Cancer Stories: The Art of Oncology

A doctor finds compromise with a patient for one last gamble.

TRANSCRIPT

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

[MUSIC PLAYING]

Welcome to JCO's Cancer Stories-- The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org.

"The Gambler," Katherine E. Reeder-Hayes.

"All he wanted was to go to Vegas. I knew Josh only at the end of his life, far into his story, after an old man's cancer had already wreaked havoc on his young body. At the age of 29 years, he lay in an intensive care unit bed, tethered to the wall and to his many medical providers by high flow oxygen tubing and intermittent and continuous positive airway pressure to deliver as much oxygen as possible to his disease swamped lungs.

His outpatient oncologist told me that like many adolescent and young adult patients with cancer, his attitude toward cancer treatment had been somewhat cavalier. He missed some appointments, declared he needed a day off on his birthday, and so on. But lately, he had been doing his best to make it to the clinic, and his oncologists had already tried two successive lines of therapy for his metastatic esophageal cancer.

On his admission, scans showed striking progression of his disease in a short period of time. My oncology consult team was called in to assist with goals of care. One of our first orders of business was to deal with the question of his code status.

As usual, I started the conversation by sharing what I had observed on his scans. My concern that his cancer was now at a point where more chemotherapy would not change its course, and my expectation that his lungs would soon become unable to take in enough oxygen, even with maximum external support. I explained that if our other best efforts failed, the only way to deliver more oxygen would be to intubate him and use a ventilator.

This conversation is usually somewhat of an art form, a gradual process that can evolve over days as I answer questions, elicit the patient's goals and values, offer emotional support, and give the patient time to think. But in this case, my powers of persuasion had barely gotten warmed up when the patient interrupted me with a stern look.

Doc, if you put me on a ventilator, am I going to die on a ventilator? I paused. This seemed to be a direct question that required a direct answer. Yes, Josh. I believe that you will. OK, there is no way that I'm going to die on a ventilator. Do not put me on one.

A couple of days into his hospital stay, as we toyed with antibiotics and tried to optimize anything fixable that might affect his breathing, while discussing whether getting him even as far as an inpatient hospice unit was feasible, we got a call from the ICU team that the patient wanted to leave. At first it seemed ludicrous. I quizzed the unfortunate fellow leading our team. Leave? He's on 80 liters per minute. What do they mean leave?

Did they make him mad or something? We sped to the bedside. The ensuing conversations were lengthy and many. Patient and palliative care team, patient and ICU team, patient and family, patient and oncology team. The upshot was pretty simple. Josh's big wish had been to go on a trip with his father.

His dad had supported him a lot through his illness, and they had grown closer than before. The initial plan was to visit Las Vegas. However, flying was now out of the question. Instead, they had planned a weekend trip to Nashville to stay at a fancy hotel and visit the honky tonks.

The trip was supposed to have taken place the week that Josh was hospitalized. After mulling it over, he had cooked up what he saw as a compromise. He would leave the hospital and drive to a casino town approximately three hours away for one last great weekend.

He informed me that he had won $1,500 betting on basketball from his hospital bed to fund the trip. And a GoFundMe page was apparently doing well. This influx of cash, in his opinion, erased the major barrier to the feasibility of his weekend plans. As far as I could discern, there was no plan for Monday.

I'd taken care of many patients near their end of life who decided to take gambles, wise and unwise, but I had never been faced with one who wanted to gamble in the literal sense. We discussed the many potential downsides to his plan. The amount of oxygen we could deliver through a portable tank was vastly less than his current need, meaning that he would rapidly become hypoxic.

He might die in the car. He might feel so bad by the time he arrived that he would not be able to enjoy it anyway. The resort was at a higher altitude, and I had little idea whether that change would worsen his oxygenation.

He might collapse in a public place, alarming strangers and traumatizing his family members. He might die alone in a hotel room. I couldn't guarantee that paramedics would honor a "do not resuscitate" form stapled to the shirt of a young, healthy looking man. I couldn't even guarantee that we had a stapler on the unit. Hospice does not, I am almost certain, serve casinos.

I called a psychologist who had worked with Josh regularly in the past, hoping for some backup from someone who had an established rapport with him. I resorted to some dramatically nonmedical language in my attempts to describe the patient's state of mind. He basically has a mental image that he wants to go over the cliff, like the last scene of Thelma and Louise. But this isn't a movie.

Patients with cancer don't die by driving off a cliff. He's going to scare some hotel manager out of their wits. He doesn't even have a plan for what to do if he makes it back.

The kindly psychologist agreed to evaluate the patient, although it is possible he may have been evaluating the oncologist as well. I began my conversations with Josh assuming that either he had not thought of these things or that he was in denial about the severity of his illness. Thinking back to our ventilator talk, however, I gradually realized that he was not, generally speaking, that sort of patient.

I began slowly to wrap my head around the fact that this patient was not afraid, at least not of the things that I feared on his behalf. It was not that he didn't believe the scenarios I presented. To him, dying on the floor of a casino after a great night out was not the worst possible scenario. Dying in a cage in our ICU, the last days of his life orchestrated by others and mimicking the death of a man three times his age, waiting around in the least fun place on earth for his time to die, that was what scared him.

The things that I would want for myself at the end of life-- quiet and calmness, being surrounded by loved ones, help to ease my physical symptoms-- were not things that would comfort him. I was not going to make him a middle-aged man in the course of three days in the ICU. And quite quickly, I began to like him for it. One has to admire the spirit of someone who can hold out against such a large team of experts telling him how he ought to die.

Slowly, with almost audible creaks from our collective old age, the team turned its focus to making the most of Josh's plan. An oxygen tank and wheelchair were procured. Several copies of a large yellow form with a "do not resuscitate" order were signed. The palliative care team provided oral morphine for air hunger. The primary oncologist and nurse urged Josh and his family to contact them immediately if he made it home so that they could mobilize hospice to keep him from returning to the hospital.

We all wished him good luck. As I pressed the button to leave the ICU on the last day of Josh's stay, a thought occurred to me. I turned and walked back into the room. Hey, Josh, there is one more thing I want to ask you.

His face took on a good humored but slightly exasperated look, the look of the teenage boy bracing himself to endure one more well-intended mom lecture. Doubtless he thought I'd come up with one more excellent reason why he should not carry out his plan. Yeah, he said.

Well, I sometimes write stories about my patients. Usually I write about people I've taken care of who taught me something important or made me think about things in a different way. And I think that one day I might want to write about you. Would that be OK with you?

He straightened up in the bed, pushing his hands under himself in the effort to be more upright. Yeah, I'd like that. But just one thing, you have to use my real name. No pseudonyms. And so I'm telling Josh's story, the story of a patient who is young enough and reckless enough to tell us all exactly how he wanted to live the rest of his life, even when his plans did not fit into his medical team's boxes.

Josh made it to the casino. He sent our fellow picture of himself surrounded by what seemed to be groupies. I'm told that he won $1,100 and bought his father a ridiculously large television. He lived for six days, long enough to return home and die comfortably with hospice care. Somewhere I sense he's laughing at me. To the end, his gambles paid off.

For our patients at the end of life, how often do we try to assign them a pseudonym, one that fits neatly into our medical boxes? And do we know how to listen when they ask us to acknowledge their real identities and to help them conclude their lives in the way that fits them, not in the way that would fit us? Perhaps we too can stand to take some risks.

I am grateful that I got in one last gamble with Josh. That, believe me, is his real name."

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With me today is Dr. Katherine Reeder-Hayes, who is an assistant professor of medicine at the University of North Carolina, and the author of "The gambler published online July 30th of 2019. Welcome Katherine.

Thank you. Thanks for asking me.

You are most welcome. You are a masterful storyteller. "The Gambler" is such an incredible story of a young man with cancer who is so determined to live the end of his life the way he wants to, on his terms. And he sounds like he taught you a powerful lesson. Tell us a little bit about Josh.

Sure. So I think Josh was challenging to me as a clinician for a reason that I think many of us identify with. I didn't know him very long. And sometimes I think, as impatient physicians, we are faced with situations where something dramatic is happening in a patient's life, and we are the provider who circumstantially needs to stand with them at that time.

But we really don't know them. And we really don't have a relationship or a prior knowledge of them to draw from. And so I really felt like I spent the first few days that I was caring for Josh really just trying to figure out who he was. And particularly, as a younger patient, I think most of us as oncologists care for midlife and elderly patients a lot. And our skill sets at caring for younger patients, particularly those of us who care for solid tumors, are maybe not as honed, or not as sharp, or it's been a little bit longer time since we were in that person's shoes.

So just by virtue of the fact that he was young and he was male, he wasn't a patient that I could necessarily put myself in his shoes or claim to be knowing where he stood, just from a demographic standpoint. But I think it's always easier in these difficult situations when they can be diffused with humor. And Josh was a very funny person. And so I think that was something that he and I had in common immediately. And I think that that initially helped to lighten a little bit what was otherwise, obviously, a very dark situation.

One of the points you make in the essay is that Josh taught you to listen more deeply. And one of the themes in the essay, and one that you just alluded to, is the fact that his youth made him so special. Can you tell us a little bit more about what you learned about listening deeply and attentively to young patients who are faced with a horrible cancer and nearing the end of their lives?

Sure. So I think as a 40-something myself, I hate to think that I am set in my ways, because I think of being set in my ways as something that describes an older person. But I think as physicians, we get set in our ways pretty quickly. There is a culture to our hospitals. There's a culture to the way that we take care of patients.

There's a power dynamic where the physician or the provider in the hospital setting is the one in charge and the patient is the one taking advice. And I think one of the things that was good and challenging about Josh is that he didn't really sign up for that. So he didn't want to do things the way things are usually done in the hospital.

And a patient who reacts like that, I think if we're at our best, makes us go back and question, well, why do we do this this way? Why do we have this rule? Why do we usually try to discharge the patient to hospice?

Well, why couldn't he leave the hospital hypoxic? What would be so-- what would be bad about that, right? And thinking through not only what we usually do, but what could we do? And so I think that was one of the things that I enjoyed about taking care of Josh was that he pushed me to think about not only the way we usually do things, but the way that things could be done. And I think that had something to do with his youth and just how flexible his mind was as a 20-something.

So let's go back to this theme of the power dynamic here that you just talked about and that also is clearly developed in your essay. You describe finding Josh sort of tethered to a wall. And then you describe to Josh what end of life looks like in a hospital and in intensive care settings and so on. And he basically rebels and begins to work on this power dynamic by saying, absolutely not. I will have none of this.

What did it take for you, as the team leader and as the professional who did not have a long standing relationship with Josh, to absorb all this? And how did you respond? What did it do to you?

So I think patients have two things on their side, or at least Josh had two things on his side in this power dynamic that were powerful. I think one of them is that the patient always has the power to refuse, right? So sometimes that's the only power patients have left to exercise is their autonomy, their ability to tell the team no, this is my body, and I'm not going to do that. And I think that's something that Josh was exercising to feel like he was regaining some control of the situation.

And for patients in extreme situations like this, they also have the power to command attention as a dying person. I think as a society and as providers, we have some respect for the immense value of those last days of life. And so I think sometimes we're more prone to listen to a patient and to their wishes and preferences when they have that persuasive argument, that these are not just any five or 10 days of my life. These are the five or 10 days of my life.

And so I think those were the things that Josh had on his side, at a point where perhaps we weren't on the same side-- although I like to think we ended up on the same side-- that were persuasive to me and to other people that we needed to think more carefully about how he wanted to do things. And whether the requests he was making really, really weren't feasible or whether we did just hadn't thought creatively enough about them.

I think Josh was lucky that you were the attending, because sometimes what I've seen colleagues do is actually sort of get-- bear down on their position. And sometimes this could even rise to a confrontation. And it seems you absorbed the message, empathized with Josh, and then worked with him to help him get his way. Is that a correct understanding of what happened?

I hope so. I hope that that's what I did. I think I was lucky in my team. And I say that to say, first of all, that I was paired with a fellow who was a very warm person, a person who is extroverted and just enjoys getting to know people. And she was, of course, younger and more of Josh's contemporary.

And I think they had a good rapport. And so that kept the tone of the team's interactions with him more friendly and warm and collegial, as opposed to I think sometimes these things can get confrontational. Although I think we should always strive to not have them be confrontational. I think the fact that Josh was just a very likable person also helped.

He was putting forth his requests in a forceful way, but he wasn't angry. He wasn't mean. He wasn't abusive to anyone who was taking care of him, even though he really had every right to be.

And so I think his own attitude and personality made it easier for things not become confrontational. And then in the background, there was Josh's primary oncologist. And she was the person that I phoned up and said, oh, you have to let me get to know this person better.

You have to tell me some background. Is he crazy? Has he been a rational decision maker in the past? Fill me in.

And she was very supportive of us trying to do, to the extent that we could, what Josh wanted. And even to accept the responsibility for if he left the hospital and traveled and then found that he urgently needed to be plugged into hospice. When he made it back to his home, if he did, that she was willing to take on the downstream consequences after he left the hospital if he needed further care. As opposed to pushing me to definitively solve the problem in the hospital as though he were a problem. So I think I was fortunate in the whole team that was around me and was connected to him as well.

So here's this young man who says to you, there is no way I'm going to die on a ventilator, and I want to gamble. And there he goes to gamble. So we have the two levels of gamble-- the gamble that this is going to work out and this young man who was in the hospital on 80 liters of oxygen is going to be able to take the trip, and then the literal gamble.

So my question to you, and something I'm sure you've thought about is, what if his gamble had not paid off? What if he had had a horrible death someplace outside of the hospital or in the casino? How did you think about that?

So I think I certainly did think about that. And I have had other patients who made decisions at the end of life that wouldn't have been my decisions, and that I was sad about. And it hasn't always worked out. And they have had deaths that I thought incorporated more suffering, either for themselves or for loved ones, than I was wishing for them.

And I think although we were able to rejoice for Josh and be so happy for him that his gamble did work out for him, and that was certainly a happy ending to this story, we didn't know that at the time we were making the decisions. And so I think that is the hard part of truly letting patients have autonomy, is that we may be able to see a future, maybe not the definite future, but a future that isn't a happy ending. And that to truly respect people's choices means being able to let them go anyway, certainly with informed consent and with making sure that they understand your concerns.

But I think that's part of listening to patients is that when we get answers we don't want to hear, if we're confident that the patient has listened to us and understands our side or our concerns about them, then we have to give them that same respect in return when they're telling us, yes, I've heard you. Yes, I understand your points. But that's not-- that's not me. That's not my decision. That's not what I want to do. And I think it's hard. It continues to be hard.

Let me go back to this idea of Josh-- Josh's youth influencing this whole process. And in what ways do you think that being very young shaped these findings and these conversations? And how would you react to a middle-aged Josh?

So I think being young made Josh courageous in a way that perhaps he wouldn't have been if he was middle-aged, in a few ways. I think even for a person who is physically very ill and has plenty of evidence that they have advanced disease, I think it is very difficult for a 20-year-old to truly imagine themselves dying. And that's appropriate in most circumstances to feel a little bit immortal when you're in your 20s.

I think that can be a bad thing if it causes people to be in denial. But I think it also imparts a kind of bravery. I think the choice that Josh made was a courageous choice. I think also by being young, many times that's the time in our life when we don't have as many ties to people who are dependent on us, right?

And part of what enabled Josh to make the choice he did, he did have some family members and he had some concern for them and their concerns and emotions, but he didn't have a spouse whom he had a commitment to and had to think about their feelings. He didn't have children who needed to be considered, whose mental health needed to be considered, their ability to say goodbye in a certain way or to witness or not witness certain things. So I think that gave him a freedom. So I think a middle-aged person might have different ties, different concerns, and also different kinds of fears about the end of their life.

So those might make the story play out differently. But I've certainly had middle-aged patients who also didn't want some of the things that we would imagine they wanted at the end of life. And that's OK too.

That's a deep reflection, and I thank you for that. How long ago did you look after Josh?

I believe we're coming up on a year.

And how long did it take you to process through it and turn it into this beautiful essay that's full of humor and respect and love for Josh, by the way?

Thank you. I would say it happens in stages. I think anytime I lose a patient in a particularly memorable or emotional or even traumatic way, there are stages. In the immediate term, I think probably the most therapeutic thing for me almost always is talking to colleagues.

And in this case, I think there was some joy and humor in the reflections with colleagues about taking care of him and about the things about him that had really stood out. I think that's one stage. Because being a writer, I often will put something on paper about an experience with a patient that's been particularly meaningful pretty quickly, I mean within weeks perhaps, but it's not usually a finished something.

I kind of jot down what really struck me, or perhaps the outline of something, or a message that I got out of that situation. And then I sort of tuck it away and then go back to it later. And I think that's sort of the process I went through with this story over the course of a few months.

That's incredibly helpful. Thank you for that. My final question is about your fellow. Was your fellow OK with how the story unfolded?

I think she is. And I don't think she would mind my saying her story and his story intersected in an interesting way in that, at the same time that we were doing this end patient consultation together, she was making some hard decisions about changes in her career planning, and in the direction that some people were pushing her to go. And that she had been encouraged to develop her career and her future plans in a certain direction, and she was coming to feel that that wasn't the right direction for her. And really needed to pull the trigger on just saying that out loud and making some changes in her plans for training so that she could get back to a place where she really felt like she was doing something that was right for her.

And so in a way, I think Josh was an inspiration in that sense to do something that is hard and may feel scary, but that ultimately is going to be true to who you are. So it was, I think, a good thing for us to all work through together in that sense.

Well, thank you, Katherine. It's always a pleasure to read your work and a real pleasure to have a chance to have this conversation.

Well, thank you so much. I really appreciate being invited. Thank you.

You're very welcome.

Until next time, thank you for listening to this JCO's Cancer Stories-- The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode.

JCO's Cancer Stories-- The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all of the shows at podcast.asco.org.

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Dr. Hayes interviews Dr. DeVita about his role as Director of NCI and his time with CHOP and MOPP.

Dr. Daniel F. Hayes is the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center. Dr. Hayes' research interests are in the field of experimental therapeutics and cancer biomarkers, especially in breast cancer. He has served as chair of the SWOG Breast Cancer Translational Medicine Committee, and he was an inaugural member and chaired the American Society of Clinical Oncology (ASCO) Tumor Marker Guidelines Committee. Dr. Hayes served on the ASCO Board of Directors, and served a 3 year term as President of ASCO from 2016-2018.

TRANSCRIPT

[MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

[MUSIC PLAYING]

Welcome to JCO's Cancer Stories, The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the role of cancer care. You can find all of the shows, including this one, at podcast.asco.org.

Welcome to Cancer Stories. I'm Dr. Daniel Hayes. I'm a medical oncologist and a translational researcher at the University of Michigan Rogel Cancer Center. And I'm the past president of ASCO. I'm really privileged to be your host for a series of podcast interviews with the founders of our field.

In this series of podcasts, I hope to bring appreciation of the courage and the vision and most importantly the scientific background among the leaders who founded our field of clinical cancer care over the last 70 years. I hope by understanding the background of how we got to what we now considered normal in oncology, we can all work together towards a better future for our patients and their families during and after cancer treatment.

Today, my guest on this podcast is Dr. Vincent T. DeVita, best known as Vince. Dr. DeVita is generally considered one of the so-called Gang of Five, including Doctors Canellos, Young, Chabner, and Schein, who I've been trying to get on for this podcast in the future, all at the NCI, and who brought many of the concepts we now accept as standard into the clinic in the 1960s and '70s.

Dr. DeVita is currently a Professor of Medicine and Epidemiology and Public Health at the Yale School of Medicine. I think it's also fair to say, Dr. DeVita was instrumental in the passage of the 1971 National Cancer Act. And I want to hear more about that as we get into this.

He was director of the NCI and the National Cancer Program from 1980 to 1988 and then moved to Memorial Sloan Kettering Cancer Center as Physician in Chief and subsequently became the Director of the Yale Cancer Center in 1993. Among his many honors-- and I don't have time to go through them all-- but he has served as President of the American Cancer Society. And I think most dear to me, he was President of ASCO in 1977 and 1978. Dr. DeVita, welcome to our program.

Nice to be here, Dan.

I've done a little background. I know you grew up in the Bronx. And I know you went to William and Mary for undergrad and George Washington Medical School. And I also read what I didn't know, which is that you did your internship and residency at the University of Michigan.

We're recording this just before the NCAA basketball tourney. And I have to say, go blue. We're all excited here in Ann Arbor about our basketball team.

[LAUGHTER]

What I'm really interested in is, were your parents physicians? Or what made you choose medicine out of the Bronx?

Well, no, my father was a banker. And my mother was an interior decorator. So it was kind of a funny mix.

But I think it's kind of peculiar. I was growing up, and my mother-- I tell this story in my book. My mother was kind of frightened by the fact that I really, as a seven- or eight-year-old kid, really thought the guy who delivered the ice-- in those days, we had ice boxes-- was terrific. And I wanted to be like Nunzi the iceman.

And she panicked and said, no, no. You're going to be a doctor. And every time someone asked me what I was going to be, I just said I was going to be a doctor. And when I went to school, I decided I'd be a doctor. It was sort of Mama driving me in that direction.

So you had a choice of being an iceman or a doctor [LAUGHS].

Right. I like-- I mean, biology was always a favorite subject of mine. So it was a good fit.

And tell me about how you ended up going to the NIH and choosing oncology. Was that serendipitous? I talked to Bob Young the other day. And he said, fundamentally, he hadn't planned to be an oncologist and got to the NIH and liked it. Was that your role, or did you know you wanted to do cancer from the start?

No, I was going to be a cardiologist. In fact, when I was a first-year resident, I did cardiac catheterizations and was a co-author on a paper that for a long time was well-cited in the field. So I applied to both the Heart and Lung Institute and the Cancer Institute.

And those are very competitive positions. And I had an interview with Robert Berliner, which didn't go well [LAUGHS]. So I didn't get invited to the Heart Institute. And I went to the Cancer Institute.

And when I walked in, Dr. David Rall was the chief of the pharmacology branch. And I asked him if I could work on the pharmacology of digoxin. And he, wise person that he was, said, sure. Go ahead if that's what you want to do.

And I was surrounded by people who were working on anti-cancer drugs. And I actually became fascinated with them. And it was only a few months, because I was also on the wards at the time, that I said, oncology is the way to go. It was an exciting new field. It was kind of a funny field in those days. But I found it exciting, so I switched.

So just to give you a plug here, I think many of us know that you wrote a book, The Death of Cancer, published a couple of years ago, co-written with your daughter Elizabeth by the way. But in it, you described a number of things. And one of those that I loved were your stories about Gordon Zubrod.

And I trained with Dr. Frei at the Dana-Farber. He always had great things to say about Dr. Zubrod. And I wonder if you could tell the folks listening in who he was-- I think most people don't even know that-- and the impact he had on our field.

Yeah, I used to call him the great umbrella. The field was very controversial at the time. And so the people who were doing things like saying, I'm going to try to cure this cancer-- leukemia in Frei's case and Hodgkin's in our case-- were considered just a little bit this side of insane. He was somebody who was distinguished.

Now, Frei had-- Zubrod had been at St. Louis as a professor and also at Johns Hopkins. And he was a very distinguished-looking man and a very polite, careful man. And so he used to provide sort of the umbrella for all of us, so that [INAUDIBLE] he'd take the heat. And we could go on and do our work.

So he was-- he did enormous number of things. I mean, the whole clinical trial structure was established by Gordon Zubrod. The phase I, II, III trials was all done in a paper by Gordon Zubrod in the late 1950s. So I think he was just a guy who had foresight and was a great leader.

I ultimately took his job. He got tired of bucking the bureaucracy and retired and went to Florida as the director of their cancer center there. So I got to know him pretty well. And like Frei, I have great admiration with him.

I mean, it's interesting how we take phase I, II, and III for granted. And when he came in, and not too long before you came in, those things weren't-- nobody really knew how to do this stuff. Doctors Frei and Freireich were already at the NCI when you got there, correct?

Yes, indeed. Yeah, they were.

Yeah.

And so they must have been inspirational.

They were, and especially Freireich. Freireich was always on the wards. And Tom didn't come over to the wards very much. He was sort of the direct-- he was chief of medicine. And Freireich was the chief of the leukemia service. So we saw Freireich all the time. Tom came over once in a while.

And Jay was a super doctor. And it was very hard to stay ahead of him. You'd get an x-ray on a patient. And he'd call you up 20 minutes later and tell you what it was. He was already down looking at it. So you had to stay on your toes with Jay.

And of course he was, as everybody knows-- Jay-- he was a bold guy, who-- I mean, he looked like he could walk through a wall. So he frightened a lot of people. But he was an inspiration. So I'm always grateful for what Jay Freireich taught me.

There's a great story in your book, that Dr. Frei has told me as well, about the first platelet transfusion at the NCI. Can you elaborate on that? I think most folks don't know about that story.

Platelet transfusion was, again, one of those radical departures. But Freireich reasoned that we were losing more people from bleeding than we were from leukemia. So he worked out a way of plasma pheresing people and collecting platelets. And we didn't have a lot of the expertise we have now.

And they came in quart bags. I mean, they were plasma bags that were huge. And we were treating little kids. So they were-- throwing them into heart failure was a problem. So it was pretty radical. And he was told to stop doing it by the clinical director at that time.

And in fact, he was told that if he didn't stop doing it, he was going to be fired. And he told me-- he said, I went back to my office, sat down, and thought about it. And I decided I didn't want to work at a place where I couldn't do that. So I just kept on doing it. And the person who said he was going to fire him never did. But that was Jay Freireich.

[LAUGHS]

He believed so strongly in it. And when I went to Yale right after I left the Cancer Institute-- I finished my residency up there. And I told them-- when I saw leukemia patients who were bleeding-- and I said, what you should do is platelet transfusions. And they said, they don't work.

And I said, I used them. And I saw them work. So I think we're losing patients unnecessarily. It was just very controversial. So eventually I left the program.

I was going to take a residency and then a fellowship in hematology there. And I decided to go back to the Cancer Institute where these adventurous things were going on. Times are different now, of course.

Dr. Frei once told me a story that he-- you may have been with him-- that he was making rounds in the clinical center. And in those days, apparently, the adults and the kids were in the same ward. And there was a child with essentially no white cells, who'd been induced for leukemia, and a man next to him with CML.

And so-- and actually, when Dr. Frei told me this, I kind of said, I don't think I want to hear this story, because he said, well, you know, the kid didn't have any white cells. And the guy next to him had way too many white cells. So [LAUGHS] I said, tell me you didn't do this.

He said, yeah, we took platelets out from the guy and gave them to the kid. And the kid got better for a while. It was really exciting. I thought, boy, you don't see that anymore.

Yeah, I mean, it was a very reasonable thing to do, because the white cells in a chronic myelogenous leukemia patient work very well in terms of fighting infection.

Yeah.

So there was no reason. And the kids, otherwise, wouldn't survive. And so, yeah, I was there when we got these-- we gave these. I mean, they weren't easy to give, because they stuck in the lungs. And we didn't have HLA matching at the time. So they were-- a lot of them were mismatched.

But for a while, they were effective. And then we went to collecting white cells from normal people. But the white cells had not worked as well as platelets had worked.

Platelets have been a lifesaver. Now it's a couple of hundred million dollar business each year now. So it's routinely done, as many things that Jay started are routinely done now.

Of the many things for which you are credited, I think it's the use of combination chemotherapy for Hodgkin's and then subsequently non-Hodgkin's that is one of your lasting legacies. There must have been a lot of drama around doing that. I mean, I think we all just assume you're going to start protocol. You write the protocol. You get funding for it. And you go forward.

But can you give us some stories about sitting around at night and thinking about how to do this? Or how did you choose those drugs and why and how to give them and the obstacles that were involved?

Yeah, actually, it was a very complicated process. And we didn't have the information we have now. What we had was-- I was doing this with Jack Moxley, who left active medicine and became a dean after he left the Cancer Institute. But we're still in touch.

And Jack was working with [? Sy ?] [? Perry ?] using the new isotope, tritiated thymidine, looking at the bone marrow of CML patients and also of mice. And I was doing the same thing with the leukemia 1210, which was a model that we used for chemotherapy all the time. And what we were trying to do was figure out the kinetics of human versus mouse marrow, so we could develop schedules that humans would survive.

We quickly found out that you can't use the mouse as a model, because their blood cells went through a kinetic phase about half the length of humans. So you had to schedule in a different way. So we worked that out.

And then we looked at very simple-- something that people really ignored is that when you give a chemotherapy agent that is toxic to the marrow, you don't get abnormal blood counts right away. For a week, you'll have a normal white cell. And then on day seven or eight, it begins to fall, because the storage compartment in the marrow works well for about a week. And then there's no replenishment. And the white count falls.

So between the two, looking at the marrow and looking at the white cells in the periphery, we came up with a schedule for MOPP. And then the other things were simple. We just decided that you'd have to have three or four drugs that worked by themselves.

There had been people doing combination chemotherapy before-- Tom Hall in Boston and [? Alan ?] [INAUDIBLE] at Yale. And their rationale was they're looking at a sequential biochemical blockade. But they ignored whether the drugs actually worked against the tumor, assuming that if you gave them together, that the biochemical blockade would dominate.

And it didn't work. In fact, it was very discouraging. But we decided the way to do it was take drugs that had some activity in the disease and use them together and use them in full doses in the schedules that we worked out because of the prior work I was telling you about. So it took a while to put that together.

And then Jack Moxley and I used to do this at a bar in Georgetown called the Lehigh Grill, where we used to-- my cardiology desire-- I used to go to Georgetown where there was a wonderful cardiologist Proctor Harvey, who used to hold Thursday night sessions. You had an auditorium that was wired. So you could hear heart sounds. And after that, we'd go to the Lehigh Grill. And we sort of put together the protocol.

When we presented it to Tom, he thought it was a good idea. But the other people around him thought it was insane and really tried to stop it.

Tom Frei?

Yeah.

Tom Frei, yeah, yeah.

Well, Tom was supportive. Yeah, Emil Frei was his real name. But everybody called him Tom. Yeah, he was supportive. But the people around him and my immediate boss was very much against it, because he thought it would interfere with the protocol that they were doing and so forth.

So Tom worked out a solution worthy of Solomon. He said, OK, we could do-- the magic number for phase I trials in those days was 14. If you got nothing in 14 patients, then you didn't go any further. So we could do 14 patients with the first protocol, which was called MOMP-- M-O-M-P.

And we had to do the workups ourselves. We couldn't use other colleagues to work up the patients. And we had to go get the patients ourselves. So Jack Moxley and I did all those things. And the results were very encouraging.

And then Jack left. And I sat down and decided that we'd put procarbazine. I was working on procarbazine. It was then called [INAUDIBLE]. And I was working on it and doing the pharmacology in the phase I study with it in Hodgkin's disease. It was a promising candidate. So we put it in. And that became MOPP.

Also in those days, six weeks of therapy was it. They didn't get more than six weeks. We reasoned that the marrow problems would be acute. But you'd have to give it probably for a long period of time to affect the tumor.

So we gave it for at least six months or to a complete remission plus two months. And we assumed that there were cells left after we couldn't see them. So it was a lot of good thinking that went into it that turned out to be correct, because most of the-- since then, a lot of protocols follow the same sort of routine. And it really works for a lot of cancers.

But it was controversial. I went to the AACR meeting. This was before ASCO. And I presented it as an abstract. And David Karnofsky, who was sort of a god at that time at Memorial Sloan Kettering, just tore me apart.

And what was I doing using the term complete remission for a solid tumor. He said, that was a term that was used in leukemia. Now, I didn't say it. But I'm thinking, the reason you use them is you can get complete remission. So we had complete remissions.

And I was kind of shaking with the microphone in my hand at the time. So it was a scary but it was a good experience.

I have to say--

So it just gives you an idea that people were not receptive [INAUDIBLE].

Those of us who are junior to you can't imagine that you were intimidated by somebody else [LAUGHS].

Well, I was a youngster, then. I was-- Jack Moxley and I, I would say, thinking back, we were cocky. But the big guys in the field could scare me. And Zubrod was a-- I mean, Karnofsky was a big guy in the field.

Yeah.

He just had a hard time getting out of the leukemia mind frame. And so of course, we've used complete remission since then in any kind of solid tumor where you can get one.

In your book, you have a great quote that you presented somewhere. And Dr. Frei was there. And Wayne Rundles was there. Wayne, of course, has been at Duke for 100 years. And he said, do your patients speak with you after you're done?

Well, Wayne Rundles-- when he first saw the MOPP protocol, Wayne Rundles said, that's nonsense. He said, I get the same thing with nitrogen mustard by myself. Well, nobody had ever got that with nitrogen mustard. So we actually had to set up a controlled trial and do it and prove that MOPP was better.

So when I presented it when we were first starting it-- at a meeting. Tom had arranged this meeting with all the bigwigs in the field. And when I presented it at that, everybody was sort of quiet. And then Wayne Rundles raised his hand. He looked pale. He raised his hand and said to me, Dr. DeVita, do your patients speak to you after you do this?

[LAUGHS]

So he-- a few years later when we were obviously getting good results, he invited me to grand rounds. And by then, we were good friends. And I was up on the podium. And after I gave the talk, he was sitting down below smiling at me.

And I said, Dr. Rundles, if you remember, you asked me if your patients speak to you when you do this. And I can tell you that they do for a lot longer. So it was fun. But it was fun. He was a good friend by then. And I had great respect for him.

Actually, he was a very nice man.

He was.

When did you start thinking that you had a success? Was it during those first 13 patients or 14 patients that you treated? I mean, was it obvious right away, or did you start [INAUDIBLE]--

Well, it was obvious--

--you were in the wrong place?

We put-- no. We thought it pretty early, because we were worried. We put patients in reverse isolation. Nobody knew whether you were going to kill them if you gave them all these drugs together. And it turned out the first surprise was, yeah, they had the usual toxicity. But it really wasn't that bad. So it was doable.

And the second was-- we had a small number. But we had-- something like 80% of the patients went into a complete remission. And I think nobody had seen that. Now, the question was, how long were they going to last?

So we were optimistic. And when we put patients on it, there was no cure for them at that time. And we said, we're optimistic that this is going to be something that will last. But we don't know.

And then by three years, it looked pretty good. And I think I presented the first abstract four years after we started. And by that time, we had relapse-free survival curves. And again, nobody before that time had presented relapse-free survival curves in any of the lymphomas. So by then, by four years, I think we felt we had probably cured some patients with the disease.

I asked Bob Young this same question. Did you feel a sense of history at the time, that this was really historical? Or did that come later when you looked backwards?

I think what people don't realize about those days is neither Freireich nor ourselves were treating leukemia and Hodgkin's disease. In other words, we weren't out to develop a treatment for those diseases. We were out to prove you could cure cancer with drugs, because nobody believed it. If you said that, they really thought you had gone balmy.

So we were out to look-- so we knew if we could do it, it would be historic. So we were excited when we looked like maybe it was going to happen. By that time, when we had first reported it, the VAMP program that Freireich did, which was an historic program-- he only had 17 patients. And they actually never published a paper on VAMP. And I asked Jay why they never did that. And he said because he didn't think they would accept it anywhere.

So but by that time, they were getting about a 50% complete remission rate going four or five years. And they were thinking they're curing leukemia. And we were getting 80% complete remission rates. So I think everybody felt that we were going to prove that you could cure cancer with the drugs. And we did.

So yes, in a sense, we set out to do something that would be historic. And so when it happened, I think, it is. It was a sort of a door opener for medical oncology in Hodgkin's disease.

I'd like to turn now for just a minute to your role in politics. You were pretty instrumental, I think, when the National Cancer Act was signed in 1971. And that also sounds like a TV drama to me. It sounds like-- and I know this anyway, but in reading your book, it was not clear that was going to get through. Can you give us some of the playground behind that and Mary Lasker's role and how that happened?

Well, Mary Lasker played a big role. The MOPP program actually played a big role, because Mary Lasker was sort of working in the background. Cancer was always a cause for her.

But when we did the MOPP program, there was a guy named Luke Quinn, who she had hired to be a lobbyist, who was sort of hidden in the American Cancer Society so they wouldn't realize it was Mary Laskers' lobbyist. And he was referred to me by Sidney Farber.

And I didn't want to take him at first, because he was diagnosed as having gall bladder cancer. And I said to them, you know-- I said to Sidney Farber, I don't really treat patients with gall bladder cancer. And there was silence on the phone. And he said, (SOMBER, COMMANDING VOICE) you will take this patient.

[LAUGHS]

So I took the patient. And when I examined him, when he came down and I examined him, he had adenopathy in both axillae. And gall bladder cancer just doesn't do that. So I had to do another biopsy.

He was not a pleasant guy. So it was not easy to do these things. I had to get another biopsy. And it turned out that my pathologist at the time, Costan Berard, when he compared the biopsy, he said, it's a lymphoma, clearly. It was a diffuse, large cell lymphoma.

What they had done is, because Claude Welch did the surgery-- a very famous abdominal surgeon-- and he said it was gall bladder cancer, that the pathologist sort of assumed it was. And it was a compression artifact. Long story short, he went into remission.

And Mary Lasker went gaga. Wait a minute. We got something here. And that was what pushed her to get her friend, Senator Ralph Yarborough, to put up a committee on cancer to come up with the Cancer Act. And--

So it must have been quite a day when President Nixon signed that.

Yeah, well, it was-- I wasn't at the signing. I wasn't high enough up in the chain to be invited to the signing. But yeah, I have all the photos of him signing it. And later when I met him-- I have a picture in the book of he and I shaking hands and him looking like he's having a roaring laugh. People ask me what I said that was funny. And I have no idea.

But when I asked him, I said what is your greatest achievement as a president? He said two-- opening up China and signing the Cancer Act. So he was--

Really?

Yeah, so I think he was proud that he did that.

That's a great story. Actually, the other story I had not heard, but read in your book-- I'd like you to tell me about your lunch with Mr. Featherstone.

[LAUGHS] Featherstone Reid, his name was. Well, this was a very-- this was a regular occurrence. Mary Lasker, when she came to town, would stay with Deeda Blair, Mrs. William McCormick Blair, who was a Washington socialite and had a lovely house on Foxhall Road.

And they would have lunches and dinners. And they always arranged it so that people-- the scientists sat next to somebody with influence. And this is how they influenced the Congress to put more money into the cancer program.

So one time, I got a call in the morning from Deeda Blair, saying, I'm having a lunch. We'd like to have you there. And I said, gee, I-- it's too short notice. I can't do it. And she said, well, Mary really wants you to be there. Mary was hard to say no to.

So I rearranged my schedule, drove down to Deeda's house. And there was a big black limo sitting in the front of the house. I went in, and they introduced me to Featherstone Reid. I had no idea who he was. And every time Mary would say, we want more money for research with leukemias and lymphomas. Vince, tell him about what's going on. And I would tell him about.

At the end of the lunch, he left. And Mary and I sat down on the couch to have a cup of coffee. And I said, Mary, who is Featherstone Reid? And she said, he's Warren Magnuson's driver. And when she saw the shock on my face-- Senator Warren Magnuson was the chairman of the appropriations committee of the Senate.

When she saw the shock on my face, she said, wait a minute. When Mrs. Maggie-- he takes Mrs. Maggie shopping during the day. And Mrs. Maggie-- he fills her with all this information we're giving him. And then Mrs. Maggie is the last person to put her head down on the pillow next to Warren Magnuson.

This is the way she worked. She would take someone like Magnuson, who was a good friend, but she would surround him with extraneous people who would say the same thing. So it was sort of like subliminal stimulation for him. He was always hearing these positive things. And then he supported the program. She was a piece of work.

I never got to meet her. But it sounds like she was a force of nature.

She was.

And of course, the Lasker Award is now named for her and her husband and sort of the American Nobel Prize. She's had such [INAUDIBLE].

Yeah, and our crew won it in 1972-- Frei, Freireich, myself, and other people for other things. So I'm very fond of Mary Lasker, obviously.

It's just a wonderful story.

And I got to know her pretty well, so.

I have one other question. And I'm not sure you'll want-- if you don't want to go off on it, we can edit it out. But in your book, you talked about Howard Skipper and Frank Schabel. And Dr. Frei used to talk about them all the time.

And I think it's worthwhile to bring them into the history of what we do. Did you actually work with them or collaborate with them, or just base some of your ideas on what they had in mind?

When I was starting at the Cancer Institute, I thought Schabel worked at the Cancer Institute-- I mean, Skipper worked at the Cancer Institute, because I would be working in the lab. I was doing the tritiated thymidine studies on L1210 mice. And he would be looking over my shoulder.

He was doing the similar studies, but he was just doing it with cell counts in the abdomen of the mice. And he thought that was good enough. And he was there at a weekly meeting we had, which George Canellos named the Society of Jabbering Idiots. It was a great, great meeting, actually.

[LAUGHS]

And he was there all the time. And my view and Tom's view differ a little bit on Skipper. I think he was a real driving force, that he did the studies in mice that we were doing in the clinic with people.

And he actually-- in 1964, he wrote a paper showing that you could cure L1210 leukemia. It was the first example of curing a mouse with leukemia. And I think-- so it was sort of a feedback mechanism between the Cancer Institute and the Southern Research Institute.

So and he did-- he used to do these booklets. And I think he published hundreds of these booklets. Some of them, we convinced him to actually publish as papers. But I have the collection. There may be 100 booklets he wrote.

And he would take a concept that we were working on and then work through it in mice. It was very, very important. And he was a wonderful person. His only problem was he smoked like a chimney. But he was-- I liked Frank and Howard.

Yeah, Dr. Frei had the entire set of monographs on his bookshelf in his office and would encourage us to come in and borrow them and read them and come back. And frankly, he basically predicted what you've done with combination therapy. He predicted adjuvant therapy working. There were just a number of things he saw in these mice that we've gone on to apply in the clinic. It's pretty remarkable, I think, so.

Yeah, I mean, it's not only he predicted it. But he actually showed the concept worked in mice. So as we know, mice and human are very different [INAUDIBLE]. There was a guy in Boston, Stuart Schlossman, a very fine scientist. And he didn't like mouse models. And when asked what he would do when he saw a tumor-bearing mouse, he would say, I would step on it, because he didn't believe mouse models.

And but Frank and Howard did experiments and made allowances for the difference between humans and mice. So it was always good to know. I mean, I have the summary he wrote on Hodgkin's disease after he saw the MOPP program. So I think they're very instructive booklets. So I kept them. Like Tom, I think that we sort of live by them.

Well, thanks for discussing them. I think our listeners need to remember these two guys. They were great.

We're running out of time. I've really just touched the surface of what you've done and contributed to the field. And the people you've trained is sort of a who's who of oncology, frankly. But at the end of the day, what's your-- I'll ask you the same question you asked President Nixon. And that is, what is your legacy? What do you want people to remember that Vince DeVita did?

I get asked that question a lot. And I don't have one thing that I can say. I mean, I've been lucky in my career that I've had a chance to do many things.

Being the Director of the Cancer Institute was wonderful. You could sit on top of the whole field and just sort of scan it and see what's going on. And it was very important, because you've become the spokesman of practicing physicians at the same time.

MOPP, of course, was important. Putting out the first comprehensive textbook in the field and watching it-- we just came out with the 11th edition-- is also very exciting. So there-- we were the first to successfully treat Pneumocystis carinii pneumonia. And we reported it in a paper in the New England Journal. I mean, there were a lot of things.

I'm best known, I think, for MOPP, probably, and the principles of MOP, which I'm very proud of. But there's so many that I have a hard time. I like opera. And people ask me, what's my favorite opera? And I usually say, it's the one I just saw.

It's very hard for me to pick one opera. There's so many that I like. So I'm not dodging it. But I just never can say, well, it's this.

That's very fair. Frankly, I think, without your contributions, I probably wouldn't be sitting here doing what I do. And I think there are thousands of us who would say that. So we're--

Well, that's very flattering.

Well, not only are we appreciative, more importantly, there are a lot of people who are alive who wouldn't have been without what you and your colleagues did at the NCI that so many years ago, so--

[INTERPOSING VOICES]

I was involved in the training of 93 medical oncologist. At one time, something like 40% of all the [INAUDIBLE] directors were our graduates. So they have gotten around. And that was good for the field. They went out with the same principles we were developing at the Cancer Institute, so that's very gratifying.

Have you kept in touch with any of the patients that you're treated back at the NCI? I talked to Saul Rosenberg. And he told me he still sees people that he treated 30 or 40 years ago when he first moved to Stanford.

We're writing a paper on the 45-year follow-up of the first 188 patients. Again, nobody has 45-year follow-ups. And we called every one of the survivors. And there's something like 60% or so of the complete remissions are alive.

So I talked to some of them. But we had a nurse talk to a lot of them. And I got messages from them after the call. And some of them still contact me, after sort of an anniversary of their treatment. So yeah, I've kept up with them.

The gratifying thing is most of them are suffering from the same illness as most people who are getting into their 70s or some of them 80s. They have hip problems and so on and prostate cancer. But there doesn't seem to be any really major increase in anything in these long survivors.

Now, mind you, these were patients who got MOPP as their only treatment. And so when you see second tumors in these kinds of patients, it's usually patients who got radiation therapy plus MOPP. So these patients who are 45 years had just got MOPP. And they seem to be perfectly fine.

That's remarkable. I love your comment that they are getting the same illness as the rest of us get as they get older. That's great.

Yeah, we don't cure bad hips and bad knees and--

Yeah, we can't cure old age. When I was at the Dana-Farber, I had a patient who had been one of Sydney Farbor's original patients from the early '50s. And by this time he was obviously an adult. He was older than I was. And he was fine, as you've said.

Although he said Dr. Farber kept treating him and treating him and treating him. And then finally, when Dr. Farber passed away, someone else picked up his chair. And they said, why are you still getting this? And they stopped it.

Yeah.

So he got a lot of treatment.

I had one of Freireich's VAMP patients. She was a girl in her early teens. And she was a wildcat. But she had had something else, and it failed. And she was one of the first patients on VAMP. And she went into remission. And she stayed in remission.

And I followed her for many years. She went to college. She got married. She had children. She brought her children in to see me. And last time I had any follow-up with her, she was in her 60s. And she was one of the really first long survivors of that particular program. So it's really neat to see these patients.

And it's not rare for me to go to a meeting and have people walk up to me and say they got MOPP 25 years ago. Someone else gave it to them. And they're alive and well. So that's one of the great gifts of having a chance to do this kind of work.

What a privilege. Well, I think we need to end. Again, I want to thank you for being on with us today and filling us in with some of these stories. Had really good feedback for my podcast series. And it's because of the people I've had on it. So thank you very much for all you've done.

It's really good talking to you. And I look forward to listening to all your podcasts.

[MUSIC PLAYING]

Until next time, thank you for listening to this JCO's Cancer Stories, The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcast or wherever you listen. While you're there, be sure to subscribe so you never miss an episode.

JCO's Cancer Stories, The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.asco.org.

[MUSIC PLAYING]

Dr. Hayes interviews Dr. Young about his time with CHOP and MOPP

Dr. Daniel F. Hayes is the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center. Dr. Hayes' research interests are in the field of experimental therapeutics and cancer biomarkers, especially in breast cancer. He has served as chair of the SWOG Breast Cancer Translational Medicine Committee, and he was an inaugural member and chaired the American Society of Clinical Oncology (ASCO) Tumor Marker Guidelines Committee. Dr. Hayes served on the ASCO Board of Directors, and served a 3 year term as President of ASCO from 2016-2018.

TRANSCRIPT

Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Hayes: Welcome to JCO's Cancer Stories, The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org.

Welcome to Cancer Stories. I'm Dr. Daniel Hayes. I'm a medical oncologist and translational researcher at the University of Michigan, Rogel Cancer Center. And I've also had the pleasure of being past president of the American Society of Clinical Oncology.

I'm privileged to be your host for a series of podcast interviews with people I consider the founders of our field. Over the last 40 years, I've really been fortunate to have been trained and mentored and inspired by many of these pioneers. It's my hope that through these conversations we can all be equally inspired by gaining an appreciation of the courage, the vision, and also the scientific understanding that led these men and women to establish the field of clinical cancer care over the last 70 years. By understanding how we got to the present and what we now consider normal in oncology, we can also imagine and we can work together towards a better future for our patients and their families during and after cancer treatment.

Today, my guest on this podcast is Dr. Robert Young. Among many designations he has, my favorite I think for Dr. Young is that he was considered one of the, quote, "gang of five," end of quote, I think self-named, who were responsible for developing the first curative chemotherapy regimen for Hodgkin's disease and non-Hodgkin's lymphomas at the National Cancer Institute in the early 1970s.

Dr. Young is currently president of RCY Medicine, a private consulting firm based in Philadelphia. He was raised in Columbus, Ohio, where he couldn't get into the University of Michigan. So he went to a second-rate community college in Columbus called Ohio State. My bosses made me say it that way, Bob, here at the University of Michigan.

Dr. Young: Not the correct way, The Ohio State University.

Dr. Hayes: So he received his MD then at Cornell in 1965, followed by an internship at the New York Hospital. He spent the next two years as a clinical associate in the medicine branch at the National Cancer Institute. And then he completed his residency in medicine at Yale New Haven Medical Center. In 1970, he returned to the NCI, where he stayed for the next 18 years, serving during most of that as the chief of the medicine branch. Dr. Young accepted the role as president of the Fox Chase Cancer Center in Philadelphia and served in that role and then chancellor in 2009.

Dr. Young has authored over 400 peer reviewed papers regarding a broad range of both scientific and policy issues in oncology. But in addition to the I consider astonishing and precedent-setting reports of cures in Hodgkin's disease and non-Hodgkin's lymphoma, perhaps most importantly with his longtime colleague and friend Dr. Robert Ozols, he led many of the early and groundbreaking studies in ovarian cancer diagnosis and treatment that I think still guide our care today for patients with this disease.

He's won too many awards and honors for me to go through. But of the major ones, he won the prestigious Bristol-Myers Squibb award, which he shared with Dr. Ozols in 2002, the Margaret Foley Award for Leadership and Extraordinary Achievements in Cancer Research from the American Association of Cancer Research, and ASCO's Distinguished Service Award, one of our highest awards, for Scientific Leadership in 2004. Of note and close to my own heart, Bob served as the ASCO president 1989/1990, which I consider a really critical time in the evolution of our society. Dr. Young, welcome to our program.

Dr. Young: Thank you.

Dr. Hayes: So as I noted, you grew up in Columbus, Ohio, or again, as we say in Ann Arbor, that town down south, but more importantly that your father was a surgeon. And I've heard you tell the stories as a boy you went on rounds with him and that inspired it. Was he academic or was he a really community physician or both?

Dr. Young: Well he was a little of both. He was primarily a community physician. But he did, particularly at the time of the Second World War, because he was a very skilled hand surgeon, he got involved with a lot of hand surgery related to a company called North American Aviation that produced a lot of World War II planes. And there were a lot of injuries in that setting. And so he became quite a skilled hand surgeon and actually taught at Ohio State's Medical Center. So he had both an academic and community-based practice. But primarily he was a practicing community surgeon.

Dr. Hayes: And did you actually go into the OR with him as a boy?

Dr. Young: Oh, yeah. Oh, sure.

Dr. Hayes: Wow.

Dr. Young: You know, in those days, there weren't any rules and regulations about that. And so I went in and watched surgery and held retractors and participated, you know, when I was a youngster.

Dr. Hayes: Wow. What a privilege. You're right, that would not be allowed now. That's a good story. What did you see, bad and good, compared to medicine now then. I mean, if you had to say here are a couple things that we've lost that you regret.

Dr. Young: Well, I think that it was more under the control of the physician than it is in this day and age in so many ways. For instance, my father practiced in three different hospitals. And he admitted patients depending upon what kind of surgical support and nursing support they needed. If they were complex, he went to a bigger hospital. If they were very straightforward cases, he put them into a smaller hospital. And so he had a lot more control over how his patients were dealt with and the circumstances under which they were cared for.

And, of course, most of his practice was before Medicare and all of the insurance sort of thing, so that people paid what they could pay. And so it was a much simpler and much more physician-driven practice than it is today.

Dr. Hayes: Just as an aside, there's a wonderful book called The Brothers Mayo, written by a woman named Clapesattle in the 1930s after both Charlie and Will died. And it's a history of the Mayo Clinic. But in it, she says that Will basically charged people what they could afford to pay. So if you were wealthy, he charged you a lot. And if you were poor, he gave it to you for free and everything in between. And he sort started made up the billing schedule the way he wanted it to happen. And one of his more wealthy patients challenged him on this, and he said, go somewhere else.

Dr. Young: Yeah, well, that's exactly the kind of practice my father ran.

Dr. Hayes: Yeah. Anyway, I'm intrigued by year two-year stint at the NCI in the late '60s before you then went back and finished at Yale. And hopefully this is not insulting and I know you're considered one of the so-called yellow berets. But tell me, tell us all about your choice to interrupt your residency and go to the NIH. I don't think our young listeners really understand the political climate and the circumstances of the time that led so many of you to go there.

Dr. Young: Well, I think that's a great question, because it will lead to some of the other discussions we have later. But essentially, I graduated from medical school in 1965 at the height of the Vietnam War. And in those days, there was not only a general draft, there was a physicians draft. So graduating in medical school in those days, you had one of three choices. You could either take your chances-- and again, the numbers, your priority scores at the time, didn't really have anything to do with it, because they took as many doctors of whatever kind of type they wanted for whatever purpose they wanted. So that you couldn't be sure if you had a low number that you'd not be drafted. But you could take your chance. And in those days, a lot of people did. And a lot of people got drafted. Or you could join the Berry Plan, which was at the time an opportunity to continue your specialty training until you were finished. But then you owed back the military the number of years that you had been in specialty training. Or you could do a much less well-known track and that is with the US Public Health Service. And amongst the opportunities for the US Public Health Service were things like the Indian Health Service and the Coast Guard Service and those sorts of things, or the National Institutes of Health, about which at the time I knew almost nothing except that it existed. And I owe it to some of the folks that I worked with at Cornell, primarily a hematologist oncologist by the name of Dick Silver, Richard Silver, who's still at practice at New York Hospital, who when I was working in the labs there, because I was doing some research when I was at Cornell, and they were telling me about the fact that you could actually apply for a position at the NIH. And you would be in the US Public Health Service. So it took me about 3 milliseconds to figure out that for me that was clearly a track that I wanted to explore. And I had done some research in platelet function and platelet kinetics and so forth. And there was a guy by the Raphael Schulman who is at the NIH at the time. And I said, that would be a miracle if I could get this. So the way it worked was that you applied. And then you actually interviewed with a whole bunch of different people. And as it turned out, I didn't get a position with Dr. Schulman. But I was introduced to the National Cancer Institute and both the leukemia service and the then called the solid tumor service. And I applied to various things like that. And I actually got in on the leukemia service. So I walked in after I signed up and was taking care of little kids with acute leukemia, having never been a pediatrician or knowing anything about leukemia. But it was a baptism of fire and a very exciting place even then.

Dr. Hayes: I want to get back to that in a second because that's a critical part of this. But, again, going back to the political climate, my opinion, this entire issue and your personal journey and many others had a profound effect on both the scientific and medical community of this country as a whole. I think it was an unintended effect. But because of the Vietnam War and because the NIH was such a great place to train in those days. Do you agree with me?

Dr. Young: You are absolutely correct. I mean, one of the things that needs to be said is that this was a transformational phenomenon for cancer research. But it also took place in every other field. And the NIH at the time was just swarming with people of all medical disciplines who were coming to take advantage of the opportunities that existed within the NIH, but also to serve in this capacity as opposed to some of the alternatives that were around. And I think I heard a figure one time, which I'm sure is true, and that is at one point in time, 30% of the chairmen of medicine in the United States had done training at the NIH before they ended up being chairmen of medicine. So that gives you an idea of the impact of this. And you're absolutely right, it was a totally unintended consequence. Nobody ever designed it that way. Nobody ever planned for it to happen that way. But in retrospect, when looked at it and you can see exactly why what happened happened.

Dr. Hayes: Yeah. And I interrupted you, but I did it on purpose, because it didn't sound to me like you really had a plan to go into cancer treatment, but sort of landed there serendipitously. Is that true? I mean how do you end up there?

Dr. Young: Oh yeah, oh, yeah, I mean I did get very interested in hematology when I was in medical school. I first went to medical school, of course, thinking I was going to be a surgeon, because my father had a great practice and he had a wonderful experience with surgery and it was really cool. But I just found that I just wasn't designed just the same way. And it was increasingly clear that cancer was not my not my goal-- I mean, surgery was not my goal. And so, you know, I knew I wanted to stay in internal medicine. And I got interested in the research. And I had done some significant research and in platelet function, as I said. I knew that's what I wanted to do, some sort of clinically-related research in medicine. If I'd had my choices, of course, I would have gone into a sort of pure hematology track. And, of course, it's worth saying that it's difficult for oncologists nowadays to understand how big an outlier oncology was. There was no subspecialty in oncology at the time I went to train down there. There was a subspecialty in hematology. And, of course, all of us, the Gang of Five that you mentioned, all of us took hematology boards. And that's because it wasn't clear that there was going to be oncology. When oncology came along we all took the first oncology boards ever given. So that gives you an idea of how early in the history of oncology we were in the late '60s, early 1970s.

Dr. Hayes: So we're talking 1970 or so right when you started?

Dr. Young: Well, 1967 to '69, I was a clinical associate. Then I was at Yale for a year. And then in 1970, I came back on the senior staff.

Dr. Hayes: And who were the characters above you when you came in? I know Doctors Frei and Freireich had been there before.

Dr. Young: Yes. Frei and Freireich had just left the year before. One went off to MD Anderson, the other went off to the Memorial. And George and Vince-- George Cannellos, Vince DeVita-- had stayed on, with Vince as the head of the medicine branch. And then when we came back, Vince sort of brought two of us back that he'd had before, Bruce Chabner and I. He'd sort of sent us off to Yale and said they could buff us up a little bit. And he didn't offer us a job coming back. But we went off, and we were training up there. And he called us both up and says, why don't you to come back and join the senior staff. He recruited Phil Schein as well. And so that was the Gang of Five that we started out. Four of us ended up being president of ASCO at one time or another. And I suspect the only one who didn't, Bruce Chabner, probably would have except for the fact that he was the director of the Division of Cancer Treatment of the NCI for a long time. And the NCI and the NIH changed its attitude toward allowing people to participate in major leadership positions nationally, a tragedy as far as I'm concerned, which has I think affected the morale of the NIH and a lot of other things and deprived a lot of good people of opportunities to serve nationally. But that was the way it was, otherwise we would all ended up at some point leading--

Dr. Hayes: So the Gang of Five was you Bruce Chabner, George Cannellos, Phil Schein, and Vince DeVita, right?

Dr. Young: Right, exactly.

Dr. Hayes: And what were the dynamics among you? I mean, so were you and--

Dr. Young: Well, I mean, it was an incredible time. You know, there was enormous talent that had poured into the NIH, as we talked before. And an enormous amount of talent was present and was recruited in during this period of time. I mean, you know, Paul Carbone was still there. John Minna was recruited. Harman Ayer, who was the longtime chief medical officer of the American Cancer Society. Tom Waldman was a world class hematologist. Max Wicha was a part of this group. Sam Broder, Allen Lichter, an other ASCO president, Steve Rosenberg, Phil Pizzo was the head of the pediatric oncology branch, now dean at Stanford. And it goes on and on and on. And so there's a massive amount of talent and a lot of freedom. And so Vince was clearly the leader, he had a lot of ideas and a lot of creativity. But he let out a lot of people do whatever they wanted at the same time. And it was sort of a situation in which we all participated, because we were all attending at the same time. So Vince and George did a lot of the lymphoma and Hodgkin's disease stuff. We all participated. I got interested in ovarian cancer. And you talked about that. Bruce Chabner and Phil Schein were always very pharmacologically oriented. And so they did a lot of the phase 1 and phase 2 trials and a lot of the laboratory backup associated with the studies we did. And everybody shared. And so there was really not a lot of competition in that sense. Everybody was I think very competitive. Because it was all sort of shared, it worked out so that everybody felt that they were getting a substantial part of the recognition that was going on in the group. Another thing that was unusual about the NIH, but it had unintended, but important consequences is that nobody had anything to do with what they got paid. So that you could go to events and say, well, you know, I deserve to be paid more, but it didn't have anything to do with what you got paid. We had no control over anybody's salary. So that I don't think the whole time I was there, the whole 14 years I was chief of the medicine branch, I don't think I ever had a conversation with anybody about money, because I didn't have anything to do with what people got paid. Let me tell you, that's a big change. It actually has a remarkable, remarkable effect on the way people work. Because if for some reason somebody wanted to make more money, they just had to leave. There wasn't any way to do it. So you either had to accept that this is what everybody got paid and that you were rewarded by the opportunities to do the kinds of research that were done. Or you said, look, I need to go on and go somewhere else.

Dr. Hayes: Now, just between you and me, and maybe a few thousand other people who are listening to this, who is the first guy to say let's give combination chemotherapy to Hodgkin's disease?

Dr. Young: Well, actually, I don't know the answer to that. I think if I had to guess, I would say Vince, because Vince and George had been around in the Frei and Freireich days. And of course, you know, they'd already had experience with the impact of combination chemotherapy in leukemia. And so the concept was you took drugs that were active in the disease and put them together if they had different kinds of toxicity. And you were then able to utilize the combined impact on the tumor and sort of spread around the toxicity. So it was more tolerable. And that was the concept. And I think that because Vince and George were treating chronic leukemias and treating Hodgkin's disease, the notion of combining it with combinations was pretty straightforward evolution from the experience in leukemia. There are other people who claim that. I think from time to time both Jay Freireich and Tom Frei have claimed it. I think that there was a dust up between Vince and Paul Carbone and George because there was some suggestion by somebody that Paul was the one who originated the idea or Gordon Zubrod. And quite frankly, I don't know. If I knew, I would tell you. But I don't actually know. I can tell you this, that the emotional and passionate driver of the concept of combination chemotherapy as a successful modality in Hodgkin's disease and lymphoma was Vincent.

Dr. Hayes: Your answer is very consistent with what other people have said the same thing. It must have been somewhere along the line that all of you began to see that there really were cures. And did you realize, as a group, that you were making history? Or was it just day to day--

Dr. Young: Well, you know, it's interesting. I can tell you one of the most transformational experiences that I had in the early days is, of course, we were following all these patients who had started on MOP. And so to do that you had to sort of go back and pull out the charts and all this kind of stuff. You know, we didn't have electronic systems that had all the stuff recorded. You just had to go down and pull off the charts. And what struck me so tremendously was the attitude of the physicians that had first started some of these patients on this therapy, because the notes made it very clear that they were sort of flabbergasted when these people came back after the first couple of months and they were watching their disease disappear, and that they really didn't anticipate at all, initially, that they were going to see these people after a couple of weeks. And it was very clear in the notes. By the time we had gotten there, of course, there were a significant number of people already on the trial. And it was already clear that we were seeing things that nobody had ever seen before. And I think that's when it first began to dawn on everybody. And as soon as we saw it in Hodgkin's disease based on the experience that we'd seen with non-Hodgkin's lymphoma, we had a suspicion that it would likely be the case as well there.

Dr. Hayes: So you already bounced across it, but as I was looking through your CV I knew this anyway, you really mentored a who's who of oncology-- Rich Schilsky, Dan Longo, Max Whishaw, Dan Van Hoff-- and you noted already that oncology training has evolved. I mean BJ Kennedy pushed through boards I think in '74 or '75, something around there. What have you seen in the evolution on oncology training that you think is good or bad?

Dr. Young: Oh, I think in general, it's much better. And I think it's much better because, of course, there's a lot of success that's been built into what's been accomplished. And that makes it a lot easier to teach people about how to treat Hodgkin's disease well, than we ever could at the time we were doing it because nobody knew the answer to those things. And I think there's also a lot more of it. You know, I think at the time we were at the NIH, you know, I think credibly you could count on both hands the number of really established academic oncology programs in the United States. And now, there are probably 100. And so the quality of training and the quality of mentoring is dramatically better than it was in those days. In those days, you know, hematologist we're doing most of the treatment of cancers. And they were all sort of in the Sidney Farber mode. You take one drug, and you give it as long as it works. And then you switch to another drug and use that as long as it works. And that was pretty much the way hematologists approached the disease. And by all means, you don't cause any toxicity.

Dr. Hayes: I picked up several adults who had been Sidney Farber's patient when I was at the Dana-- Sidney Farber Cancer Institute in those days in the early '80s. So I had his handwritten notes. And sadly, I did not photocopy them. I would have love to have had it. But he had a very different mindset in terms of the way--

Dr. Young: Oh, absolutely, absolutely. And as far as I can tell, this is just my own personal reaction, is that I don't think either George or Vince at the time we got here shared any of that attitude. George is a little more cautious than Vince, as everybody knows. But neither one of them for a minute ever suggested that we were being too aggressive, that it was unfair and immoral to treat people with these kinds of toxicities, not that they desired to make people sick. But they were absolutely convinced that aggressive therapy could make a dramatic difference in the natural history of these diseases.

Dr. Hayes: Yeah, certainly, Dr. Frei felt that way too.

Dr. Young: Yes. And well, they were his mentors. I mean, you know, all these guys were there at the same time. And they were all influencing one another.

Dr. Hayes: You know, it's amazing, I think all of us-- there are 44,000 members of ASCO now-- basically are derived from about 10 people in the 1950s and '60s, most of the DNA, not completely-- Karnofsky and some others around, but--

Dr. Young: Oh, yeah.

Dr. Hayes: Well, the other thing is actually, you were talking about the safety, what are the war stories? I mean, how did you give chemotherapy? Were you guys mixing it up and giving it yourself? You know, we got all these bells and whistles.

Dr. Young: Well, I mean, for instance, you know this is the first time really protocols were written. And the reason that we wrote protocols was simply because we were working with fellows. And they literally needed the recipe of what it was they were supposed to give and when. And so we wrote up these what were the first of the clinical trial protocols. There was no formal informed consent at the time of these studies. We had, of course, informed consent, the same way you do informed consent now, really. And that is you talk to the patient. You explain to the patient what the treatment is and what your expectations for the treatment are. And the patient understands the disease they face and decide that they can do it or not do it. And it's actually still the same today. The only difference is we now have 14, 17-page informed consent documents that make lawyers happy, but don't really impact, at least in my view, whether patients decide to participate or not. But we didn't have those. So I think that was the other one of the great things about the setting at the NIH, not that I'm anti-informed consent, but it was simpler. It was easier to get something done. You could do unconventional treatment and nobody looked at you and said, "you can't do that, that's never been done before, you're not allowed to do that." We didn't have academic constraints. One of the things that always surprised me is when, you know, we would develop a particular technique, like peritoneoscopy or laparoscopy for ovarian cancer staging, and when guys left the program having been well-trained to do this, they couldn't do it when they went to their new institutions because gastroenterologists did this. That was the sort of thing that the constraint wasn't here. There were also very easy-- I mean, all you had to do was to get an idea and write it up. I took a look at ovarian cancer and said, you know, "It seems to me, here's a disease that's now being managed by gynecologic oncologist. Internists never see these patients. They're all treated with the melphalan. And those that happen to live a long time develop acute leukemia from that treatment. They ought to be something better than what we're doing." And so we just decided that we would begin to take patients with advanced ovarian cancer into the NIH. And the rest sort of is history. But you couldn't do that in another hospital. You know, the biggest treaters of ovarian cancer probably program-wise was MD Anderson. But all his patients were treated by gynecologic oncologists. You couldn't have gone into the MD Anderson and said, "OK, we're going to take over the treatment of advanced ovarian cancer." They would have laughed in your face.

Dr. Hayes: Actually, you just segued into my next question. And again, you and Dr. Ozols, in my opinion, completely changed the course of ovarian cancer treatment. Did you get a lot of pushback from the gynecologic community?

Dr. Young: Well, no, actually. It's interesting. Now I don't know what we got behind the lines, you know when they were all sitting around the bar after the meetings. We really didn't. First of all, one of the other advantages of being at the NIH is that when you said something, people listened. And the other thing is, of course, when we got really going with ovarian cancer-- this was after the passage of the National Cancer Act-- and there was money at the NIH. So one of the things we did, for instance, was to put on a series of symposia about ovarian cancer treatment, what was going on, what wasn't going on, and brought the movers and shakers of this field together in meetings and talked about what was being done and what should be done and what information we didn't have that we needed. And we actually got funded for a period of time, a group called the Ovarian Cancer Study Group, which eventually evolved into the Gynecologic Oncology Cooperative Group, National Cooperative Group. So we had some other tools that we could bring to bear to drum up an interest in new research in ovarian cancer. And, of course, gynecologic oncologists couldn't prevent us from taking patients that were referred to us. And our surgeons, for instance, none of whom were gynecologic oncologists, were happy to help and to operate on them when they needed to be operated on. And Steve Rosenberg's group has fantastic surgeons. So we didn't have any problem getting state of the art surgery done on these people. And, in fact, they are general surgeons learned some gynecologic oncology at the same time.

Dr. Hayes: Yeah, you know, it's been interesting to me that the surgeons, the general surgeons, willingly gave a systemic therapy. But that still in this country, there are very few medical oncologist who do GYN oncology. It's still mostly done by GYN oncologists.

Dr. Young: Yes.

Dr. Hayes: And there are very few trained medical oncologist in this. And I think it's gotten too complicated for a surgeon to do both. I don't really see why that hasn't happened based on, especially your model and Bob's model, that's my own soapbox.

Dr. Young: Yeah, that's an interesting point, because at the NIH, when we were there, Steve Rosenberg and Eli Gladstein in radiation therapy, there were no rules that said that they couldn't do chemotherapy. And, in fact, they did it sometimes. And we didn't say anything about it. Usually, they called on us and said, hey, look, you know, we need you to help us or participate with us or whatever. But there were no rules that said that they couldn't. And sometimes they did. But for the most part they said, "look, this is not the business we're in. We want you guys to do the chemotherapy." And so for the most part we were able to do that.

Dr. Hayes: The entire NSABP, those guys were all given their own surgery, their own chemotherapy. And they ultimately handed most of it over to medical oncology through the years. But that's not happened so much in GYN. OK, I want to go into your role in ASCO at the end here. And as I noted, I think you were president during a really critical turning point for the society. And just a few things, you already mentioned that I think you were already at Fox Chase when you ran. So you'd left NCI. And what made you run? But more importantly, tell us about your role in the evolution at that time of the society.

Dr. Young: I think actually they recruited me to run just at the time that I was looking to leave. And so I left in December of 1988. And I was president of ASCO 1989 to 1990. At the time, I had moved from the medicine branch and ran the cancer center's program for a year. And I decided that I liked it. I thought, well, maybe I'll just stay here for the rest of my life, the way Steve Rosenberg did and others have done very successfully. But I said, well, you know, it's either sort of now or never. And so I decided that I would make the jump. But when I got into the sort of ladder, if you will, of ASCO through the board and so forth, it became clear that there were a couple of things that were a real challenge for the society. The society had at the time for the most part been essentially run on contract, that there was no organization of ASCO at all. It was it was all run by a contract organization. And it was clear that we had grown to a size such that we really needed to begin to recruit our own leadership staff. And so my year as president was actually the first year we hired a full-time employee. And she was based in a law firm that we used for ASCO legal business. But that was the first employee ever hired by ASCO. And that was in 1990, or 1989, I don't remember which, put in that year anyway. The other thing that was going on, which was critical for the society, is that, of course, there's always been a 'town gown' challenge in all aspects of medicine. And medical oncology was no different. So it had originally been the province of academic oncologists. But the numbers began to change dramatically. And it became clear that there was an enormous number of community-based oncologists, who looked at the challenges that face the organization somewhat differently than the academics. And this is one of the things that I think I benefited from growing up with a father that had both his feet in the community-based practice and the academic practice. And I realized how private practicing physicians view academics and view academic control of organizations. And I realized-- and others did too. I wasn't alone on this-- that we really needed to build up the recognition of community-based oncology as a first class citizen in the society. And so we began to create and bring in all of these state society organizations. And we began to get leadership roles who were based in community oncology, rather than just academics. And Joe Bailes was our first head of the Public Relations Committee of the society and grew this into a national presence and became the first community-based president of ASCO. So I think I think those are the two things that I saw that hopefully I made an impact on. And it always amazes me to realize that the society was really that young. I mean, people can't believe that it's just, what, 30 years ago when we had our first employee.

Dr. Hayes: Yeah, that's why I'm doing these podcasts. We make sure we get this history. You know, it's interesting, I often give you credit for the ladder. As president myself, it was made very clear to me that 90% of the patients in this country with cancer are treated by community oncologists, maybe 85% or so. And about 2/3 of our membership are community oncologists. So we now have designated seats on the board of directors. We started a Department of Clinical Affairs that Steve Grubbs is running. That's just a few years old. But, boy, it's been fabulous. We now have a designated chair, the state affiliate council is invited to the board of directors and sits in and presents. And the state affiliate councils meets at ASCO headquarters at least once a year. And we've had a couple presidents who are, besides Joe, Doug Blayney and Skip Burris now coming in in June. So I think we've been reaching out. It always struck me when I sat in the headquarters, the seven founding members were, for the most part, community people. They met just to talk about how do you give chemotherapy. It wasn't, you know, about Tom Frei or Freireich or Jim Holland. It was folks in the community. And then it grew into an academic society. And I think you and then Joe Bailes and others kind of brought us back and grounded us. And to me, that's a really critical evolution in our society. I think it's made us much stronger.

So those are most of my questions. You've answered almost everything I had written down that I always wanted to ask you if I got a moment in a cab with you. I want to thank you for taking time to do this. But more importantly, I want to thank you for all the contributions you have made to the field. I mean, I don't think I would be here and I don't think most of us who do oncology would be here if it weren't for you and the Gang of Five and the things you've done, both by the courage to moving forward to giving the kinds of chemotherapy and stuff, establishing science in the field, but also the policy stuff. Your articles in The New England Journal over the years, I think have been classics. You should put this all in a book and send them out to everybody because they have to do with not just giving chemotherapy, but the whys and hows of what we do. So I know I'm being long-winded, but that's because I'm a big fan. Well, thank you very much.

Dr. Young: You know one of the things, I got to say is that I've just been a very lucky person. I happened to have had great opportunities. And I think I was able to take advantage of those opportunities. But somebody gave me those opportunities and put me at the right place at the right time. And so I am a very lucky guy.

Dr. Hayes: Well, and I want to finish up and say how nice it is to see at least one graduate of Ohio State University do well. You know, it doesn't come very often. So congrat--

Dr. Young: Yeah, yeah, yeah, yeah, yeah The team up north, the team that will not be named, yes.

Dr. Hayes: Thank you so much. And appreciate all you've done. Again, appreciate your taking time with us.

Dr. Young: Thank you very much, Dan.

Dr. Hayes: Until next time, thank you for listening to this JCO's Cancer Stories, The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listened. 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 ASCO's many podcasts. You can find all the shows at podcast.asco.org.

A daughter considers the differences in being a supportive family member rather than a primary caregiver.

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 world of cancer care. You can find all of the shows including this one at podcast.asco.org.

The cattle don't care. Stephanie L. Graff, MD. The silence is filled by the sound of a long, slow Midwestern freight train rumbling past. The sounds reverberate off the brick buildings that line the parking lot of the Save A Lot grocery store.

I'm in the front seat of my father's Ford pickup truck. I close my eyes and breathe in the smell that has long penetrated everything about my father-- paper feed sacks dusted with ground corn, manure and dander from our cattle, and machine oil.

His words are circling around my mind as I try desperately to remember everything I learned in anatomy, physiology, and pharmacology. He said it is just some high blood and chronic leukemia. He says they just found it in his blood but that he feels fine so the damn doctors are probably wrong.

If he is asymptomatic, it is probably early, right? Chronic leukemia is one you can live with for years, right? He's only 71 years old. He still farms full time and owns a general contracting business that constructs steel buildings around the Missouri River Valley.

He'll be fine. He has to be. The financial situation of a Midwestern farmer is too tenuous for illness.

I snap from my reverie as he hands me copies of his laboratory work and says, now you can't tell your mother. She doesn't know. Then he opens the truck door and heads into the grocery store. The conversation is over.

My father lost his hearing during his time in the reserves. When he came home in his early 20s with significantly damaged hearing, he went to see a doctor. It has never been clear to me what kind of doctor he saw.

Was it a primary physician, an audiologist, or a specialist? I'll never know. He won't talk about it. The doctor told my 20 something year old father that the nerves that stimulated the teeth and ears are the same so if he wanted to get his hearing back, he would have to pull all his teeth to stimulate the nerves.

The doctor referred him to a dentist who happily pulled a full mouth of completely healthy teeth to save my father's hearing. Needless to say, it didn't work. At age 20 something, my father was deaf and wearing dentures. Doctors have been damn doctors ever since. When questioned about his deafness, he often replies, the cattle don't care.

At the age of 21, I was home for medical school to live with my parents and do a month of rural medicine, a routine part of the curriculum in my Midwestern school. I know the only reason my father shared this diagnosis with me is that he assumed that his doctor, who was my preceptor for the next month, will tell me if he doesn't.

It is an unfounded assumption. My preceptor is a consummate professional. And over decades as a small town doctor, he has learned to respect the privacy of the community.

Dad climbs back into the truck. The small pickup bounces and rebounds with his weight as he climbs in. He puts the truck in reverse and pulls out of the parking lot without bothering to latch the seat belt that I have never seen him use.

I thumbed through the laboratory results I just remember I am holding. Elevated glucose, slightly abnormal lipids, and normal hemoglobin and platelet count. The WBC count is 87,000, predominantly lymphocytes.

I glance at the clock and mentally start the countdown until I get to the city library-- my family home does not have internet-- to look up everything I can on chronic lymphocytic leukemia, CLL. But first I will be helping to complete all the farm chores. I breathe in the smell of my father again.

Years pass by. My research that day reinforced the positive message I vaguely held from my early medical education. Over the years, two truths became apparent to me. First, my dad's CLL was not an aggressive or rapidly progressive type. Second, my father truly didn't believe he had the disease.

During my residency years, he was hospitalized with sepsis from a farming wound. I sat in the bedside chair while he explained to the hospitalist that he just had a touch of anemia. My mother had already proudly explained to the hospitalist that their daughter was a doctor too, all but giving out copies of my diploma.

The hospitalist raised his eyes to meet mine and I just shrugged. Trying to scream talk to my deaf father and explain the nuances of his hematologic condition while he's hospitalized with a far more pressing health issue doesn't seem like the best strategy. Plus my mother is still in the room. And I am sworn to keep Dad's CLL secret.

I have suspected for a year or so that Mom knows, but she has never asked me directly so I am never forced to make the decision about moving from my life of omission to either an outright lie to my mother or a betrayal of my father.

When the hospitalist left the room, my father handed me a handwritten note. I unfolded it, expecting it to reveal something about his CLL and the doctor or my mother. Instead, he has handed me a list of farming chores that need to be completed. The cattle don't care I'm in here. Still need to be fed. His singular focus is simultaneously irritating and endearing.

My father is now in his 80s. Though I only live three hours away from home, I rarely see him or my mother. My mother doesn't like to drive alone. She worries about her eyesight.

My father can't bear to be away from the cattle overnight. The rhythm of farm life seems to function like a pacemaker for him. Plant harvest, lub dub, seed water, lub dub, build repair, lub dub. He is as fiercely independent at age 80 as he was at age 30.

My father hates asking my brother who farms alongside him to help him with farming tasks like fence repairs or feeding the cattle. They each have their own tasks and responsibilities and neither would ever burden the other. They have an unspoken rhythm moving around the farm chores, separate but vital responsibilities. Systole, diastole, lub dub.

My physician husband and I spent much of our Christmas visit whispering about how much weight and muscle mass my father had lost in the six months since we had last seen him. My brother pulled me aside to complain of how not right dad had been lately. My mother complained about how he falls asleep on the couch every night with the TV blaring.

I probed as much as is possible with a patient who doesn't want to open up. How have you been feeling? Are you still getting around OK after your knee replacement? How are things going with work down on the farm? Are you still eating fish for lunch every day?

I get a series of grunts and nods, answers that don't correlate with my questions. He can't hear me. Even with my scream talking, he is confabulating because he doesn't hear the questions. The only chief complaint I can elicit from my aging father is that it is getting dark already and he needs to get back to the cattle.

By early January, my mother is calling with stories of dad's abdominal pain. She thinks he has a hernia but she isn't able to answer my questions of a hernia where. My brother calls to tell me something is really wrong with dad's belly, that he isn't able to farm, is in a foul mood, and has been seen doubling over in pain. Did it occur to me? Nope.

I am a board certified medical oncologist and hematologist. My 80 something year old father has unspecified abdominal pain, fatigue, weight loss, sarcopenia, and a 10-year-old CLL diagnosis. Do I even for a second think, oh, splenomegaly, his CLL is acting up? Nope.

Hearing my family try to explain their medical symptoms bends my mind in knots. My parents will confuse medical jargon, downplay symptoms, omit critical details, and elaborately describe incidental findings, all of which makes it hard to find the medical truth. In my father's case, I have attributed it to his eighth grade education and the stoic, no complaint, German heritage farmer mentality so I gave up long ago.

I remember the moment years ago that led me to stop trying to interpret their medical issues. My mother called me. She said, "Stephanie, I didn't want you to worry but I had a colostomy. I just had my follow up appointment and everything is OK so I thought I would call and let you know now."

I screech in panic into the phone. A colostomy. What? Why? My mother calmly chides me. Well, you know, because of my brother Stanley. My uncle had died of metastatic colon cancer when I was still in high school. At the time, my uncle's death had rocked me to my core with the idea that my parents were not immortal.

But Mom, that isn't really a reason to have a colostomy. Sure it is, she responds. They recommend it at 50. You know that. Anyway, it all turned out OK. It was clean. Just a few A-D-E-N-O-M-A-T-O-U-S polyps.

She spells the word for me. Even over the phone, I can tell that she had dutifully asked her physician to write it down so that she could report back to me accurately. I sigh with relief. "Mom, do you mean you had a colonoscopy, like a doctor looked with a scope inside your bowels, or a colostomy like you have a bag outside your body to collect your stool?"

I can hear her getting annoyed with me. "Like I said, Stephanie, I had a colostomy. They just checked me. Why do you always have to be so critical?" After that, I let it go.

My parents are adults. They are never going to lean on me for medical advice. They value independence and privacy. They do not like to make others worry or fuss over them. This is just how it is going to be.

After relentless harassment from my mother, Dad acquiesces and goes to his primary doctor. His spleen is three times the upper limit of normal. He has lost about 30 pounds. And both his RBCs and platelets have plummeted. They consult with his oncologist. And to my surprise, my father agrees to do the chemotherapy that the damn doctor recommended.

My mother, who slides through the process smoothly, the only telltale sign that she's always known the diagnosis, calls me and spells out the chemotherapy drugs. I ask whether she has questions that I can answer. She doesn't.

My phone call with dad is tedious. I'm yelling into the receiver louder and louder. No, he does not have questions. No, he does not want me to come down. He will be fine. He understands it all. He importantly exclaims that he was able to arrange the treatment late enough in the day that he can still get all his work done on the farm with the cattle before driving into the city for treatment.

I chat with my mom off and on leading into that first treatment. I can tell she is scared, not of the disease or the treatment but of the unknown. Her questions are metaphysical, not medical. For reasons that are unclear to me, she tells my father's oncologist that I want to talk to him and gives him my cell phone number.

Given our established pattern wherein my parents conceal their health issues until they can be assured it is nothing bad, I did not even imagine that they would be comfortable with me talking to dad's damn doctor, oncologist to oncologist.

He calls and I don't really have any questions. The broken reports I get from my parents are pretty clear. I have no doubts about his choice of treatment. Dad's oncologist and I end up chatting about some clinical research I am doing.

As we end the call, he says, you know, your father is really hard of hearing. It makes it hard to take care of him. Have you ever talked to him about hearing aids? I laugh out loud. And I'm still laughing days later.

Yes, I explain, we have had conversations about hearing aids. By the time he consented to talk to a damn doctor about his hearing, it was beyond the point that hearing aids would help. But I calmly reassure my father's oncologist that the cattle don't seem to mind in the least.

The first crisis hits when my father is asked to schedule a second cycle of chemotherapy prior to leaving the oncology clinic after completing cycle one. He doesn't hear any of the interaction. So when my mom hands him the follow up on an appointment card in the parking lot, he explodes.

Why would he ever need to go back? He already did his treatment. It should be better now. He feels fine. Damn doctors. My mom calls me crying in fear, and anger, and frustration. Can I talk to him? I remind mom what it must be like to undergo cancer treatments without being able to hear about them.

When I call, he is calm back on the farm. He tells me he doesn't know why mom called or involved me. He will do whatever the damn doctors say. So instead we talk about farming, weather, and if he will be able to get the fields planted.

The experience of being a supportive family member rather than a primary caregiver or physician in charge has opened my eyes to two fundamental truths. First, every patient has a central identity that is unchangeable. My father is a farmer. Nothing is going to mess with that. Chemotherapy or not, he has cattle to tend and fields to plant.

Second, barriers can be invisible from either side. While physicians are sometimes blind to barriers like transportation, literacy, food insecurity, and financial concerns, patients can be blind to barriers within their interactions with the health care system.

My father is deaf. It doesn't seem to bother him. He isn't going to read printed material. He won't take any other steps to overcome a barrier he doesn't see. Caregivers like my mother, dutifully writing down appointments and putting her phone number in the patient phone number blank on forms, allow invisible barriers to go unnoticed.

Dad has laboratory work done at our rural community hospital. And his big city oncologist is able to review them without an extra trip. The morning before the second cycle of chemotherapy, he has his laboratory work completed and heads to the farm.

The clinic has been calling my mom with everything. Screaming at my dad through the phone is not ideal. Her phone rings around noon. The nurse explains that my dad won't be able to receive his second cycle of chemotherapy tomorrow. He is N-E-U-T-R-O-P-E-N-I-C.

That means he might get sick and the chemo is working, my mom explains to me. That nurse was so nice. She talked me through these precautions. She said that dad needs to stay clean-- I wrote that down for him-- and about cooking food and checking his temperature. "She spent at least 30 minutes with me on the phone, Stephanie. So nice."

My mom teaches me everything she learned about neutropenic precautions while I try to stuff in my lunch during my own busy oncology clinic. So when she was done telling me about all that stuff, I asked her what we needed to do about the cows to be safe. I don't think she really knew. She kind of stammered a bit. What do you tell your patients about cattle?

I take a deep breath. And I can smell the essence of my father. On a farm 200 miles away, my 80-year-old father is living his best life surrounded by his fields and his cattle with an absolute neutrophil count of zero. I smile into the phone and respond, oh mom, the cattle don't care.

[MUSIC PLAYING]

I'm Lidia Schapira, editorial consultant for JCO's Art of Oncology, and the host of "Cancer Stories, the Art of Oncology" podcast. With me today is Dr. Stephanie Graff. Dr. Graff is the director of the breast oncology program at Sarah Cannon Cancer Institute in Kansas City and the author of "The Cattle Don't Care." Welcome to the program, Stephanie.

[Dr. Graff]

Thanks, I'm excited to be here today.

[Dr. Schapira]

We loved your essay. And before we start talking about the essay and the message, tell me a little bit about your writing. Have you always been a writer?

[Dr. Graff]

Yeah. I actually really fell in love with writing even in grade school and middle school and always entertained the possibility of a career in English literature. And so it's always been something that I turn to to deal with being an oncologist and the emotional weight of our career sometimes. And it's always been a really powerful form of expression for me.

[Dr. Schapira]

Fantastic. So writers usually love to read. What is on your night table now?

[Dr. Graff]

Well, right now I am reading a book called "Inheritance" by Dani Shapiro, which is about how basically doing an ancestry panel completely upended her identity. And it's fascinating.

And I just finished "Between the World and Me" by Ta-Nehisi Coates, which was fantastic. "Ordinary Grace" before that by William Kent Kruger. Yeah. I've got a pretty diverse reading list. And I love to read.

[Dr. Schapira]

And when do you find time to read?

[Dr. Graff]

I do a fair amount of Audible while I'm commuting back and forth to the hospital. But it is my unwinding at night strategy so I tend to read a few chapters every night before bed, not only to myself but to my kids as well. So lots of reading in the Graff house at night.

[Dr. Schapira]

That sounds wonderful. And what are you reading to or with your kids?

[Dr. Graff]

So my oldest and I are just reading "James and the Giant Peach" and we finished "The Phantom Tollbooth" before that, so just reading through some children's classics and having a really great time doing that.

[Dr. Schapira]

That's wonderful. So let's turn our attention to the story of your dad. Your dad, his deafness, his leukemia. It's so interesting because it's so dramatic and yet there is no drama. It's funny. And that makes it so incredibly amazing. How did you put this all together?

[Dr. Graff]

You know, it's just really my life actually. My parents are fantastic people. They're very stereotypical Midwestern farmer salt of the earth people. And I am proud to be their child and to have been raised with them. But they really are very amusing now as an adult and a physician to sort of interact with this just in their perception of what's happening with their health care and the way that they open up to me at seemingly random times about what's going on.

Watching my dad's experience going through treatment for this diagnosis of the CLL of progressing has just been really interesting to watch. And I've been experiencing life as a caregiver rather than as a physician or a patient myself and trying to find wisdom in those moments of interaction with my parents.

[Dr. Schapira]

So take us to the beginning of the story. You're 21 years old. You're a medical student visiting your parents. And your dad just gives you these lab tests while he's going into the grocery store. Take us to that moment and tell us how you felt.

[Dr. Graff]

I was still pretty early in my medical school career at that point. And I pretty early on had an interest in oncology. That information had seemed to stick a little earlier. So when my dad told me that he had high blood and handed me the stack of paperwork, and I started flipping through it and saw the lymphocyte count was markedly elevated, I pretty instantly thought, OK, it's just CLL so chances are it's going to turn out great and everything's going to be fine.

But I was a little flabbergasted at trying to figure out what it was that he wanted. Was he telling me because he wanted advice? Was he telling me because now as an adult child he wanted to start including me in these discussions and decisions more?

Was he telling me this because, again, I think he was worried that the primary care doctor I was shadowing on this preceptor rural medicine month would tell me if he didn't. And I don't think he wanted to be outed by someone else for this diagnosis. And so part of it was maybe pride in him telling me first.

And so I think my reaction in the moment was just sort of shock and confusion. He hadn't really been transparent with me about health care issues in the past. And it made it difficult for me to even figure out how to respond much less then grapple with what that meant medically.

[Dr. Schapira]

That's so interesting. I imagine it must have influenced you in some way as you approached your career in medicine and took your first steps from student to a doctor. And then you bring the reader again to another scene where your dad is hospitalized for sepsis some years later.

And there you are now during your residency. And you think then there is that he's bringing you into the conversation and finally hands you a note. And you think this is going to be some deep thought. And what he really is giving you is a list of farm chores that need to be completed. Tell us a little bit about that scene.

At that hospital stay, my dad and mom had both thought that I didn't need to come down to see him, that he was fine, and that it was just sepsis. And they were sort of dismissive of my plan to come down and check out how he was doing with that diagnosis.

And so I arrived. And I was trying to get a little bit of information from the nursing staff and waiting for the physicians to round. And my dad got this note out to me. And I think he's going to disclose something private and important that maybe he hadn't wanted to share on the phone or hadn't wanted to share with my mom.

And I think it was telling me to go to a certain property and make sure that there was hay, corn out for the cattle. But I did touch base with my brother about some of the other things that needed to happen on the farm. I just remember thinking, well, he's still good enough to give me farming chores so he's probably going to be OK, which was very true. At least he hadn't lost sight of what was truly important.

[Dr. Schapira]

That's so funny. And in my reading of your essay, perhaps the central theme also is his deafness. And it seemed to me as a reader that he uses deafness almost as a shield so that he would protect himself from the things that he didn't want to face or talk about, and that he used this very well to stay in control. And that perhaps suited him and his identity as the farmer, the grounded guy who was supporting his family. Was that your intention in conveying the deafness in the way you did?

[Dr. Graff]

Yeah. And I think my mother would 100% agree with your assessment that you just articulated so beautifully. He really is not bothered in any way by not being able to hear and had used it to avoid talking about things that he's not interested in talking about and has used it to augment his own stubbornness in any given situation where his way or the highway kind of because he can't hear with anybody else's way might be.

And that's a really interesting dynamic in our family not just when it comes to health care but just in all the little day to day stuff that's happening in any extended family is communicating effectively with my dad.

Through the years, he ran a successful business. He did some general contracting on the side of being a farmer and did great doing those detailed business things even with a hearing loss. Does a good job reading lips if you are making good direct eye contact with him when you're talking more German so there's lots of hand waving going on and hand gestures to communicate anyway which help fill the gap.

And I think a lot of it is just very intuitive. He is, I think, very empathetic and can know what people are feeling around him even if he can't understand their words. Even though there's a clear barrier in our communication, I always still feel like we're able to get it done.

Sometimes it's hard to talk to him. Like he'll call me when I'm at work and I have to yell so loud into the phone that I'm like, oh my gosh, everybody in my clinic can hear me on the phone right now until I close the office doors. And even then I know that people can hear through the walls if I'm screaming at him through the phone. But it's sort of our normal at this point.

[Dr. Schapira]

So it sounds to me in reading your essay several times, it sounds that you are completely connected to your dad and that the deafness certainly has not come between you. But have there been times in your life when you felt sorry for his not being able to hear or felt you needed to defend him from others perhaps who didn't understand or relate to him because of deafness?

[Dr. Graff]

For me, and I hadn't anticipated before-- the only part of his hearing loss that's ever been heart wrenching for me that I know he doesn't hear my children. I have three kids.

And I know that when they say, "I love you, Grandpa," or "thank you for my present, Grandpa," or those little things that they tell him that he doesn't hear what they're saying because they have little kid voices, and they mumble, and he can't read their lips. And little kids speech patterns aren't always predictable or follow a normal conversation line. So he can't confabulate the gaps in what he understands and what they're really saying.

And my oldest child who's nine now, the last time him and my dad were together, he was trying to ask my dad about farming and what it's like to be a farmer and about the cattle because he knows that that's something that's a real interest to my dad. And my dad just kept responding with yeah kind of responses, like clearly wasn't understanding what my son was asking him at all.

And that was really difficult to see and watch because there was not a real good way for me to foster the connection without getting in the middle of it. So I did end up repeating his questions for my dad several times but I can tell that that sort of spark and intimacy that you'd like to see your children and their grandparents have is just going to be fractured a little bit because of my dad's hearing loss.

[Dr. Schapira]

In your essay talking about this point, you talked about the fact that there may be barriers that can be invisible from either side from patients to clinician or clinician to patient. How does your dad's experience and your experiences as a caregiver affected the work you do every day when you're with patients and thinking about perhaps invisible barriers that you're not aware of?

[Dr. Graff]

You know, I tried to be more intentional asking the family members that come with my patient toward the end of a visit. So during the visit, I'm trying to stay very focused on the patient, making sure that all of their questions are answered and making sure that they understand everything.

But then toward the end of a visit, particularly a new patient consult, or one of those disease progression heavier oncology clinic appointments, I try to look at that family member and say, is there anything that you wanted me to know or that you thought was important that we haven't covered yet, to see if something comes out if there is that barrier. And I think I mentioned in the essay something about food insecurity.

There's been several times where in that moment, the family member has shared that they are really worried that they're not able to get to the grocery store to get healthy food, or that they see that they're skimping on their blood pressure pills in order to pay for their cancer treatment medications, or things like that that I'm lucky to work in a place with really great resources that I can help and support a lot of that but the patient never would have volunteered that if I hadn't specifically called out their family member to offer that additional information. And so that's been a real opportunity for me to grow professionally to see that specifically giving the caregiver an opportunity to share their concern strengthens my ability to care for the patient.

[Dr. Schapira]

So my final question to you is this. You talked about your dad having had bad experiences early in life with doctors and referring to them as those damn doctors. What do you think your dad thinks about your career?

[Dr. Graff]

You know, I think that my dad is really, really proud of me. But I don't know that that has anything to do with my career. I mean I think he would have been proud of me if I was a farmer, or a teacher, or anything. I mean I think he's a parent and he loves me and is proud of me. I think that he has seen some of my professional achievements and better understand why I love what I do.

I suspect it's actually helped make him a little bit better as a patient. I mean I think he understands a little bit more what a physician looks like outside of the clinic and all the things that go into getting a physician in a clinical practice, all the years of work, obviously that lead up to that moment. And so I think he's proud of me. I don't think he considers me a damn doctor, which is probably a feather in my cap. And I think he's proud.

[Dr. Schapira]

Well, thank you so much for sending your essay to us. "The Cattle Don't Care" is beautifully written. It's rhythmic, and breezy, and funny, and addresses one of the most important themes in our lives. And that is our parents, ourselves, our love for our parent, and the enormous distress or impact of having a parent who is ill. And you did it in such a beautiful way. Thank you, Stephanie.

[Dr. Graff]

You're welcome. And thank you so much for inviting me to this podcast. It's been fun.

[Dr. Schapira]

This concludes our interview today with Dr. Stephanie Graff. I'm Lydia Shapira, the host for Cancer Story and the "Art of Oncology" podcast.

Until next time, thank you for listening to this JCO's "Cancer Stories, the Art of Oncology" podcast. If you enjoyed what you heard today, don't forget to give us a rating or 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. Muggia about his time at NCI.

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 carrying 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] Hi, and welcome to Cancer Stories. I'm Dr. Daniel Hayes. I'm the medical oncologist, and I'm also a researcher at the University of Michigan local cancer center. And I'm the past president of the American Society of Clinical Oncology. I am truly privileged to be your host for a series of podcast interviews with the founders of our field. Over the last 40 years, I've really been fortunate. I've been trained, mentored, and I've been inspired by many of these pioneers. It's my hope that through these conversations, we can all be equally inspired and gain an appreciation of the courage and the vision, and frankly, the scientific understanding that led these men and women to establish the field of clinical cancer care over the last 70 years. I hope that by understanding how we got to the present and what we now consider normal in oncology, we can also imagine and work together towards a better future for our patients and their families during and after cancer treatment. Today, I'm pleased to have, as my guests on this podcast, Dr. Franco Muggia. He's generally considered one of the pioneers of new drug development oncology going all the way back to the 1960s. Dr. Muggia is currently a professor of medicine and co-chair of the GYN Cancer Working Group at NYU, and a member of their breast cancer program. He was born in Turin, Italy before the war. But when he was about three years old, his family fled to Ecuador to escape Mussolini's fascism. After growing up there at the age of 18, he moved to the United States in Danbury, Connecticut, to finish high school. And then he received his undergraduate degree in biophysics from Yale in 1957. In 1964, he became a US citizen. But he's remained true to his roots and has been very involved with both US/Italian cancer collaborations and mentorship, and also with South America for decades. He went to medical school at Cornell, followed by an internship at Bellevue in New York City, and a residency at Hartford Hospital in Connecticut. He completed a fellowship in medical oncology hospital in 1964-1967. And we're going to talk about that, Franco. And since he's had a number of important academic positions at Einstein, the NCI, University of Southern California, and New York University on two different occasions, and that's where he still practices. He's been involved in the development of clinical trials of hundreds of new drugs through the years, perhaps most notably, cisplatinum. In regards to ASCO, he served on our cancer education committee and on the editorial board of JCO. In fact, I understand you were the first editor of the Spanish edition of JCO. Correct. Correct. And perhaps more importantly, he's been a direct, and an indirect, mentor of hundreds of medical oncologists of the decades at that many institutions he's served, including myself, frankly, in my association with his good friend, George Canellos. Dr. Muggia, welcome to our program. Thank you very much, Dan. And I would just say, just a comment on the citizenship. So once I became a citizen, I actually became eligible for the draft. And that was the main reason why I ended up at the National Cancer Institute. So it had a-- it was a great effect on my career, that I actually volunteered for the Public Health Service in 1969. Because Lyndon Johnson changed the rules for physicians. And if you hadn't served, you had to serve up to age 35. So I decided I should join, not head to Vietnam like the rest of my classmates-- like many of my classmates from Cornell. And it really was a career change for me. Actually, that's a recurring theme in my podcast series. I have interviewed several people at the NCI in the mid to late '60s and early '70s sort of pejoratively, but actually not. You all became known-- as you've put in some of the things you've written-- as the yellow berets. Right. But in fact, it's really, I think, fundamentally changing-- NIH in general, and especially the NCI. We'll talk about that more later. I know your father was a pediatrician. Leaving Europe in the 1930s must have been extraordinarily painful for him and your family. Can you tell us more about that, and getting to Ecuador? Well, he was-- he never joined the fascist party. In fact, he was best friends with the socialists that remained at that time. Mussolini was brutal. He wanted everybody to become a fascist. And anybody who served at the University lost their jobs. He was in a bit of hot water as well. So that, plus the racial laws, which made Jews not be citizens, led to a big decision in the family. It was a phone call, whether we wanted to join an enterprise-- whether he wanted to join an enterprise in Quito, Ecuador in a pharmaceutical company. And my mother said, I don't know where the place is, but let's go. So that's how it happened. So in a matter of a few weeks, we were gone. And I was three years old. So how did you end up getting to Connecticut? Well, that was-- the American School of Quito, which I was a founding member in kindergarten. There was this person who became Ecuadorian, who was actually born in New York because his father was a consult here in the early 1900s, Galo Plaza Lasso. He decided, hey, we need a school-- a private school that-- non-religious, that competes with the German school that's there. We're going to call it the American School of Quito. So I was a founding kindergarten pupil, and ended up going right through to graduation with my class, except that the last year, I was an exchange student in Danbury, Connecticut. Because our principal, who was a champion swimmer-- Ashby Harper-- and John Verdery, who was at the Wooster School principal, they were together in Princeton. And they decided to make this exchange program, which ended when-- I was the last one, actually, of six years. My brother, he was there three years before. But they sent a person, or two people, to be there for their last year. And now I know you went on to Yale to study biophysics. I'm always fascinated by why people end up making decisions. So you were biophysics major. Why did you go into medicine? Was it your father? Well, my father and my two grandfathers were physicians, actually. So my brother was already-- he preceded me at the Wooster School, and then he went to Harvard College. I decided to go with some of the-- it was a small class. We had 16 people. Four of us went to Yale. So I decided to join the group that went to Yale. And my father thought that I should go into the sciences, but not medicine. One doctor was enough. So I started off, and I was actually doing very well in math and physics. And I was friends with a lot of premeds. But I didn't want to take any pre-medical-- the usual biochemical courses that were given at the medical school. So I decided to go with the head of biophysics major, and that suited me fine. So I started with that. And then I decided, well, you know, that's good. But let me head to medical school. So you had no choice. Actually, the really great story, I know you went to Cornell Medical School. Tell us about the lecture by Dr. Karnofsky, which I think has ended up changing oncology. Yeah, so-- yeah, actually, it was the first lectures we had in medical school as freshman. And we had-- in our 30th reunion a few years later, I talked about Karnofsky, how he inspired me to think about the clinical matters in cancer and his performance status evaluation. I remember that very well. Nobody else did. I have to tell you-- I guess it resonated with me, but not with my other mostly surgeons in my medical school. Well, this is, frankly, a recurring theme in these podcasts too, which is many of our pioneers hadn't thought about going into cancer. In fact, in those days, it almost didn't exist. And then one person made a light bulb come on. I have the same issue in my own career with Dr. Einhorn. So I think all of us need to keep in mind, you never know what influence you're going to have on a medical student. Yes, mentorship is extremely important. And going to class, face-to-face meetings are important. I know you've told me some of the stories too, but when you were at Cornell and located through Memorial, that you ran into some of the luminaries-- Joe Burchenal, Irwin Krakoff, Miriam Isaacs-- Well, I took-- well, that's partly mixed with my internship because I did my internship at Bellevue Cornell division. Yeah. And also, my clerkship. So yeah, that's when I took some electives, too, at Memorial as well. What did Miriam Isaac bring into this one? I think a lot of us know about-- Miriam Isaac was head of the metabolism group. Where did you know her from? I've just heard her name, yeah. Yeah, she was part-- Parker Vanamee and Miriam Isaac ran this physiology. It was called physiology elective. And it was ideal for a third year student. I learned everything, because you saw so many derangements that were concomitant with what was happening with the progression of cancer. But they examined all the issues regarding what led to hyperuricemia, hyperkalemia, any electrolyte imbalance. So you really learned a lot. So that almost gets to the birth of translational medicine, in many respects. We think this is new. It's not. It goes way back. Right. It goes way back. I know then you went on and finished your residency. And most importantly, you are an alumnus of the Francis Delafield Hospital. And that spurred me. I've heard this hospital's reputation my entire career. But I never knew who he was, or what it's all about. Tell us about-- Well, so the city of New York, the city of New York, they really had very good outstanding commissioners of health who decided that cancer hospitals were important to take care of New Yorkers with cancer. And they set up one at Cornell, which was called James Ewing Hospital, which was right inside Memorial Hospital. So they were-- I mean, people don't really remember the James Ewing Hospital because it was annexed into Memorial Sloan Kettering. But the one at Columbia was a separate building. And it was Francis Delafield Hospital. And it had real luminaries from the Columbia faculty, including Alfred Gellhorn, who was a professor of medicine and very charismatic. It was an outstanding group of individuals. Gellhorn presided over a group of about 10-12 internists who were dedicated to cancer and also translational research, as you say. And one of my papers that I wrote to my fellows was on hypercalcemia malignancy with Henry Heinemann, who was one of the internists. He devoted all his effort into physiology, so to speak. So it was kind of the same segue to what we I had at Memorial as a student. But the Francis Delafield Hospital had problems. They had staffing problems because the head of medicine would not send their residents to-- stop sending their residents through the oncology services-- I guess that's what it would be, if you're taking care of medical oncology services. They were in all that way. But it was the Department of Medicine at Francis Delafield. And it was kind of a bit of envy, in part, as one interprets, that Gellhorn was so popular with the students. And so there was all this internal discord with these services at Columbia and Francis Delafield, although Francis Delafield was part of Columbia. So at one point, when the residency finally stopped including, the Bellevue first division residents did rotate through. The first division residents were Columbia service at Bellevue. And they rotated through. So when Gellhorn and another name, the president of ASCO later, Jon Altman-- who was a terrific teacher whom I worked with-- he then left and went to the University of Chicago. And Gellhorn left and became dean at the University of Pennsylvania. I was told to get another job. I was there, starting to be an attending physician. And I went to Albert Einstein. So as you see, I've moved around. I've moved around a lot, but I've moved around always twice to the same place, except the University of Southern California. And there, I go every year. I've maintained my ties with the Trojans. I know that Ezra Greenspan came out of there, and Jim Holland. Jim has told several of us this story, that he was in the military. And when it ended, he thought he was going to go back and be an internist with Dr. Loeb at Columbia at the main hospital. Dr. Loeb called him, and told him there was no space. And why don't you go work at Francis Delafield? And apparently, Dr. Loeb said because somebody always gets mental problems or tuberculosis. And we have to replace them anyway. And so Holland went to Francis Delafield and took care of a young girl with leukemia who sadly died. But it changed his life. That's what made him go into oncology. I deeply regret that I won't get the interview Jim Holland. Yeah, Jim Holland was the first alumnus of that program of the Francis Delafield Hospital. And, yeah, 10 years before I went there. And Jim and I remained friends for many years. We had that friendship in common. Jim gave a-- he was an extremely articulate individual. And when Alfred Gellhorn died in 2007, he gave one of the most touching memorials in his honor. We actually interacted recently through various collaborations here in New York, with first, Jim Holland set up this New York gynecology/oncology group. He was kind of the leader in that, even though he was not involved in gynecology. But he loved to host a group-wide effort. And it happened to coalesce first in gynecologic oncology, because everybody-- they all loved Jim Holland, teaching the gynecologists, but chemotherapy in general. And he's a great leader. So he became very active in the Chemotherapy Foundation, which is a New York foundation, and spoke at the meetings. And his wife, Jenny Holland, was on the board of the Chemotherapy Foundation. We gave them-- we gave Jim an award last year in November, of the Chemotherapy Foundation, for scientific excellence. And he gave one the most unbelievable talks there. Everybody who was there, which were fellows from the New York institutions and lay audience that was there at that event, they really learned a lot by Jim's presence. And unfortunately-- unfortunately, two months later, Jimmy Holland passed away-- less than two months. And of course, Jim passed away in March of 2018. We all miss him. And any of us who had been to the Chemotherapy Foundation, especially when Dr. Greenspan was running it, I always loved that meeting. Actually, when you were at Francis Delafield, what was giving chemotherapy like? It can't be as well-organized. Well-- [LAUGHS] Well, it was organized in the lymphoma service, which John Altman ran. And I was-- so my fellowship at Francis Delafield, it was a bit unusual. It was six months of hematology, six months chief resident, six months again hematology/general oncology, then six months chief residency. So we were involved during the fellowship in running some of the-- and orchestrating the work for the medical residents. In our spare time, we did work in the clinics. And in hematology, I worked with Jon Altman. Did you guys mix up your own chemotherapy in those days? Oh, sure. Yes. Well, that went on when-- actually, that went on when I became attending here at New York University. When I came back from the NCI, we mixed the chemotherapy. So yes. Our younger colleagues don't know this. Nowadays, it's all the pharmacists do it. And the nurses hang it up and start the IVs. And in those days, you guys were on the front lines doing the whole thing, right? Yeah. I mean, we gave vinblastine primarily, but the clinic stereo was vinblastine that we gave. Because the other drugs were procarbazine, nitrogen mustard, of course. There is Chuck Martel of Mayo Clinic fame and florouracil fame. He said he used to do morning rounds to give florouracil at the Mayo Clinic. I don't know who mixed the florouracil for him. I mean, it came in already mixed. But he used to deliver the drugs. Life was different then. Actually, I want to change tracks a little bit, and that is because I know you had a lot to do with the development of supplying them when you were at CTEP at the NCI. You and I were fortunate enough to get to attend the 40th anniversary of the approval of cisplatinum by the FDA. It was held in east Lansing. And that's because Professor Barnett Rosenberg discovered it at Michigan State. Can you give me just some history of that, of what your role was, and why Dr. Rosenberg thought that cisplatinum was a good idea in the first place? Well, I mean, it goes of the drug development program, which was one of the major efforts of the chemotherapy program that was the first program that had oncology involved in it. It was mostly the team in lymphoma, with Gordon Zubrod being the head. And he's the one who recruited Fry/Frederick, and then Carbonne/DeVita group. And they were doing the clinical oncology part. Drug development was a very much part of it. And of the drugs that-- they developed drugs for some of the pharmaceutical industries because pharmaceutical industries had no trials. They had their own pipeline. Now their own pipeline had drugs like nitrosoureas, which didn't go anywhere, and dacarbazine. They were not so robust related to the screens that they used for drug development. But they also had drugs from academia and from the Department of Agriculture. And from academia, they got cisplatin, which was isolated by Barnett Rosenberg at Michigan State, as you heard in that great event that they had, the 40th anniversary of its approval. And he was running electrical currents in bacterial cultures and found that the bacteria were developing-- stopped dividing and developing filamentous forms, which were very unusual. And then he thought it was electricity at first, but then only platinum electrodes had that property. And he and his co-workers made the right assumption that it was platinum. They isolated cisdichlorodiamine dichloroplatinum which was known from a century before to be an inorganic platinum salt. That drug, when I was first at the NCI, my first tour duty as a senior investigator, was broadcasted because it had tremendous anti-tumor activity in the screens. And so when there were press releases, like it often happens, lay people call in and they want the drug for their relatives, or for themselves. And I remember answering phones and saying, no. We don't have that drug. It hasn't been given to people. But the story in 1972, the phase I study was-- I attended the ACR, where they presented. Chuck [? Kerlia, ?] from the University of Illinois, he did the first study. And it had activity. But it bumped off some kidneys and some hearing. And I said, well, who needs a drug in head and neck cancer, or Hodgkin's, where you have such terrible toxicities? Well, guess what? I was wrong. First, you deal with the cancer, then you deal with the toxicity. But it was Jim Holland. Actually, Higby, Don Higby, who worked with Jim Holland at the Roswell Park in the Holland service, who identified remarkable activity in testicular cancer. And that's what carried it. And then Larry Einhorn, of course, carried the ball on that on the development of cisplatin in testicular cancer. The group in the [INAUDIBLE] showed tremendous activity. Eve Wilshaw showed tremendous activity in ovarian cancer, but not quite curative, which is an interesting facet. And then, well, the rest is history. The FDA, that was my second time at the NCI. I had the pleasure of sitting with Vince DeVita at the FDA with Bob Kraut, who said, no, this drug is too toxic. You've got to do some randomized studies. And that was 1978 then. Vince pounded the table and said, the best thing that's happened to oncology, you can't recognize it? You know, there's something wrong with your procedures. So that led to some rethinking. And sure enough, it was approved. No need for randomized studies, given that it was curing testis cancer, but a need for educating how to deal with and cope with the toxicities. Actually, I have-- So that's the story of cisplatin. And it was even further detailed by-- when you were there at that meeting-- by Larry Einhorn and his patient. Yeah. Actually, I have three remarks to this. One is that when I was a fellow, Dr. Fry used to teach us that if the drug works and is curing cancer, we'll figure out the toxicities later. That's a little ruthless, but it's always stuck with me. Yeah. Yeah, we don't want to say it too loudly because toxicities are very important in anything you do. But of course, if you are-- you know, if it's the last resort you're looking for, for something to help the patient-- and it is helping-- you kind of have to bite the bullet sometimes. Those were the days where we had many cures anyway. The other thing that struck me at that meeting is cisplatinum is now used in more than half of all cancers-- adult cancers. I didn't realize it was that common. But that's true. The other thing that I didn't realize, that the number of publications continued in research, continued to increase more than imatinib and trastuzumab. Yeah. And that's the other thing I heard. And the final thing, just, if there are any chemists listening, to get lucky from all this-- it turns out, that trans-diaminoplatinum doesn't work, and cisdiamine does-- dichloro, I'm sorry. And the reason why is entry into the cells, is that the trans doesn't get in the cells. And the cis does. And it just goes to show how important that clinical chemistry is in our drug development. I think a lot of us forget that in the pharmacology. Right. There are actually a lot more things to learn in how the platins interact with DNA. Yes. Actually, another layer I want to go into is your importance and the really remarkable growth in the cooperative groups in the late '90s. Can you kind of give us a brief history starting in 1955, when Drs. Fry and Frederick and Holland started? And then what your role was later on in making it really take off? You're talking about the chemotherapy program? Well, weren't you involved with the qualitative groups and-- With our comparative groups, yeah. Oh, yeah, they came together. Yes, no, for sure. I was there first as an intramural person. And I was briefly on loan to the solid tumor service with Vince DeVita and George Canellos. And then I was in their new-- Paul Carbone had put me in the lung cancer study group there, that led on. So I was strictly intramural. When I returned to Einstein after to doing my service, Vince DeVita became the director of the Division of Cancer Treatment, which is the evolution of the chemotherapy program. As director of the division, he gave me a choice of couple of positions. And I actually took the cancer therapy program position as his associate director for CTEP. His predecessor had been-- my predecessor in that position had been Steve Carter. I don't know if you know about Stephen Carter. No, I met Dr. Carter. He was encyclopedic in the knowledge of all the trials that were done in the-- sponsored by the National Cancer Institute and also abroad. So he became a great face of the NCI internationally. And he spurred the development of the EORTC as well. So that was developed initially through a grant of the National Cancer Institute. So he was involved in the EORTC. But the cooperative groups had started during the leukemia program with the acute leukemia group B, which was the counterpart of acute leukemia group A, which was the intramural program. Jim Holland became the chair of the group. He was such an inspiring leader of the cooperative group. His cooperative group was amazing, to go to one of his meetings, which lasted two afternoons. He really commanded-- it was like a plenary session, and doled out all the projects in one afternoon. And then, in the second day, they kind of review whatever had developed. But other groups started. And the Eastern Cooperative Oncology Group became-- I had joined that when I had gone back to Einstein. It developed under founder Paul Carbone. He had assumed chairman-- no, Paul Carbone became the chairman later on. Initially, it was run by-- it'll come to me right now. I have a lapse on who was the group chair. But it was kind of Boston nurtured. And they were primarily devoted in solid tumors. And they started with making inroads into solid tumor beyond the acute leukemia. But in GI, for example, where I was in the GI committee, Chuck Martel did a number of studies. He ran those meetings, floated ideas. A week later-- we didn't have emails, but a week later, he had the protocol on your desk. Let me ask you a final question, to begin to tie it up here. When you were at the Delafield and then at the NCI, was there a sense that you guys were doing historic stuff? Or was it just day-to-day, same old, same old. Then you look back and say, boy, look what we did. Was there a sense that something big was happening in those days? Oh, no. There was always a sense. Well, when senior investigators, there was always a sense there are a lot of things here developing of interest, you know? And there was a full head of steam in part related to the combination chemotherapy. Now in acute leukemia, it was obvious. But the big thing about the solid tumor service since DeVita and Tom Fry, who started the work in lymphomas. Peter Wernick, George Canellos, they found that the combination chemotherapy did something in lymphomas, and also later on with, also, Jim Holland's work. And you've mentioned Ezra Greenspan. They had seen that combinations of drugs did help, to a large degree, breast cancer. Now the same drugs didn't tried to be extended-- the same principles-- to other solid tumors. It didn't work so well. But breast was somewhat sensitive to the drugs, the alkylating agents and the antimetabolites. So those were the first combinations, and the vinca alkaloids. Let me ask you this, my final question. But I've been a breast cancer guy all my life. And Cushman Haagensen, of course, is a giant. That's the name from the past. Yes. So when you were at Delafield, did he try to oppose the chemotherapy because he felt that a chance to cut is a chance to cure? I mean, he was one of the biggest knives of all time. Yes. Actually, no, he opposed it for different reasons. I never understood why. He didn't only oppose chemotherapy, he opposed hormone therapy, which was coming along. Because he thought that any sex hormones were detrimental to the course of disease. But it was also mostly rivalry with a medical service, I think. Because we saw responses. I did my first trial with progestational agents. So I did some clinical trials, actually, when I was a fellow. So we published an observational series of patients treated with medroxyprogesterone acetate, and presented at the American College of Physicians in '67. So you know, he opposed Gellhorn's intervention in breast cancer medical intervention. He liked to give steroids. And we used to see the patients because the patient developed diabetes. So that's how we got involved in some of the disseminate at the patients with metastatic breast cancer. He wouldn't refer them. So I got involved because I saw a lot of diabetes. And then we started our own treatments. We bonded with the patients and started our own treatments. Again, a recurring theme is how much courage it took for you and your predecessors to do what you do. And the confrontation, if not hostility, between the surgeons. I have to say, that what that really does is it brings up Bernie Fisher and Umberto Veronesi, and the courage they had to adopt systemic therapy as opposed to obstruct it. I don't think our younger colleagues are aware of the battle. Oh, yeah, no. Bernie deserves a lot of credit. And I can tell you of arguments he had with Jerry Urban and other surgeons when he came to a meeting in New York. And Sam Hellman was there. He said, Bernie, we agree with you. I think it's taken us some time to process what you just-- the great thing you have done, to rely on other than surgery. Because they came after him, even I'm talking early 1980. Oh, I was at a meeting. I was at a meeting maybe '83 or '4. It was the first time I'd ever met Dr. Fisher. And he and Urban were sharing a podium. I thought there was going to be a fistfight. Yes. I mean, it was really contentious. And that was an eye-opener for me, where I thought, there's a surgeon up there telling us we should do things that will put him out of business. That's a very interesting approach. Well, yes. And the one thing about Bernie Fisher, he understood trials. And I remember, they said-- Jerry Urban said, why do you think that that curve isn't just going to go down and plummet? He said, it's called probability, Doctor. [CHUCKLES] All right. Well, we've run out of time. I hate to say that because these are great stories. But I want to thank you for taking time. Thank you, Dan, for the interview, for sure. And we do share some common background. And we didn't get to talk about all the international things that came out of the National Cancer Institute. As Jim Holland said in that congressional hearing, the National Cancer Institute was the best international weapon we have had. Yeah, I think that's a great point. And I do regret we've run out of time here. Maybe we can do that in another interview. But I want to also thank you for all you've done for the field and the hundreds of people you've trained. I don't go anywhere where I don't bring up your name, and somebody goes, oh, yeah. I worked with that guy. Well, that's a motive a great satisfaction, I have to say, for sure. It takes just the ability to listen to what your fellows are saying and responding to them. Yeah. That's been my secret. And you're very good at that. I've seen you in action. So thanks again. I appreciate this, and look forward to seeing you soon. Thank you, Dan. I appreciate very much all your questions, and your interview, and your friendship. [MUSIC PLAYING] Until next time, thank you for listening to this JCO's Cancer Stories, the Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or a review on Apple Podcast, or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories, the Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.asco.org. [MUSIC PLAYING]

One oncologist provides his take on responding to "compassionate use" requests

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.

[DR. LIDIA SCHAPIRA] 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.

[GREG GUTHRIE] "Compassion and Compassionate Use," by David J. Einstein. The email came down to this. This patient is running out of options, and he and his family are starting to think outside the box. Two months prior, the sender was my co-fellow. Now, after a blissful vacation month entirely unplugged from oncology, he and I were junior attending physicians, launched into the dual frontlines of inpatient and outpatient oncology.

He was staffing the consult service, I the inpatient oncology service, both of us simultaneously trying to keep our backburner outpatient clinics and research projects from boiling over. He was letting me know about my newest admission, a patient with advanced choriocarcinoma, which was ostensibly within my area of expertise of genitourinary cancers.

During years of residency training, we had learned to eyeball patients and differentiate sick from not sick-- or really, those who might be imminently dying from those who were OK for now. As oncology fellows, we recognized a new group-- the patients who seemed to be imminently dying on paper, but in person looked amazingly normal. The patient referred to in the email was such a patient-- an energetic engineer in his 50's, with a more than slight Boston accent, despite his years in California and Texas, and plenty of Red Sox gear to match.

On paper, he was in dire shape, with treatment-resistant advanced cancer and increasing toxicities of treatment. The patient and this family had taken on his disease with a battle mentality that works for some and makes others cringe. After multiple rounds of chemotherapy, resections, and radiation treatments failed to cure his disease, he moved on to the high-dose chemotherapy with autologous stem cell rescue that is the standard of care in this setting. If some chemotherapy is good, more is better.

However, he eventually exhausted his supply of stem cells, still without having achieved remission. Time to think outside the box, turning to his identical twin brother as a source of new stem cells. The patient proceeded to a last-ditch effort at high-dose chemotherapy, this time with syngeneic transplantation. It worked, for approximately three months.

Despite the most intensive efforts, his disease kept bouncing back. At this point, it was clear that chemotherapy would only transiently suppress his cancer, but not cure it. Meanwhile, his treatments left him with hearing loss severe enough to require hearing aids, poor kidney function, foot numbness, and bone marrow that, even on imaging, looked exhausted, plus prolonged cytopenias to prove it. What could be done?

This patient and his family had crossed the country in search of an outside the box treatment that might offer him the benefit that stand treatments had not. We are used to patients looking online for new diets and complementary medicines. We understand that this is a way to seek an active part in their care, when they otherwise feel like passive recipients.

The patient and his family had gone further, identifying a clinical trial available at our hospital that they desperately wanted to join. But the trial was in a different tumor type. And moreover, he would not be a candidate for any of the trial, given his accumulated treatment-related toxicities.

Undaunted, his sister found an online poster from our peer institution across the street, describing a novel compound used to treat a patient with his disease, with the resulting and seemingly miraculous remission. Again, we are accustomed to the patient who brings in the latest online research to an appointment. Sometimes it is not scientifically valid. Sometimes it is valid, but not applicable to the situation. And occasionally, it is both valid and applicable, and actually does result in a treatment change.

As I scrutinized the information the patient's sister provided, it actually seemed both possibly valid and applicable. I could find no obvious toxicity that precluded use of this drug. And yet, it was early in testing, far from full approval. "What about compassionate use?" the family asked.

Compassionate use was a term I had only heard spoken of dismissively. We oncologists prided ourselves on always being compassionate, whether we were administering therapies or stopping them. Treating outside of standard care without the structure of a research study is dangerous territory.

But this concept has a popular appeal. Who wouldn't want to try anything that could help in a desperate situation? Recently, proponents of so-called "right to try" legislation claimed that the Food and Drug Administration, or FDA, regulation was interfering with patients' access to experimental therapies outside of trials. The FDA replied that they approved 99% of expanded access requests.

Indeed, compared with the regulatory hurdles I faced from my own institution, I discovered that the FDA was the smallest barrier of all. As I learned, creating a single-patient investigational new drug application for compassionate use was the ultimate in personalized medicine-- a clinical trial created for one person. In fact, it was a desperate hope thrown into the slow-moving and opaque gears of our clinical research regulation, only to be chewed into a million track changes documents and flurries of emails.

I was rapidly assembling a trial protocol to use highly experimental therapy into patients whose disease was bound to cause suffocation or bleeding at any moment. It was a terrifying, anxiety-provoking situation for a physician, patient, and family alike. I felt caught between-- on the one side an eager and aggressive patient who wanted to sign anything, cover any cost, just to have a shot at a miracle, and on the other side, a process purposefully built to be as cautious as possible. I caught myself erupting in frustration, unfairly lashing out at the secretary who emailed me with Institutional Review Board, or IRB, edits on an informed consent form that the patient would never read.

Just as we were getting ready to sign this consent form, the patient's disease was making itself more plainly visible in the form of a bleeding superficial metastasis. Now, another regulatory catastrophe-- between the bleeding lesion and the need for radiation, he was ineligible for the trial because of the strictly-worded inclusion criteria used in the rigid old protocol. Time for yet another urgent amendment pleading for the IRB not to hold me to the rules that I myself had provided.

When, after months of work, the patient received a single dose of the study treatment, we all felt like we had climbed Everest. All along the way, I tried to frame this as a victory in and of itself, hoping he would die feeling he had tried everything. But he, of course, wanted to live, through sheer will and perseverance. And I'll admit, a small portion of me wanted to prove my doubts wrong, to be the junior attending daring enough to try something audacious and land a huge unconventional win.

It was not to be. After many tense clinic appointments and late-night calls during my drive home, our last conversations unfortunately occurred in the intensive care unit. With the rush of the high flu nasal cannula as background white noise, I told the patient that his disease was not even responding to the chemotherapy I had tried a week ago in an ultra last-ditch effort to get him back to the study drug.

I could not pull him back from the edge of that ultimate cliff. Although I had tried hard to have the appropriate discussions with the patient and his family on many occasions, trying to refocus their hopes on spending good time together, freedom from pain and breathlessness, and another day outside the infusion area and the oncology ward, I knew they felt I had failed them, that maybe pushing just a little harder would have made the difference. One morning, I awoke to an email from the intensive care unit resident, letting me know that the patient had died that night. Thankfully, we had agreed that aggressive interventions in his dying moments would be even less effective than our chemotherapies. And instead, he had received much more effective supportive care. I let out a breath of simultaneous relief and regret.

I knew this moment had been coming, of course. I disagreed with my patient and his family about how to prepare for it. But my team and I had tried to make the patient and his family feel that every effort had been made on his behalf. I felt the failure, not in his inevitable death, but in never arriving at a moment of shared celebration for our combined efforts, when we could say together, even in that intensive care unit room, it was all worth it.

And when I went to contact his wife and sister, I never heard from them again. I certainly do not fault them for not returning my calls or emails during the midst of intense grief. Yet I never heard whether they felt that our compassionate use of a single dose of experimental treatment had helped or hurt. He went from being my all-consuming focus to a vanished spirit. And I had to wonder whether the family's silence gave me my answer.

The recent right to try legislation cleared the US Senate last year and the House of Representatives in March alone mostly partisan lines. Opponents, including representatives from the American Society of Clinical Oncology, as well as the American Cancer Society, pointed out the value of FDA oversight and the existing pathway for access to experimental therapies outside of clinical trials. Regardless of the fact that this legislation does not affect the institutional barriers I encountered, I do wonder whether it will inspire a growing number of desperate patients to exercise their right to try.

How should oncologists respond? Except in the cases of a drug that seems to have particularly exciting preclinical justification or early clinical data, I suspect most will advise their patients with advanced cancer to stick to more trodden territory, to try accepted anticancer therapies when they are judged to be reasonable and to switch to supportive care alone when the risk seems to outweigh the benefit, individualized to patient preferences. As we continue to chase progress in cancer, Wachter recently wrote, let's be sure that we don't rob dying patients of a smaller, more subtle miracle: a death with dignity and grace, relatively free from pain and discomfort. But there will always be the patients like mine: unsatisfied to do nothing, as much as we try to reinforce that intensive supportive care is far from nothing.

I recall the words of another oncologist who had seen the patient for a second opinion. These patients with refractory testicular cancer die with the chemo going in, chemotherapy, or perhaps increasingly, experimental drugs. If we are to routinely offer such patients access to experimental drugs outside of clinical trials, then we will need to address several issues in advance.

First, federal and local regulatory burdens will have to be substantially lower. We will need to simplify the process of writing a protocol, obtaining a IRB approval, and amending the protocol as clinical circumstances evolve. As a word of advice, oncologists embarking on such a process should be careful about recycling protocols written for standard trials. In particular, because these protocols are designed around a specific patient, the inclusion and exclusion criteria should be minimal.

Second, directors of clinical trial programs will have to decide whether their operations are capable of diverting resources from standard trials to these urgent and unfunded projects. Finally and most importantly, individual clinicians will have to develop strong end-of-life communication skills to help frame a shared decision-making process properly. And they may even have to make especially difficult decisions about when to exercise a right to deny such requests.

I hope that all of my patients will feel that I have treated them compassionately and with the tools best suited to their situation, whether or not this includes compassionate use of unproven therapies. And I hope that my patient did indeed feel that we left no stone unturned and that he felt some small satisfaction in this.

[DR. LIDIA SCHAPIRA] Welcome to Cancer Stories. I'm Lidia Schapira, editorial consultant for the Journal of Clinical Oncology's Art of Oncology, and the host for this podcast. My guest today is Dr. David Einstein, a medical oncologist at Beth Israel Deaconess Medical Center in Boston and an instructor at Harvard Medical School. Dr. Einstein is the author of "Compassion and Compassionate Use."

David, welcome to our program.

[DR. DAVID EINSTEIN] Well, thanks so much for having me. It's a real honor.

[DR. LIDIA SCHAPIRA] It's terrific to have you. Tell me a little bit about your writing. Have you always been a writer?

[DR. DAVID EINSTEIN] Yeah, actually this goes back to my intern year, oddly enough, when I was signing out a patient to the night float intern. And I was telling the story of what had happened that day. And the night float intern told me, wow, that's a really interesting story. And that was the first time I had ever thought of translating what I did on a daily basis onto paper. And that was a very moving experience, which I'm happy to share, as well.

But that sort of got me started about reflecting on patients and key moments in my medical practice. And now, all these years later, and being a first-year attending, I'm on a similar learning curve. And I wanted to, again, take an opportunity to step back and reflect on what it was that I was doing.

[DR. LIDIA SCHAPIRA] And can you tell the listeners a little bit of what that reflecting process is like for you?

[DR. DAVID EINSTEIN] Yeah. So I think that, a lot of times, these things seem to pop up at unexpected times, so on the commute home or the shower in the morning. And it's sort of these nagging thoughts that just keep coming into your head. And eventually, they've been bouncing around for long enough that you feel the need to actually put that down on paper and reflect on what it is that your mind's trying to work out.

[DR. LIDIA SCHAPIRA] And do you have a writing group, or is this pretty much a solitary activity for you?

[DR. DAVID EINSTEIN] I'd say fairly solitary. But oftentimes, it's sparked by discussions with colleagues. And then also, once I've actually put something down on paper, I very much solicit colleagues' input, just as I would for any kind of difficult medical case or difficult psychosocial case. And so on everything that I've written, I've always tried to circulate it among a couple of trusted colleagues for their input, as well.

[DR. LIDIA SCHAPIRA] And so if this was, perhaps, sparked by a difficult clinical scenario, can you tell us a little bit about what made this particular case so challenging and difficult for you?

[DR. DAVID EINSTEIN] Yeah. I think that, early on in elementary school, we're sort of taught that stories are conflict and resolution. And the really unique thing about this situation was that there were a variety of conflicts and really very little resolution. And that, I think, was what made it keep recurring in my mind as something that I really felt the need to reflect on.

[DR. LIDIA SCHAPIRA] Tell us a little bit about this patient and how you were drawn in in his very desperate fight and his wish to have a shot at a miracle.

[DR. DAVID EINSTEIN] Yeah, so again, this was early on in my attending career. So you've got all sorts of your own anxieties anyway about staffing an inpatient service and keeping an outpatient clinic going and starting up research projects. And as I'm starting, I hear from my colleague about this very sick gentleman. But I go in to meet him, and he looks like an ordinary guy off the street. And it was sort of hard to reconcile those two things at first.

And he always traveled as a group. He had this whole support team that had been with him through everything. So his wife was always bedside. She was a high school sweetheart. And his sister was always bedside, and she was actually a biotech lawyer. And he was an engineer.

And I think, especially between the lawyer and the engineer, they had a very go-getter attitude. They did their own research. They came up with treatment plans. They really were extremely thoughtful people, and also, in a sense, very aggressive people to have pushed through everything that he had already been through even before I met him.

[DR. LIDIA SCHAPIRA] And that resonated with you, as well, right, the idea that, here is somebody who has done all of this research and put in this incredible effort. And then what happened?

[DR. DAVID EINSTEIN] Right. So it's not so dissimilar from what we as physicians do, and I very much respected their efforts. They came to us, clearly, after all standard treatments, and even some non-standard treatments, had not gotten the hoped for result of a cure. And that's one of the things that makes testis cancer so difficult, of course, is that, we aim for cure so much of the time. And those times where we fail or the disease overwhelms us, that's that much harder to prepare for. And so I started looking over other palliative chemotherapy regimens and the toxicities and the relative benefits and response rates of all of these. And the more I thought about it, the more I thought, what is this a bridge to? What am I trying to get out of any of this?

And with them, I started to explore the ideas of targeted therapy, which we've heard so much about, and immune therapies, which he had actually already tried. And we got to that point where I was saying, there is no treatment, no matter how efficacious, that's going to work with what I see in front of me, with all these toxicities. And they processed that.

But they came back, and after doing a little more research, came up with this case report from just across the street, about a patient with a similar disease getting some long-term response out of an experimental drug, which had completed Phase 1 testing. And so they said, how do we get this? And I looked through the traditional routes of trying to get him on trial or trying to get exceptions. And the more I looked, the more I ran into roadblocks.

And eventually, they asked me about this compassionate use concept, which I had heard only vaguely about, and certainly no personal experience with that. And as I started asking around among my colleagues, I found out that, really, very few people have much experience with this, other than one other at our institution. And so it really was sort of reinventing the wheel, as far as treatment protocol.

[DR. LIDIA SCHAPIRA] It sounds like this gentlemen, if we are to sort of give a title to this scenario, is one of those, as you say, engaging people who is a fighter, but for whom death is really not an option. Am I right in saying that, that they just would not have that conversation with you? They were really searching for something that could be done, an action solution to this problem.

[DR. DAVID EINSTEIN] Right. They were very intelligent people. They knew that he was in a dire situation. I try to use the word death and dying in my conversations to be as clear as possible. And they weren't able to process that and talk about that. But it was very clear that this was not the kind of patient who would feel comfortable going home and focusing on symptoms.

And in a sense, there wasn't much to focus on, until the end really came. Because with these diseases, they just progress so rapidly. And so for him, he very clearly was on the side of, I would rather die in a hospital with treatment toxicity, even if none of that stuff helped me, rather than-- if you can't tell me that any of these treatments are going to help, then I'd rather not be here. Which I would say a good 3/4 of my patients are a little bit more in the latter camp.

And there's a point at which everyone sort of feels like, let's do whatever is in our power to work on the symptoms of your disease and stop assaulting you with therapies that might not help and could certainly hurt. He was very clearly on the polar opposite end of that spectrum. And for him, I think, a little bit of his engineering personality, it was important to think up a new way of treating this disease, and to go for that incredibly slim shot of a long-term remission, however slim that might be.

[DR. LIDIA SCHAPIRA] That's so interesting. So you bring in his profession as an engineer. He was probably a problem-solver. And as you say, at the moment you met, he didn't have symptoms, really, to palliate. And he was as prepared as he could be for what was likely going to come next. But you use the word 'compassion' in your title, and I want to bring you back to this a little bit.

What did you feel in the role as his physician? And I wonder if, as thoughtful as you are in your approach to your patient, if you wondered, if he had a long-term relationship, perhaps, with another physician along the way, or how could you give him what he needed, even if it wasn't exactly what he wanted?

[DR. DAVID EINSTEIN] Mm-hmm, yeah. It's really tough coming in at that kind of position, of course. He had a very, very solid relationship with this previous oncologist in a different state, also at a tertiary care academic center. So he was very used to working with that individual and had that trust built up. I'm meeting him, of course, in the worst possible scenario, when he's already gone through everything that we would normally try and even some more off-the-beaten-path treatments.

So it's definitely difficult to meet somebody in that position, to gain trust, to build a rapport, to have a long-term relationship to work off of, before you start launching into really difficult end-of-life decision-making, and all the particulars of trying to do what we did, which involves a myriad of details and logistics. And so communicating all of those things, we really had to have this incredibly intense time together to start working on all these things as a shared group.

And I think, all along, I felt that I really wanted to emphasize that we were all on the same team. I didn't want him feeling like he had come to me, and that I was in any way shooting down his dreams or not offering anything, from an oncology standpoint. And so time and time again, I really emphasized the fact that, whatever my recommendations are, let's make it about what makes sense for you and what makes sense for your disease, that our common enemy here is the cancer. And that whatever happens, that needs to be the focus.

So the focus should not be on the details so much, as how those details get us to the big picture plan. So I think that I really identified with this urge to research and his urge to come up with novel mechanisms. That's what we do as oncologists all the time.

But I also had a little bit of trouble getting to understand a guy who was so clearly focused on being in hospital and receiving treatments, even in the situation where I think most of us would feel very uncomfortable with that idea. And so building that understanding took longer, and I think, ultimately, led to a little bit of misunderstanding as things went on.

[DR. LIDIA SCHAPIRA] As we about the end, first of all, it sounds like, for you, this felt like climbing Everest. And that's what you say in your essay, and that you certainly were deeply engaged in an active relationship. And then the treatment doesn't work, and he dies. He dies, fortunately, without an aggressive attempt at resuscitation. But then the end leaves you, I think, with a bit of a sour taste, in that there is no final parting with the family or expression of gratitude. Tell us a little bit about how you felt about that and how you've managed to think about it, with a little bit more time.

[DR. DAVID EINSTEIN] Yeah, so all along this process, there were really just so many hurdles, quite a large team that I was working with. And a lot of people expressing doubts and frustrations of their own about how much work this was and how quickly it all had to happen. So I pushed through those things as much as I could.

And I explained everything that was going on behind the scenes to the patient and his family. And I wanted them not to bend over backwards and thank us for all these efforts. I think it was much more important that he just feel like he had some degree of control and understanding of the situation in an otherwise very out of control situation.

So as we got to the end, we had some, obviously, very serious conversations in the ICU and, ultimately, worked on how to plan for his survivors and how to treat symptoms at the end. And we had such an incredibly intense relationship this entire time, where we were constantly in phone and email touch about all of these hurdles that we worked through together. And when you get that email in the morning, saying your patient died overnight, of course, I rushed into the hospital, tried to see if anyone's still around. But by that point, everyone had gone home.

And I was actually never able to make contact with them again. I usually like to give a family a couple of days, of course, since it's such an intense time. And I did my best to reach out and leave it very open-ended, that I would love to talk if it made any sense to them, but certainly no pressure. But really what I wanted to reconnect with them about was this incredibly intense experience and how they perceived that that might have helped or not helped him feel like he had been well cared for at the end of his illness. And it's very odd, as the physician, to go from an intense relationship to 0 relationship. And it makes it, I think, a little bit tougher as you go forward to say, was I doing right by this patient? What should I learn for the next experience?

[DR. LIDIA SCHAPIRA] David, that was of a beautiful summary. And I'm sorry we need to end it there. We could go on talking so much longer. Thank you for sending the essay. That was Dr. David Einstein, sharing his thoughts on his essay, "Compassion and Compassionate Use."

Join me next time for another conversation 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're there, be sure to subscribe so you never miss an episode of JCO's Cancer Stories-- The Art of Oncology podcast. This is just one of many of ASCO's podcasts. You can find all of the shows at podcast.asco.org.

Dr. Hayes interviews Dr. Freireich on his involvement with combination chemotherapy.

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. Welcome to JCO's Cancer Stories, the Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org. Welcome to Cancer Stories. I'm Dr. Daniel Hayes. I'm a medical oncologist and a translational researcher at the University of Michigan Rogel Cancer Center. And I've also had the privilege of being the past president of the American Society of Clinical Oncology. I'm privileged to be your host for a series of podcast interviews with the people who founded our field. Over the last 40 years, I've been fortunate to have been trained, mentored, and also, frankly, inspired by these pioneers. In fact, it's my hope that, through these conversations, we can all be equally inspired by gaining an appreciation of the courage, the vision, and the scientific understanding that led these men and women to establish the field of clinical cancer care over the last 70 years. In fact, by understanding how we got to the present and what we now consider normal in oncology, we can also imagine, and we can work together towards a better future for our patients and their families during and after cancer treatment. Today, my guest on this podcast is Dr. Emil J. Freireich, who is generally considered one of the pioneers of combination chemotherapy. Dr. Freireich is currently the Ruth Harriet Haynesworth chair and distinguished teaching professor in the Department of Leukemia at the Division of Cancer Medicine at MD Anderson Cancer Center in Houston. He was raised in Chicago during the Great Depression, the son of Hungarian immigrants. Dr. Freireich attended the University of Illinois College of Medicine in Chicago starting, unbelievably, at age 16. And from there, he also received a medical degree in 1949. He completed his internship at Cook County Hospital and his residency at Presbyterian Hospital in Chicago. He then moved to Boston, where he studied hematology with Dr. Joseph Ross at Mass. General. And then he went to the NIH in 1955, where he stayed until he moved to MD Anderson a decade later. And there he still remains. He and his colleagues at the National Cancer Institute, Drs. Jim Holland and Emil "Tom" Frei, were the first to demonstrate that administering concurrent combination chemotherapy, rather than giving it sequentially with each episode of disease progression, resulted in complete responses in childhood acute lymphocytic leukemia. And that paper was first published in the now classic paper in Blood in 1958. In the mid-1960s, they ultimately developed the VAMP regimen. And that was reported in 1965, with really, in my opinion, the first cures that we'd seen with chemotherapy in an advanced cancer of any sort. This work was the groundbreaking basis for the subsequent cures of advanced Hodgkin's disease, non-Hodgkin's lymphomas, adult leukemias, testicular cancer, and, in my opinion, the striking results of adjuvant combination chemotherapy in breast and many other cancers. Dr. Freireich has authored over 500 peer-reviewed papers, numerous reviews and editorials. He's edited 16 different textbooks. And he's won too many awards and honors for me to even begin to list. But in particular in 1972, he received the Lasker Award, America's most highly regarded medical honor. And most importantly to me, frankly, is that he proceeded me as president of ASCO in 1980 to 1981. Dr. Freireich, I'm sorry for the long introduction. But your career is pretty substantial. Welcome to our program. Thank you. I have a number of questions. And to start with, I know, as I said, you grew up in Chicago during the depression and that you entered college at the age of 16. And I think our listeners would love to hear more about those circumstances. That's pretty unusual. And I've actually read about some of your childhood. You want to tell us more about that and how was it you chose medicine in the first place? I was born 1927 of to immigrant Hungarians. I had an older sister three years older. And they had a Hungarian restaurant in Chicago. And 1929, when I was two years old, there was a big event in the United States. They lost their restaurant. My father died suddenly, I believe of suicide, but not proven. And my mother, tough mother, went to work in a sweatshop. She worked 20 hours a day. She had two children. She found an Irish lady who worked for room and board only, no salary. Her name was Mary. So Mary was my ex officio mother. And I grew up, as you pointed out, in a ghetto community. I spent my life stealing things, hubcaps and windshield wipers, and avoiding getting crushed by the roving gangs. When I finished elementary school and when I went to a ghetto high school called Tuley, T-U-L-E-Y. In Tuley High School, I majored in typing and shorthand. My mother thought I could make a living as a secretary. I was prepubescent, short and fat. And I was a frequent victim of my colleagues in school. When I was very young, I can't tell you when, about eight or so, I developed tonsillitis. And we had in our little ghetto community one of these Tree Grows in Brooklyn physicians. His name was Dr. Rosenblum. And he took care of people in the ghetto for favors. My mother made him goulash. Dr. Rosenblum came to your house. He didn't have an office, because we didn't have any transportation. So my mother called him. And I had tonsillitis. He came and looked to me. He was wearing a suit and tie. I'd never seen that. During the depression, all the men wore coveralls and dirty pants. And he looks very elegant. He had a suit and a tie. He looked in my throat, and he said to my mother, the treatment for tonsillitis is ice cream. I always remember Dr. Rosenblum, because my mother had to go out and buy ice scream. And it's not bad treatment. It actually cools off the hot throat. So when I went to high school, taking shorthand and typing and getting beaten up by the bigger guys, a professor appeared like Dr. Rosenblum, suit and tie, young guy, PhD. Came to a ghetto high school to teach physics. Physics fascinated me. So I worked very hard in physics. He had a contest. I did a project on the Bernoulli theorem. And the classic project is a jet of water. You put a ping pong ball in it. And the ping pong ball stays in the jet, amazingly. That was because of Bernoulli. What happens when the ping pong ball goes off to one side, the fluid goes faster on the other side. It reduces the pressure, and that pushes it back in the stream. And that's the principle of airplanes and so on and so forth. So I won first prize. And he called me to his office. He said, Mr. Freireich, you should go to college. I said, what's college? He said, well, there's-- [LAUGHTER] He said there's a place down south of here called the University of Illinois where you can get advanced studies. What do you want to be when you grow up? So I thought a minute, and I said, I want to be like Dr. Rosenblum. I want to be a family doctor. He said, well, you have to go to college first. So I said, what do I need to go to college? He said you need about $25, which in that day was a lot of money. So I went home, and I told if it was my mother, my professor wants me to go to college. And I need $25. My mother, she's hardened in the depression, working in sweatshops. And she said, OK, I'm going to get $25. She asked around in the little Hungarian ghetto community. And we found a lady who had lost her husband and had an insurance policy. And so she had money. And she distributed it to her colleagues in the ghetto community for good causes, wonderful lady. So my mother dressed me up in a borrowed suit. And we went to see Mrs. so-and-so. And she patted my head and gave my mother $25. It's an incredible story. In fact, I'm struck by the fact that one of the founders of our field was a juvenile delinquent stealing hubcaps. Oh, yeah. I did that to hubcaps and windshield wipers and everything you could take off a car. I got a ticket on the Illinois Central Railroad, $6. I got off the Champaign-Urbana. And I said to the guy, where's the university? He said, over there. I went over there. I said, where do you register. They said, over there. So I went over there. And I said, I'm Freireich, and I'm registering for college. The guy said, where's your transcript. I said, well, they told me at the high school that they would send everything they needed. He said, we've never had a student from Tuley High School. I was the first to go. I was the first Tuley student to go to college. And he said, OK, I'll register you. And I'll write the university, and I'll get your transcript. I presume you're qualified. So how much is registration? $6! So I'm down to $13. I'm getting pretty poor. So I registered. And then I said, where do I live? He said, there's a list over there. And I went over there. I found the lady who lost her husband. She rented his bedroom for $6. And then I had to figure out how to eat. And I asked my friend the registrar, where do I eat? He said, go to work in one of these rich sorority houses. You get free meals. So I waited tables in a sorority house. I got good grades. When I had to elect a language, I took German, because at that time, all the science was in the Festschrift. The Germans had invented the chemical industry. And my advisor said, that's good for you if you want to be a doctor. So I took German. My professor in German, he taught stage German. And he read the role the first day. And he came to my name and he said Freireich, [EXAGGERATING "CH" SOUND] because, he said, Americans can't say. [EXAGGERATED "CH" SOUND] Everybody called me "Freireish." But he called me Freireich [EXAGGERATING "CH" SOUND]. And our book was called, Ich lerne Deutsch, I'm learning German. So "ich" was important. Freireich was important. I got an A in German because of my great name. And I did well in physics. And everything was accelerated during the war. So the university had three semesters a year instead of two. There was no summer. And the requirements for medical school were dropped from three years to two years. So two years is four semesters. So at the end of the first year, I was eligible for medical school. And my physics professor said, you better apply, because all the guys coming out of the military want to be doctors. So I said, aw, damn, I'm having such a good time scrubbing floors and smoking and getting along with good looking girls. He said, you better do it. So I applied. And I was accepted. So I had to leave the beautiful campus of Champaign-Urbana and go back to the ghetto of Chicago where my mother and my sister were living. And I couldn't figure out where I was going to get the money to pay for medical school. I had a friend who had had polio. Polio was rampant in those days. And I said to him, how do you get money to go to college? He said he gets money from the state, rehabilitation. And he said my rehab guy is coming to see me tomorrow. Why don't you come and see if you're eligible? So the rehab guy came. He said, what's wrong with you, Freireich? I said, I had a broken leg in college. He said, OK, fill in the forms. And I became a ward of the state of Illinois Department of Rehabilitation. From that point on, they paid all my tuition, all my supplies, all my microscope rentals, and so on. So I went to medical school free thanks to the State of Illinois Department of rehabilitation. So I went to Chicago. And a bunch of us sat in the room for the opening introduction. And the dean of the medical school came in. His name was Andrew C Ivey. I don't know if you know the name, famous GI physiologist. And Dr. Ivey said, you guys are lucky to be in medical school. There were 20 applicants for everyone accepted, 20. Isn't that's amazing? Because all the guys who were medics in the military realized that being a doctor is a soft job. So they all wanted to be doctors. But they didn't have as good an academic career as I did. So anyhow, I went to medical school. I did pretty well. It was complicated, medical school. I had to ride the L in Chicago. It cost a nickel. And I lived at home. And I rode the L in the morning. And I walked to the university campus. I attended classes. I walked to the L. And I went back home. And I did that for four years. And then, as I said, I graduated number six in the class. And I graduated. And I had to decide where to do an intern. I wanted to be a family doctor like Dr. Rosenblum. So I interned at Cook County Hospital. Cook County Hospital was an abattoir, terrible place. In that year, 1949, the two most prominent diseases were tuberculosis and polio. So my first rotation was the TB ward. That was horrible what you had to do to those men. 90% of them died. Then my next rotation was infectious diseases. And that was all children in iron lungs who were doomed to die. So I started off pretty badly. And then I got to the good things like surgery. I delivered a hundred babies. I did the ear, nose and throat. So I did everything. And I felt ready to go into practice. And then I got to internal medicine. Internal medicine was not like OB and all that stuff, not mechanical. It was intellectual. You had the worry about the blood flow to the kidney. And you had to get diuretics and blood and stuff. So internal medicine fascinated me. When I was on-call, I would admit 20 new patients a night, 20. And one guy I admitted was very interesting. He was a learned guy. And he was dying of heart failure. And I had to figure out how to treat him. And I admitted him. And when I got done, exhausted in the morning, I went to make rounds. And I didn't see him. And I said to the nurse, where's Mr. so-and-so. She said, don't worry about him. He's gone. I said, where did he go. She said he goes into the death room. Cook County Hospital, the problem was they had too many patients for the beds. And the head nurse made rounds every day. And the sickest patients went to the death room. And I went in there. And I found my patient. And I said to the nurse, I want my patient on the ward. I'm a young squirt. How old was I? I was 19, I think. So the next day, I get a call from the hospital director. He says, Freireich, I think you better leave County. I said, what do you mean? I'm having a good time. I'm learning everything. He said, you don't know how we operate. The nurses run the ward. And you make trouble. And that means you've got to leave. Uh-oh. So I said, well, the only thing I can do is get a residency in medicine and learn all this complicated stuff. So next door was Presbyterian Hospital, which had the Rush Clinic. Have you heard the rush clinic? They were a bunch of famous guys. I made rounds with Roland Woodyatt, the first physician in the United States to use insulin. I made rounds with-- I forgot the name of the cardiologist who described coronary artery disease. He was the first to recognize the association between chest pain and myocardial infarction. So these guys were great. And Olie Poll, who taught me EKG-- And I was going along fine. But again, the chair of medicine was a Harvard import, S Howard Armstrong. And he had a teaching service. And all the house staff wanted to be on the teaching service where they learned stuff. Private doctors, of course, were offended. So they descended on administration. And they fired the chair of medicine. Armstrong was fired. The house staff teaching service was disbanded. And Armstrong tried to tend to his house. He called me in. He said, Freireich, what do you know about medicine? I said, Dr. Armstrong, you got a wonderful department. I learned EKG. I learned diabetes. I learned heart. I learned everything. The only thing I don't know anything about is hematology, because the guy who teaches hematology is a jerk. Armstrong said, don't worry, Freireich. Go to Boston, that's where the new medicine is coming from Europe. And he gave me letters to the three great hematologists in Boston, Bill Dameshek, Joe Ross, and Dr. Israel, who was a clotter. So I took everything I owned. I put it in my 1946 fastback, broken down Oldsmobile. And I drove to Boston. When I got to Boston, I met Dr. Ross. The guy in the lab who was the chief was so Stuart Finch. I think he just retired. And I collaborated with a young man named Aaron Miller who worked at the VA hospital. And my project funded. Dameshek gave me a job but no money. Israel gave me a job, no money. Ross gave me a job and paid me $5,000 a year, wonderful. So I became a hematologist. I worked on the mechanism of the anemia of inflammation. I studied patients with rheumatoid arthritis. And we had radioisotopes. So I was able to study the iron metabolism and the binding to transferrant. And we did experiments in dogs. And we worked out the mechanism of the anemia. The biggest hematology group in the country, the Wintrobe group, who wrote the textbook, had proven that the anemia of inflammation was due to a failure to incorporate iron into heme. And we found that that was false. When we put the ion on transferrant, it went right into heme. The difficulty was the reutilization of iron from hemoglobin to new heme. And we proved that in dogs. We did experiments with turpentine abcesses in dogs. So I was on a roll. I was doing Nobel laureate stuff. I mean, I gave a paper to the AAP. I gave a paper to the ASCI. I was doing well. And one day I got a letter. You are drafted into the army as a private. If you don't want to be a private, you can become a second lieutenant if you accept the assignment we give you. So I told Ross, I'm leaving. I got to go. I tried to finish up all my experiments. I told my wife we're in trouble. We didn't know what we'd do. We had one baby, one-year-old. She was pregnant with our second child. I didn't tell you the story about my wife. What happened is the head nurse in the clinic, like me, she came for a visit to Boston. They broke into my car and stole her luggage. And so we became attached. And we got married. And we've been married 65 years. But anyhow, she got a job at Mass. General. I had a job at Mass. Memorial. We had enough money to live. And as I say, she got pregnant, and we had babies. And I got this letter that I'm drafted. So I said to my wife, we have to go to the Army. The next morning, I get a call from Chester Scott. Keefer, who you already mentioned-- Dr. Keefer was the physician in charge of the penicillin distribution during the war. He was a very famous infectious disease doctor. He was a brilliant teacher and respected and loved by everybody. When Eisenhower was elected president, as you probably know, like all Republicans, he wanted to decrease the size of the government. So he decided to combine three cabinet departments, Health, Education, and Welfare, into one. That was obviously going to save positions and money. And he appointed Oveta Culp Hobby, who was the publisher of the Houston Post newspaper. She didn't know anything about health. She didn't know anything about education or anything about welfare. So what she did was she hired three people as department heads. And she picked Dr. Keefer to be head of health. Dr. Keefer would not give up the dean of the medical school. So she agreed to have him do both jobs. He was dean of the medical school and Secretary of Health. And he called me to his office. And we all respected Dr. Keefer. You dressed up in a new coat and clicked your heels and said, yes, sir. He said, Freireich, Dr. Ross says you're doing good. Thank you, sir. Have you ever heard of the National Institutes of Health? No, sir. There's a place in Washington where they have a hospital out in the country. And they can't staff it. So we have to send young people who are drafted there. If you go to the public health service, you don't have to go in the army and get shot during the war. Yes, sir. He picked up the phone. Fred, I have a doctor Freireich in my office. He'll be there tomorrow morning. Bye. Thank you. I went home. I told my wife, I have to go to Washington. I got in my car, drove to Washington, 200 miles in a broken down car. I got there. I found the guy at the HEW. He said, Freireich, you have to go to NIH. So go out here and take the bus. It takes you to the clinical center. Before the war, they decided to put a clinical center in the campus of the National Institutes of Health, which were all basic science institutes. There was no medicine. So here was this hospital, and they couldn't staff it. So they took all the draft dodgers. They called us yellow berets. And they staff the NIH with guys right out of their training. So anyhow, I got in my car and drove out there. Where's NIH? There. Who do I talk to? There, you go there. I talked to all the clinical directors. No one needed me. I got to Gordon Zubrod, who had just come from St. Louis University. He was an infectious disease guy. Do you know Gordon Zubrod? Yeah, I actually met him a couple of times with Dr. Frei. Good, yes. Actually, I'd love to hear this story. Dr. Frei has told me the story, your first day at the NCI when you, quote, "found your office." Can you tell us about that one? Yeah. So anyhow, Dr. Zubrod said, what do you do, Freireich? I said, I'm a hematologist. He scratched his head. And he said, I'll tell you what, you have to cure leukemia. I said, yes, sir. You know I'm in the military, so you have to do what you're told. He said, your office is on the 12th floor. I went up to the the 12th floor. I walked along, looked for a name. I came to room that said Emil Frei. I said, isn't that like the damn government? They can't even spell my name. So I walked in. And there was a tall, skinny guy with no hair. I said, sir, you're in my office. He said, your office is next door. I'm Frei. You're Freireich. And we've been friends for a lifetime. He told that story to us many, many times, I'm going to tell you. He thought that was hilarious that this guy walked into his office and said, you're in my office. And he said, no, you're in my office. The other thing I want to talk about then, as you moved on, what made you and Dr. Frei and Dr. Holland decide to go at combination therapy? I think it was based on the infectious disease stuff. Correct, totally. At the time, we had three drugs, 6-MP, methotrexate, prednisone, 48, 53, and about 54, something. Each individually gave some responses. They lasted six to eight weeks. And the children all died. So the world's authority on hematology, Max Wintrobe, wrote a review. And he said, these drugs are simply torturing these children. And they don't do anything. Dameshek wrote editorials in Blood saying they're just killing children. So we were not very popular. But Zubrod came from infectious disease. And Tom Frei was infectious disease. And they had just discovered that in tuberculosis, if you use sequential streptomycin PAS, they became resistant to both drugs. If you gave them simultaneously, their effectiveness was prolonged. So combinations of agents were more effective than the sequences. So Zubrod said, why don't we do the same thing for cancer? We'll do 6-MP and methotrexate in sequence. And we'll do them in combination. To do the combination, we had to work out the doses. Dave Rolle did that in mice. 60% of two immunosuppressive drugs make one. And we gave 6-MP and methotrexate concurrently and in full dose sequentially, that is until they failed, we gave the other one. And the study was called Protocol 1. Jim Holland had gone to Roswell Park. And he agreed to join us. So we became the first acute leukemia cooperative group, Holland at Roswell Park, Frei and Freireich at MD Anderson. Freireich treated the children. And Frei protected Freireich from the rest at NCI and from Zubrod. Zubrod trusted Frei. So if I needed to do anything radical, I'd talk to Frei, and he'd talk to Zubrod. So we were a great team. That was really the start of the cooperative group set, right? That would be CALG, the cancer and leukemia group, is that right? That was the first cooperative group in the country. That's incredible. The cooperative group had to two institutions, Roswell Park and MD Anderson. Who tried to block you on these things? I know it must have taken a lot of courage to put all these drugs together. You mentioned Wintrobe. But were there others who were fundamentally opposed to using combinations? Oh, I'm getting to that. So with the first study, Protocol 1, Russell Park and MD Anderson, children received 6-MP and methotrexate simultaneously and in sequence. And it turned out that Protocol 1 was published. The combination had more frequent remissions and longer duration. So we were onto something. Next we did the prednisone. Prednisone's not myelosuppressive. We could do full-dose prednisone with 6-MP, full dose prednisone with methotrexate, same result. In every instance, the combination was superior to the sequence. So one day I'm sitting in my office. About once a week he'd come around and look. He came in one day. He said, Dr. Freireich, this ward is a mess. Everything is full of blood, the nurse's uniforms, the curtains, the ceiling. Well, anyhow, I was taking care of my bleeding children one day when a guy from Eli Lilly showed up. I think his name was Armstrong. And he said, we've got a new drug that was founded by-- you know who that was. Let me see his name. Mike Black. He discovered it in mice, periwinkle extract. Periwinkle had 80 alkaloids. And they screened them all against mice. And this one was active in one kind of mouse leukemia. But it wasn't active in L1210. So he said, we have this drug. And we offered it to Dr. Farber at Dana Farber. And we're going to offer it to you if you want to do it. I said, wonderful. So I wrote a protocol. And Zubrod said, but this drug is not active in L1210. And we know that the drugs active in L12101 leukemia are active in human leukemia. So this drug cannot be studied. Aha, time for Emil Frei III. I went to Tom. I said, look, Tom, vincristine is not myelosuppressive. As a single agent, it causes 80% complete remissions. I want to vincristine to 6-MP and methotrexate. Zubrod says no. Frei said, leave it to me. He talked to Zubrod. I told Zubrod, these children are dying. I've got to do something. So they approved it. And we did decide the VAMP. We knew prednisone was not myelosuppressive. We could add it to 6-MP and methotrexate, full dose. We knew this dose of 6-MP and methotrexate. Vincristine turned out to be not myelosuppressive, CNS toxicity. So we designed the VAMP drug. Then we said, let's let Holland and the other members of the cooperative group join so we can get this done quick. The cooperative group refused. Jim Holland refused. He wanted to do them one at a time, prednisone, 6-MP, methotrexate, vincristine, prednisone, vincristine, and so on. It would have taken us five years. We went through the same thing with MOPP. They wanted to do it one at a time. So we had to do it alone in the cancer institute. So Frei went to Zubrod and said, why can't we do it? Zubrod said, if you say it's OK, you can do it. Frei was chair of the group. And I'm not going to put my patients on the group. So Frei had to resign. Holland became the chair. And Frei was an advisor. So we started out with VAMP. We had 98% remissions. The remissions lasted about six weeks. We realized that they weren't cured. So we said to the parents, this treatment was toxic. It was full-dose 6-MP and methotrexate. And the parents said they're going to risk their children's life, but we're going to do what we called early intensification. That is, the children in complete remission would get full-dose induction therapy, never done before. And I met with the parents every morning and went over each child to be sure that they were with us. The parents were wonderful. We had solved the bleeding problem with platelet transfusions. We'd had white cell transfusions and so on. And they went along with us. So we did early intensification. We did it in about 12 patients. Two of them almost died, very severe infection on the brain. But we saved them. So we knew this was dangerous. But they all relapsed. Median duration remission was about eight weeks, even though we did early intensification. So MC Li had cured choriocarcinoma. I don't know if you know that story. MC Li and I were residents at Presbyterian at the same time. We were good friends. I was his advisor on this strategy. He measured chorionic gonadotropin in the urine. And he knew that as long as there was gonadotropin in the urine, they weren't cured. So he kept treating them. So we decided to follow the Li model. And what we did was we did early intensification, which they all survived, fortunately. And then we did intermittent reinduction. Every four to six weeks, we'd bring them in and give them another course of treatment. And we did that for a year. And then we stopped. And then we watched them. And that's when we found 20% of the patients were in remission at, I think, 18 months. Never been reported before. And I did report that to AACR. I've seen the AACR abstract. And I would love to know what was the energy in the room when that was presented. Did people stand up and throw rotten tomatoes at you, or did they stand up and applaud, or everything in between? No one applauded. Everybody was incredulous. The people in the group didn't believe it. Most people thought we were lying. If it wasn't for Frei, I'd have never gotten away with it. Let me ask you another question. Dr. Frei told me that the first patient you gave platelets to, you had to sneak out at night and do it. Is that true? He said there were people who did not want you to give platelet transfusions. The platelet transfusions were a bigger fight than the chemotherapy, because everybody knew that platelets were not the cause of it. Dr. Brecher had studied patients in the war from radiation injury. He had dogs that he completely phoresed, zero platelets. And they didn't bleed. So obviously, platelets were not the problem. The problem was a circulating anticoagulant. And I did experiments in the lab and proved that that was false. But anyway, the platelet transfusions are what made all of this possible, because the children all died of hemorrhage. And once we had platelets, we could treat them with the chemotherapy. Is there a story behind the first patients who got platelet transfusions? Again, Dr. Frei told me that-- Oh, boy, that's a wonderful story. I actually published it. This was a young man who was bleeding to death whose father was a minister. And since it was proven that platelets were not important and there was a circulating anticoagulant, I decided that the only way to arrest the hemorrhage was to do an exchange transfusion like you do in eritroblastosis fetalis. So I said to the minister, if you bring me 10 healthy volunteers, I want to do this experiment on your son. And he was desperate. His son was a beautiful 8-year-old boy. His name was Scotty Dinsmore. How do you like that? [LAUGHTER] Scotty Dinsmore was bleeding to death. And he arrived the next morning with 10 volunteers. And I sat down in the treatment room. And I did an exchange transfusion with 50 cc syringes, 50 ccs from Scotty in the trash can, 50 ccs from the donor in Scotty. And we calculated I had exchanged three blood volumes to get to where the concentration was detectable. And when I finished this four-hour procedure, bending over my back with syringes and volunteers, his platelet count was 100,000. And is bleeding completely stopped. So we thought we'd made a breakthrough, but we were smarter than that. We watched him every day and did a platelet count. And we found that the platelet lifespan was four to six days. And when the platelets got below 10,000-- we had done a retrospective study, and we knew what the threshold for bleeding was. And he started bleeding again. So it was obvious that it was not an anticoagulant. I did experiments in my lab. I took the serum and mixed it with the plasma and so forth. So we proved that it was platelets and not an anticoagulant. And then we had to figure out how to get platelets. And Allen Kleiman in the blood bank and I worked together to do platelet phoresis. We took the unit separate platelets, put the blood back, volunteer donors. And we proved that platelets stopped the bleeding. And we published that, a great paper, citation classic. I was going to say for the young folks. And I asked Dr. Frei this too when I was at the Dana Farber. Did you ever doubt yourself? Did you think, we need to quit doing this? This is more than we can handle. I know Dr. Farber was widely criticized in Boston for-- Oh, boy. He studied vincristine at the same time we did. Yeah. So did you ever say, maybe we should set this whole system down and give up? No, I was never intimidated, because Dr. Zubrod gave me orders, cure leukemia. So I was going to do it. Yeah, my impression from talking with Dr. Frei is Gordon Zubrod was the sort of unsung hero in all of this. He is. He is. He had the courage to back a 25-year-old guy and his resident to do things that were potentially insane. We could have gone to jail for what we did. We could have killed all those kids. That's what Dr. Frei-- Dr. Holland has told me the same story. So we owe you a great debt. So let me ask you. When you were the president of ASCO, in those days, what made you decide to run for ASCO? It was still pretty early in the early 1980s. Well, that's a very good story. I'm a pioneer in that regard too. When you became a cancer doctor, you had to join the AACR. AACR was dominant. I joined the AACR. I sent my papers on platelets and chemotherapy to AACR. They accepted all of them. But they put the clinical papers on Saturday morning. When I gave my first paper at AACR, the chairman of the session, my wife and my son were the only ones in the audience. Nobody stayed till Saturday morning. So I got mad. I said, I'm discovering things, and I can't present them at AACR. No one's listening. So we said, let's form a society that is clinical oncology and meets the day before AACR the clinical scientists who want to go AACR don't have to go to two meetings. So we organized a plenary meeting the day before AACR began. In the first session, we had a lecture on CML from-- I forgot who the talker was who is treating CML, Berechenal or someone. Karanovsky? I don't know. So we had lectures, not papers. And we did that for a couple of years. And then AACR knew what we were doing. We were totally cooperating. But we hired a manager. And we started a scientific exhibit. So we had lots of money. And AACR needed money. And we were rich. So I got a call from the president of AACR. And he said, we don't want to continue to meet at the same time, because all of our doctors want to get these free samples. And they go to your meetings, and they don't go to our meetings. So we're separating from ASCO. I said, that's terrible, because the ASCO doctors all want to go AACR. He said, sorry, we can't take you anymore. I forgot who was president at the time. So ASCO had to separate from AACR. They separated from us. Most people think we separated from them. They separated from us. You were there at the very start. So I really appreciate your contributions to the field. And I appreciate your taking time today. And I appreciate all the things you did to help all the patients who've now survived that wouldn't have if you hadn't. Thank you very 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 a review on Apple podcast or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories, the Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.asco.org.

A doctor describes her 50+ history as a survivor of lymphoma treated with mantle radiation. Read the related article on JCO.org.

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. The Arc of Therapy-- From Cure to Humbling Legacy, Gene Bishop, M.D. In June 1965, at the age of 18, I sat in a room with my parents and heard an oncologist tell me that I had Hodgkin lymphoma. If I shared that diagnosis with people, he said, they would look at me as if I were dying, because almost no one with this disease survived, but I would. With breathtaking confidence, the oncologist said a new treatment, radiation, would cure me. In October 2018, at the age of 71, I sat in an oncologist's office as he told me I had stage IV non-small-cell lung cancer, presumably as a result of that radiation in 1965. He offered palliative therapy. His goal-- more good days than bad. He called me "our humbling legacy." I reflect now on that arc, from optimistic cure through a mounting problem list of likely consequences of radiation, to the almost certainty that I will die of the treatment of a cancer I had in 1965. I received the best treatment there was in 1965, and I'm getting the best treatment there is in 2019, but I am no longer being promised a cure. Both my oncologist and I are living with the reminder that no treatment does only what we want it to do, and that one year's miracles may have serious consequences, even 50 years later. And although some of these may be known or theoretically possible, many are not even imagined until one, two, three, or many case reports begin to appear and random events turn into warnings and known consequences. For the patient seeking cure and life, an unknown but potentially dangerous future is hard to imagine. Some new miracle will come along. Physicians waiting for data, recruiting patients for the next clinical trial, or facing pressure from patients for positive results can also be focused more on immediate results. They may minimize the known or unknown future. How will physicians be both wise and humble? The first oncologist was right. I was cured of lymphoma. I graduated, went to medical school, and had a family and a full life. I shared the story with friends, patients, and colleagues when I thought it was appropriate or helpful. Look, I said to families facing radiation, I had radiation, and here I am, alive and well. A little hope never hurt anyone I never thought of myself as a cancer survivor on an ongoing journey. I thought of myself as a cure. And I certainly didn't think about the difference until many years later. If oncologists were no longer interested in me, then cancer was over. There was no concept or field of study of adult survivors of childhood cancer. Certainly no physician, neither the oncologists I saw initially nor the internists who later followed me when the oncologists lost interest, raised the issue. Why and when did I even begin to consider that I might be at some kind of risk? In 1979, 14 years after my treatment, the worst domestic nuclear power accident in US history occurred at the Three Mile Island nuclear plant in Pennsylvania. I was more than sympathetic to the nuclear disarmament movement. And although I understood that nuclear war and my radiation treatment were considerably different, I did begin to wonder if the treatment could have had unexpected consequences. I began to ask questions of physicians, with very few answers. Thus began almost 20 years of symptoms and consequences of being in the earliest cohort, not part of any study, before the age when anyone could request, if it occurred to them, weekly updates from the National Library of Medicine on consequences of earlier cancer treatment. In 1981, at age 34, I asked whether I should start mammograms early, and my internist asked the mammographers. "We don't know," I was told, "but it might be a good idea." In 1985, seeking answers to a persistent tachycardia cardiopulmonary testing and a Holter monitor showed a baseline heart rate in the 90s. I was told I was deconditioned and anxious. In 1986, a physician studying effects of radiation on the heart-- he had a seven-year follow-up at that point-- told me the only known effects was constrictive pericarditis, which I did not have. "Don't worry," I was told. Both were correct. I was anxious, but my ectopy and tachycardia were not symptoms of anxiety, they were the cause of the anxiety. I was anxious about the effects of radiation. I never tried to be my own doctor. But only I looked through the lens of a radiation treatment survivor. Not until 2006 did I find early consensus-based guidelines of which my physicians were unaware. In the late 1980s, I was denied life insurance because of the new right bundle branch block, but not until 2001, 36 years after my initial treatment, did a cardiologist name it radiation-induced heart disease. I imagined it as static rather than dynamic. Not only was my heart not static, but the entire field of radiation-induced heart disease was evolving. I didn't have a permanent scar, I had ongoing damage. And neither I nor my doctors had the evidence for where it was heading. I found a cardiologist who focus on cardiac consequences of cancer treatment. When I mentioned that hiking in the Canadian Rockies and trekking in Vietnam had ceased to be fun, the cardiologist found critical aortic stenosis. My already damaged conduction system did not survive an aortic valve replacement, and now I had both a pacemaker and a new aortic valve. In 2015, at age 68, I read a published report of abnormal exercise response in long-term survivors of Hodgkin lymphoma treated with thoracic irradiation. I recognized myself in graphic detail. No amount of training at the gym would get my heart rate below 90. That article appeared 50 years after radiation and 30 years after I first sought help, one of several sobering lessons in the length of time it can take to discover the effects of medical treatment. The truth is, in my own therapy arc, I was lucky. Every consequence until the lung cancer was treatable with the promise of a good outcome. I saw the article recommending breast magnetic resonance imaging for those who had received mantle radiation, appealed my insurance denial, and found my breast cancer early. However, two medical oncologists, two breast surgeons, and three radiation therapists all had vastly different treatment recommendations for my situation, reflecting the murky state of knowledge on treatment of Hodgkin survivors. A huge thyroid nodule was benign, but out came my thyroid with a different small focus of cancer. I faced each challenge, albeit with some depression and fear, with the knowledge that I would get better. Cure was still the operative word. In the arc of my disease, radiation had consequences, but they were not insurmountable. As I reached more than 50 years out, I think I breathed an inward sigh of relief. I expected to have progressive cardiac disease. I imagined I would develop congestive heart failure. I worried about lung cancer. It had been reported 40 years out. But there were few studies on 50 years out. I thought I was done with my cancers. When I developed a sudden and persistent cough, I began to worry. I could hear gurgles high in my mid-chest, but my doctors heard nothing. I doubted the pulmonologist's diagnosis of cough-variant asthma newly-present in a 70-year-old. My doctors began gently suggesting what they do when a patient has unexplained symptoms. "Perhaps you are anxious," they said. The classically-trained psychiatrist noted he hadn't seen a conversion symptom in a long time, but thought I might never have really thought through what it meant having cancer at age 18. Several unexplained symptoms and normal computed tomography scans later, I contemplated what a non-physician would do. What if I weren't thinking like a doctor, but more like my fellow survivors? Off I went to Facebook, an unimaginable resource in 1965. I typed "Hodgkin's survivors" in the search box, and up popped a closed group-- Hodgkin's Lymphoma Disease Survival and Late Effects, 1960s to Early 2000s. Here were 500 people from around the world who had received radiation, chemotherapy, or both. It was hardly a tidy cohort. Their treatments for Hodgkin's spanned the years from mantle radiation, to chemotherapy, splenectomy, improved imaging, and actual staging. As befits a social media site, they were seeking support, medical advice, and shared experiences. I was one of only two survivors on the site who were more than 50 years post-treatment. Initially, I felt lucky, at least until the lung cancer diagnosis. The number of valve replacements, arrhythmias, pacemakers, and stents was extensive. Many had severe neck contractures from radiation. Breast cancer seemed to be an everyday occurrence. The question of prophylactic mastectomies frequently was raised. Cough, lung disease, and esophageal reflux with aspiration all appeared. I briefly let myself be reassured that my pulmonologist was correct, and my cough had a reflux component, even if I never had a classic reflux symptom and a gastroenterologist was doubtful. If the medical world has been slow to recognize cancer survivorship, this non-random group has not. Many of them travel hundreds of miles to find survivorship clinics in various countries around the world. The more recently-treated ones had both the good fortune to benefit from the new field of cancer survivorship, but the bad fortune to be beset constantly by worries about what the future holds. As with much of the lay public, many believe that screening and early diagnosis are always beneficial, and are unaware that the evidence in our cohort is scant. I found myself alternately fascinated, riveted, terrified, and reassured, but refrained from diagnosing myself from Facebook. I also knew I had found my peeps, a cohort more aware of their risk factors than much of the medical world. One woman expressed relief when her new oncologist said, "this is all our fault." Others chimed in they had never heard a physician acknowledge that. My new oncologist had fancier words, "you are our humbling legacy." I am the living-- or perhaps I should say dying-- history of one of our more successful efforts to treat and cure cancer in the last 50 years. There are now numerous other efforts, especially to treat childhood malignancies. Awareness of long-term consequences, the concept of survivorship, and the concept of shared decision-making are but a few of the inflections in the arc of therapy. Many patients make difficult decisions choosing extremely toxic therapies that will extend life only months, with imminent consequences that are known. But many also make decisions on the basis of limited information, filled with hope. In early 2019, should an American woman wait while the Food and Drug Administration continues to investigate textured breast implants, or imagine she lives in France where sales have been halted because of reports of an association with a rare lymphoma? What will be the effects of the successful immunotherapy in 10, 20, or 50 years? Of course, physicians are focused on near-term cure, yet they must also acknowledge the uncertainty regarding possible late effects of the very treatment that is now saving their patients' lives. But if I am a humbling legacy, humility is needed. We need clinicians to provide guidance and information to patients as they find themselves in unknown and often frightening terrain, years or decades after completing their course of treatment. In my primary care practice, I often told patients I had left my crystal ball at home along with my magic wand. But I was usually referring to when they could return to work after a viral illness, not whether they would get a terminal illness 50 years later. I tried to imagine my 18-year-old self, and the doctor peering into his crystal ball. "You will have symptoms no one will believe. You will happily marry and successfully have one child." As long as he has a crystal ball, I might as well learn everything. "You will develop heart disease and require an artificial valve and a pacemaker. You will develop three other cancers, two of which will be treatable, but the third, at age 72, will be the cause of your death. Would you like the radiation and cure we can offer you now?" [MUSIC PLAYING] Cancer Stories, the Art of Oncology Podcast, presents the essay, The Arc of Therapy-- From Cure to Humbling Legacy, by Gene Bishop, published online in Journal of Clinical Oncology, June 10 issue, 2019. I'm Lidia Schapira, editorial consultant for The Journal of Clinical Oncology's Art of Oncology, and your host for Cancer Stories. My guest today is Dr. Gene Bishop, who is a retired general internist, and primary care physician and a clinical professor at the University of Pennsylvania. Dr. Bishop's essay, The Arc of Therapy-- From Cure to Humbling Legacy, addresses the personal and lived experience of a cancer survivor. Gene, welcome to our program. I'm so happy to be here. Thank you for having me. We're absolutely delighted. And your essay is so inspiring, and also so educational. I wonder if you can tell us a little bit about what you wish to convey to the audience of cancer clinicians about the experience of being a long-term cancer survivor. That's really an interesting question. Because one of the questions is how many long-term cancer survivors are still seeing oncologists. And to the oncology community, I want them to always have an open mind about possible effects of the medications they're using. I could see how it easily could become so exciting to find people in recovery, if not cured-- always a tricky word-- from new therapies that it's hard to think what it might be like 10, or 20, or 30 years down the line. And I think that just needs to be acknowledged. I think the more difficult question is how to have an open mind about therapies people might have received years ago, and to sort out possible unknown effects. This is such a challenge, and it is such an important point, I think, for all physicians-- not just cancer clinicians, but all specialists and all primary care physicians and generalists, because we may not know what to look for. And you have this unique experience of having being among the first in the cohort of very young patients who were cured by radiation. Tell us a little bit about what it was like for you as you were encountering symptoms which perhaps you thought were related to that therapy, but nobody really knew what to do with you. Yes, and I think that that's terribly important. One thing to remember is I was young. I was 18 when I was treated. And I probably didn't actually realize the import of what was going on. My 96-year-old mother is still alive. And needless to say, now still facing the fact that her 72-year-old daughter will die before her. But she really thought she was going to lose me at age 18. But I never skipped a beat. You know, I got radiation, didn't get sick, never missed a day of college, and thought everything was behind me. But once I became a physician-- which I don't think has anything to do with that, with my illness, it really had to do with the women's health movement of the 1970s-- once I became a physician, I noticed that I was having symptoms that didn't seem to me to be normal for a woman in her 30s and 40s. And I couldn't get anyone to consider that these could be an effect of radiation. They were right on board with, you're cured, that was a long time ago, and a seven-year follow-up somebody had. And they were way too willing, as many doctors are, to ascribe them to psychological symptoms. Now I didn't expect anybody to know that, 30 years later, particular effects of radiation would be reported, but I expected people to at least have an open mind, and say, you know, we can't find anything now. Maybe this has to do with your treatment. Let's make a follow-up plan. And I think that's terribly important. And nobody I saw was an oncologist. The oncologists were done with me. I was cured-- until I wasn't. And as I said, we don't have crystal balls. But one of the things that I learned from the Facebook group, which is quite an amazing place, is that people treated for Hodgkin's even much later than I am, and I presume other cancers, are still facing, from primary care docs and other doctors, "this happened a long time ago, it cannot possibly be affecting you now." And I think doctors need to remember there's a lot we still don't know about the human body and what we're doing to it. And default should be, "this happened a long time ago, I don't know anything about this, but let me look into it." And that's not always the default. You know, one of the things that struck me in your narrative is that here you are, 70-plus, a medical educator, and where you found your people was in an online community. You know, it was not exactly where I thought you would take a story. Well, I'm going to modestly say that I have a lot of faith in myself as a clinician. And I just knew I didn't feel right, and that nobody was coming up with an answer that made sense to me in terms of explanations of various symptoms. And I thought, well, what do people do? Oh, they go online. So I searched Facebook, which is not something I-- I do have a Facebook page, but it says, "I don't actually use this page. If you're really my friend, you know other ways to reach me." And I went on Facebook, and there is a closed group of Hodgkin's survivors. You have to apply to be in it. And it's moderated by a woman in the UK. And it was an unbelievable cohort. Of course, it wasn't, as I said in the article, tidy. Because it included people like me, who were treated only with radiation, before CAT scans, before staging. I've always been thankful that I missed the splenectomy stage. [BOTH CHUCKLING] I have my spleen. And for being such an untidy cohort, they had experienced many similar problems and were extremely well aware that they were lucky to be alive and that the treatments they had been given had serious long-term side effects. And although I had to refrain as a physician-- I basically didn't participate, I would say I was a lurker-- what I did do was post the previous article I have written, and I posted anything that I thought would be useful from the medical literature. I was not the only medical professional on the site. But when people say, gee, I'm having chest pain, what do you think I should do, let somebody else say, you should go see a doctor or you should go to the emergency room. But an incredible number of people who had seen doctors and gone to survivorship clinics but also been dismissed as, "this can't have an effect." And I realized-- I always thought I was pretty special, and I realized that it was a pretty large community, particularly in regard to Hodgkin's, of successful cures but with was sequelae. And what did you find in this community? Was it the connection with others or was it specific information? What kept you going back? Well, after a while, I got kind of tired of it. Not tired of it, that's not the right word. It was became disturbing, actually, because of the seriousness of the problems. What I found in the community were, one, people were supporting each other. And two, I found other people who had unexplained cough, who-- at one point, a physician was trying to convince me that my cough was all due to reflux even though I'd never had a reflux symptom. And I found many people who had shared some of the symptoms that I had had, which didn't make me think, oh, good, now I have this, but it made me realize that I was very far from alone, and that even I, who thought I had spent quite a lot of time learning about long-term effects of radiation, had not understood how many people were living with serious neck contractures, reflux so severe that they had to be hospitalized, chronic cough. It seems that because I had escaped them, I hadn't realized. And I'm not sure anywhere I had seen the collection of symptoms that you can see in this cohort. So I didn't feel necessarily supported by the community. I wasn't looking for emotional support. But I was looking-- in the National Library of Medicine I hadn't found a good explanation for my symptoms. And so I thought, well, let's see what social media has to offer. Maybe somebody will have something that I can go back to my doctors with. I was astounded, around the world, by the community of survivors. It's so interesting. Because through social media, we can actually find out so much about how patients and survivors experience their disease and their trajectory after we say goodbye, thinking that, as you put so nicely in your essay, that we're done. I have a question for you based on one of the things you just said. And mentioned survivorship clinics. How do you think they are now helping patients who have similar stories to yours who are long-term survivors have they developed in the way that you anticipated? Do you think they're helpful? Well, that's a good question. And I can easily get out of it by saying I know nothing about it. Because in my own case, there were no survivorship clinics. And I was the only person who kept trying to think, gee, is this a problem that I'm going to have, or how do I think about this. And so for instance, the University of Pennsylvania where I'm now being treated, has a survivorship clinic. But I've never been there, because I already, as a primary care doctor, have two oncologists-- I mean, I already have such a team that the survivorship clinic has nothing to offer me. So the most I know about the survivorship clinics is really from the Facebook group, where people find them quite helpful. Because a knowledgeable person is can actually look up and see who they are, what year they were treated, what treatments they received, and what they now know that they're at risk for. So I think there's probably a good use to survivorship clinics. I think, as a former primary care doc, there's just no way I could know that about every treated cancer patient that I see and what the treatments they might have received. So I think that survivorship clinics are probably quite useful, but I have no personal experience with them at all. I think if I were still in practice and I saw somebody who said to me, I was treated for childhood leukemia, or sarcoma, or whatever, I would refer them, at least for an evaluation, and then see them back and see what they thought. But I have no personal experience. I think survivorship has gotten pretty trendy. And one of the interesting questions is, how do you even define a survivor? So as we bring this interview to a close, I have one question for you. You end the story by saying that even if you knew then what would happen as a result of treatment, you would do it again. At least that's what I understood. Can you tell us a little bit about the emotional journey of being a cancer survivor. Sure. I mean, of course I would do it again. I was 18, and I'm 72. I've had a life. But I think, for me, there was a turning point between thinking of myself as a cure-- over and done with-- and being a survivor. And I wrote about that a little in a Journal of General Internal Medicine article that's referenced in my article, called "Seeking the Proper Tense." I spent, I'd say, the first 20-something years just feeling like it was in the past, that whatever was going to happen, I could deal with, that I had really escaped. And getting breast cancer-- which, by the way, was very lateral, and there was no agreement among my physicians whether I got breast cancer because I was a 60-year-old American woman or because I had had radiation-- getting breast cancer really hit me in a different way. And I said, oh, I could actually have a lot of problems, and I could have a lot of different problems than people who randomly get some other cancers. And I felt like I really had to make plans for the latter part of my life to think about what the consequences of this treatment might be. Could I continue to live in a three-story house? It was clear to me that I had ongoing heart disease. And I made a transformation in my head between being a cure to being a survivor. I joined a writing group at Penn for cancer survivors. And before that, I never thought of myself as a survivor because I hadn't lost my hair or vomited, which I think is what a lot of people think of if you have cancer-- If you really have cancer then you have to undergo therapy that makes you ill. And none of that was part of my past. But I realized that I was a survivor, and that something had changed in my body, and I would have to deal with it. And it's been very difficult. I'm very sad right now, you know? And it was hard to write the article. I imagine. I imagine. Well, those of us who read the article and continue to learn from it appreciate that you did write it. We thank you for it. And we wish you also good health. And thank you so much for sharing your reflections. You're welcome. I hope they are helpful to physicians. I really appreciated my oncologist-- his calling me "our humbling legacy" really sparked the article in a way. I'm far from cure at this point. Thank you. Thank you for sharing your story. That was Dr. Gene Bishop sharing her reflections on being a cancer survivor and living with lung cancer. This is Lidia Schapira, your host for Cancer Stories. Join me next time for another conversation about the Art of Oncology.

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. The Bomb, Andrea M. Watson. I sit paralyzed at my desk. Everyone has left the clinic. I can hear the sound of the broom in the hall as the after hours cleaning begins. No phones ring. No patients hurry to appointments. No chatter lingers in the air. The silence is oppressive, the air is heavy, and the distance from my office to the hospital an eternity. I've just hung up the phone with the radiation oncologist. His words echo in my head. "Radiation will cause more harm than good. I'm sorry. I wish there was something more I could offer." Dread rises like a tide as my last hope recedes. I want to share the burden of this terrible news. But all my colleagues have left for the day. And I am alone. I'd been taking care of Mallory for nine months when the progression of her disease took me by surprise. Her tumor had responded so well to upfront radiation followed by nine months of intensive chemotherapy. With just a few months of treatment left, the end was in sight. Mallory was an avid JRR Tolkien fan. And plans for a Make a Wish Foundation trip to New Zealand were underway. She wanted to see the Lord of the Rings filming location and visit the small hobbit village she'd read about in travel books. She wanted to wait until it was summer there, our winter time, to travel. When Mallory's disease progressed on therapy, that fall, the timeline shifted. Goals shifted. There was no realistic hope for cure. There was just hope for time. The trip became the goal. And she bravely chose to continue with aggressive treatment, hoping it would open a window of time for travel. But further progression got in the way. When the futility of chemotherapy became clear, hopes were pinned on radiation to buy time. Now hanging up the phone, I realized that this strong, brave, beautiful 16-year-old girl who had been through so much will never get to New Zealand. And I have to tell her that tonight. I start out toward the hospital. But walking through the hall, my steps slow, my chest becomes tight, and my head swims with the devastating message I carry. I stop and look blankly at the man sweeping the floor wondering if he can tell I am carrying a bomb meant for a young girl and her family. He keeps sweeping, unaware. I trace my steps, fighting back tears. Back in my office, the sobs come. I cry for Mallory, for her parents, for her little brother and her best friend, her sister, for all they would never share together and for all the sorrow they had already faced. I cry for myself and for the terrible burden of delivering the blow, extinguishing the candle of hope that this trip had become, and speaking the words they'd dreaded since the moment we met. And when the tears finally stopped, I am empty. I take a deep breath and walk out the door. Mallory is not surprised by my news. Her gaze shifts away from me to a far off place. Silent tears stream down her face. And she says, "I know." That's all she says. I meet with her parents alone in the family room. Their reaction is raw and palpable. Flooded by tears and sobbing, they cling to one another lost in a storm of grief. When her brother and sister join us, I unfold the news slowly, choosing my words with great care as the disbelief on their faces quickly melts into sorrow and then tears. My heart feels as if it will break. I sit quietly by trying to fade from the scene that plays out before me. I fight back the tears but lose. I have done my job, delivered the bomb. There is nothing more to do but bear witness. Then something beautiful happens. Mallory's parents silently hug one another with new resolve and in turn embrace their children. Without a word, they stand up and walk together into Mallory's room. Hand-in-hand, they pull her in and encircle her with fiery love. I quietly take my leave feeling the power radiating from the room as I walk down the hall and out of the hospital into the night air. Mallory's funeral program bore a poignant quote from the Lord of the Rings film in which Gandalf assures Pippin that death is not the end, but rather another path we must take. The journey doesn't end here. Death is just another path, one that we all must take. The gray rain curtain of this world rolls back and all turns to silver grass. And then you see it. "The journey doesn't end here. Death is just another path, one that we all must take. The gray rain curtain of this world rolls back and all turns to silver glass. And then you see it." "What, Gandalf? See what?" Pippin asked anxiously. "White shores and beyond, a far green country under a swift sunrise." Shortly after Mallory died, her sister reflected that although she never saw the lush green of New Zealand, Mallory's journey had taken her somewhere even better. Likewise, the journey of those left behind continues. Families lives are forever changed after a child dies. And our lives are never the same either. Each patient we care for can teach us lessons about how to live well even when you die young. The privilege is great and the responsibility that comes with it greater. Delivering devastating news to beloved patients and their families may be the most dark and difficult moments of one's career. But compared with the burden that families carry, it is light. And if you stay long enough and you listen hard enough, you may see the blinding love shining through the darkness. Now the end of the day. After the noise and activity fade, I find myself thinking of Mallory. Some days, it's with a renewed awareness of the heavy burden we carry. Other days, it's with a lightness of being and gratitude for those who go before us leaving their courage as testament to what they've believed in. The silence unearths a deep ache in my heart. Sometimes I cry. Then I hear the comforting sound of sweeping in the hall. I take a deep breath and walk out the door. Welcome to Cancer Story, The Art of Oncology series podcast brought to you by the Journal of Clinical Oncology. I'm Lidia Schapira, editorial consultant for Art of Oncology and your host for this program. With me today is Dr. Andrea Watson, a general pediatric hematologist oncologist working at Essentia Health in the Duluth Clinic in Minnesota and the author of The Bomb published ahead of print, February 11, 2019. Andrea, welcome to our program. Thank you, Lidia. It's a pleasure to be here. I've been looking forward to it. That's terrific. Let me start by asking you a question I ask many of our authors. People who write usually like to read. What are you reading now? Oh, that's a great question. I, on any given day, I do read quite a few children's stories. Not only am I a pediatric oncologist, I have five children. So there's a lot of bedtime story reading, which also cuts into my leisure reading. I don't have a lot of time for fiction. But right now, I am reading a book called Invitation to Love, which is by a Cistercian monk about centering prayer. And I'm in the middle of a series that he has written about the topic. And it's wonderful. That's so interesting. So with that, let's talk about your writing. You have written and published before. So tell me a little bit about how you write and when you write and why you write. Yeah, thank you. I have discovered writing in my career in the past few years, although I recall my grandmother giving me a journal when I was 12 or 13. And it was called The View From my Window. And I really have been journaling on and off throughout my life since that time. And it wasn't until I experienced a series of patient deaths that were all very close and difficult for me three or four years ago that I really took to writing as more than just journaling. And I would say looking back, it really felt like more of a compulsion than anything else. After one of the deaths, a few weeks had gone by. And I just-- I felt physically drawn to it, almost I had to get this out. And I just-- I started on my computer. And from that came the essay that you were kind enough to publish a few years ago called Let It Be Hard. And that was just such an incredibly rewarding experience for me, not only in the process of writing and processing these deaths and all of the events surrounding it, but also in the aftermath in connecting with others who had read it or who were also writers or who had a similar experience. It was a very rich, rewarding experience. And subsequently, I have come back to that kind of as needed. I had another very difficult patient death last year. And she has become the topic of this essay, which was very much more raw and intimate for me. But that's-- I guess that's where I am in my career. It's been 10 years now that I've been practicing in a smaller town in northern Minnesota. And this has been a really important way for me to stay balanced and keep coming back to work every day. That's so interesting. And I really appreciate how you take readers also to a place of deep, deep emotion. I remember in the first essay you published, you talked about how difficult the work is. And you also said, and I wouldn't want to be doing anything else. And in this particular piece, The Bomb, you walk us through the process of delivering incredibly terrible news. And you do it with such sensitivity. Tell us a little bit more about this, the reservoir of emotion and how you handle it, how you keep it from bubbling over. Well, that is the question. And luckily for me, writing is part of the answer. In this essay, The Bomb, I think I really was looking to dive into that time where you as a provider, as an oncologist, are aware of information but have yet to deliver it. And I really hadn't experienced it so intensely before this case, although it happens all the time. It happens every day as we look at scans or look at the lab reports and then meet with patients. But in this particular instance, this whole essay is about the backstory and the aftermath. But I really wanted to focus on those minutes where it's so dark. And it's so hard. And it's so heart-- gut-wrenching and heart-wrenching to carry that without being able to share it or get rid of it or change it. And for me physically, I wanted to paint that scene to try to bring people to what it feels like and physically walking from one building to the next and how everything around you is life as normal-- life as usual. The janitor is sweeping and cars are passing by. But in fact, it's this horrendous bomb that you are delivering. And then the incredible grace that comes after, I mean, for me writing really is a meditation and a way to honor these children, these families, and their strength and their resiliency. And I think without taking that time away, that time apart, to look at that and to tell that story, you don't really appreciate it. I don't. And when I am able to do that, that turns all the intense sorrow and grief and just the horror of it all into something quite beautiful. And I think many of your guests have alluded to that in oncology. Whether it's adults or children, there's such great suffering but so much life and growth and love that comes out of that that that's what I think is just an amazing aspect of what we do. And that's certainly what keeps me coming back every day and picking up a new patient and kind of moving through it again because there's no end. So you have brought up so many very deep and insightful, wise pearls there. I think this idea of connecting through love and beauty and that is sort of almost like the antidote to the sorrow. It's beautiful. But I want to take you back a little bit to this idea that you are holding this bad news, this bomb, because delivering the bomb sounds so dramatic and so explosive. Is that, in fact, the way that you experience this delivery of bad news? Well, it certainly is a dramatization of it. I wouldn't say that every day, I feel like I'm running across the field with a bomb. But when I was first drafting this essay, and I went to save it, that title just-- I said-- it just came-- it's The Bomb. That's what I'll call it. And in that case, because we had such a strong relationship, and it was just-- it felt so tragic in part because she was such a special girl and so, so just wise beyond her years and this wonderful family. She was also the age of one of my children, my oldest daughter. And that, as many of us in pediatric oncology at least know, that makes the-- it turns up the intensity. And it's a much more emotionally challenging situation. So that particular news delivery I think was probably the most poignant for me, the most difficult. And it happened as I describe it. But that's not what every day is like thankfully. No, I-- thankfully not. But what I want to bring us back because you say that the bomb is really the way it felt to you. And then you also talk about the fact that, I mean, one of the things that I loved about this essay so much is you talk about starting to walk towards the room and then having to go back to your office and close the door and sob and feeling empty. Because I do think that the emotional impact is huge on us as well as you describe as the oncologists here. And then of course, you pull yourself together in the most professional way to deliver this therapeutically. But it is important to remember that it is emotionally a very dramatic. And it feels that way. And you certainly have made that so beautifully clear to the readers. Thank you. I think one of the things I learned from the first piece I wrote, Let It Be Hard, was just that. And that was something that one of my palliative care idols said to me one day when I was struggling with this case. He said, let it-- it is hard. Let it be hard. And that I think is what got me to where I am now with the story about Mallory and that I learned from him it's OK to shut the door and cry. And it's OK if those cries are sobs. Now we can't function on a daily basis if we're emotionally out of control. And that certainly wasn't my-- what I was trying to depict. But that let-down I think and just letting it hurt is moving through it. And from that, I-- that and by the grace of God had the strength to go over and very calmly and peacefully relay this news, which, of course, as often is the case, she already knew and help be a support person as the family really absorbed the reality that was unfolding. And that's, for me, all we can do is walk through it. We can't run away. We can't escape it. And it has only made my work and my relationship with these families richer and deeper. And that's another important piece for me. With both of the families, actually, many-- three kids that I talked about in the first one and this one, we maintain a relationship with these families long after the children have died. And they are part of our healing as much as we are part of theirs and keeping that memory alive and honoring their struggle and what they taught us. So personally, for me to do this difficult, very painful work has been offset by those relationships and the knowledge that you're growing through a very difficult time, the worst time in a family's life, and a hard time in your career. But there is growth. And there is hope. And there is meaning. And you beautifully did your work as a writer by framing this high-intensity emotional moment against that sound of that gentle sweeping, the man who was cleaning the floor. And you just remind us that there is normalcy all around this chaos and this crisis. But it's a beautiful piece. Thank you so much for sending it in and for sharing your wisdom. I want to thank Dr. Watson and hope you will join me next time for another conversation about The Art of Oncology.

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 Cancer Stories. I'm Dr. Daniel Hayes. I'm a medical oncologist, and I'm a researcher at the University of Michigan Rogel Cancer Center. And I'm also the past president of the American Society of Clinical Oncology. Over the last and now the next several podcasts, I've been really privileged to be your host for a series of interviews with the people I feel are the founders of our field. Over the last 40 years, I personally have been fortunate to have been trained and mentored and I've also been inspired by many of these pioneers. And it's my hope that through these conversations. We'll all be equally inspired by gaining an appreciation of the courage and the vision and the scientific understanding and the anecdotes that let these men and women to establish the field of clinical cancer care over the last 70 years. By understanding how we got to the present and what we now consider normal in oncology, I think we can also imagine and work together towards a better future for our patients and their families during and after cancer treatment. Today, I'm really pleased to have my guests on this podcast Dr. Norman Wolmark, who was his mentor and longtime colleague, Dr. Bernard or Bernie Fisher, was responsible for the unbelievable success of one of the most influential cancer cooperative groups in the world, the National Surgical Adjuvant Breast and Bowel Project, or the NSABP, which of course, in recent years has now been merged with two other corporate groups to become the NRG. Doctor Wolmark as a professor of surgery at Drexel served as the executive medical officer from 1979 to 1994 during Dr. Fischer's leadership of the NSABP. And then he became the chairman and PI of the group until 2004 when he assumed the same role with the merger into the NRG. The NSABP is generally credited with what is now called de-acceleration of therapy, in particular of local therapy of breast cancer by applying the scientific method to compare a modified radical mastectomy to radical mastectomies and subsequent breast conserving treatment a modified radical mastectomy, as well as testing the concept of sentinel node mapping, which we now use routinely. NSABP was also one of the pioneer groups to test the value of adjuvant systemic therapy. They started with adjuvant chemotherapy, comparing L-phenylalanine mustard, or L-PAM to nothing in the 1970s, and later, tamoxifen versus nil. Other successes of the NSABP include one of the first trials or adjuvant trastuzumab. And further, NSABP was the first to report the prognostic value of the genomic test to guide the use of adjuvant chemotherapy in ER-positive breast cancer. Incidentally, it also conducted the largest and the most definitive set of studies of chemo prevention, first with tamoxifen versus nil, and then later, comparing raloxifene to tamoxifen. Not just breast cancer-- in gastrointestinal malignancies, the NSABP made seminal observations regarding radiation for rectal cancer and adjuvant chemotherapy in colorectal cancers. Dr. Wolmark himself has published over 300 peer reviewed papers, numerous other commentaries and reviews, and frankly, I started to list your honors, Dr. Wolmark, but I ran out of space. You've just had too many to count here. I think it is safe to say that the reduction of both mortality and toxicities related to breast and GI cancers over the last four decades, coupled with improvement on how we treat people, is in large part due to the brilliance and the courage and the hard work of doctors Wolmark and Fisher. Most importantly, I think they showed so many of us the importance of challenging dogma, for example, how study and thinking in breast cancer and applying the scientific method to clinical research and practice. [GASPING] I have to take a deep breath, Norm. Welcome to our program, and thank you for joining us. Well, thank you, Dan. I think after that glowing and complimentary introduction, which was far too generous, probably the most strategically sound decision that I could make is to thank you and to terminate this discussion, because I don't think that I can possibly improve on it. But I don't suppose that that's the purpose of this endeavor here. Yeah, no. People aren't tuning in to hear me. They're tuning in to hear you. And this is hero worship on my part. I want to start out with your background. I know you grew up in Montreal. You graduated from undergraduate, medical school, and later, you did your surgical training at McGill. What were the circumstances that your family was in Canada? And what got you interested in medicine and, specifically, surgery? Well, that's an interesting question. I did not grow up longing to become a physician. As a matter of fact, my interests at McGill, certainly during undergraduate school, included biochemistry. And I was in the honors biochemistry program and was going to pursue a career in nucleic acid research. And at the last moment, I had a change of heart and decided to go into medicine at McGill. And McGill was not an embracing environment for surgeons. I think surgery, certainly in our era, was regarded as a sub-medical species. And it wasn't until my internship and early residency that I embraced the possibility of developing and evolving a career in surgery. Was that attitude out of also having been at McGill-- long before you were there, I know, but most places were dominated by the surgeons. And then medicine came along after that-- Mayo Clinic, for example. Do you know? Was this an outgrowth of Osler's influence? Well, I don't know that it was an outgrowth of Osler's influence, but it was certainly difficult for us to escape Sir William Osler. I think at the graduation after our second year, we were provided with a leather bound copy of Aequanimitas, which of course, nobody read, because medical students are not interested in the history of medicine. It was only years later that I read most of Osler's non-scientific works. That's interesting. So then you went to Pittsburgh to do your surgical residency and then two years at the NCI and a year at Memorial. But then, you returned to Pittsburgh. Why Pittsburgh in those days? Well, what drew me to Pittsburgh in 1973 was my interest in clinical trials. And in 1973, there was a lot of excitement going on in clinical trials and breast cancer directed by Bernie Fisher and the NSABP. So that was something that attracted me, that one could apply the scientific method to evolve therapy. And this was something that I desperately wanted to participate in as a result of my background in basic research and biochemistry. So tell us about the heady days in the early '70s and even further back, if you'll recount sort of Dr. Fisher's history as well, of starting the NSABP. What was his vision? What was his plan? Why did he do that? How did you get involved? The whole evolution of cooperative groups and in particular, the NSABP, was an outgrowth of the initiative of the National Institutes of Health and more specifically, I think, to Bernie Fisher's mentor, IS Ravdin, at Penn. And that led to the creation by the NIH of the Cancer Chemotherapy National Service Center. And this was started by three surgeons and Michael Shimkin at the NIH, who was a medical oncologist, or what was then called a chemotherapist. And from that grew a number of disease-oriented initiatives called the surgical adjuvant chemotherapy projects for specific diseases, breast being one of them. And this was 1957. And by 1958, the NSABP had randomized its first patient. And certainly, Bernie Fisher was amongst the founders of the NSABP and then, of course, became chairman of the group in 1967 and moved it to Pittsburgh in 1970. What did it take to get a bunch of surgeons to believe that more than just surgery was important? The group started in a modest fashion. There were 23 institutions. And I think it's certainly an enormous credit at Bernie Fisher for demonstrating that a cooperative group could indeed be cooperative, with multiple heterogeneous surgeons joining under the rubric of the NSABP to evolve the state of the art breast cancer and challenge existing dogma. One of my first meetings, Dr. Fisher and Dr. Irvin of New York City were in a debate that I thought was going to get into a fistfight, with Dr. Fisher trying to explain the systemic therapy of cancer and that it was more than just surgery, and Dr. Irvin believing if you did super-radical mastectomies, you could cure more. You must have been in the middle of some of those discussions as well. I was, and remember them, and remember the acrimony, the hostility that existed at that time. As a matter of fact, there were societies that were created to counter the influence of the NSABP. The retreat from radical mastectomy was highly contentious. And of course, the debate of the two mutually exclusive hypotheses was certainly extant in Halsted's era. But Bernie Fisher determined instead of debating the issue to test the two mutually exclusive hypotheses using the scientific method, namely the randomized prospective clinical trial, which convinced surgeons that variations on the theme of operative nuance were not going to increase survivorship, that breast cancer was a disease with systemic components at its initiation, and the retreat from a radical mastectomy and the ascent of systemic therapy are inextricably intertwined. And they are so largely because of the efforts of Bernie Fisher and the NSABP. This is an interview with you, except that you know Bernie Fisher better than any of us-- who, incidentally, turned 100 years old in August of this year. What were the driving forces for him to think this way? Do you know? Was there a sudden aha that systemic therapy ought to be as important as the surgery? I know he did some preclinical studies to suggest this. Can you give us more background of what he was thinking and how he got there? Well, when I first joined him in 1973, it was a unique environment. There was a continuum between the laboratory and the clinic. And hypotheses were generated in the lab from murine models and applied to clinical research, which we now call translational research. And certainly, I think he was influenced in many ways by the preclinical work that he did in murine models on metastases and multiple other observations to challenge the sanctity of the radical mastectomy, which was based on the belief that breast cancer was a local, regional disease and spread in a logical, predictable, stepwise manner, again, along fascial planes. This, of course, to scientists, was something that did not stand up to a solid review of the data. Through the years, I've picked up many pithy comments from Dr. Fisher. One of them is that-- what was it? In God we trust. And for everything else, we like data, which I always thought was a great statement, something to that effect. The other was, you may be logical, but breast cancer is not. That really has stuck with me through the years, which is, it doesn't follow a logical string of linear progression. But rather, it becomes systemic, or it doesn't, which I think changed the field. Well, Bernie always challenged existing dogma that was based on empiricism. I think Bernie taught us to challenge the individual who ascends to the professorial pulpit armed with a retrospective case series. And based on personal charisma or the institution that that individual represented, such an individual was able to influence the way a disease was treated for decades and then close to 3/4 of a century. Challenging that dogma, insisting that therapy be evolved based on data rather than retrospective case series, I think, is a lasting contribution. He blazed the trail for the rest of us. Since you were there for a lot of this, how about some of the other luminaries of the time? Dr. Crile had a lot to do with the early thoughts that maybe you didn't need to do mastectomy. Can you enlighten us on some of the other folks that were some of the early pioneers in the field? There were certainly proponents of lesser operative procedures starting with [INAUDIBLE] and in the UK, Vera Peters, in Canada, Barney Crile, or George Crile, Jr. at the Cleveland Clinic. But again, these were based on anecdotalism. There were very few randomized prospective trials challenging the sanctity of the radical mastectomy. There were some-- Sir Hedley Atkins, the Guy's Hospital trial comparing breast-preserving versus mastectomy, a trial that had few patients and was reported, I think, in 1971 was a case in point. And then Umberto Veronesi with the quadrantectomy study, which was reported in 1981, preceded B-06. But certainly, B-06 had an enormous impact in 1985. And I think to Bernie's credit, he was able to convince his colleagues, even his detractors and his coevals of the value of breast preservation. But more importantly, I think he was able to convince surgeons of the biologic behavior of breast cancer with its systemic components. Yeah, I agree. I remember that paper. Actually, I remember most your papers. B-04 for was the predecessor. And of course, if there is a Rosetta Stone for the NSABP, it was comparing radical mastectomy to total mastectomy, which was a heroic trial to have initiated in 1971. If there is a bellwether turning point, it was B-04. This was the trial that truly compared the two mutually exclusive hypotheses to enormous, enormous resistance by the surgical community. And the paradox was that the 23 institutions that participated in the NSABP were run by surgeons. I came into the field in 1982. I have seen maybe three radical mastectomies in my life based on the fact that B-04 was beginning to change that whole field. And the three or four patients I saw had horrendous qualities of life because of that radical mastectomy. So I think our listeners, the younger ones, need to understand how courageous this was. Let me ask another question. I don't think you were part of it then, but as Dr. Fisher began to, then, think about adjuvant chemotherapy, why L-PAM? Most of the people listening to this probably have never heard of L-PAM, let alone used it. Why was that chosen as the chemotherapy to use in the first trial? Well, that's an interesting question. CMF was being developed at the NCI-- Paul Carbone, Vince DeVita, George Canellos. And L-PAM was an oral agent. And we speculated, sotto voce, of course, Bernie and I, that the reason the NSABP got L-PAM was that it was oral and could be given by surgeons, whereas the CMF, which was more difficult to administer, went to Gianni Bonadonna, who reported on the CMF data in the adjuvant setting a year after the L-PAM data were reported in 1975. Ironically-- correct me if I'm wrong-- but I think the relative benefits of both were almost identical. And the reason L-PAM fell out of favor was the secondary leukemias. Is that your perception? Well, L-PAM fell out of favor, certainly. We did L-PAM, then L-PAM 5-FU, then L-PAM 5-FU plus doxorubicin in a stepwise, sequential manner. I think CMF was embraced. Had there been a direct comparison earlier on, perhaps L-PAM would have had a role. But I think it faded away. And it faded away for us largely because when we compared CMF to four cycles of AC, which could be given in a much shorter time, there was no difference. So AC became the standard, certainly for us. Moving on a bit, as I've already-- another of Dr. Fisher's statements that I've lived on is that the hallmark of a good clinical trial is that it raises more questions than it answers. I love that because it means you have to keep thinking. Can you give us examples how you and Dr. Fisher started designing the next trial as the first one was starting to finish, and how that led, one way to the other? I've always been struck by the fact that the NSABP has been more linear in its trial design than most of the other cooperative groups. Well, it was a continuum. The next trial was based on the results from the previous trial or the anticipated results from the previous trial. A case in point, B-04, total mastectomy, where lymph nodes are not fulgurated, left behind completely untreated, compared to radical mastectomy, where they were removed. 40%, it turned out, of the total mastectomy group had histologically positive nodes. And yet, the outcomes were the same, which supported the use of systemic therapy, that patients were failing not because inattention to operative detail, but because they had systemic metastases. Well, you can ask, how did you transpose this data or know about this data to start your next trial? Well, in that era, the results were available to us in real time. We had a magnetic board, for example, for B-04, where every patient that was entered into the study, of course, anonymized, was on that board, and we could see the treatment failures in real time. So we had a pretty good understanding of what the results were when B-06, for example, was started, and certainly when the L-PAM trial was initiated. To us, in that era, alpha-spending meant buying a suit at Bergdorf Goodman. It's only later that these restrictions, appropriately so, were initiated. So we were able to be very nimble in transposing the data from one trial to formulate the hypothesis for the next trial. And that led to, I think, a very elegant, sequential, logical, stepwise series of trials, which I think in this era, could not be conducted. Did you ever get concerned that you were jumping ahead to the next trial with insufficient follow-up with the last one, and you'd get ahead of yourself in terms of unexpected toxicity showing up or, for example, in the deacceleration of therapy, that in fact, you were wrong, and then you had a bunch of patients that you had given less than enough therapy? I can't think of the fact that you have. But was that a concern as you were designing these? Every clinical trial is a concern. And yes, there was a concern. But we believed that we were basing these trials on objective data, data that were generated through clinical trials and the scientific method. So let me ask another question, because I was never in the NSABP, but I was always struck by the fact that your statisticians sat at the table and thought as much about the biology as they did the p-values. Do you want to talk about some of the statisticians you've had the chance to work with? Absolutely. I think that's an accurate description. Carol Redmond was the first statistician with whom I came in contact and was an integral part of clinical trial development, discussing not only sample size, p-values, interim analyses, but also the biology of the disease and what the biologic end points were going to be, and what the ancillary end points ought to be, and calculate appropriate sample sizes to answer these questions. We were very fortunate to have outstanding biostatisticians who were giants. Sam Weiand, who followed Carol Redmond, who was at the University of Pittsburgh, went to the Mayo Clinic, and returned to us around 1994, '95, and John Bryant, who was absolutely instrumental in the joint analysis for the Herceptin trials, B-31 and N9831, who was a driving force, and was certainly a driving force behind the development of the Oncotype DX genomic profiling. These weren't simply numbers people. They were colleagues. They were part of the assault on the hill. I have to jump in for two reasons. One is I never worked directly with John Bryant, but I can't say how many times I called him and said, what do you think of this? because I knew he would understand the biology as well as the statistics. I miss him dearly. He sadly passed away about a decade ago. As do I. The other is, as you know, we lost Jim Holland this year. My first presentation at CALGB, Dr. Holland was sitting in the back of the room and yelled from the back of the room, because he never used a microphone, not unlike my colleague on the line right now, by the way. Dr. Holland yelled from the back of the room, Hayes, if you need a statistician, it's not worth doing. And I said, well with all due respect, Dr. Holland, and there's a lot of respect here, I have to disagree with you. Did Dr. Fisher get along with the statisticians the way you have? Did he feel that this was a two-way street? Or were there times he said, my way or the highway? There's always robust dialogue and discussion. I think that both Bernie and I embraced our statisticians as colleagues. I have to be very careful. This was not unwelcome embracing. But they were always an integral part of developing and analyzing the protocol. And they were colleagues. And certainly, Bernie had that approach and philosophy as well. So let me, perhaps, describe in 1973, when I first arrived, what struck me as extraordinary. There was passion, excitement, drama. We weren't sure where we were going. But we knew we were getting there fast. And we embraced the journey, the quest. And that was an extraordinary time where we knew that the standard of care was going to be changed. We couldn't predict the outcomes, but we knew that what we were doing at the time would have a lasting impact on the field. Actually, that was my question, which was, did you realize what you were doing in the late '60s and early '70s was as exciting as it was? Sometimes, I think we're in the middle of something, and we don't realize how it's going to turn out. And you've just answered my question, which was it must have been years-- It was challenging the basic sanctity of the dogma, the tyranny that existed at the time. And that, in itself, was a courageous and extraordinary thing to do. And I have to say because of that work, and others, but we've seen a remarkable reduction in mortality due to breast cancer over the last 30 years, probably by more than a third, not quite half. And it's because of these kinds of challenges of dogma and courage to move forward. So I think we all owe you and Dr. Fisher and those who were involved in the early days, then also in the other groups, just an enormous debt of gratitude. My final question to you, Norm, and everybody asks this where did you get your style of presentation? I've argued, although I know you're Jewish, you could have been a Baptist minister. Where did this come from? I have no idea. Everybody loves it. Well, that's certainly very gracious of you, Dan. I've certainly, in the era of protocol B-04 and B-06, I have been summarily booed by an audience in unison. So that may not be a uniform perception. Well, I hope that our listeners who are driving to work or having their morning cup of coffee and listening to this have enjoyed it. I certainly have. Thank you for being so gracious and taking the time to do this. Thank you for all your contributions to the field and for mentoring so many, including myself, frankly. And I consider you a great mentor and a great friend. So I appreciate it deeply. Thank you, Dan. It's been my privilege.