Dec 7, 2018
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 ASCO's podcast series of cancer stories. I'm Dr. Daniel Hayes, a medical oncologist and a translational researcher at the University of Michigan Rogel Cancer Center, and I'm also the past president of ASCO. Over the next several podcasts, I'm privileged to be your host for a series of interviews with the founders of our field.
Over the last 40 years, I've been fortunate to have been trained, mentored, and inspired by many of these pioneers. It's my hope that through these conversations, 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 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 where we offer patients better treatments, and we're also able to support them and their families during and after cancer treatment.
Today, I'm fortunate to have my guest on this podcast as Dr. Saul Rosenberg, who is generally considered one of the pioneers of cancer chemotherapy, especially for lymphomas.
Dr. Rosenberg is currently a professor emeritus at Stanford University, where he served as the director of the lymphoma program for several decades dating to the early 1960s.
Dr. Rosenberg was raised in Cleveland, where he went to medical school at Case Western Reserve and followed that with an internship at University Hospitals in Cleveland. He then did his residency at Harvard's Peter Bent Brigham, now the Brigham and Women's Hospital in Boston, and completed a fellowship at Memorial Sloan Kettering in 1958.
He then moved to the west coast, where he joined the radiation oncologist, Dr. Henry Kaplan, to transform the approach towards lymphoma from one that was principally radiation-based to using radiation and combination chemotherapy.
Dr. Rosenberg has authored over 150 peer reviewed papers. He has edited several textbooks, in particular one of the classic textbooks on lymphoma. And his teaching and his mentoring skills are legendary among Stanford trainees and frankly as well as the rest of us.
Dr. Rosenberg has won more awards than I can count, but most importantly to me is that he also served as president of ASCO in 1982 and 1983.
Dr. Rosenberg, welcome to our program.
Thank you. I'm glad to be there. One thing you did not mention [INAUDIBLE] was I spent six years in the radiation oncology laboratory while I was in medical school. That helped start me on my career very much.
Actually, you beat me to the punch. I didn't mention it, but I was going to ask you if you had trained there.
In fact, that segues. I know you grew up in Cleveland. Can you tell us just a bit more about your background? I know that you entered college at a pretty young age during World War II and then had to step out for a while. Can you give us the background and your circumstances and what led to all that?
All that's true. I tried to get into medical school when I was 17 in order to not get into World War II. That wasn't successful at the medical school for various reasons. They thought I was too young and they'd [? hit ?] Jewish quota, so I dropped out for a while, went back to night school, and then reapplied when I was 22. They didn't accept me at that time because of my unusual activities, and so they assigned me to a research lab that I did not pick, which was the atomic energy research lab in Cleveland.
It had the initial goal to teach radiation oncologists and to use radioisotopes, but that set my whole career toward radiation. And during the two years in the lab and then four years in medical school, I studied radiation oncology, radioisotopes, tumors, and I developed a great interest in the lymphomas at that time.
So did you ever actually then do clinical radiation oncology, or this was all when you were in med school before you became faculty?
It was all before my faculty, but I've always been a member of the radiotherapy department. I've taken courses in radiation research and physics, and I'm an honorary member of the radiation societies.
That's terrific. And so that must have served you well when you worked with Dr. Kaplan.
It was necessary because I presented papers at the radiation meetings, and he recognized me, and when I was searching for a job and the one worked out perfectly at Stanford. And that's how we connected.
So can we go back for a moment? I'm very interested in these interviews in why, for example, you chose to go into medicine in the first place. What led to that?
And more importantly, especially in the 1950s, when there was no real medical oncology, what got you into doing medical oncology?
Well, medical oncology was all an accident because I went into this laboratory and studied radiation in tumors. Before I went to medical school, I didn't have any particular interest in that. When I was a youngster-- five, six, 10 years old-- no one in my family had ever gone to college. Nobody was a professional.
But the most respected man in our community was our primary care physician. And since I was a good student, my family and my teachers all encouraged me to try to continue to go to college and be a doctor. And that's what I did.
You sure did.
Actually, the other thing that was fascinating to me when I looked over your background was your days at Memorial. And so that must have overlapped for sure with Dr. Karnofsky. Can you give us some war stories of that time and what he was like?
Well, again, there was a great mistake that turned out so well. There was no oncology program when I left the Brigham, and I wanted to study chemotherapy and medical oncology. The only fellowship was called medical neoplasia, which I applied to at Memorial where David Karnofsky was.
I received that fellowship, and in July of 1957, I went to Dr. Karnofsky's office. And he said, "You didn't have a fellowship with me. You have one with Lloyd Craver."
So in fact I spent that time not with Dr. Karnofsky but with Dr. Lloyd Craver, who turned out to be the leading lymphoma specialist in the world. And I learned more about lymphoma during that year than anyone could possibly teach me.
I did, of course, know Dr. Karnofsky and during that fellowship period, I was acquainted with chemotherapy, nitrogen mustard, [INAUDIBLE] antagonists and [INAUDIBLE] antagonists. So it was a combination of some chemotherapy but mostly lymphoma research. And that set my whole career-- that mistake. I didn't have a fellowship with Karnofsky.
I actually always worry about someone I interview who knows exactly what they want to do. I usually say, you know, most of what I did was by luck. [LAUGHS] So sounds like you were too.
You know, with both of them, how are they putting things together for the treatment of one problem, though? Is it just let's pull stuff off the shelf, or was there actually some direction in terms of the science they understood at the time? What was the atmosphere at the time?
Well, it was very minimal. We had only three lymphomas that we knew we diagnosed-- giant follicular lymphoma, small cell lymphoma, and reticulum cell sarcoma, and of course Hodgkin's disease. But the pathology was so crude that there were very little specific therapies or much difference among the approaches to them. We, of course, used radiation therapy for local treatment.
And of interest was that with Dr. Craver, I would make rounds, and we would decide where to give the radiotherapy. We'd outline it on the patient with a red crayon, and we'd write a prescription for the radiotherapy and send them down to radiotherapy.
Now that's a remarkable story, because nobody nowadays could even believe that internists could do that.
It's unbelievable. Actually, I interviewed Dr. [? Hellman ?] for a previous one, and he gave a similar story that there were very few technicians, and you just kind of drew crayons on the patient and sent them down. [LAUGHS] It's a lot different than it is today.
Yes, it is.
But the interesting thing was there were no computers at that time, and Dr. Craver's experience with lymphoma-- there were 1,269 cases that I reviewed for him and wrote a wonderful paper, I thought. It was published in Medicine in 1961 on 1,269 cases of a lymphosarcoma. And that set my whole career and my experience that was far above most other people of my age and my training. And that's what really made my career was that study.
Now, we had no computer, but we had a IBM cell sorter-- card sorter. And I completed 240 questions on each of 1,269 patients according to their charts, and the data I had was terrific.
So you did that with shoe boxes full of punch cards?
Oh, at least eight box-fuls because we had 1,269 cases-- three cards for each patient. But the card sorter could just spin out anything that I wanted to know and had so much data that there was no computer. And we had that-- was the first of the data systems that made it possible. And--
And you did all the chart reviews yourself?
I did all of it myself because I was disappointed I wasn't with Dr. Karnofsky. But I made the best I could. And it was actually a wonderful experience with Lloyd Craver.
Now, were most of those patients treated with radiation or was chemotherapy part of the game yet?
Well, we didn't have much chemotherapy at that time. We had steroids. We had radiation. We began to have some Leukeran and Cytoxin by the time I left there, but most of it was radiation and medical treatments with steroids. And very few patients had prolonged survivals, except for the follicular lymphomas which have such a good natural history.
Yeah. You mentioned that the very few classifications of the lymphomas-- can you give us some insight into when-- I live in Ann Arbor, for example, so the Ann Arbor classification, of course, is near and dear to the hearts here. But how did that all begin? I know you were involved in that early on too.
Well, I did very much. And the important work was done by three people-- Henry Rapoport, who at the time was in Chicago, Robert Lukes, who was in USC, and the German group. And they began to separate out the different forms of lymphoma. Henry Rapoport described the difference between follicular and small cell. And Lukes was careful about the Hodgkin's disease.
So their classifications began to be used in the 1950s and in the early 1960s. And they make dramatic differences. Ron Dorfman was a student of Rapoport at the time, though he came from South Africa. And fortunately, he came to Stanford, and that gave us a really-- step ahead on good classification.
Eventually, there was great debate about which the right classification it was. And we did a study for three years comparing six classifications around the world and which one gave the most data. And I was the principal investigator of that, and that led to a unusual classification called the National-- I can't even remember the name of it now. But it was a very unusual name, and nobody adopted it. Eventually this classification was dropped, and the new classification came out with immune markers and made a great difference.
But that classification in pathology was the stimulus that led to the more modern treatments of that time. And that was one of the great advances that led to two important research studies-- one in Paris and one in Rye, New York, which were virtually entitled "The obstacles to the control of Hodgkin's disease." But the pathology classification systems facilitated that along with tremendous advances in radiotherapy.
And I would assume almost-- what's called precision medicine now and targeted therapies-- those allowed you to begin to separate out patients who really didn't need systemic therapy and those who were more likely to benefit from the chemotherapy part of it. That must have really been an eye opener for you as you began to realize that.
Well, chemotherapy began to become more successful, of course, for leukemias and lymphomas during that period of the 1960s-- the early '60s. But radiotherapy was the only successful treatment that could control disease for long periods of time until good chemotherapy and combination chemotherapy became available. But the radiotherapy advances really advanced the treatment of Hodgkin's disease and some of the lymphomas dramatically.
So that actually, in some ways, segues to my next set of questions. How do you get from New York to Stanford? You said Dr. Kaplan had seen you present. Did he see you as joining him as another radiation oncologist, or did he see you as bringing in the therapy to complement what he did?
Well, the truth is I was offered a job at Harvard by Farber, and he told me I could treat patients with cancer at the Brigham, but not lymphoma and leukemia. So then I went back to Cleveland, where they did offer me a job in radiotherapy. But the new chairman of medicine did not think that oncology was an appropriate field for medicine. So I had to call Henry Kaplan as a third choice. And he rapidly accepted me and insisted that I had a role in the department of medicine, which they gave me. So I had faculty appointments in both, which I still have today.
Why did Farber not allow you to treat lymphoma?
Because he thought it was his property. He didn't want it over in the other hospital.
Ah ha. That's-- he had passed away before I got to what was then the Sidney Farber Cancer Institute, but I've heard stories like that.
So when you got to Stanford then, how did you all start working at chemotherapy? I know that was before the time that the folks at the NCI had really reported the high response rates with combinations. You must have taken that along with you.
Well, I knew that, but the treatments with more than one drug wasn't really popular at least until the early '60s. When I got to Stanford, they put me in the hematology department where I was supposed to do hematology, which I only had minimal training in. But I had a lab in radiation oncology, and I was in the clinic with Henry Kaplan, and we decided that we would treat Hodgkin's disease because of the development in radiotherapy.
But I insisted that I would treat cancer in the department of medicine, and that was not popular anywhere in the country. And after they found out I couldn't do much red cell medicine, I started a program for cancer patients, and we needed a name for it.
And I got together with four people, BJ Kennedy, Paul Carbone, and the fellow at Hopkins-- what's his name? I'll remember it. But with four of us decided that we would have cancer treatments in the departments of medicine, and we would call it oncology. And that's where the name began.
And several of them at Hopkins and at Minnesota had separate departments of oncology-- eventually departments of cancer. So it was very unpopular in departments of medicine, and hematologists to try to prevent us from treating cancer in departments of medicine for at least 10 or 15 years.
Gradually, we established what we were, and now it's one of the largest divisions of most departments of medicine.
Yeah, I think most of our younger colleagues would be surprised by that. I came in in the early '80s and was struck by the fact that most of the major departments of medicine had given oncology away because they felt that the smart folks were working on in red cell stuff, as you pointed out, and the dumb folks could go get 5-FU. What they didn't realize was that there was a tsunami of academic interest and advances just down the pike. And it's interesting that you had to go make your own department just to be able to do that.
What were the facilities you had at Stanford to give chemotherapy? Did you just have a nurse that followed you around and gave it, or did you actually have a fusion space or--
Nothing like that. I separated from the hematology clinic, and I would see patients in my own room. There was only one room. I found one fellow who had trained as an [? NCI ?] named Richard Shaw. And we began treating patients with breast cancer and ovarian cancer and children with various childhood malignancies and leukemia.
And curiously, when we gave nitrogen mustard, we did it in the hallway of our clinic, and start an IV and mix up the nitrogen mustard and inject it rapidly.
There were no infusions facilities whatsoever. It took many months and years to develop what you now think of as a cancer clinic.
So you mixed up your own chemotherapy?
We did, and I treated any kind of cancer, including children. And we began to see some responses. But the drugs began to come in in which we had a little bit of benefit, but before we could get combination chemotherapy, especially for the lymphomas and leukemias, we didn't have a lot of success.
And how did you get Referrals As the department of medicine didn't like what you were doing, did they all come from the surgeons and the radiation oncologist or--
Where'd they come from?
Mostly referrals, but also Stanford began to let it be known that we would see patients with cancer and make a diagnosis and refer them to the proper departments for treatment, and that we had medical treatment. So we attracted patients from the community. Stanford didn't have a big clinical program until it was transferred from San Francisco, but our cancer program became known.
I must give great credit to Henry Kaplan, who was a tremendous power and leader of the field. And that attracted a lot of cancer patients to Stanford. And of course, you know that Henry Kaplan and his colleagues invented the linear accelerator, and that made a huge difference in the way we treat patients even today. So he and Ed Gintzon, who is a linear accelerator man, invented the linear accelerator which provided us with super voltage therapy of one million electron volts or more. And that completely revolutionized the treatment of cancer.
Yeah, even when I broke in in the early '80s, that was not universally around, but you would see patients who basically were put in front of the machine. They turned it on for a couple seconds-- not at Harvard but outside the Harvard. I know nothing about radiation oncology, except I knew that wasn't right. [LAUGHS] And so we owe Dr. Kaplan for lots of reasons, really-- in great debt, but that probably is one the greatest step forwards.
Can I ask another question. I've always been struck that you were one of the early proponents of randomized trials of lymphoma. That must have taken a lot of courage.
Well, it was necessary for me because Henry Kaplan wanted to use very broad fields in high doses, and he thought that he was improving the cure and survival of patients.
And I admired that and accepted it, but I thought that he was giving too much-- too wide a field and too high a dose for various reasons. So I insisted that if I were to see patients in radiotherapy that we would do trials that would compare two strengths of treatment primarily with radiotherapy-- one with very extended fields and high dose and to just the involved sites. And that's what my program was. And he wanted to extend the fields beyond where the disease was.
And we did randomized studies beginning in 1962. They were one of the very first clinical trials that were done in cancer and certainly the first ones in lymphoma. And those clinical trials modified and went on for years. We gradually proved that both of us were correct. Neither of us had an advantage over one or the other, but we learned a great deal about the diseases and their natural history and how to modify the treatments. And of course, eventually chemotherapy came in, and we combined it.
But it's a very long story the trials continue to today. We've treated over 3,000 patients with Hodgkin's disease on these trials. And we couldn't have been more successful.
Yeah, I think and again that was just about the time that Dr. Fry and others were starting the cooperative groups that could do randomized trials in those days. And you couldn't have had many role models. And again, "courage" is the word I coming up with to get patients to agree to be in a trial where the treatment wasn't assigned until after they signed up. These days we take it for granted, but it was not then true.
Well, it's true, but also Dr. Kaplan and I were very good clinicians, and patients trusted us. And they all accepted going on trial as long as both of us agreed that we didn't know the best thing to do. So that was the basis for a randomized trial. And our numbers of our patients were very small-- would never be accepted today as a trial. In fact, we could-- our statistics would not really show the advantage of one treatment over the other.
But what our statistics showed was we had patients surviving with a relapse free period-- a plateau-- that went beyond 10 years. And that was unknown in Hodgkin's disease at the time. It became unknown in large cell lymphoma as well as at the time.
The late Jim Holland who I loved and helped mentor me in some ways, but when I first joined [? TLGB ?] was sitting in the back of the room when I was presenting the proposal for randomized trials and yelled from the back of the room, "Hayes, if you need a statistician, it's not worth doing."
I said, "With all due respect, Dr. Holland, I think it is-- we're doing. But we need a statistician for that." [LAUGHS]
All right, so Dan, I had this same argument with J. Fry, right? He said that it was a scandal to have a control group. And I remember in public meetings, I would tell him only you and God know the difference between these two groups.
We argued for 50 years until he finally came to Stanford as a visiting professor, and we connected and admired each other's work tremendously.
I want to ask another question. You've been involved with ASCO almost from the start, I think, and I noted you were present in the early 1980s. What made you run for president of ASCO? In those days, there wasn't much of an organization. It was 3,000 or 4,000 people. What did you see in ASCO that maybe others didn't at the time?
Well, I was forced to join by Vince DeVita. He was a member a few years before I was, and he talked about what he thought was right. And I thought that I was right. But the society made a big difference about bringing us together. And then Al Owens, who was at Hopkins, became president, and he invited me to be on the board and then to be his program director. So that's how I got in. Both DeVita and Owens forced me to join them. Then I became a member of the group and committed to it because there was so much value in sharing our information and data.
Well, I don't want to put you on the spot. This year we had 43,000 attendees at the meeting, I believe, in Chicago. Do you recall what year and where your first meeting was, and how many people were there?
I can't recall.
I think when I was president, there were about 8,000 attendees at the meeting. And we all went from one city to the other-- San Diego, New Orleans, St. Louis, San Francisco. But it got out of hand when we got up to $25,000, and the only place we can meet was in Chicago, which was a great loss because Chicago is a great city, but it was great fun to go all over the country.
Yeah, I think we'd agree with both of those, but Chicago handles this pretty well. So it's worked pretty well.
We're starting to run out of time a little bit, and I want to ask you a big picture question. And you've hit some of these. So what really is your legacy? How would you like the world to remember what Saul Rosenberg has contributed to the field? Is it your science or the administration issues you set up so that people actually accepted our field or the teaching and mentoring? I mean, you've mentored, in my opinion, some of the great oncologists in the world. How do you think this will come out for you?
There's only three things that I'm going to leave after me-- my children, my students, and my patients. And my advances for treatment were tremendous but are all now overturned and built upon. But my students, whether it be medical students or postdocs or my colleagues, were my greatest advance. I am so proud that they have succeeded so much. I felt that I have been a trunk of a tree, and every branch that comes off carries twigs and flowers and plants and exaggerate or emphasize-- multiply what I have done just because I started them off.
So nothing has been more important to me than to be a good teacher. And my students all know that I'm a wonderful doctor. That's what they tell me. And to be a careful, caring physician, how to talk to patients, how to examine them, how to tell them good news and bad news-- the skill of being a medical oncologist, and actually to be a physician in general is such a joy. I mean, to have these people depend on us and believe in us the moment you walk in the room, if you're gentle and you know how to touch them and to talk to them-- this is such a joy. I can't think of any other word in being a physician but especially being a medical oncologist. It has been a joy.
And are you still seeing patients?
I saw several this week. I've cut way back.
I see patients every other Monday. I see mostly my old patients or recent Hodgkin's patients, but gradually fewer and fewer. But there's-- I have 20 patients, perhaps, I won't give up. None of them have lymphoma anymore, but they all have complications of treatment, and they will not let me retire.
And 60 years ago, did you think you'd say that you have a bunch of patients who look like they're cured of lymphoma?
Yeah, it's something else.
Well, Dr. Rosenberg, you've been a great role model for all of us in the field, and we very much appreciate what you've contributed. I have to say your final statement is very similar to what other people have said to me as well-- George Canellos and others-- about their greatest accomplishments are the people they trained, and those of us who you have trained take that very seriously.
So thank you.
It's a great honor to talk to you. I hope the new therapies-- immunotherapies-- are going to make a big difference. I think they have promised to do so. And sometimes I get to be cynical. I mean, I've been through about six waves of great enthusiasm in treating cancer, chemotherapy, immunotherapy, the old-time advances in radiotherapy, genetics. And gradually there's been improvements but not the great breakthroughs that I want to see. Maybe this new approach will make a difference. I hope so.
Yeah, it looks like it. I said to a first year fellow last week that never in my lifetime could I think I'd say it looks like 20% of people with metastatic melanoma may be cured, and that looks like what's happening. That's pretty exciting, I think.
How about 90%--
--of Hodgkin's patients?
Well, actually a lot of that you had already knocked off before I got in the field.
Yeah, and I thought this is going to happen again. And it didn't for quite some time. But I agree with you. I think things right now are really, really starting to happen.
And we actually have just scratched the surface of the immunotherapy world. I think there are a bunch more checkpoints that are going to be discovered and therapies for them. So the toxicities are considerable, but as Dr. Fry always taught us, "Cure the cancer first, and we'll figure out how to take care of the toxicities later." And I think that's a pretty good strategy, actually.
Thank you. I actually--
OK, that's all. Thank you very much. I really enjoyed this.
You know, I've told other people it's like if I hop in a cab with Saul Rosenberg, what would I ask him for the next 35 or 40 minutes on the way to the airport? So this is fun for me.
All right. Thank you for asking me.
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