Cancer Stories: The Art of Oncology

Dr. Hayes interviews Dr. Lichter on his involvement with early breast preservation. 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 the podcast is Dr. Allen Lichter Dr. Lichter has a long and really storied history in the field of oncology over the last five decades. With his colleagues at the NCI, Drs. David Danforth and Mark Lippman, he was the radiation oncologist PI for one of the four studies that demonstrated that breast preserving therapy was as effective as mastectomy for newly diagnosed breast cancer. He more or less single-handedly started the Department of Radiation Oncology at the University of Michigan, now considered one of the top programs in the world. He is one of only three radiation oncologists to have been a dean at a major university in the United States, serving as such at the University of Michigan Medical School for eight years. And he is one of only three radiation oncologists who have been president of ASCO. The others are Sam Hellman, who I've interviewed previously, and our current president, Dr. Lori Pierce, who, by the way, is also from the University of Michigan. And his term was from 1997 to 1999. Dr. Lichter was born and raised in the Detroit area. He received his undergraduate and his medical degrees at the University of Michigan, after which he completed an internship at a community hospital-- St. Joseph's in Denver-- and then a residency in radiation oncology at the University of California, San Francisco. Following that, he joined the faculty at Johns Hopkins University, but after two short years there, he moved a few miles south to the National Cancer Institute in 1978, where he was head of the radiation therapy section of the radiation oncology branch. I believe you couldn't have been more than 32 or 33 years old, Allen, at the time. I counted up the years. He then moved back to Michigan to start the department here, which he chaired for eight years, and then became the dean for eight years. And then he went on to become the Chief Executive Officer of ASCO from 2006 to 2016. In spite of spending the last 20 years of his career as an administrator, Dr. Lichter has authored over 120 peer-reviewed papers. He was the co-editor of Clinical Oncology, one of the major textbooks on oncology, and has really been a leader, especially in radiation oncology, but in cancer in general in this country. I also want to add he was my boss for eight years when I first moved to University of Michigan, and during which time he was also my next door neighbor here in Ann Arbor. And I got to be his boss for one year-- if anybody could be Allen Lichter's boss-- from my term as ASCO president. Dr. Lichter, welcome to our program. It's great to be here, Dan. So a number of questions. I know, first of all, you grew up in Detroit and you went to Cass High School. And while this podcast is supposed to be about the history of oncology, having moved to Ann Arbor, I find the history of Cass High School awfully interesting. Has a number of famous alums, including Diana Ross, Lily Tomlin, Ellen Burstyn, Della Reese, David Alan Grier, Jack White, Alice Coltrane, and-- my guess is, Allen, you don't even know who Big Sean is, but he's a rapper. He's very famous right now for the younger generation. Any memories from your time there? Did you run into celebrities when you were there? It's quite a place to say you're from, I think. It's an interesting school, mostly a technical high school, located in downtown Detroit, but with a small college preparatory program that took students from all over the city with a competitive entrance exam. And I don't know what possessed me to get on the Second Avenue bus and ride downtown back and forth every day, but it was a fascinating experience. It takes you out of your normal peer group. I met young people-- friends-- from all walks of life, from all corners of the city. And it was a pretty rigorous education. I enjoyed it a great deal. And I played on the golf team. And it sounds to me like you knew you'd be a doctor then. Your father was a family practice doc in a small community just outside of Detroit. Was that true? Did you plan to go to medical school? Or did you have some epiphany when you were at high school? No, I never remember a single day not wanting to be a physician. My dad was a general practitioner and really instilled in my brother, and in me, a love of science and a love of medicine. My brother went on to be an ophthalmologist and was chair of the department at the University of Michigan for 34 years, President of the American Academy of Ophthalmology. So my dad and my brother set great examples for me, and into medicine I went. So I have to tell you, my father was a business man and was disappointed that I was in academics because he never understood why I wasn't generating income. My brother went to work for Eli Lilly. He was a doctor, too. And dad always thought he was doing something productive because he worked for Eli Lilly. So I don't know if your dad was disappointed you went to academics instead of family practice, but-- It was interesting. When I started my residency training, I was certainly confident that I would head into private practice and live a life much like my father did. And when I finished training, I decided I just needed a little more buffing up. I figured I'd go into academics for a couple of years, just to make sure I had a good grounding, and then go into private practice. I love the academic life and stayed there my whole career. I've been fond of asking previous interviewees-- why'd you choose oncology, and specifically radiation oncology, in your case? What led you to go into this path? Especially 40 years ago-- there wasn't a whole lot of oncology to go into. Well, you know, I was one of those medical students that loved virtually every rotation, and after that rotation I was going to become a fill in the blank. In my senior year of medical school, we were allowed to take an away elective, and I wanted to explore radiology as a potential field. My brother had a very good friend who was a radiation oncologist at the University of California, San Francisco, and the chance in the early 70s to go to San Francisco-- especially avoiding the Michigan winter-- was very compelling. So I signed up for the electives, and when I got there, I found that it was six weeks of diagnostic radiology and six weeks of radiation oncology. I hadn't expected that, but what the heck. So I did my six weeks of down in the basement looking at teaching sets, which was really quite inspirational. And I went into radiation oncology. And after my first day, I called my father and I said, I found what I'm going to do. I'm going into radiation oncology. It was instantly fascinating. I love the camaraderie in the department. I love the blend between the physical exams of patients, the treatment of cancer, the use of very high technology equipment and physics. It just struck me and I never wavered from that point on. So I've heard you talk about this-- and I'm 10 years behind you and even was true when I trained-- was that there wasn't a whole lot of science in radiation oncology back 40 years ago. And the field has evolved. And there are two things-- one you already hit on, which is it was combined with diagnostic radiology. And the second is it split away from diagnostic radiology to become its own field, and a lot of science. I've spoken with Saul Rosenberg and Sam Hellman and sort of asked them the same question. Give us just a background of the last 40 years of the evolution of radiation oncology because you had a lot to do with that. Well, of course, the field grew up, as you point out, inside the broad field of radiology. I always would tell my trainees that when Rankin discovered the X-ray, he forgot to discover the instruction manual. So there was a trial and error learning with this very useful technology, but very dangerous technology over a long period of time. For quite some period of time, you trained in general radiology. You had some time in diagnostic a little time in therapy, and you went out and could do both. But as I entered the field, it was becoming more and more difficult to learn radiation oncology in just the few weeks that they rotated in from their diagnostic duties. And I was one of the earliest group of trainees who trained in straight radiation oncology-- no diagnostic training, per se. And the field, as you say, split from diagnostic radiology. Had our own boards. I was amongst the earliest group to take the specialty board in radiation oncology. And the other thing that was true, certainly back in the late 60s and early 70s, is that so much of the field was experiential-- that is, people wrote papers like, you know, the last 100 patients with cancer of the lung that I treated. And this was valuable, but the need to do rigorous, well-controlled clinical trials was obvious to everyone inside the field. And so the field did become much more scientific. Never quite much as medical oncology, and part of that is because devices are treated differently at the FDA than drugs. Drugs you have to prove through scientific investigation that the agent is safe and effective. And then you can release it for patient use. For devices, you just have to prove that it basically doesn't kill anybody. And you can get an approval of a device and often get a billing code for the device. So the approval comes, and then you're supposed to do the science. Well, a lot of people, at that point, they're just too busy using the technology, then, to actually step back and do the science. And, of course, if you spent a lot of money for a piece of technology, to do the science to find out that wasn't a very wise investment is not in your self-interest. So our science lagged behind. I think it is certainly catching up, but it's still, in fact, in many cases, has a ways to go. I have enormous respect for our colleagues in the FDA on the devices side, and their hands are tied a bit. But I liken some of what they do to being like underwriter's laboratory. If you plug it in, it doesn't blow up, so they approve it. Yes. It's a little more than that, but you're right. And so much of the device approvals are based on a predicate of a similar device. And it goes from A to B to C and finally, you know, years down the road, the equipment and its use and its underlying structure is so different from the original device that was approved years ago that you rely on, at every step of the way, it really has-- there's been a lot of scrutiny about changing that, and I think over time it will change. You know, historically, it's interesting, by what you just said-- some of the first prospective randomized trials in all of medicine were radiation versus nil to the chest wall with breast cancer. To my knowledge, streptomycin versus nil for tuberculosis was the first, but then a whole series of radiation versus nil. But who would you give credit in the United States-- I would give part credit to you with the work you did with Drs. Lippman and Danforth. Probably one of the first randomized trials in radiation in this country. Well, you're correct that the first chest wall radiation trial started in Manchester, England in 1948. And at that point, doing randomized trials-- giving some patients the therapy and other patients observing or giving them a placebo-- that was not in widespread use in medicine. And over time, those types of trials began to become more common. I think in radiation oncology, our big advance was becoming part of the national co-operative group system, where many of the co-operative groups-- maybe all of them-- had a radiation oncology committee. And our studies were often integrated with surgical care or combined modality care with chemotherapy. And so we began a series of very important studies in breast cancer and lung cancer. The pediatric group did many, many trials that involved plus or minus radiation. I don't know that there's any specific person I'd give credit to, but it was the movement inside the field to join our other oncology colleagues in testing things rather than just doing observational work. You know, in that regard, let's circle back to your work at the NCI. That must've taken a fair amount of organizational and political skills to mount a breast preserving therapy, just at the NCI. The data that breast preserving therapy was safe was just beginning to be reported. The randomized trials in other places were ongoing. Give us some story there, how the three of you got that going and how you ran that. Well, of course, virtually everything at the NCI, from a clinical standpoint, is a clinical trial. Patients aren't treated there, just as going to their community hospital. You come to the NCI-- the travel is paid for, the care is paid for, et cetera, based on your agreement to enter into a study. At the time that I went to the NCI, the NSABP was doing their very large trial of lumpectomy versus mastectomy under Bernie Fisher's direction. My concerns were twofold. Number one-- this was being done at many, many centers around the country, and one could, I think, logically ask the question whether the quality of that care was going to be uniformly high enough to truly test breast preservation therapy. And secondly, I believed-- and many of us believed at the time-- that a boost to the tumor bed was quite important as part of having a low rate of local recurrence, and the NSABP study did not use the boost. They just treated the whole breast and stopped. And I said, you know, let's do a trial where it's done at a single institution, where the quality is going to be absolutely top notch, where we're going to use a boost and all of the technical tricks that we knew how to do this, just in case the NSABP study didn't come through. We'd have a backup. If both of them were negative, we could forget about lumpectomy and radiation, but if the NSABP was negative, we'd have this. As it turned out, the NSABP study, as you know, was positive, established for sure the equivalence of preservation therapy, and our study was sort of a little caboose at the end of the train. But that's OK. It confirmed what Ernie and colleagues confirmed very emphatically. Actually, there's an interesting article in the JCO written by Ian [INAUDIBLE] and his colleagues, about six months ago, that he preluded when he won the award your last year as CEO at ASCO. Was it your award? I can't remember. Yes. But anyway-- yeah. And in which, he designated the term I hadn't heard before of statistical fragility. And he made the point that many single prospective randomized trials are positive and the subsequent ones are not. And I give you and, of course, the Italians and the Brits also ran similar trials. It's nice to have four trials that all show the same thing. There's no statistical fragility in this observation. Yes, well, the NSABP trial was 1,800 patients. Our trial was about 240. We weren't going to change the world, but it was at least comforting to me that we had this trial coming along just in case. The other academic success that I give you credit for and would love to hear more about it is that you're interested in CT planning, which I think, really, was the forerunner, now, of stereotactic radiation and I would call precision radiation, as opposed to just blasting an organ and hoping you hit the cancer. And I think, really, a lot of that you brought when you started the department here. But how did you get interested in that? When I went to the NCI, my first day there, they took me on a tour of the department and we walked by a room with a locked door. I said, what's in there? And they said, oh that's our CT scanner, but we never use it. So I said, well, let me see it. And, you know, this was an EMI 5005. This was one of the early scanners. It was a body scanner, but it had a fairly small aperture. You could not get a lot of Americans into this machine. And I said, well, why don't we start scanning some patients. As long as-- does anybody know how to use this thing? Yes? OK, let's start scanning some patients. And it didn't take long to recognize that this was a machine that was almost tailor made to do radiation therapy planning. It gave you the contour of the patient's surface. It showed you the inside of the patient. It showed you the tumor in most settings. And remember, at that time we were facing radiotherapy treatment planning on plain x-rays taken on the simulator where, for example, when you treated the prostate, you never saw the prostate. You knew where the pubis was. You knew where the rectum was. You knew where the bladder was. And you knew the prostate had to be in there somewhere, but you never saw it. When we started to CT scan the pelvis in prostate cancer patients, there was the prostate in all its anatomic glory. And so we began to plan on this. And then it became pretty clear that if you took these slices and stacked them back up, like if you took a loaf of bread and it was laying out on the table as individual slices and stacked the slices back up, you could rebuild the three dimensional picture of the loaf. We decided that that might be a good thing to do with CT scans. And that's when I went to Michigan, and that's when we brought together some terrific physicists and brilliant programmers and spent a lot of money on a roomful of computers and began to do three dimensional reconstruction. And that led to a transformation in radiation therapy from a two dimensional specialty to a three dimensional specialty. And you could start firing at the tumor from cross sections from different directions. We didn't have to be in the actual plane, et cetera, et cetera, et cetera. And then we put a multi-leaf on the aperture, and so you could shape the field in real time. And it just went from there. So I have to tell you, when I was a first year fellow at Sidney Farber Cancer Institute, and I saw a patient who had received chest wall radiation-- not at our institution, by the way, not even in Massachusetts. She'd come from one of the other states. And basically, they had just stood her up in front of the machine and turned it on, as far as I could see. And the amount of normal tissue damage that she had suffered from this was incredible. And I called your friend, Jay Harris, and said, is this what we do here? He said, no way. Had me come down-- he showed me the beginnings of their CT planning and that sort of thing. I didn't know [INAUDIBLE] at the time, but then I learned later, mostly because of your doing. There were a number of outstanding institutions that were involved in this, and a lot of the inspiration for this came from some of the work that Sam Hellman was writing about, in terms of how we might better use imaging. So it was a team effort across the whole specialty. By the way, you bring up Dr. Hellman. We just lost Eli Glatstein in the last few months. I'll give you an opportunity to say some nice things about him. I know that you worked with him, and he was a giant in the field. The reason I was attracted down to the NCI is that this little short pudgy guy, Eli Glatstein, was recruited from Stanford by Vince Devita to come and run the radiation oncology branch. It was a pretty interesting time. There were five of us with Eli. All five of us became department chairs after our time at the NCI. He was just a phenomenal individual. He gave you a lot of rope. You could either hang yourself, or you could do the work you wanted to do. And we accomplished a lot. The other thing that I remember-- so I went to the NCI 1978. 1980, Eli said to me-- he handed me a piece of paper. I said, what's this? He says, it's an application form to join ASCO. You need to join ASCO. So I said, OK. That's not typically what radiation oncologists do, but I'll join. He sponsored me. And then he said, I'm going to see if I can't get you on a committee. And he did. I was on early Grants Award Committee. We handed out five or six young investigator grants. And I became chair of that committee. And then they said, well, you know, you did a nice job. We're going to put you on another committee, and way led to way. It was entirely because of Eli that I got introduced to ASCO and became such an important part of my life. He was a giant and will be sorely missed by all of us. And that's a perfect segue into my last question, which is changing gears completely, and that is your career at ASCO. Give us some ideas of what ASCO was like in the late 70s and how it has evolved-- principally, I mean, I know that's a whole hour long discussion, but I think you've had such a huge footprint in the society-- and what you saw changed, and the important changes. You know, ASCO was founded in 1964. There were no oncologists in 1964. There were doctors who were treating cancer-- some of them with surgery, some of them with radiation, some of them with these very early, highly toxic drugs. And so the society was formed. And it specifically says, when you read the early writings about this by the founders, that this was not a society of what they called chemotherapeutists. It was a society of physicians who wanted to treat cancer. They brought together all of the clinical specialties. I like to joke that the most interesting thing is that the medical oncologists forgot to found the American Society of Medical Oncology. They're the only specialty in medicine that doesn't have a specifically focused society just for them. They used ASCO, and to this day, it remains that way. And so I got involved. And the leaders of ASCO in the 70s and 80s and into the 90s, espousing how wonderful their multidisciplinary work was. And they used to have annual member meetings at the ASCO annual meeting. And the board would sit up on the dais, and the peanut gallery would ask questions. So I raised my hand, and I walked to the microphone, and I said, you know, it's great how you extol the multidisciplinary nature of the society. But I look at the dais, and I see the 12 members of the board of ASCO, and they're all medical oncologists. You are not practicing what you preach. And I sat down, and they mumbled a few things. And then the next thing I knew, darn it, they created board slots for a surgeon, a radiation oncologist, and a pediatric oncologist. And then they said, all right, big mouth, now that you held our feet to the fire, we're going to run you for the board. And I did get elected to the board, and then, eventually, got elected president. And then when they needed a CEO in 2006, they asked me if I was interested, and I interviewed for the job and then moved to Washington and then Alexandria and did that for 10 years. It was really-- you know, I say that I have been involved with two great organizations during my career-- the University of Michigan Medical School, and the American Society of Clinical Oncology. And to have the privilege of leading both of those organizations was just truly amazing. Well, there are many more things we could talk about, but for our listeners, you should know there's an Allen Lichter Visionary Leadership Award and Lectureship held at every annual meeting now. And for those of you who attend meetings at our headquarters in Alexandria, you'll notice you're sitting in the Allen S. Lichter conference center. Those weren't done by accident, by the way. They were done because of my guest today and all of the contributions he's made, not just oncology, frankly, but in my opinion, to medicine in general. As a dean, I know many of the things you've done, which we don't have time to get into. So on behalf of our listeners, and behalf of myself, and behalf of all the patients who have benefited through your work through the years, thanks so much, Allen. [INAUDIBLE] Dan, it was great being with you. Thanks for talking to me. 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.

A medical team empowers a family to love fully by allowing them to feed their child. 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. Alonzo was a 10-year-old boy with a recurrent refractory brain tumor whose disease progressed through multiple therapies over many years. When no additional cancer-directed options remained, Alonzo was admitted to the hospital for symptom management as he approached the end of his life. Although Alonzo was unresponsive and posturing, his family continued to hope desperately for a miracle. As they kept vigil around the bedside of his frail body, praying and waiting, they gradually began to notice, and then fixate on, how the sharp angle of his bones protruded more with each passing day. Alonzo's mother believed fervently that his body needed nutrition. She understood that Alonzo was dying, that modern medicine had failed to keep the cancer from ravaging his brain, yet, as a mother, she continued to feel a profound desire and duty to nourish her child. She couldn't bear the idea that he might be feeling hungry, while unable to ask for food. She felt that, if he were to die of starvation as opposed to cancer, she would have failed him as a mother. She also continued to pray for God to create a miracle to heal Alonzo, and she believed that a healthy, nourished body was essential to host this miracle. Each day, our medical team spent hours debating how best to partner with Alonzo's family to align his medical management with their deeply held goals and beliefs. We worried about the provision of enteral nutrition, as Alonzo's gut was impaired in the context of his disease progression, placing him at significant risk for aspiration. We discussed the sizable risks related to the placement of a nasogastric tube to initiate enteral feeds with the low likelihood of long-term benefit. His mother expressed understanding, yet her broken heart steered her to feed him soup in secrecy later that evening. Alonzo choked, turned blue, and developed respiratory distress. It took several days to restabilize him. His mother was traumatized and racked by guilt, and yet she continued to speak of nothing but his need for nourishment. Fearful of oral and gastric feeds, she turned her energy to the prospect of intravenous sustenance. She begged us to consider total parenteral nutrition. As the days passed, we gently explained how the acute risks of volume overload and hepatic dysfunction outweighed the negligible long-term benefits. She expressed understanding, but with tears brimming, she pleaded for us to find some way to give him something. Just a little fat, sugar, and protein. His brittle, translucent skin was breaking down at each bony protrusion, and she believed that even a small amount of nourishment might help to heal his festering wounds. By this time, our medical team was emotionally overwhelmed. Upon admission, Alonzo's prognosis was days to a week or two. By the eighth week, the inpatient team was incredulous and exhausted. We spent multiple hours each day at the bedside with Alonzo's mother, bearing witness to her grief, validating her wish to be a good parent, affirming her spiritual belief in the possibility of a divine miracle, reiterating the limitations of medical interventions, and sharing in her wish that Alonzo not suffer. Our medical team gathered to debrief. Oncologists, nurses, palliative care clinicians, nutritionists, chaplains. We all shared a common desire to partner with Alonzo's despairing family without causing undue harm to our frail, voiceless patient. We talked about Alonzo's mother's love, how she never left his side, her warm hands gently caressing his emaciated limbs. Our nutritionist wondered aloud, might there be a safe approach for the topical application of essential fatty acids? We called our pharmacy, and they had not previously dispensed topical oils to patients. We then turned to the literature, and found several citations that suggested possible benefits associated with the topical application of oil, with no evidence of inherent risk. One study suggested that topical administration of essential fatty acids might lessen the progression of pressure ulcers in individuals with poor nutritional status. A few published manuscripts theorized that the absorption of essential fatty acids through topical application was feasible, predicated on case reports and theories describing the reversal of essential fatty acid deficiencies with cutaneous application of the essential fat linoleic acid in pediatric patients ranging from neonates to adolescents. A randomized controlled trial looked at transcutaneous absorption of massaged oil in 120 newborns in a tertiary care neonatal intensive care unit, demonstrating a significant increase in serum essential fatty acid profiles in the cohort that received topical safflower oil, with no appreciable adverse effects. Yet, even more compelling than the potential to offer a gentle nutritional boost was the possibility of empowering Alonzo's family with a hands-on intervention that could manifest, both literally and figuratively, their love and desire to nourish him. In the context of his family's profound spiritual distress, we also wondered whether coupling two forms of love, nutrition and touch, might offer comfort to the caregivers suffering at his bedside. Prospective evaluation of a systematic intervention to promote physical contact between a caregiver and a seriously ill child in the pediatric intensive care unit has been shown to improve caregiver spiritual well-being. In partnering with his family, perhaps we could minister to their spiritual distress, as well. Our team also became encouraged by reading the growing body of data cataloging the benefits of therapeutic touch for infants and children. We learned that premature infants who receive massage at the bedside gain weight faster and discharge days earlier than those who do not receive therapeutic touch. Within pediatric oncology populations, evidence suggests that the provision of simple massage techniques, either by trained health care staff or by parents who receive training from staff, is feasible and effective for improving anxiety, sleep fatigue, and overall quality of life. Of note, in addition to positively affecting caregiver distress, therapeutic touch may also mitigate patients' suffering, as evidenced by reductions in analgesic administration. Emboldened by these data, and united by our shared mission to support this child and his family, our oncology team sprang into action. A team member drove to a local grocery store and purchased a bottle of safflower oil. A pharmacist officially answered the oil into our formulary for the bedside nurse to dispense. The inpatient team placed an order for one teaspoon of safflower oil gently massaged into the patient's skin by caregiver four times per day. At the bedside, our oncology and palliative care teams explained to Alonzo's family that the topical absorption of oil would not cause Alonzo to gain weight. We discussed transparently that, although a small amount of essential fatty acids would be absorbed, this was extremely unlikely to replete his nutritional stores or prolong his life. Through tears, his mother expressed understanding. A team member trained in pediatric massage demonstrated and taught his mother a series of simple, safe massage techniques to provide comfort at the bedside. We encouraged her to nourish Alonzo with her bare hands, to caress his arms and legs gently with the safflower oil. In synergy with the topical oil, we also started intravenous fluids with 5% dextrose at a few milliliters per hour, plus a tiny daily dose of 5% albumin. We shared frankly with the family that the small amounts of sugar and protein would not yield weight gain. However, the total amount of fluid was low, mitigating the risk of worsening secretions or pulmonary edema. With unified consensus, we gave Alonzo just a little fat, sugar, and protein, less so to nourish Alonzo's cachectic frame, and more to nourish the minds and hearts of those who surrounded his bedside with love. Alonzo's family expressed deep gratitude for these offerings of sustenance. The excruciating daily conversations, which previously had fixated on feeds with circular dialogue, evolved into forward-looking discussions about end of life, grief, and resilience. Alonzo's mother assumed primary responsibility for the application of the oil, creating a formality around the process that culminated in loving caresses and gentle massage. For a hands-on parent, this single intervention carried profound therapeutic power. It allowed his mother to fulfill her duty to feed her child, thereby affirming her desire to remain a good parent, even as she watched her child die. It empowered his family to provide tender, devoted touch as part of their loved one's care, thereby gifting a small sense of control and contribution in the respective faces of perceived powerlessness and uselessness. It eased his mother's spiritual distress, as she felt successful in her advocacy to nurture Alonzo's corporeal host, as she prayed for a divine miracle. It created a deep therapeutic alliance between the medical team and the family that felt heard and honored, thereby smoothing the path for future difficult discussions as imminent end of life approached. And it eased the distress experienced by a clinical team that felt helpless in the face of extreme caregiver suffering, ultimately bringing us together through a unified mission to honor the family's goals while providing high-quality and holistic medical care. 24 days after we offered nourishment, Alonzo died, peacefully, surrounded by his loving family, his frail body gleaming with soft swirls of oil. His mother cried, holding his hand, her face pressed against his. When she lifted her eyes, tears falling, she reached for our hands. "Thank you for listening. Thank you for sustaining us." Hippocrates, revered father of medicine, allegedly said, "let food be thy medicine, and medicine be thy food." Just as we administered medications to ease Alonzo's physical suffering as his disease progressed, so did we offer nourishment. And for his family, just a little fat, sugar, and protein was the medicine that yielded the most profound comfort. As our team debriefed this difficult case, we grasped a salient truth-- to nourish is to love. By allowing his family to feed their child, we empowered them to love fully. Alonzo's story helped our team to realize that addressing nutrition at the end of life is paramount. We have a responsibility to be proactive in discussing nourishment when a patient is dying so as to better support families who feel helpless to nurture their loved ones. We acknowledge that traditional approaches for nutritional support through enteral nasogastric feeds or total parenteral nutrition are not inherently inappropriate for patients who are at the end of life. Our team believes that it is essential to avoid drawing arbitrary lines in the sand that automatically negate the use of low-volume nasogastric feeds or total parenteral nutrition. Rather, we advocate for the consideration of nutritional interventions on a case-by-case basis, weighing the risks and benefits for each unique patient and family. In this case, the clinical team believed that even small volumes of nasogastric feeds and total parenteral nutrition carried significant risk for incurring harm, without hope for benefit. Initiation of topical essential fatty acids, in synergy with low-volume intravenous dextrose and albumin, however, brought Alonzo's family substantial comfort, with no evidence of harm incurred. Since the culmination of this difficult case, our team has offered the option of administration of topical essential fatty acids and massage training to multiple other families who expressed a desire to nourish their children in the context of approaching end of life. For each family, this simple, non-invasive intervention has provided comfort, without appreciable detrimental sequelae. We believe that the interdisciplinary team should explore the nutritional values and goals of every family at the bedside of a dying patient, and all caregivers who express distress or uncertainty should be given an opportunity to learn about topical essential fatty acids and nurturing touch as comforting options. In the context of families perceived to be difficult, clinicians often worry that offering any intervention will result in a slippery slope of demands for additional escalation of care. In our experience, however, we have observed the opposite. These simple and relatively benign interventions lessen tension, facilitate trust and partnership, and create space for dialogue about other goals as death approaches. Cost and accessibility are also important considerations. Compared with enteral or parenteral fats, the price for topical oil is negligible, and options are available at most local grocery stores. Practically, our team typically offers safflower oil, which contains 60% to 70% linoleic acid and has shown potential for topical absorptive qualities. On the basis of prior studied regimens, we recommend the administration of 5 mL topically to extremities through light, gentle massage four times per day, as desired by family. However, sunflower, sesame, soybean, and corn oil each contain linoleic acid, and might be used interchangeably, depending on which oils are most readily available. Among our team and with our families, we acknowledge that topical essential fatty acids and a trickle of dextrose and albumin provide negligible nutritional content if one's metric for efficacy centers on weight gain or repletion of nutritive stores. However, we also recognize that, in these difficult cases, the sum, nourishment, can be so much greater than its individual parts-- a little bit of fat, sugar, and protein. Beyond the concrete value of food, we saw the power of nourishment to support families by gifting them an invaluable sense of control within a situation that is otherwise uncontrollable. Within the quintessentially human belief that food is love, we discovered a unique opportunity to offer a family in crisis a few concrete tools with which to honor and affirm their roles and responsibilities as primary caretakers and good parents. By listening and aligning our medical management with the values and goals most important to the family, we identified a path to build trust, ease regret, and accompany them along the painful anticipatory grief journey. Through this partnership, we found a way to alleviate stress for both the family and clinical staff. Of importance, we also discovered an intervention that bridged multiple medical disciplines, bringing unity and collaboration as sustenance for clinicians practicing each day within a poignant space. When Alonzo's mother carefully reported the safflower oil into her hands, she did so with reverence, determination, and purpose. When she laid her palms on his broken skin, she brought together nutrition, touch, and love in a single, simple, therapeutic intervention. Empowered with the knowledge that she held in her own hands, the ability to provide comfort, she nourished her child and herself, and by doing so, she sustained us all. Welcome to Cancer Stories: The Art of Oncology narrative series. I'm Lidia Schapira your host. And with me today is Dr. Erica Kaye, a pediatric oncologist and hospice and palliative medicine physician and researcher at St. Jude Children's Research Hospital. Welcome, Erica. Thank you so much for having me today. It's great to have you, and love to chat with you about this new piece that you just published in Art of Oncology, which addresses the need to provide nourishment to children who are sort of in the ultimate phases of their illness. Tell us a little bit about the inspiration for this piece. Thank you. So this piece was inspired by a real-life patient for whom our pediatric oncology and hospice and palliative medicine team had the privilege of caring. He was hospitalized at the end of his life, and died very slowly over the course of multiple weeks in our inpatient unit. And during that process, his family struggled profoundly with their inability to feed him. And we began to think quite a bit about what it means to nourish a child, and how nourishment takes many forms, not just corporeal, and not simply food going into the mouth and through the gut, but the many ways that parents love and support and nourish their child and themselves spiritually and emotionally, and the ways in which teams are deeply affected by parents as they struggle in that space. And so we decided to share the lessons that we learned from this complicated and very difficult case at the end of life, and how we found beautiful compromises to help promote the importance and value of nourishing a child even throughout the dying process, what that looked like and what they taught us. In the essay and now, you just talked about the effect this has on the team. In the essay, you mentioned that you all thought this child would die, and then by the eighth week, you say the medical team was both incredulous and exhausted. And it sounds like you needed to find sort of a creative or resourceful way of sort of opening up and aligning again with the family, and that you did this by listening to what the mother was saying, was asking, and by giving her the opportunity to give the child a little fat, and then you provided the sugar and protein. Tell us a little bit about that nourishment, and that idea of sort of the gifts that were exchanged from your team to the family, and then the family back to the team. Thank you. That's such a thoughtful question. And this family, and in particular the child's mama, struggled very deeply with her inability to feed her child as she sat minute by minute at the bedside watching the child slowly die. And I think, in the sort of paradigm of a good parents narrative, how we internalize our role as, quote unquote, "good parents," to a certain degree, the concept of food as love is quite integral to that good parent narrative. And although she fully understood, from a medical standpoint, why giving enteral or parenteral nutrition would likely cause more harm than benefit to her child, the inability to give him fat and sugar and protein created tremendous existential, emotional, and spiritual distress for her. And as we listened and validated and affirmed her wishes and goals and fears, we, as an interdisciplinary team, began to try to think creatively about how we could honor the needs that she had to fulfill her role as a good parent, while also not introducing undue harm or suffering to the patient. And through some research and creativity and exploration of limited existing literature, we decided to empirically trial teaching compassionate touch through gentle massage in conjunction with the application of topical essential fatty acids. And our thought process was that not only could we create a space for his family to offer a small amount of nutrition, the fat that was so important to them, but we could couple that with empowering them to be that good parent, that caregiver at the bedside, participating in the offering of not only sustenance through fat, but sustenance through touch and through love. I think what was most profound as we partnered with the family in this process was seeing their palpable relief, and how much their trust in the team grew through this experience. And the therapeutic alliance that was engendered through these simple offerings was very meaningful and profound, and I think created a remarkable positive feedback cycle. The more they trusted us, the more they listened to our recommendations. And I think it's really important to note that, often, we on the medical side fear a slippery slope hypothesis, that the more we offer, the more the family will ask for. And that has not been our clinical experience. I think when we listen carefully and thoughtfully, with an eye towards partnering genuinely and authentically with families, it does not create unreasonable requests for more. And I think it instead creates trust and love and support bidirectionally. And that was a very meaningful lesson, I think, that our clinical team learned. Yes, and to the reader, Erica, it comes across as the suffering of caregivers, both the professional caregivers, the members of your team, and the family caregivers, the informal caregivers, it was reduced in sync. So what helped the family also helped the team. And there's something very beautiful on an existential level of thinking about that, sort of the power of connecting. You connected with each other, and then with the child. And then, as a reader, what is really impactful is that the child is slowly dying for these eight weeks that feel so exhausting, and then, within 24 hours of relieving this caregiver distress, it's as if everybody can let go and the child dies. Did your team have a chance to think about that? Absolutely. So quick point to clarify, I'd say within hours of beginning the interventions, there was palpable relief at the bedside, and all the conversations evolved in an organic and very meaningful way. The child actually lived another 24 days after initiation of those interventions, which, on some level, was an ongoing difficulty for both the family and the staff because a prolonged dying process is very emotional. But on many levels, those 24 days were such a gift to the family and the staff. There was an opportunity for intentional and thoughtful legacy-building and memory-making, and there was provision of a significant amount of psychosocial supports throughout that process. And I think because we were able to relieve the stress intrinsic to feeling powerless and unable to nurture the child, we were able to focus instead on meaning making, in all of its many, varied forms. And I think that was incredibly useful, not just for family, but for the staff to see and participate in. So wearing your research hat now, if you're looking at this and think about ways of studying it, I have a couple of questions. One is, is your team studying it? And the other is why you chose to tell this story as a story to this readership, in order to perhaps help to start a dialogue or-- you know, what were you thinking? Why present it as a story? Thank you. Those are both incredibly important questions and considerations. The former I think is very interesting. I have been reticent to design a research study to the gold standard that I think is deserving for answering important and unknown research questions, in the sense that I believe strongly in the meaning making inherent to this offering and am quite reluctant. I feel like it is borderline ethically fraught to withhold the opportunity to consider this intervention. I think it's really important to talk about nutrition and nourishment on many levels with the families of all children at the end of life. And so I feel quite conflicted about the idea of offering this intervention to some and withholding it from others. And think it's a very deeply personal decision, what feels meaningful to a family and what doesn't, and would like to empower families to make the choices that most align with their goals and their belief systems. That said, I think it would be very interesting to try to study the value added by this intervention, even if retroactively, through interviews and focus groups with families whose children have died, and ask them, you know, what conversations around nutrition, if any, were had? What was meaningful to you? What do you wish had been discussed? What are your thoughts about this type of intervention? Might it have been helpful to you, or if this or a similar intervention were offered, what was helpful and why? And so that's something that I have been thinking about, and that we will likely be moving towards in the future. To respond to your latter question, I am quite biased as a personal believer in narrative medicine. I think that the narrative, the patient's story holds such tremendous power, not only in allowing for self-catharsis and self-reflection, but also in the transference of meaningful lessons learned and in advocacy, in helping to empower others to learn and teach and move the needle at their respective institutions. And so we were quite intentional about our decision to share the lessons that we learned through the lens of the stories that impacted us. And in this particular case, the one patient who really got us thinking deeply about this issue. I think there's a lot of emotional valence intrinsic to the sharing of a true story, and that emotional valence allows us to connect with and remember lessons learned in ways that, often, objective didactic does not. And so I believe that this format is very meaningful for all of those reasons, and I also think that it reaches a wide and diverse target audience of readers within the field of oncology, all of whom may interpret and synthesize this information in unique and personal ways, and then, I hope, take it with them to share with their colleagues and to help inform the clinical experiences that they go on to have in the future. Well, Erica, that has been so enlightening. I look forward to reading some of that qualitative research that you'll probably do by interviewing families. I love the idea that there's an almost sacred aspect of the experience that perhaps we should always strive to improve, but shouldn't tinker with. And one of those has to do with the expression of that incredible emotional connection between a parent and a dying child. And so we should definitely support it in any way we can. And then how we can strengthen our own community of thoughtful oncologists to be creative, to be resourceful when they are faced with a situation that, at some level, may almost appear to be a conflict, but if you sort of peel back all the layers through narrative, through listening, you actually can find that you can align with the family around a common goal. And that makes everybody better, and certainly relieves caregiver distress, in addition to family suffering. So thank you so much for your beautiful writing, for your advocacy, and for sharing it with the readers of Art of Oncology. Thank you so much. It is an honor to be able to share these stories and, in doing so, honor the patients and families for whom we care. Thank you. Thank you so much. 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. Canellos on his involvement with CHOP, MOPP and CMF as well as his role as Chief of Division of Med Onc at SFCI/DFCI for 25 years. 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 world of cancer care. You can find all of the shows, including this one, at podcast.asco.org. Hello. Today my guest on the podcast is Dr. George Canellos. Dr. Canellos was instrumental in early treatments for breast cancer, lymphomas, -- and chronic leukemias, and he's generally considered one of the so-called Gang of Five with the National Cancer Institute in the 1970s, along with Drs. Vince DeVita, Robert Young, Bruce Chabner, and Philip Schein, who ultimately demonstrated that chemotherapy could be used to cure a fraction of patients with Hodgkin's and non-Hodgkin's lymphomas. Dr. Canellos was raised in Boston, and he attended Boston Latin School. He then received his undergraduate degree at Harvard and his medical degree at Columbia in New York City. But he remained a Red Sox fan, so he returned to Boston for his residency in internal medicine at Massachusetts General Hospital. But he then trained in oncology at the National Cancer Institute where he stayed until 1974 when he once again returned to Boston to join the faculty of the then Sidney Farber Cancer Institute where he served as the Chief of Medical Oncology until 1995. He is currently the William Rosenberg Chair at Medicine at the now Dana Farber Cancer Institute and a Professor of Medicine at Harvard Medical School. Dr. Canellos has authored over 300 peer-reviewed papers and too many reviews and chapters to name. Most importantly, he served as the Second Editor in Chief of the Journal of Clinical Oncology, a role he filled from 1987 until 2001. And during that time, he directed the Journal to become the leading journal in our field. Perhaps even more importantly, he served as ASCO President in 1993 and 1994, and he's been recognized as an ASCO Oncology Luminary, and he's been recognized with the Statesman Award and the Distinguished Service Award for Scientific Achievement from our society. Dr. Canellos, welcome to our program. Good to talk to you. Great to talk to you. You know, I spent a lot of time with you at the Sidney Farber and then Dana Farber Cancer Institute, and I've heard you say, and I've also read, that you originally seriously considered becoming a surgeon because of the work you did with Dr. Oliver Cope, one of the leaders in surgery of our last century and especially related to thyroid and other cancers. So what led you to get away from surgery and become a medical oncologist? Well, I served as a surgical intern at Mass General at that time, which was a lot of exposure to serious illness and surgery. But it dawned on me. Two things dawned on me. One is that if one was interested at all in malignancy that surgery really wasn't the answer, certainly, in any way. And in those days, of course, even radiotherapy was not the answer. And so the other thing I realized, that I had the manual dexterity of a California fur seal. I didn't really feel, being left-handed, I didn't feel that I really had the dexterity required to do some of the complicated surgery that was going on in those days because I held retractors as an intern for some very long operations that really didn't achieve more than taking out a gallbladder. It took three hours. Now, we can do it with a laparoscope in a half an hour, probably. So I switched into medicine at Mass General and stayed in medicine at Mass General. And being inspired to really think about other treatments for malignancy in those days, there were very few really textbooks available that talked about chemo. There was some. I would nip up to the library of the hospital rarely and try to read about them. There were new drugs coming out at that time, but there was very little really known about the action of the drugs and the potential of the drugs that might have existed at that time. Then I went to NCI, as one had to because there was a doctor draft. And two years of residency in medicine, I actually went to the medicine branch of the NCI. And there, under Emil Frei III, another investigator named Freireich, Jay Freireich, who were around at that time and running the program, such as it was, we first were experience-- I was thinking that I would do research there, and I did. But at the same time, the Clinical Associate Program entailed a year of clinical exposure, of clinical care, and I had several colleagues. The first major colleague was Vincent DeVita who really, at that time, decided to approach a treatable more solid malignancy, as acute leukemia of childhood was being approached, with combination chemotherapy. However, there weren't many drugs that were very active at that time. There were some. An alkylating agent, nitrogen mustard, steroids, a vinca alkaloid that had just been relatively new introduced for adult disease. And there was no procarbazine. Of course, it hadn't been invented yet, but methotrexate. And so the first combination regimen that came out of that program was MOMP, M-O-M-P, and that had some activity, but it was only given for a relatively short period of time. Eventually, the tolerance of patients to these drugs was considerable, a considerable issue, because we didn't really have granulocyte support. There were a lot of things that we'd take for granted now that were not available then. So the toxicity of some of these programs, such as the M-O-P-P Program when procarbazine came along, the MOPP program was considerable. But the interesting thing is the patients that we had were generally on the younger side, younger than 45, let's say, and they could tolerate the therapy. And I found that, honestly and subsequently, with testes cancer, that younger people who get a lot of toxicity from these drugs, despite that, if they think there may be a cure around the corner, will tolerate it. And you don't hear a great deal of complaints about it, about the toxicity, interestingly. But the older patients, of course, are far more vulnerable. Their bone marrow reserve not being great, these regimens were quite toxic. But, fortunately, the first targeted disease was Hodgkin's disease, and it's generally a disease confined to younger people, in general. About 20% of them are in the older group. But we first tested the aggressive chemotherapy, known as MOPP, in the younger patients, actually. But what was surprising to us, and surprising to everybody, was the fact that they failed to relapse as they were all expected to do at that time. In the single drug agent era, of course, Hodgkin's disease would relapse eventually. As house officers, we just expected that to happen. Now, the training in the major academic hospitals in those days, oncology was not an important part, or even a desired part, of the program, if you will. And so most who arrived at a place like NIH really didn't have much background at all in the treatment of cancer because they probably didn't see it all that much. I know I didn't. As a surgeon, yes, but not as internal medicine. I was going to ask you that. When you were at Mass General and you said you noticed that surgery wasn't curing people, there couldn't have been anybody around that was mentoring you or said, why don't you-- how did you even hear about-- No, no, there wasn't. There were some docs there who really cut their teeth on giving hormones to breast cancer patients, and that was about it. But very few people were giving-- I couldn't think of anybody who was giving-- one person who was giving chemotherapy, a lady, a fine lady, fine physician actually, but on the private side, but nobody on the academic side that amounted-- So what made you-- What made you say, I'm going to go to the NCI and learn how to do this? I mean, that seems like that was completely out of the blue. Well, you weren't given much choice. Of the two institutes, I applied at the Heart Institute and the Cancer Institute. The Cancer Institute accepted me, and the same with Vince DeVita. He applied to the Heart Institute but got into the Cancer Institute. And we were both there, probably you could say, as our second choice at the time. Because-- Yeah, that's interesting. Yeah. Very little was known about oncology as a field, and there we were. On the other hand, seeing these patients at least respond to these drugs in the way they did, and seemingly not relapsing, made you wonder whether or not, in time-- when I went back to the NIH, I came back to the MGH to be a senior medical resident. I can tell you what was interesting, because there was no oncology Fellow, per se. They would ask me to see a patient if the patient had a malignancy. And I remember going in and seeing a patient with ovarian cancer. She had a huge belly full of ascites, malignant ascites, and I said that the drug for this disease is thiotepa, an alkylating agent. I wrote out the recipe, if you will, how many milligrams, et cetera. And I wrote in the note, and I will give the first dose, which I did. The intern covering the service, a surgical intern covering the GYN service, obviously read part of my note but not all of it, or decided he was going to give another dose as well, but somehow the woman was double-dosed. And there was a certain panic by the nursing staff, et cetera. She tolerated the drug surprisingly well. But more surprising, everything went away. She had this dramatic response to therapy. The ascites went away. The abdominal masses went away. And she was discharged. And I said to myself, at that time, this is a precedent for something, and that era will arrive once-- if it's not the right drug, we'll find the right drug for the disease. But I can tell you, it was very uplifting to me. I had already been to NIH. That's a great story. When you guys were at the NCI, a similar question is, when did the light bulb come on that it looked like you were actually curing Hodgkin's disease? Well, you're talking about a two-year appointment. At the end of the two years there, the remissions were already clear. That is to say, the disease had not come back, and the people were being followed. But two years is just two years. I mean, it's not a long time. And when I went back on the faculty-- see, I went for a year in England to become a hematologist because everybody had to be a hematologist in those days if you were interested in cancer. Anyway, that's what I did. And when I got back, they recruited me to the faculty, and the patients were still in remission, and that was great. And then we put our attention to the non-Hodgkin's lymphomas and modified the MOP regimen by putting cyclophosphamide instead of nitrogen mustard, which was a horrific drug by the way, nitrogen mustard in the doses that we gave. But like it or not, we put Cytoxan into it and we called it CMOP. It was like MOP but it was with C instead of the M. So we called it CMOP. And early in the 1970s, we did a randomized trial with the radiotherapists who were throwing radiation at everything that walked in with a non-Hodgkin's lymphomas, and we did a prospective randomized trial stage by stage, histology by histology. And I remember looking at the data for the large cell lymphomas with the CMOP and I said, Vince, you know, if we judged everything by median, the median survival of our patients was what you'd expect historically. But just below the median, the line straightened up, flattened out, and was going out now several years, at least four or five years, flat in a disease that usually recurred very quickly and killed everybody who was affected by it. And I remember when the Board of Internal Medicine decided to create a specialty called Medical Oncology and have an exam, et cetera, Vince thought it was because of Hodgkin's. And I'm sure it contributed, but I said it must be also the non-Hodgkin's because it's far more common. It's far more common. We helped far more people. And indeed, it probably is. Can I interrupt you for a moment? I interviewed Saul Rosenberg for this series, and he told me just [INAUDIBLE] the radiation psychologist. So Dr. Kaplan had referred to him from Memorial to come to Stanford and do radiation, and Dr. Rosenberg told Dr. Kaplan, I think we need to give these people chemotherapy, and Kaplan agree. But the Chair of Medicine did not and would not let Rosenberg see patients in his own clinic and give chemotherapy. So he wrangled a room from a hematologist, and he told me he would see patients in the room. He had a chair in the hallway. If the patient needed chemotherapy, he'd have the patient go sit in the chair in the hallway. Get an IV pole. He'd start the IV himself and then mix up the chemotherapy himself, hang it up. While the patient was getting chemotherapy in the hallway, he'd see the next patient in the room. Those are the kinds of obstacles he had to do. And the other thing I have to say, I didn't get to interview Dr. Holland before he passed away, but relative to your looking at the Kaplan-Meier curves, I'll never forget his yelling at me one time that, if you need a statistician to see what you've done, you probably haven't done much. I said that, 'cause I remember saying that as well, but anyway. Let me ask you another question. Yeah. You're know for lymphoma and chronic leukemias but also for breast cancer, and generally you're credited for coming up with the so-called CMF regimen. Vince and I were called into the director's office. At that time, the director of NCI was [INAUDIBLE]. And they said, all this lymphoma stuff is wonderful, but we want you to do solids. Now, we didn't have a referral pattern for solids at all. The only breast patients we saw were relatives of employees of the NCI. So Vince wanted to do ovarian, and I said ovarian is a good disease because they have malignant cells floating around, and we can do stuff on those. And Vince really wanted to do ovarian. I chose breast. And, again, we had no mastectomy surgical group or anything. And so what we did was make deals with medical oncologists in the community, two of them who actually trained-- one of them trained at the Brigham Hospital, actually, and they lived in the area. And they liked to come to our conferences and things. They would refer patients. And what we specified, initially, was that we have patients without isolated bone lesions only, that they had to have measurable lumpy, bumpy disease. And so to design a therapeutic treatment for them, we had to use the principles that we learned from the lymphoma experience. And that's where CMF came. CMFP, we used to have prednisone in some circumstance. And so that was the regimen that-- if you notice, the design of it would be like the MOP program. Anyway, so we started treating people like that. Suddenly, they did respond and some responded quite well. They had some toxicity, of course. And the very first paper we wrote was on the toxicity of CMFP. It was hard to get things published in medical oncology areas, and the Lancet was wonderful for us. The Lancet was very helpful, and we published a lot of stuff in the Lancet. But the first one was in the British Medical Journal, the toxicity of CMF program in patients, and we especially cautioned patients who had compromised liver function because they seemed to get worse toxicity at that time in our imagination. But it worked. It did work. We published it in the Annals of Internal Medicine eventually. But the important thing was, our friend Johnny Bonadonna would come over periodically to find out what we were doing. And he came over with an offer. He said he had all these patients who would get mastectomies and then nothing. Let me interrupt you for a moment 'cause I was going to ask you about Dr. Bonadonna. Yeah. Would you, just for the audience, a lot of them may not know who he is. Oh. Well, Johnny Bona-- Do you want me to describe him? Well, at that time, he was a young investigator working in Milan at the major hospital there in oncology, and he trained at Memorial before and then went but back to Italy. So he came and he wanted to know what we were doing. We showed him the protocol that we were doing for breast, and he was interested. And what he offered was the opportunity of doing a randomized trial on patients with a higher risk, if you will, breast cancer, node-positive patients. And he said that in Italy that nothing was done for them and that he could randomize them nothing to chemotherapy, and we offered him a contract. He required money. We gave him a contract. We gave him our protocol, at least the chemotherapy protocol. He went back to Italy and did that trial. And he left the prednisone out. He made sure it was of just CMF. And the patients, apparently, I guess, knew what they were getting, but I don't know whether they had strict requirements or informed consent and things like that. We didn't ask. We didn't ask. All we wanted was randomized data, and he certainly had it. And I remember being at the ASCO meeting in 1976, I think it was, '75 or '76, in Toronto when the first data was presented by Bonadonna. And the media people were there. People were barely hanging from the rafters to hear. The room wasn't big enough, really. None of the rooms were big enough because they never expected the attendance, that there were that many young oncologists around or people interested in oncology. And so he gave that first data, and that was a shot in the arm for adjuvant therapy, certainly for breast cancer, but for other things as well. I think, in general, he and Dr. Fisher, who sadly passed away before I had a chance to interview him, are responsible for thousands and thousands of people. Yeah. Absolutely. Absolutely. Absolutely. But I'm giving you the NCI side, my personal side of it, and you're right. Bernie was a real pioneer because he had so much opposition from the surgical establishment at the time. I can tell you that. From a surgeon's point of view, they really thought he was the Antichrist. I mean, it was terrible. I saw him and Jerry Urban get into a verbal argument at a meeting. I thought it was going to be a fistfight, actually, over-- Really? Yes, yes. Yes, they're severe. But anyway, let me go-- let me go to my next question, which has tended to change gears for a moment. You may or may not remember this, but when you were ASCO President, in your presidential address, I was in the audience and you said something to the effect that the greatest clinical experiment you have conducted are the Fellows you have trained, or something like that. Yes. Yeah. And I was in tears, of course. But you certainly can claim success on that. The division chiefs, department chairs, cancer center directors, most recently a Nobel Laureate, [INAUDIBLE], all of them came out of the program. But when you returned to Boston, you could not have envisioned all of this. What was the atmosphere, and what was Dr. Farber's vision? Well, Dr. Farber had died by the time I got there. Oh, he was already gone? OK. He was already gone. And when I was leaving, when Tom Frei recruited me, Vince thought I was mad because they made me Clinical Director. At least have a go at acting job as clinical director of the NCI. But really, down the line, it was a bureaucratic evolution. And I said, I don't really want to be an oncocrat at this age, anyway. What I said was, Vince, I said, the doctor draft is over. The best and the brightest and the youngest and the cheapest are all going to be in these hospitals, and there are a lot of them in Boston because I happen to know Boston, including house staff at the Brigham, house staff at the BI and Mass General. And I said, that's the future, or at least the future challenge. And I think he accepted it, but he didn't like it. I mean, he thought-- well, we were great buddies and we worked well together, and that goes for Bob Young and Bruce Chabner too. They thought I was very-- Where else-- at that time, there must have only been two or three places to train in oncology in the whole country, I would imagine. Yes, yes, yes. And people were just starting to set up cancer centers, sometimes without funding. And then there were all these, not many, but job requests for me to go and look at the job at Wisconsin or you name it, but I didn't want to do that. I really wanted to do medical oncology and not be a bureaucrat in any way. And many of the places, Dan, would say come and be a head of our cancer program, and it was also translated in parentheses, come and write a CORE grant. A lot of places who didn't deserve a CORE grant were asking me for people to come and write a CORE grant. You knew forever they would never get one because they really didn't have the makeup for it, yet. So what were the hurdles in Boston when you got there? Well, the hurdles in Boston were twofold. One is the fact that oncology had a very slow start in Boston, and that goes at the Brigham and at the MGH. The MGH was even disinterested in oncology at that time, actively disinterested. They didn't think it had any academic merit and therefore didn't put any effort into it. I have to say that Gene Braunwald, who was Chief of Medicine at the Brigham at the time, was interested because he had been at NIH at the Heart Institute, he knew Tom Frei, and he wasn't sure about it yet because he couldn't swallow it, I guess. And the fact was that it was growing a bit, and one of his very close associates developed large cell lymphoma and he got chemotherapy, he got to see MOP. And he was long-term remission. And I remember telling Braunwald, he was shocked that it was so successful. And I kept telling him, I said, this is not a rare event. This is happening. But the big challenge, Dan, at Dana Farber was that there was no oncology known, and we had to build the program from the bottom up. We hospitalized our patients at the Brigham before we opened the beds at the Dana Farber, but we needed the volume of patients. And we had all these beds, I think 59 beds, licensed beds, open. And I kept saying, we don't have the patients. But Tom Frei opened the beds. The next thing you know, I was talking to trustees because Tom said, we'll bring George up and we'll grow. The clinical program will grow. So the trustees thought the program would probably grow the next day. It didn't. It took a lot of effort without the [? scare ?] and myself going around giving talks in every little hospital that existed. And one of the big things I had my mind, because the house staff looked after our patients as well, was to show them what we could do. Now, in those days, other than the large cell lymphomas, of which we did not have many because they were in the hands of hematologists, was testes cancer. And the head of urology at the Brigham Hospital used to have these Saturday morning urology rounds inviting all of the practicing urologists around to come and they'd present their problem cases, et cetera. But he asked me to come along and give a talk about this new drug called cisplatin, which was having a big effect in testes cancer in other places. And I did. And I would come and talk about the early results in other places in testes cancer and that we were interested in actually starting a program. Then, they would-- of course, urologists are anything but chemotherapists, and so they would refer the patients in because, A, they couldn't give any chemotherapy. There was nothing oral that would work. What we would do is, if they sent patients in, we would do an early trial and we would publish the series in a, let's say, not spectacular journal and get reprints. We would send them reprints. And in some instances, I put the name of the referring doctor, if he'd sent us more than one patient, on the paper for, let's say, testing some antineoplastic thing. And we would put their names on the papers and send them reprints. And there's nothing a urologist loves more than to see his name on a scientific paper, a medical paper. And we started getting a ton of testes cases eventually and did trials and wrote papers about them. And I remember, when we recruited Phil Kantoff, a Fellow of mine, and I thought he was going to go back to the NIH and do gene therapy. And he walked in one day and he said, I'd like to apply for the GU job, and I said, it's yours. And he wrote quite a few papers based on the accumulated testicular data and the [INAUDIBLE]. Oh yeah. Yeah. And he was wonderful. He's Chief of Medicine now at Memorial. He's Chief of Medicine at Memorial, yes. I want to bring up one more thing that this segues into, though, and I believe now almost every medical oncologist who has trained in the last 10 years thinks that multispecialty tumor boards have always existed. But I believe that another of your trainees, Dr. Craig Henderson, who was my mentor, frankly, and you really started the first multispecialty clinic perhaps in all of oncology in this country. Do you agree with that? We called it the BEC, the Breast Evaluation Center. Yes, and we got cooperation but from surgeons. There were surgeons around, more nihilistic surgeons, if you will, not wanting to do radical surgery and radiotherapists, like Sam Hillman. And they were all around and doing those things. And we brought them into this BEC, the Breast Evaluation Center, and your mentor, Craig, was a little rough on the Fellows, I can tell you, in those days. Just his demands. Anyway, whatever it was. And so I would go to that clinic as well and see breast patients just to calm things down a bit at times. Anyway, it worked. And I know that the breast people elsewhere were recognizing that Craig had a nice thing going there with the multidisciplinary aspects. You know, it was so awful that breast cancer was treated so badly. I mean, they'd have a radical operation. And God knows, if there was some disease, that they would then get radical radiotherapy to their chest. And they were walking around sort of mutilated. And we had a part-time psychiatrist when I first arrived to see these patients because many of them had body image problems. So the idea of not doing radical mastectomy was revolutionary at that time. And I remember being called by the local Blue Cross to serve on a committee to decide whether or not Blue Cross should pay for breast reconstruction on these poor patients, and we voted. There was a committee of medical oncologists from MGH, me, and a plastic surgeon, and we voted 3 to 3 to they should pay, and they didn't. Then they said, thank you for serving on this advisory committee, but we're not paying. We've decided not to pay. Then, I can tell you, a women's agitation group got a hold of the facts. And one of them called me up and she said, I heard you were on this committee that voted not to pay. And I said, absolutely we voted to pay. They told us, thanks very much but we're not going to pay. So within two weeks then the insurance company changed its opinion because they went bananas at the insurance company. Yeah. The strength of advocacy, that's been something. Anyway, we're running out of time. I'd like to thank you for taking your time with us. Not at all, Dan. Not at all. It's a pleasure. And as I have done for every other interview in this series, I want to thank you not just for taking time with us but for all you've done for the field, for those of us who trained with you or are in the field, and most importantly for all the patients who have benefited. You look back over the-- Yeah, I know. I still follow them. My clinic has follow-ups of cured patients. You become the primary care doc for cured patients. Well, you think of the 60 years of your career and other fine folks that you were with at the NCI and then beyond, and the thousands or millions of people who have benefited, it's pretty remarkable. Yeah, well. Thanks again. I appreciate you being on. Not at all. And enjoy the rest of the day. Thank you very much, Dan. 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.

Dr. Hayes interviews Dr. Mayer on his training at NCI and running DFCI's fellowship. 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. Today, my guest on this podcast is Dr. Robert J. Mayer. Dr. Mayer is the Stephen B. Kay Family Professor of Medicine at Harvard Medical School where he is also the Faculty Associate Dean of Admissions, in addition, the faculty Vice President for Academic Affairs for Medical Oncology at the Dana-Farber Cancer Institute. Dr. Mayer was raised in Jamaica, New York. And, Bob, I always thought you were raised in Brooklyn, but I looked it up on the map. And it looks like Jamaica is about two blocks in the middle of Brooklyn. So we'll say you're from Jamaica. Actually, I was a little bit to the east of there in Nassau County. That counted a lot then, Queens versus Nassau, but anyway. So it gets even more esoteric. Bob received his undergraduate degree in 1965 from Williams College, which is way out west in Massachusetts, and then went to Harvard where he got his MD in 1969. He did his residency in internal medicine at Mount Sinai in New York City and then was a clinical associate in the medicine branch of the National Cancer Institute from 1971 to 1974. He served a fellowship in medical oncology at what was then the Sidney Farber Cancer Institute. And then he joined the faculty in 1975. He has spent much of his career at leading clinical research in leukemia and GI malignancies. He was the chair of the CALGB, now called the Alliance TI Cancer Committee for years. But, perhaps more importantly, he was director of the fellowship program at, originally, the Sidney Farber and then the Dana-Farber Cancer Institute for 36 years. And then he was also head of the fellowship program at the Dana-Farber/Partners cancer program from 1995 until 2011. And, frankly, he was my fellowship director from 1982 to 1985. So I owe a great part of my career to Dr. Mayer. He's co-authored over 400 peer-reviewed papers and another 130 chapters and reviews. He serves as associate editor for both the Journal of Clinical Oncology and The New England Journal of Medicine. And, as have many guests on this program, he served as president of ASCO, in his case, in 1997, 1998. And he received the ASCO Distinguished Achievement Award in 2019 for his ongoing leadership in our society. Dr. Mayer, welcome to our program. Pleasure to be with you, Dan. So I have a lot of questions. And, again, I usually do this, you know, two guys in a cab. How did you do that in the first place? What got you interested in oncology coming out of Williams and at Harvard? And, at that time, there wasn't much in oncology. What made you want to take care of cancer patients? Well, I was a third-year medical student at Harvard sort of sleepwalking through the curriculum, undecided what my life was going to be, planning to go back to New York, and I came across an attending physician on a pediatrics rotation, a hematologist by the name of David Nathan. And we hit it off. And I became really interested in blood cells and how looking at smears and bone marrow morphology could tell you a lot about the status and health and nutrition of individual patients. Nathan took a shine to me. And, when I was a fourth-year student and was going to face probably a military service, and there were military actions going on in Southeast Asia, he called me to his home one night and shoved a whole pile of paper in front of me, said fill this out. I want it back tomorrow. And this was an application to be a clinical associate at the National Cancer Institute where he had spent several years I guess a decade before. So I did what I was told. And, when I was a intern, I guess my first day as an intern, I got an overhead page from the-- in the hospital, call from Bethesda informing me that I had been accepted. I had had 10 or 11 interviews. One of them turned out to be a person who would be important in my life as a friend and a mentor, George Canellos, who was first time I met him. And, in 1971, I found myself at the NIH. That's quite a story. And Dr. Nathan, of course, went on to start the Jimmy Fund, probably had already started the Jimmy Fund Clinic at the time, and became the CEO, I think, of Children's Hospital in Boston. He became the CEO of Dana-Farber actually. I do want to just recollect with you my first day or two in Bethesda because some of the people who found themselves there took it more seriously than others. And I was assigned to the medicine branch. And the medicine branch had a chief who was a breast cancer-oriented investigator by the name of Paul Carbone who went on from there to an illustrious career as the founding head of the Cancer Center at the University of Wisconsin and the leader of the Eastern Cooperative Oncology Group. And Paul, at that point, the first day I met him, told us that, if we messed around, moonlighted, didn't show up, we'd be on a Coast Guard Cutter as fast as he could do the paperwork because, technically, we had a position in the Public Health Service. Under Carbone, there were two branches. One was leukemia, and that was headed by Ed Henderson. He was a lanky guy from California, a wonderful man, went on to a career with Cancer and Leukemia Group B and with the Roswell Park in Buffalo for many years. And he was my branch chief. And the other branch was solid tumors. They weren't solid tumors like we think of them today. They were lymphomas. And that was headed by Vince DeVita and had Bob Young, George Canellos, Bruce Chabner, and Phil Schein, all illustrious founders of so much that has become oncology. So that was the setting. And the last thing I'll mention was about this. I came there as a trained internist, but I was assigned to pediatric leukemia. And I learned very quickly that what separated the wheat from the chaff, in terms of families, parents thinking that you were a good doctor, was your ability to maintain the 25 gauge scalp vein as venous access in these children because there were no port-a-caths, no Hickman lines, and, obviously, access was something that was critically important. You know, I think everybody who is listening to this needs to understand that what you just described started out really with just Gordon Zubrod who then brought in Frei, Holland-- or Holland first and then Freireich. And then they brought in the next group, which I believe you would agree is Canellos, DeVita, Bob Young, and others. And then you were sort of in the third wave. And you could just see it began to expand the whole field of oncology really just from a few people going out. Do you agree with that? I do. I do. When I came to the NIH in 1971, there was no defined, certified subspecialty of medical oncology. The first time the medical oncology board examination was given was in 1973. It was given every other year. I was in the group that took it the second time in 1975, but this really wasn't a subspecialty. In 1973 also was the time that the first comprehensive multi-authored textbook on medical oncology was published by Jim Holland and Tom Frei, Cancer Medicine. And I remember devouring that as I prepared for the board examination, but there was no book like that. There was no reference, no UpToDate, no computer to surf the web and find information. And so this was all brand new. It was quite exciting to be there as part of the action. You sort of jumped ahead on what I wanted to ask you, but I'm interested in the establishment of medical oncology as a subspecialty. Can you maybe talk about Dr. BJ Kennedy and his role in that? I think he was pretty instrumental. Was he not? BJ was at the University of Minnesota. He was an extraordinarily decent man. And, somehow, the internal medicine establishment viewed him as a peer and a colleague, which I would have to say was not what they considered many of the pioneers, if you will, in medical oncology. I can remember, in my second or third year at the NIH, traveling around the country to look at fellowship programs. And I was always being met by senior established hematologists who arched their eyebrows and said now where's the pathophysiology. Where is the science here? They really thought that the animal models, the mouse models, the Southern Research Institute that Gordon Zubrod had been such a pioneer in fostering was pseudoscience. I can also remember, when I found myself back in Boston, the establishment of Harvard Medical School didn't initially take oncology very seriously, but there were patients. And there was optimism. And all of us in that generation really believed that we could make a difference, and we could learn a lot and do good for patients and for medicine. And I think we have. So, in my opinion, now, appropriately, our fellows have a very strict curriculum of what they're supposed to learn and how and when and why laid out, again, in a pretty rigorous formal manner. You told me before, at the NCI, it was just sort of learn it. It's up to you. Can you talk about that training? And then, when you went to the Sidney Farber, you then turned that into a training program. The medicine branch was fantastic training, but it was learning from taking care of patients and from your colleagues. The quality of my peers was extraordinary, but there was no formal curriculum. The faculty there each were doing research, the members of the faculty. And, for a month, they would come out of their cave, if you will, their laboratory, and they were very smart and were doing fascinating things, but they didn't have long-term patients. Or there was no real process. And the NCI was sort of like a Veterans Administration hospital in the sense that it opened around 7:30 or 8:00 in the morning, closed at 5:00 or 6:00 in the afternoon. One of us would be on call at night with a couple of nurses, but it was rather primitive in its support mechanisms. We were assigned a group of patients. And then, on rotation, those patient numbers would increase. And we were expected to do everything conceivable for that patient. And, at that time, the oncology care offered in Bethesda at the NIH or the NCI was free. It was paid for by the government. And much similar care was not available in other places. So I would have patients flying in from Omaha and New York or Norfolk or Tampa, Florida. And they would be housed in a motel that was on the edge of the NIH reservation, but, if one wants to talk about continuity of care, you knew everything about every one of those patients because you were the only person who knew them. So what were the circumstances then that you ended up in Boston? Well, that's an interesting story because it gets back to David Nathan. I was working after my clinical year in a basic laboratory as I could find. It was run by Robert Gallo, Bob Gallo, who was one of the co-discoverers years later of the HIV virus. But, one day, I got a phone call from Dr. Nathan's secretary saying that he was going to be in Washington a week from Tuesday or whatever. And he wanted to meet with me in the garden of the Mayflower Hotel. OK, fine. So I trotted over to the Mayflower Hotel, and there was Dr. Nathan. And he said, you know, Dr. Farber is getting old, but there's a new building. And there's going to be a cancer center. And he's just recruited Tom Frei to come from MD Anderson. And it's time for you to come back to Boston. Didn't say would you like to come back, would you think about coming. No, he, just applied to the NIH, shoved the papers. Here, it's time for you to come back to Boston. So, a few Saturdays after, I flew up to Boston. And, in that interim, Dr. Farber passed away. He had a heart attack, an MI. And there was Tom Frei who I met for the first time, made rounds with him. We hit it off. And he told me that he would like me to spend one year as a fellow and then join the faculty and become an assistant professor. Well, I didn't need a plane to fly back to Washington. I thought this was tremendous because I was looking at hematology scholarships around the country. And there was no career path. And this seemed to be a career path in a field that I was really interested in. And he talked to me really about coming back to do leukemia because that's what I had been doing at the NIH. And, a year later, I found myself, July 1, 1974, being part of the second fellowship class at what's now Dana-Farber. There were six of us. There were six the year before. We were piecing it together step by step. There, again, was nothing chiseled in marble. There was no tradition. This was try to make it work and learn from what works. And, what doesn't work, we'll change. You must have had a lot of insecurity coming into a program that really had just started. There had to be chaos involved in that. Well, there was a little chaos, but, to be honest, I was really engaged in it because it was exciting. I thought that oncology, as I still do, is this marvelous specialty or subspecialty that unites science and humanism. And, because other people weren't interested or maybe weren't capable of providing what we thought was the right level of care, to be able to sort of write the playbook was a terrific opportunity. We sort of-- and it extended into the year that you were a fellow as well-- followed the medicine branch mantra in the sense that we assigned fellows patients. And they took care of those patients and were expected to do everything that was necessary for them. There weren't rotations at that time that you would spend a month on the breast cancer service and then a month doing lymphoma. You would see new patients or follow-up patients. We didn't really have enough patients or enough faculty at that point to be smart enough to think about that being a better way or an alternative way to structure a trainee's time. I remember, at the end of my first year, when I finished that year as what I think Tom Frei called a special fellow, I was the attending on the next day, which was July 1. And I remember that a fellow, a first-year fellow who was just starting, Bob Comis who became also the chairman of the Eastern Cooperative Oncology Group years later, a marvelous lung cancer investigator, was the trainee. And, on that day, we went ahead and did a bone marrow on a patient with small cell lung cancer and being a fellowship director just started because there was no one doing it. And Frei said please move ahead. I have to say, when I started in 1982, I just assumed this was the way everybody in the country was training fellows in oncology. It really didn't occur to me that that was only a few years old and the way you had set it up. A few years ago, the Dana-Farber had a banquet to celebrate the 48-year career of a guy named Robert J. Mayer. And I was asked to speak. And I got up. There were over 300 people in the audience, all of whom had been trained there. And, as I looked around, I sort of put my prepared words aside and said look at the people sitting next to you. They are either former or to be presidents of ASCO, ACR. They're cancer center directors, department chairs, division chiefs, and a bunch of really terrifically trained oncologists all due to one guy, and you're the one. So you started with Bob Comis-- I've never heard you tell that story-- to really training some of the greatest oncologists in the world in my opinion, myself excluded in that regard, but, nonetheless, you must be quite proud of that. Well, yes, but I want to flip it around the other way because, for me, this became a career highlight, the opportunity to shape the patterns, to make the people who trained here leaders, and to have them-- right now, the director of the NCI is a Dana-Farber alumnus. To have people who are of that quality-- and you certainly represent that, as an ASCO president and one of the hallmark leaders of the breast cancer community-- this is what a place like Dana-Farber and Harvard Medical School, hopefully, not too much arrogance, is supposed to be doing. And to have that opportunity, to be able to fill a vacancy that nobody even appreciated was a vacancy, and then to develop it over enough time that one could really see what worked and see what didn't work is an opportunity that most people don't have. And I'm so grateful for it. Now, Bob, I want to just, in the last few minutes here, you've obviously been a major player in ASCO. Can you kind of reflect over the last 25 years since you were ASCO president, the changes you've seen, and what you think of your legacy? I know you don't like to brag too much, but I think there's a reason you got the Distinguished Service Award. And can you just reminisce a bit about what's happened and then where you think we're going as a field? Well, ASCO has been my professional organization. The first meeting I went to was in a hotel ballroom in Houston, the Rice Hotel, which doesn't exist anymore. And it was a joint meeting of ACR and ASCO in 1974. There were 250 people. And everybody was congratulating each other at the large number of attendees. I had the opportunity, in large part because of Tom Frei and George Canellos and other people, to become involved in picking abstracts for leukemia presentations, being part of the training committee, and then chairing the training committee. I actually had the opportunity to be one of the four people who started the awards program, which now has the Young Investigator Award and Career Development Award and things of that sort. These are just opportunities because they weren't there before. And, if you're willing, and you put in the time, I guess people come back to you and give you the chance to do these things. I became then involved in the JCO, the Journal of Clinical Oncology. I became involved in the debate about physician-assisted suicide and palliative care that led to some very educational debates and probably spawned the field, to some degree, of palliative care. I had the opportunity to be at the forefront of starting the Leadership Development Program that was really Allen Lichter's idea, but I was able to devote the time to make that happen. And, most recently, I've been on the Conquer Cancer Foundation now for almost two decades. And watching that grow has been a joy. ASCO, when I came, was a very small trade organization, if you will, didn't quite know the questions to ask, had a hired office, a management office, that was based in Chicago, came to Alexandria in about 1994 or somewhere in that range with its own office and its own staff, and now is the world organization for oncology. And I think that that growth, that expansion, that international, multidisciplinary pattern, if you will, is a reflection of the growth of oncology in medicine. I have to say, if you take a look at the popularity poll of what the best and the brightest young physicians choose in their careers, when I was in training and, Dan, when you were in training, most went into cardiology. Maybe some went into GI. Now there are more people going into oncology than any other medical subspecialty. Maybe that'll change after COVID, but that's the way it's been. And our hospitals now are filled with cancer patients, and those hospitals are very dependent on the care that we provide cancer patients. I guess the other thing I would say is, looking from a guy with some hair left, although gray, but looking at it from afar, all of those high-dose chemotherapy programs, the notion of dose, of cell poisons, alkylating agents, the solid tumor autologous marrow programs that were so fashionable in the 1980s, have been, in large part, replaced by such elegant, targeted therapy, now immunotherapy, circulating DNA. Who would have thunk any of that when I was taking care of those children with leukemia 45 years ago? So I think this is such an exciting field. I'm so-- continue to be so pleased and proud of the quality of the trainees. Last night, we had a virtual graduation session for the people completing their fellowship here. And I hate to say it. They're as good as ever. And, if we thought and, Dan, if you thought your colleagues that you all and we all were the best, they're all phenomenal. And it's really a reflection on how the pioneers in this field had a vision, how the need for science to understand cancer was so important, and how medicine has changed and how oncology now is a respected and acknowledged discipline of scholarly work. Well, you had two things that I'm fond of commenting on. One of those is I frequently say publicly I wish I was 30 years younger for a lot of reasons, but because of the scientific excitement that's going into oncology and, also, so that I could run the way I used to, but I can't. That's one. The second is I don't think I would choose me to be a fellow. I'm really intimidated when I do interviews with our residents and say, you know, I wasn't nearly in that kind of category of the people we're interviewing now, which is great. I think our field is in good hands, going to move forward, and things are going. Bob, we've talked about a lot of your contributions to training and education, but you've also had a major influence on the way patients with leukemia are treated. Can you talk more about where the 7 and 3 regimen came from? The 7 and 3 or 3 and 7 regimen-- 3 days of an anthracycline, 7 days of continuous infusional cytosine arabinoside, was developed in the early 1970s. And it was developed by Jim Holland, more than anyone else, when he was at Roswell Park. And it emerged from a series of randomized, phase III trials conducted by what was then called the Acute Leukemia Group B, what became CALGB and then the Alliance. In the early 1980s, the late Clara Bloomfield, who I considered a giant in the world of leukemia, invited me to write a review of the treatment of acute myeloid leukemia for seminars in oncology that she was editing. And, in preparing that, I started reading a series of manuscripts published in the early 1970s, which meticulously, step by step, examined the value of two versus three days of anthracycline subq versus IV push versus infusional cytosine arabinoside, 3 days, 5 days, 7 days, 10 days of infusional cytosine arabinoside. And this was all really work of Jim Holland. He was a magnificent scholar, a humanist, and a tremendous booster too and giant in the start of this field. Thank you. I agree. Bob, we've run out of time, but I want to just thank you for taking time today to speak to me and our listeners, but also thank you for what I consider the many contributions you've made, both scientifically-- we didn't really even get into that, your work on leukemia and GI-- but I think, more importantly, establishing a training program that's been the model for, probably worldwide, how to train people in oncology and the contributions you've made to ASCO. So, for all that, I and everybody else are very appreciative. Thanks a lot. My pleasure. It's a pleasure to be here with you. 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.

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. 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