And we were treating little kids. So they were-- throwing them into heart failure was a problem. So it was pretty radical. And he was told to stop doing it by the clinical director at that time. And in fact, he was told that if he didn't stop doing it, he was going to be fired. And he told me-- he said, I went back to my office, sat down, and thought about it. And I decided I didn't want to work at a place where I couldn't do that. So I just kept on doing it. And the person who said he was going to fire him never did. But that was Jay Freireich. [LAUGHS] He believed so strongly in it. And when I went to Yale right after I left the Cancer Institute-- I finished my residency up there. And I told them-- when I saw leukemia patients who were bleeding-- and I said, what you should do is platelet transfusions. And they said, they don't work. And I said, I used them. And I saw them work. So I think we're losing patients unnecessarily. It was just very controversial. So eventually I left the program. I was going to take a residency and then a fellowship in hematology there. And I decided to go back to the Cancer Institute where these adventurous things were going on. Times are different now, of course. Dr. Frei once told me a story that he-- you may have been with him-- that he was making rounds in the clinical center. And in those days, apparently, the adults and the kids were in the same ward. And there was a child with essentially no white cells, who'd been induced for leukemia, and a man next to him with CML. And so-- and actually, when Dr. Frei told me this, I kind of said, I don't think I want to hear this story, because he said, well, you know, the kid didn't have any white cells. And the guy next to him had way too many white cells. So [LAUGHS] I said, tell me you didn't do this. He said, yeah, we took platelets out from the guy and gave them to the kid. And the kid got better for a while. It was really exciting. I thought, boy, you don't see that anymore. Yeah, I mean, it was a very reasonable thing to do, because the white cells in a chronic myelogenous leukemia patient work very well in terms of fighting infection. Yeah. So there was no reason. And the kids, otherwise, wouldn't survive. And so, yeah, I was there when we got these-- we gave these. I mean, they weren't easy to give, because they stuck in the lungs. And we didn't have HLA matching at the time. So they were-- a lot of them were mismatched. But for a while, they were effective. And then we went to collecting white cells from normal people. But the white cells had not worked as well as platelets had worked. Platelets have been a lifesaver. Now it's a couple of hundred million dollar business each year now. So it's routinely done, as many things that Jay started are routinely done now. Of the many things for which you are credited, I think it's the use of combination chemotherapy for Hodgkin's and then subsequently non-Hodgkin's that is one of your lasting legacies. There must have been a lot of drama around doing that. I mean, I think we all just assume you're going to start protocol. You write the protocol. You get funding for it. And you go forward. But can you give us some stories about sitting around at night and thinking about how to do this? Or how did you choose those drugs and why and how to give them and the obstacles that were involved? Yeah, actually, it was a very complicated process. And we didn't have the information we have now. What we had was-- I was doing this with Jack Moxley, who left active medicine and became a dean after he left the Cancer Institute. But we're still in touch. And Jack was working with [? Sy ?] [? Perry ?] using the new isotope, tritiated thymidine, looking at the bone marrow of CML patients and also of mice. And I was doing the same thing with the leukemia 1210, which was a model that we used for chemotherapy all the time. And what we were trying to do was figure out the kinetics of human versus mouse marrow, so we could develop schedules that humans would survive. We quickly found out that you can't use the mouse as a model, because their blood cells went through a kinetic phase about half the length of humans. So you had to schedule in a different way. So we worked that out. And then we looked at very simple-- something that people really ignored is that when you give a chemotherapy agent that is toxic to the marrow, you don't get abnormal blood counts right away. For a week, you'll have a normal white cell. And then on day seven or eight, it begins to fall, because the storage compartment in the marrow works well for about a week. And then there's no replenishment. And the white count falls. So between the two, looking at the marrow and looking at the white cells in the periphery, we came up with a schedule for MOPP. And then the other things were simple. We just decided that you'd have to have three or four drugs that worked by themselves. There had been people doing combination chemotherapy before-- Tom Hall in Boston and [? Alan ?] [INAUDIBLE] at Yale. And their rationale was they're looking at a sequential biochemical blockade. But they ignored whether the drugs actually worked against the tumor, assuming that if you gave them together, that the biochemical blockade would dominate. And it didn't work. In fact, it was very discouraging. But we decided the way to do it was take drugs that had some activity in the disease and use them together and use them in full doses in the schedules that we worked out because of the prior work I was telling you about. So it took a while to put that together. And then Jack Moxley and I used to do this at a bar in Georgetown called the Lehigh Grill, where we used to-- my cardiology desire-- I used to go to Georgetown where there was a wonderful cardiologist Proctor Harvey, who used to hold Thursday night sessions. You had an auditorium that was wired. So you could hear heart sounds. And after that, we'd go to the Lehigh Grill. And we sort of put together the protocol. When we presented it to Tom, he thought it was a good idea. But the other people around him thought it was insane and really tried to stop it. Tom Frei? Yeah. Tom Frei, yeah, yeah. Well, Tom was supportive. Yeah, Emil Frei was his real name. But everybody called him Tom. Yeah, he was supportive. But the people around him and my immediate boss was very much against it, because he thought it would interfere with the protocol that they were doing and so forth. So Tom worked out a solution worthy of Solomon. He said, OK, we could do-- the magic number for phase I trials in those days was 14. If you got nothing in 14 patients, then you didn't go any further. So we could do 14 patients with the first protocol, which was called MOMP-- M-O-M-P. And we had to do the workups ourselves. We couldn't use other colleagues to work up the patients. And we had to go get the patients ourselves. So Jack Moxley and I did all those things. And the results were very encouraging. And then Jack left. And I sat down and decided that we'd put procarbazine. I was working on procarbazine. It was then called [INAUDIBLE]. And I was working on it and doing the pharmacology in the phase I study with it in Hodgkin's disease. It was a promising candidate. So we put it in. And that became MOPP. Also in those days, six weeks of therapy was it. They didn't get more than six weeks. We reasoned that the marrow problems would be acute. But you'd have to give it probably for a long period of time to affect the tumor. So we gave it for at least six months or to a complete remission plus two months. And we assumed that there were cells left after we couldn't see them. So it was a lot of good thinking that went into it that turned out to be correct, because most of the-- since then, a lot of protocols follow the same sort of routine. And it really works for a lot of cancers. But it was controversial. I went to the AACR meeting. This was before ASCO. And I presented it as an abstract. And David Karnofsky, who was sort of a god at that time at Memorial Sloan Kettering, just tore me apart. And what was I doing using the term complete remission for a solid tumor. He said, that was a term that was used in leukemia. Now, I didn't say it. But I'm thinking, the reason you use them is you can get complete remission. So we had complete remissions. And I was kind of shaking with the microphone in my hand at the time. So it was a scary but it was a good experience. I have to say-- So it just gives you an idea that people were not receptive [INAUDIBLE]. Those of us who are junior to you can't imagine that you were intimidated by somebody else [LAUGHS]. Well, I was a youngster, then. I was-- Jack Moxley and I, I would say, thinking back, we were cocky. But the big guys in the field could scare me. And Zubrod was a-- I mean, Karnofsky was a big guy in the field. Yeah. He just had a hard time getting out of the leukemia mind frame. And so of course, we've used complete remission since then in any kind of solid tumor where you can get one. In your book, you have a great quote that you presented somewhere. And Dr. Frei was there. And Wayne Rundles was there. Wayne, of course, has been at Duke for 100 years. And he said, do your patients speak with you after you're done? Well, Wayne Rundles-- when he first saw the MOPP protocol, Wayne Rundles said, that's nonsense. He said, I get the same thing with nitrogen mustard by myself. Well, nobody had ever got that with nitrogen mustard. So we actually had to set up a controlled trial and do it and prove that MOPP was better. So when I presented it when we were first starting it-- at a meeting. Tom had arranged this meeting with all the bigwigs in the field. And when I presented it at that, everybody was sort of quiet. And then Wayne Rundles raised his hand. He looked pale. He raised his hand and said to me, Dr. DeVita, do your patients speak to you after you do this? [LAUGHS] So he-- a few years later when we were obviously getting good results, he invited me to grand rounds. And by then, we were good friends. And I was up on the podium. And after I gave the talk, he was sitting down below smiling at me. And I said, Dr. Rundles, if you remember, you asked me if your patients speak to you when you do this. And I can tell you that they do for a lot longer. So it was fun. But it was fun. He was a good friend by then. And I had great respect for him. Actually, he was a very nice man. He was. When did you start thinking that you had a success? Was it during those first 13 patients or 14 patients that you treated? I mean, was it obvious right away, or did you start [INAUDIBLE]-- Well, it was obvious-- --you were in the wrong place? We put-- no. We thought it pretty early, because we were worried. We put patients in reverse isolation. Nobody knew whether you were going to kill them if you gave them all these drugs together. And it turned out the first surprise was, yeah, they had the usual toxicity. But it really wasn't that bad. So it was doable. And the second was-- we had a small number. But we had-- something like 80% of the patients went into a complete remission. And I think nobody had seen that. Now, the question was, how long were they going to last? So we were optimistic. And when we put patients on it, there was no cure for them at that time. And we said, we're optimistic that this is going to be something that will last. But we don't know. And then by three years, it looked pretty good. And I think I presented the first abstract four years after we started. And by that time, we had relapse-free survival curves. And again, nobody before that time had presented relapse-free survival curves in any of the lymphomas. So by then, by four years, I think we felt we had probably cured some patients with the disease. I asked Bob Young this same question. Did you feel a sense of history at the time, that this was really historical? Or did that come later when you looked backwards? I think what people don't realize about those days is neither Freireich nor ourselves were treating leukemia and Hodgkin's disease. In other words, we weren't out to develop a treatment for those diseases. We were out to prove you could cure cancer with drugs, because nobody believed it. If you said that, they really thought you had gone balmy. So we were out to look-- so we knew if we could do it, it would be historic. So we were excited when we looked like maybe it was going to happen. By that time, when we had first reported it, the VAMP program that Freireich did, which was an historic program-- he only had 17 patients. And they actually never published a paper on VAMP. And I asked Jay why they never did that. And he said because he didn't think they would accept it anywhere. So but by that time, they were getting about a 50% complete remission rate going four or five years. And they were thinking they're curing leukemia. And we were getting 80% complete remission rates. So I think everybody felt that we were going to prove that you could cure cancer with the drugs. And we did. So yes, in a sense, we set out to do something that would be historic. And so when it happened, I think, it is. It was a sort of a door opener for medical oncology in Hodgkin's disease. I'd like to turn now for just a minute to your role in politics. You were pretty instrumental, I think, when the National Cancer Act was signed in 1971. And that also sounds like a TV drama to me. It sounds like-- and I know this anyway, but in reading your book, it was not clear that was going to get through. Can you give us some of the playground behind that and Mary Lasker's role and how that happened? Well, Mary Lasker played a big role. The MOPP program actually played a big role, because Mary Lasker was sort of working in the background. Cancer was always a cause for her. But when we did the MOPP program, there was a guy named Luke Quinn, who she had hired to be a lobbyist, who was sort of hidden in the American Cancer Society so they wouldn't realize it was Mary Laskers' lobbyist. And he was referred to me by Sidney Farber. And I didn't want to take him at first, because he was diagnosed as having gall bladder cancer. And I said to them, you know-- I said to Sidney Farber, I don't really treat patients with gall bladder cancer. And there was silence on the phone. And he said, (SOMBER, COMMANDING VOICE) you will take this patient. [LAUGHS] So I took the patient. And when I examined him, when he came down and I examined him, he had adenopathy in both axillae. And gall bladder cancer just doesn't do that. So I had to do another biopsy. He was not a pleasant guy. So it was not easy to do these things. I had to get another biopsy. And it turned out that my pathologist at the time, Costan Berard, when he compared the biopsy, he said, it's a lymphoma, clearly. It was a diffuse, large cell lymphoma. What they had done is, because Claude Welch did the surgery-- a very famous abdominal surgeon-- and he said it was gall bladder cancer, that the pathologist sort of assumed it was. And it was a compression artifact. Long story short, he went into remission. And Mary Lasker went gaga. Wait a minute. We got something here. And that was what pushed her to get her friend, Senator Ralph Yarborough, to put up a committee on cancer to come up with the Cancer Act. And-- So it must have been quite a day when President Nixon signed that. Yeah, well, it was-- I wasn't at the signing. I wasn't high enough up in the chain to be invited to the signing. But yeah, I have all the photos of him signing it. And later when I met him-- I have a picture in the book of he and I shaking hands and him looking like he's having a roaring laugh. People ask me what I said that was funny. And I have no idea. But when I asked him, I said what is your greatest achievement as a president? He said two-- opening up China and signing the Cancer Act. So he was-- Really? Yeah, so I think he was proud that he did that. That's a great story. Actually, the other story I had not heard, but read in your book-- I'd like you to tell me about your lunch with Mr. Featherstone. [LAUGHS] Featherstone Reid, his name was. Well, this was a very-- this was a regular occurrence. Mary Lasker, when she came to town, would stay with Deeda Blair, Mrs. William McCormick Blair, who was a Washington socialite and had a lovely house on Foxhall Road. And they would have lunches and dinners. And they always arranged it so that people-- the scientists sat next to somebody with influence. And this is how they influenced the Congress to put more money into the cancer program. So one time, I got a call in the morning from Deeda Blair, saying, I'm having a lunch. We'd like to have you there. And I said, gee, I-- it's too short notice. I can't do it. And she said, well, Mary really wants you to be there. Mary was hard to say no to. So I rearranged my schedule, drove down to Deeda's house. And there was a big black limo sitting in the front of the house. I went in, and they introduced me to Featherstone Reid. I had no idea who he was. And every time Mary would say, we want more money for research with leukemias and lymphomas. Vince, tell him about what's going on. And I would tell him about. At the end of the lunch, he left. And Mary and I sat down on the couch to have a cup of coffee. And I said, Mary, who is Featherstone Reid? And she said, he's Warren Magnuson's driver. And when she saw the shock on my face-- Senator Warren Magnuson was the chairman of the appropriations committee of the Senate. When she saw the shock on my face, she said, wait a minute. When Mrs. Maggie-- he takes Mrs. Maggie shopping during the day. And Mrs. Maggie-- he fills her with all this information we're giving him. And then Mrs. Maggie is the last person to put her head down on the pillow next to Warren Magnuson. This is the way she worked. She would take someone like Magnuson, who was a good friend, but she would surround him with extraneous people who would say the same thing. So it was sort of like subliminal stimulation for him. He was always hearing these positive things. And then he supported the program. She was a piece of work. I never got to meet her. But it sounds like she was a force of nature. She was. And of course, the Lasker Award is now named for her and her husband and sort of the American Nobel Prize. She's had such [INAUDIBLE]. Yeah, and our crew won it in 1972-- Frei, Freireich, myself, and other people for other things. So I'm very fond of Mary Lasker, obviously. It's just a wonderful story. And I got to know her pretty well, so. I have one other question. And I'm not sure you'll want-- if you don't want to go off on it, we can edit it out. But in your book, you talked about Howard Skipper and Frank Schabel. And Dr. Frei used to talk about them all the time. And I think it's worthwhile to bring them into the history of what we do. Did you actually work with them or collaborate with them, or just base some of your ideas on what they had in mind? When I was starting at the Cancer Institute, I thought Schabel worked at the Cancer Institute-- I mean, Skipper worked at the Cancer Institute, because I would be working in the lab. I was doing the tritiated thymidine studies on L1210 mice. And he would be looking over my shoulder. He was doing the similar studies, but he was just doing it with cell counts in the abdomen of the mice. And he thought that was good enough. And he was there at a weekly meeting we had, which George Canellos named the Society of Jabbering Idiots. It was a great, great meeting, actually. [LAUGHS] And he was there all the time. And my view and Tom's view differ a little bit on Skipper. I think he was a real driving force, that he did the studies in mice that we were doing in the clinic with people. And he actually-- in 1964, he wrote a paper showing that you could cure L1210 leukemia. It was the first example of curing a mouse with leukemia. And I think-- so it was sort of a feedback mechanism between the Cancer Institute and the Southern Research Institute. So and he did-- he used to do these booklets. And I think he published hundreds of these booklets. Some of them, we convinced him to actually publish as papers. But I have the collection. There may be 100 booklets he wrote. And he would take a concept that we were working on and then work through it in mice. It was very, very important. And he was a wonderful person. His only problem was he smoked like a chimney. But he was-- I liked Frank and Howard. Yeah, Dr. Frei had the entire set of monographs on his bookshelf in his office and would encourage us to come in and borrow them and read them and come back. And frankly, he basically predicted what you've done with combination therapy. He predicted adjuvant therapy working. There were just a number of things he saw in these mice that we've gone on to apply in the clinic. It's pretty remarkable, I think, so. Yeah, I mean, it's not only he predicted it. But he actually showed the concept worked in mice. So as we know, mice and human are very different [INAUDIBLE]. There was a guy in Boston, Stuart Schlossman, a very fine scientist. And he didn't like mouse models. And when asked what he would do when he saw a tumor-bearing mouse, he would say, I would step on it, because he didn't believe mouse models. And but Frank and Howard did experiments and made allowances for the difference between humans and mice. So it was always good to know. I mean, I have the summary he wrote on Hodgkin's disease after he saw the MOPP program. So I think they're very instructive booklets. So I kept them. Like Tom, I think that we sort of live by them. Well, thanks for discussing them. I think our listeners need to remember these two guys. They were great. We're running out of time. I've really just touched the surface of what you've done and contributed to the field. And the people you've trained is sort of a who's who of oncology, frankly. But at the end of the day, what's your-- I'll ask you the same question you asked President Nixon. And that is, what is your legacy? What do you want people to remember that Vince DeVita did? I get asked that question a lot. And I don't have one thing that I can say. I mean, I've been lucky in my career that I've had a chance to do many things. Being the Director of the Cancer Institute was wonderful. You could sit on top of the whole field and just sort of scan it and see what's going on. And it was very important, because you've become the spokesman of practicing physicians at the same time. MOPP, of course, was important. Putting out the first comprehensive textbook in the field and watching it-- we just came out with the 11th edition-- is also very exciting. So there-- we were the first to successfully treat Pneumocystis carinii pneumonia. And we reported it in a paper in the New England Journal. I mean, there were a lot of things. I'm best known, I think, for MOPP, probably, and the principles of MOP, which I'm very proud of. But there's so many that I have a hard time. I like opera. And people ask me, what's my favorite opera? And I usually say, it's the one I just saw. It's very hard for me to pick one opera. There's so many that I like. So I'm not dodging it. But I just never can say, well, it's this. That's very fair. Frankly, I think, without your contributions, I probably wouldn't be sitting here doing what I do. And I think there are thousands of us who would say that. So we're-- Well, that's very flattering. Well, not only are we appreciative, more importantly, there are a lot of people who are alive who wouldn't have been without what you and your colleagues did at the NCI that so many years ago, so-- [INTERPOSING VOICES] I was involved in the training of 93 medical oncologist. At one time, something like 40% of all the [INAUDIBLE] directors were our graduates. So they have gotten around. And that was good for the field. They went out with the same principles we were developing at the Cancer Institute, so that's very gratifying. Have you kept in touch with any of the patients that you're treated back at the NCI? I talked to Saul Rosenberg. And he told me he still sees people that he treated 30 or 40 years ago when he first moved to Stanford. We're writing a paper on the 45-year follow-up of the first 188 patients. Again, nobody has 45-year follow-ups. And we called every one of the survivors. And there's something like 60% or so of the complete remissions are alive. So I talked to some of them. But we had a nurse talk to a lot of them. And I got messages from them after the call. And some of them still contact me, after sort of an anniversary of their treatment. So yeah, I've kept up with them. The gratifying thing is most of them are suffering from the same illness as most people who are getting into their 70s or some of them 80s. They have hip problems and so on and prostate cancer. But there doesn't seem to be any really major increase in anything in these long survivors. Now, mind you, these were patients who got MOPP as their only treatment. And so when you see second tumors in these kinds of patients, it's usually patients who got radiation therapy plus MOPP. So these patients who are 45 years had just got MOPP. And they seem to be perfectly fine. That's remarkable. I love your comment that they are getting the same illness as the rest of us get as they get older. That's great. Yeah, we don't cure bad hips and bad knees and-- Yeah, we can't cure old age. When I was at the Dana-Farber, I had a patient who had been one of Sydney Farbor's original patients from the early '50s. And by this time he was obviously an adult. He was older than I was. And he was fine, as you've said. Although he said Dr. Farber kept treating him and treating him and treating him. And then finally, when Dr. Farber passed away, someone else picked up his chair. And they said, why are you still getting this? And they stopped it. Yeah. So he got a lot of treatment. I had one of Freireich's VAMP patients. She was a girl in her early teens. And she was a wildcat. But she had had something else, and it failed. And she was one of the first patients on VAMP. And she went into remission. And she stayed in remission. And I followed her for many years. She went to college. She got married. She had children. She brought her children in to see me. And last time I had any follow-up with her, she was in her 60s. And she was one of the really first long survivors of that particular program. So it's really neat to see these patients. And it's not rare for me to go to a meeting and have people walk up to me and say they got MOPP 25 years ago. Someone else gave it to them. And they're alive and well. So that's one of the great gifts of having a chance to do this kind of work. What a privilege. Well, I think we need to end. Again, I want to thank you for being on with us today and filling us in with some of these stories. Had really good feedback for my podcast series. And it's because of the people I've had on it. So thank you very much for all you've done. It's really good talking to you. And I look forward to listening to all your podcasts. [MUSIC PLAYING] Until next time, thank you for listening to this JCO's Cancer Stories, The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcast or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories, The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.asco.org. [MUSIC PLAYING]

Dr. Hayes interviews Dr. Young about his time with CHOP and MOPP Dr. Daniel F. Hayes is the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center. Dr. Hayes' research interests are in the field of experimental therapeutics and cancer biomarkers, especially in breast cancer. He has served as chair of the SWOG Breast Cancer Translational Medicine Committee, and he was an inaugural member and chaired the American Society of Clinical Oncology (ASCO) Tumor Marker Guidelines Committee. Dr. Hayes served on the ASCO Board of Directors, and served a 3 year term as President of ASCO from 2016-2018. TRANSCRIPT Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Dr. Hayes: Welcome to JCO's Cancer Stories, The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org. Welcome to Cancer Stories. I'm Dr. Daniel Hayes. I'm a medical oncologist and translational researcher at the University of Michigan, Rogel Cancer Center. And I've also had the pleasure of being past president of the American Society of Clinical Oncology. I'm privileged to be your host for a series of podcast interviews with people I consider the founders of our field. Over the last 40 years, I've really been fortunate to have been trained and mentored and inspired by many of these pioneers. It's my hope that through these conversations we can all be equally inspired by gaining an appreciation of the courage, the vision, and also the scientific understanding that led these men and women to establish the field of clinical cancer care over the last 70 years. By understanding how we got to the present and what we now consider normal in oncology, we can also imagine and we can work together towards a better future for our patients and their families during and after cancer treatment. Today, my guest on this podcast is Dr. Robert Young. Among many designations he has, my favorite I think for Dr. Young is that he was considered one of the, quote, "gang of five," end of quote, I think self-named, who were responsible for developing the first curative chemotherapy regimen for Hodgkin's disease and non-Hodgkin's lymphomas at the National Cancer Institute in the early 1970s. Dr. Young is currently president of RCY Medicine, a private consulting firm based in Philadelphia. He was raised in Columbus, Ohio, where he couldn't get into the University of Michigan. So he went to a second-rate community college in Columbus called Ohio State. My bosses made me say it that way, Bob, here at the University of Michigan. Dr. Young: Not the correct way, The Ohio State University. Dr. Hayes: So he received his MD then at Cornell in 1965, followed by an internship at the New York Hospital. He spent the next two years as a clinical associate in the medicine branch at the National Cancer Institute. And then he completed his residency in medicine at Yale New Haven Medical Center. In 1970, he returned to the NCI, where he stayed for the next 18 years, serving during most of that as the chief of the medicine branch. Dr. Young accepted the role as president of the Fox Chase Cancer Center in Philadelphia and served in that role and then chancellor in 2009. Dr. Young has authored over 400 peer reviewed papers regarding a broad range of both scientific and policy issues in oncology. But in addition to the I consider astonishing and precedent-setting reports of cures in Hodgkin's disease and non-Hodgkin's lymphoma, perhaps most importantly with his longtime colleague and friend Dr. Robert Ozols, he led many of the early and groundbreaking studies in ovarian cancer diagnosis and treatment that I think still guide our care today for patients with this disease. He's won too many awards and honors for me to go through. But of the major ones, he won the prestigious Bristol-Myers Squibb award, which he shared with Dr. Ozols in 2002, the Margaret Foley Award for Leadership and Extraordinary Achievements in Cancer Research from the American Association of Cancer Research, and ASCO's Distinguished Service Award, one of our highest awards, for Scientific Leadership in 2004. Of note and close to my own heart, Bob served as the ASCO president 1989/1990, which I consider a really critical time in the evolution of our society. Dr. Young, welcome to our program. Dr. Young: Thank you. Dr. Hayes: So as I noted, you grew up in Columbus, Ohio, or again, as we say in Ann Arbor, that town down south, but more importantly that your father was a surgeon. And I've heard you tell the stories as a boy you went on rounds with him and that inspired it. Was he academic or was he a really community physician or both? Dr. Young: Well he was a little of both. He was primarily a community physician. But he did, particularly at the time of the Second World War, because he was a very skilled hand surgeon, he got involved with a lot of hand surgery related to a company called North American Aviation that produced a lot of World War II planes. And there were a lot of injuries in that setting. And so he became quite a skilled hand surgeon and actually taught at Ohio State's Medical Center. So he had both an academic and community-based practice. But primarily he was a practicing community surgeon. Dr. Hayes: And did you actually go into the OR with him as a boy? Dr. Young: Oh, yeah. Oh, sure. Dr. Hayes: Wow. Dr. Young: You know, in those days, there weren't any rules and regulations about that. And so I went in and watched surgery and held retractors and participated, you know, when I was a youngster. Dr. Hayes: Wow. What a privilege. You're right, that would not be allowed now. That's a good story. What did you see, bad and good, compared to medicine now then. I mean, if you had to say here are a couple things that we've lost that you regret. Dr. Young: Well, I think that it was more under the control of the physician than it is in this day and age in so many ways. For instance, my father practiced in three different hospitals. And he admitted patients depending upon what kind of surgical support and nursing support they needed. If they were complex, he went to a bigger hospital. If they were very straightforward cases, he put them into a smaller hospital. And so he had a lot more control over how his patients were dealt with and the circumstances under which they were cared for. And, of course, most of his practice was before Medicare and all of the insurance sort of thing, so that people paid what they could pay. And so it was a much simpler and much more physician-driven practice than it is today. Dr. Hayes: Just as an aside, there's a wonderful book called The Brothers Mayo, written by a woman named Clapesattle in the 1930s after both Charlie and Will died. And it's a history of the Mayo Clinic. But in it, she says that Will basically charged people what they could afford to pay. So if you were wealthy, he charged you a lot. And if you were poor, he gave it to you for free and everything in between. And he sort started made up the billing schedule the way he wanted it to happen. And one of his more wealthy patients challenged him on this, and he said, go somewhere else. Dr. Young: Yeah, well, that's exactly the kind of practice my father ran. Dr. Hayes: Yeah. Anyway, I'm intrigued by year two-year stint at the NCI in the late '60s before you then went back and finished at Yale. And hopefully this is not insulting and I know you're considered one of the so-called yellow berets. But tell me, tell us all about your choice to interrupt your residency and go to the NIH. I don't think our young listeners really understand the political climate and the circumstances of the time that led so many of you to go there. Dr. Young: Well, I think that's a great question, because it will lead to some of the other discussions we have later. But essentially, I graduated from medical school in 1965 at the height of the Vietnam War. And in those days, there was not only a general draft, there was a physicians draft. So graduating in medical school in those days, you had one of three choices. You could either take your chances-- and again, the numbers, your priority scores at the time, didn't really have anything to do with it, because they took as many doctors of whatever kind of type they wanted for whatever purpose they wanted. So that you couldn't be sure if you had a low number that you'd not be drafted. But you could take your chance. And in those days, a lot of people did. And a lot of people got drafted. Or you could join the Berry Plan, which was at the time an opportunity to continue your specialty training until you were finished. But then you owed back the military the number of years that you had been in specialty training. Or you could do a much less well-known track and that is with the US Public Health Service. And amongst the opportunities for the US Public Health Service were things like the Indian Health Service and the Coast Guard Service and those sorts of things, or the National Institutes of Health, about which at the time I knew almost nothing except that it existed. And I owe it to some of the folks that I worked with at Cornell, primarily a hematologist oncologist by the name of Dick Silver, Richard Silver, who's still at practice at New York Hospital, who when I was working in the labs there, because I was doing some research when I was at Cornell, and they were telling me about the fact that you could actually apply for a position at the NIH. And you would be in the US Public Health Service. So it took me about 3 milliseconds to figure out that for me that was clearly a track that I wanted to explore. And I had done some research in platelet function and platelet kinetics and so forth. And there was a guy by the Raphael Schulman who is at the NIH at the time. And I said, that would be a miracle if I could get this. So the way it worked was that you applied. And then you actually interviewed with a whole bunch of different people. And as it turned out, I didn't get a position with Dr. Schulman. But I was introduced to the National Cancer Institute and both the leukemia service and the then called the solid tumor service. And I applied to various things like that. And I actually got in on the leukemia service. So I walked in after I signed up and was taking care of little kids with acute leukemia, having never been a pediatrician or knowing anything about leukemia. But it was a baptism of fire and a very exciting place even then. Dr. Hayes: I want to get back to that in a second because that's a critical part of this. But, again, going back to the political climate, my opinion, this entire issue and your personal journey and many others had a profound effect on both the scientific and medical community of this country as a whole. I think it was an unintended effect. But because of the Vietnam War and because the NIH was such a great place to train in those days. Do you agree with me? Dr. Young: You are absolutely correct. I mean, one of the things that needs to be said is that this was a transformational phenomenon for cancer research. But it also took place in every other field. And the NIH at the time was just swarming with people of all medical disciplines who were coming to take advantage of the opportunities that existed within the NIH, but also to serve in this capacity as opposed to some of the alternatives that were around. And I think I heard a figure one time, which I'm sure is true, and that is at one point in time, 30% of the chairmen of medicine in the United States had done training at the NIH before they ended up being chairmen of medicine. So that gives you an idea of the impact of this. And you're absolutely right, it was a totally unintended consequence. Nobody ever designed it that way. Nobody ever planned for it to happen that way. But in retrospect, when looked at it and you can see exactly why what happened happened. Dr. Hayes: Yeah. And I interrupted you, but I did it on purpose, because it didn't sound to me like you really had a plan to go into cancer treatment, but sort of landed there serendipitously. Is that true? I mean how do you end up there? Dr. Young: Oh yeah, oh, yeah, I mean I did get very interested in hematology when I was in medical school. I first went to medical school, of course, thinking I was going to be a surgeon, because my father had a great practice and he had a wonderful experience with surgery and it was really cool. But I just found that I just wasn't designed just the same way. And it was increasingly clear that cancer was not my not my goal-- I mean, surgery was not my goal. And so, you know, I knew I wanted to stay in internal medicine. And I got interested in the research. And I had done some significant research and in platelet function, as I said. I knew that's what I wanted to do, some sort of clinically-related research in medicine. If I'd had my choices, of course, I would have gone into a sort of pure hematology track. And, of course, it's worth saying that it's difficult for oncologists nowadays to understand how big an outlier oncology was. There was no subspecialty in oncology at the time I went to train down there. There was a subspecialty in hematology. And, of course, all of us, the Gang of Five that you mentioned, all of us took hematology boards. And that's because it wasn't clear that there was going to be oncology. When oncology came along we all took the first oncology boards ever given. So that gives you an idea of how early in the history of oncology we were in the late '60s, early 1970s. Dr. Hayes: So we're talking 1970 or so right when you started? Dr. Young: Well, 1967 to '69, I was a clinical associate. Then I was at Yale for a year. And then in 1970, I came back on the senior staff. Dr. Hayes: And who were the characters above you when you came in? I know Doctors Frei and Freireich had been there before. Dr. Young: Yes. Frei and Freireich had just left the year before. One went off to MD Anderson, the other went off to the Memorial. And George and Vince-- George Cannellos, Vince DeVita-- had stayed on, with Vince as the head of the medicine branch. And then when we came back, Vince sort of brought two of us back that he'd had before, Bruce Chabner and I. He'd sort of sent us off to Yale and said they could buff us up a little bit. And he didn't offer us a job coming back. But we went off, and we were training up there. And he called us both up and says, why don't you to come back and join the senior staff. He recruited Phil Schein as well. And so that was the Gang of Five that we started out. Four of us ended up being president of ASCO at one time or another. And I suspect the only one who didn't, Bruce Chabner, probably would have except for the fact that he was the director of the Division of Cancer Treatment of the NCI for a long time. And the NCI and the NIH changed its attitude toward allowing people to participate in major leadership positions nationally, a tragedy as far as I'm concerned, which has I think affected the morale of the NIH and a lot of other things and deprived a lot of good people of opportunities to serve nationally. But that was the way it was, otherwise we would all ended up at some point leading-- Dr. Hayes: So the Gang of Five was you Bruce Chabner, George Cannellos, Phil Schein, and Vince DeVita, right? Dr. Young: Right, exactly. Dr. Hayes: And what were the dynamics among you? I mean, so were you and-- Dr. Young: Well, I mean, it was an incredible time. You know, there was enormous talent that had poured into the NIH, as we talked before. And an enormous amount of talent was present and was recruited in during this period of time. I mean, you know, Paul Carbone was still there. John Minna was recruited. Harman Ayer, who was the longtime chief medical officer of the American Cancer Society. Tom Waldman was a world class hematologist. Max Wicha was a part of this group. Sam Broder, Allen Lichter, an other ASCO president, Steve Rosenberg, Phil Pizzo was the head of the pediatric oncology branch, now dean at Stanford. And it goes on and on and on. And so there's a massive amount of talent and a lot of freedom. And so Vince was clearly the leader, he had a lot of ideas and a lot of creativity. But he let out a lot of people do whatever they wanted at the same time. And it was sort of a situation in which we all participated, because we were all attending at the same time. So Vince and George did a lot of the lymphoma and Hodgkin's disease stuff. We all participated. I got interested in ovarian cancer. And you talked about that. Bruce Chabner and Phil Schein were always very pharmacologically oriented. And so they did a lot of the phase 1 and phase 2 trials and a lot of the laboratory backup associated with the studies we did. And everybody shared. And so there was really not a lot of competition in that sense. Everybody was I think very competitive. Because it was all sort of shared, it worked out so that everybody felt that they were getting a substantial part of the recognition that was going on in the group. Another thing that was unusual about the NIH, but it had unintended, but important consequences is that nobody had anything to do with what they got paid. So that you could go to events and say, well, you know, I deserve to be paid more, but it didn't have anything to do with what you got paid. We had no control over anybody's salary. So that I don't think the whole time I was there, the whole 14 years I was chief of the medicine branch, I don't think I ever had a conversation with anybody about money, because I didn't have anything to do with what people got paid. Let me tell you, that's a big change. It actually has a remarkable, remarkable effect on the way people work. Because if for some reason somebody wanted to make more money, they just had to leave. There wasn't any way to do it. So you either had to accept that this is what everybody got paid and that you were rewarded by the opportunities to do the kinds of research that were done. Or you said, look, I need to go on and go somewhere else. Dr. Hayes: Now, just between you and me, and maybe a few thousand other people who are listening to this, who is the first guy to say let's give combination chemotherapy to Hodgkin's disease? Dr. Young: Well, actually, I don't know the answer to that. I think if I had to guess, I would say Vince, because Vince and George had been around in the Frei and Freireich days. And of course, you know, they'd already had experience with the impact of combination chemotherapy in leukemia. And so the concept was you took drugs that were active in the disease and put them together if they had different kinds of toxicity. And you were then able to utilize the combined impact on the tumor and sort of spread around the toxicity. So it was more tolerable. And that was the concept. And I think that because Vince and George were treating chronic leukemias and treating Hodgkin's disease, the notion of combining it with combinations was pretty straightforward evolution from the experience in leukemia. There are other people who claim that. I think from time to time both Jay Freireich and Tom Frei have claimed it. I think that there was a dust up between Vince and Paul Carbone and George because there was some suggestion by somebody that Paul was the one who originated the idea or Gordon Zubrod. And quite frankly, I don't know. If I knew, I would tell you. But I don't actually know. I can tell you this, that the emotional and passionate driver of the concept of combination chemotherapy as a successful modality in Hodgkin's disease and lymphoma was Vincent. Dr. Hayes: Your answer is very consistent with what other people have said the same thing. It must have been somewhere along the line that all of you began to see that there really were cures. And did you realize, as a group, that you were making history? Or was it just day to day-- Dr. Young: Well, you know, it's interesting. I can tell you one of the most transformational experiences that I had in the early days is, of course, we were following all these patients who had started on MOP. And so to do that you had to sort of go back and pull out the charts and all this kind of stuff. You know, we didn't have electronic systems that had all the stuff recorded. You just had to go down and pull off the charts. And what struck me so tremendously was the attitude of the physicians that had first started some of these patients on this therapy, because the notes made it very clear that they were sort of flabbergasted when these people came back after the first couple of months and they were watching their disease disappear, and that they really didn't anticipate at all, initially, that they were going to see these people after a couple of weeks. And it was very clear in the notes. By the time we had gotten there, of course, there were a significant number of people already on the trial. And it was already clear that we were seeing things that nobody had ever seen before. And I think that's when it first began to dawn on everybody. And as soon as we saw it in Hodgkin's disease based on the experience that we'd seen with non-Hodgkin's lymphoma, we had a suspicion that it would likely be the case as well there. Dr. Hayes: So you already bounced across it, but as I was looking through your CV I knew this anyway, you really mentored a who's who of oncology-- Rich Schilsky, Dan Longo, Max Whishaw, Dan Van Hoff-- and you noted already that oncology training has evolved. I mean BJ Kennedy pushed through boards I think in '74 or '75, something around there. What have you seen in the evolution on oncology training that you think is good or bad? Dr. Young: Oh, I think in general, it's much better. And I think it's much better because, of course, there's a lot of success that's been built into what's been accomplished. And that makes it a lot easier to teach people about how to treat Hodgkin's disease well, than we ever could at the time we were doing it because nobody knew the answer to those things. And I think there's also a lot more of it. You know, I think at the time we were at the NIH, you know, I think credibly you could count on both hands the number of really established academic oncology programs in the United States. And now, there are probably 100. And so the quality of training and the quality of mentoring is dramatically better than it was in those days. In those days, you know, hematologist we're doing most of the treatment of cancers. And they were all sort of in the Sidney Farber mode. You take one drug, and you give it as long as it works. And then you switch to another drug and use that as long as it works. And that was pretty much the way hematologists approached the disease. And by all means, you don't cause any toxicity. Dr. Hayes: I picked up several adults who had been Sidney Farber's patient when I was at the Dana-- Sidney Farber Cancer Institute in those days in the early '80s. So I had his handwritten notes. And sadly, I did not photocopy them. I would have love to have had it. But he had a very different mindset in terms of the way-- Dr. Young: Oh, absolutely, absolutely. And as far as I can tell, this is just my own personal reaction, is that I don't think either George or Vince at the time we got here shared any of that attitude. George is a little more cautious than Vince, as everybody knows. But neither one of them for a minute ever suggested that we were being too aggressive, that it was unfair and immoral to treat people with these kinds of toxicities, not that they desired to make people sick. But they were absolutely convinced that aggressive therapy could make a dramatic difference in the natural history of these diseases. Dr. Hayes: Yeah, certainly, Dr. Frei felt that way too. Dr. Young: Yes. And well, they were his mentors. I mean, you know, all these guys were there at the same time. And they were all influencing one another. Dr. Hayes: You know, it's amazing, I think all of us-- there are 44,000 members of ASCO now-- basically are derived from about 10 people in the 1950s and '60s, most of the DNA, not completely-- Karnofsky and some others around, but-- Dr. Young: Oh, yeah. Dr. Hayes: Well, the other thing is actually, you were talking about the safety, what are the war stories? I mean, how did you give chemotherapy? Were you guys mixing it up and giving it yourself? You know, we got all these bells and whistles. Dr. Young: Well, I mean, for instance, you know this is the first time really protocols were written. And the reason that we wrote protocols was simply because we were working with fellows. And they literally needed the recipe of what it was they were supposed to give and when. And so we wrote up these what were the first of the clinical trial protocols. There was no formal informed consent at the time of these studies. We had, of course, informed consent, the same way you do informed consent now, really. And that is you talk to the patient. You explain to the patient what the treatment is and what your expectations for the treatment are. And the patient understands the disease they face and decide that they can do it or not do it. And it's actually still the same today. The only difference is we now have 14, 17-page informed consent documents that make lawyers happy, but don't really impact, at least in my view, whether patients decide to participate or not. But we didn't have those. So I think that was the other one of the great things about the setting at the NIH, not that I'm anti-informed consent, but it was simpler. It was easier to get something done. You could do unconventional treatment and nobody looked at you and said, "you can't do that, that's never been done before, you're not allowed to do that." We didn't have academic constraints. One of the things that always surprised me is when, you know, we would develop a particular technique, like peritoneoscopy or laparoscopy for ovarian cancer staging, and when guys left the program having been well-trained to do this, they couldn't do it when they went to their new institutions because gastroenterologists did this. That was the sort of thing that the constraint wasn't here. There were also very easy-- I mean, all you had to do was to get an idea and write it up. I took a look at ovarian cancer and said, you know, "It seems to me, here's a disease that's now being managed by gynecologic oncologist. Internists never see these patients. They're all treated with the melphalan. And those that happen to live a long time develop acute leukemia from that treatment. They ought to be something better than what we're doing." And so we just decided that we would begin to take patients with advanced ovarian cancer into the NIH. And the rest sort of is history. But you couldn't do that in another hospital. You know, the biggest treaters of ovarian cancer probably program-wise was MD Anderson. But all his patients were treated by gynecologic oncologists. You couldn't have gone into the MD Anderson and said, "OK, we're going to take over the treatment of advanced ovarian cancer." They would have laughed in your face. Dr. Hayes: Actually, you just segued into my next question. And again, you and Dr. Ozols, in my opinion, completely changed the course of ovarian cancer treatment. Did you get a lot of pushback from the gynecologic community? Dr. Young: Well, no, actually. It's interesting. Now I don't know what we got behind the lines, you know when they were all sitting around the bar after the meetings. We really didn't. First of all, one of the other advantages of being at the NIH is that when you said something, people listened. And the other thing is, of course, when we got really going with ovarian cancer-- this was after the passage of the National Cancer Act-- and there was money at the NIH. So one of the things we did, for instance, was to put on a series of symposia about ovarian cancer treatment, what was going on, what wasn't going on, and brought the movers and shakers of this field together in meetings and talked about what was being done and what should be done and what information we didn't have that we needed. And we actually got funded for a period of time, a group called the Ovarian Cancer Study Group, which eventually evolved into the Gynecologic Oncology Cooperative Group, National Cooperative Group. So we had some other tools that we could bring to bear to drum up an interest in new research in ovarian cancer. And, of course, gynecologic oncologists couldn't prevent us from taking patients that were referred to us. And our surgeons, for instance, none of whom were gynecologic oncologists, were happy to help and to operate on them when they needed to be operated on. And Steve Rosenberg's group has fantastic surgeons. So we didn't have any problem getting state of the art surgery done on these people. And, in fact, they are general surgeons learned some gynecologic oncology at the same time. Dr. Hayes: Yeah, you know, it's been interesting to me that the surgeons, the general surgeons, willingly gave a systemic therapy. But that still in this country, there are very few medical oncologist who do GYN oncology. It's still mostly done by GYN oncologists. Dr. Young: Yes. Dr. Hayes: And there are very few trained medical oncologist in this. And I think it's gotten too complicated for a surgeon to do both. I don't really see why that hasn't happened based on, especially your model and Bob's model, that's my own soapbox. Dr. Young: Yeah, that's an interesting point, because at the NIH, when we were there, Steve Rosenberg and Eli Gladstein in radiation therapy, there were no rules that said that they couldn't do chemotherapy. And, in fact, they did it sometimes. And we didn't say anything about it. Usually, they called on us and said, hey, look, you know, we need you to help us or participate with us or whatever. But there were no rules that said that they couldn't. And sometimes they did. But for the most part they said, "look, this is not the business we're in. We want you guys to do the chemotherapy." And so for the most part we were able to do that. Dr. Hayes: The entire NSABP, those guys were all given their own surgery, their own chemotherapy. And they ultimately handed most of it over to medical oncology through the years. But that's not happened so much in GYN. OK, I want to go into your role in ASCO at the end here. And as I noted, I think you were president during a really critical turning point for the society. And just a few things, you already mentioned that I think you were already at Fox Chase when you ran. So you'd left NCI. And what made you run? But more importantly, tell us about your role in the evolution at that time of the society. Dr. Young: I think actually they recruited me to run just at the time that I was looking to leave. And so I left in December of 1988. And I was president of ASCO 1989 to 1990. At the time, I had moved from the medicine branch and ran the cancer center's program for a year. And I decided that I liked it. I thought, well, maybe I'll just stay here for the rest of my life, the way Steve Rosenberg did and others have done very successfully. But I said, well, you know, it's either sort of now or never. And so I decided that I would make the jump. But when I got into the sort of ladder, if you will, of ASCO through the board and so forth, it became clear that there were a couple of things that were a real challenge for the society. The society had at the time for the most part been essentially run on contract, that there was no organization of ASCO at all. It was it was all run by a contract organization. And it was clear that we had grown to a size such that we really needed to begin to recruit our own leadership staff. And so my year as president was actually the first year we hired a full-time employee. And she was based in a law firm that we used for ASCO legal business. But that was the first employee ever hired by ASCO. And that was in 1990, or 1989, I don't remember which, put in that year anyway. The other thing that was going on, which was critical for the society, is that, of course, there's always been a 'town gown' challenge in all aspects of medicine. And medical oncology was no different. So it had originally been the province of academic oncologists. But the numbers began to change dramatically. And it became clear that there was an enormous number of community-based oncologists, who looked at the challenges that face the organization somewhat differently than the academics. And this is one of the things that I think I benefited from growing up with a father that had both his feet in the community-based practice and the academic practice. And I realized how private practicing physicians view academics and view academic control of organizations. And I realized-- and others did too. I wasn't alone on this-- that we really needed to build up the recognition of community-based oncology as a first class citizen in the society. And so we began to create and bring in all of these state society organizations. And we began to get leadership roles who were based in community oncology, rather than just academics. And Joe Bailes was our first head of the Public Relations Committee of the society and grew this into a national presence and became the first community-based president of ASCO. So I think I think those are the two things that I saw that hopefully I made an impact on. And it always amazes me to realize that the society was really that young. I mean, people can't believe that it's just, what, 30 years ago when we had our first employee. Dr. Hayes: Yeah, that's why I'm doing these podcasts. We make sure we get this history. You know, it's interesting, I often give you credit for the ladder. As president myself, it was made very clear to me that 90% of the patients in this country with cancer are treated by community oncologists, maybe 85% or so. And about 2/3 of our membership are community oncologists. So we now have designated seats on the board of directors. We started a Department of Clinical Affairs that Steve Grubbs is running. That's just a few years old. But, boy, it's been fabulous. We now have a designated chair, the state affiliate council is invited to the board of directors and sits in and presents. And the state affiliate councils meets at ASCO headquarters at least once a year. And we've had a couple presidents who are, besides Joe, Doug Blayney and Skip Burris now coming in in June. So I think we've been reaching out. It always struck me when I sat in the headquarters, the seven founding members were, for the most part, community people. They met just to talk about how do you give chemotherapy. It wasn't, you know, about Tom Frei or Freireich or Jim Holland. It was folks in the community. And then it grew into an academic society. And I think you and then Joe Bailes and others kind of brought us back and grounded us. And to me, that's a really critical evolution in our society. I think it's made us much stronger. So those are most of my questions. You've answered almost everything I had written down that I always wanted to ask you if I got a moment in a cab with you. I want to thank you for taking time to do this. But more importantly, I want to thank you for all the contributions you have made to the field. I mean, I don't think I would be here and I don't think most of us who do oncology would be here if it weren't for you and the Gang of Five and the things you've done, both by the courage to moving forward to giving the kinds of chemotherapy and stuff, establishing science in the field, but also the policy stuff. Your articles in The New England Journal over the years, I think have been classics. You should put this all in a book and send them out to everybody because they have to do with not just giving chemotherapy, but the whys and hows of what we do. So I know I'm being long-winded, but that's because I'm a big fan. Well, thank you very much. Dr. Young: You know one of the things, I got to say is that I've just been a very lucky person. I happened to have had great opportunities. And I think I was able to take advantage of those opportunities. But somebody gave me those opportunities and put me at the right place at the right time. And so I am a very lucky guy. Dr. Hayes: Well, and I want to finish up and say how nice it is to see at least one graduate of Ohio State University do well. You know, it doesn't come very often. So congrat-- Dr. Young: Yeah, yeah, yeah, yeah, yeah The team up north, the team that will not be named, yes. Dr. Hayes: Thank you so much. And appreciate all you've done. Again, appreciate your taking time with us. Dr. Young: Thank you very much, Dan. Dr. Hayes: Until next time, thank you for listening to this JCO's Cancer Stories, The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listened. 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