Aug 7, 2020
Dr. Hayes interviews Dr. Canellos on his involvement with CHOP, MOPP and CMF as well as his role as Chief of Division of Med Onc at SFCI/DFCI for 25 years.
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Hello. Today my guest on the podcast is Dr. George Canellos. Dr. Canellos was instrumental in early treatments for breast cancer, lymphomas, -- and chronic leukemias, and he's generally considered one of the so-called Gang of Five with the National Cancer Institute in the 1970s, along with Drs. Vince DeVita, Robert Young, Bruce Chabner, and Philip Schein, who ultimately demonstrated that chemotherapy could be used to cure a fraction of patients with Hodgkin's and non-Hodgkin's lymphomas.
Dr. Canellos was raised in Boston, and he attended Boston Latin School. He then received his undergraduate degree at Harvard and his medical degree at Columbia in New York City. But he remained a Red Sox fan, so he returned to Boston for his residency in internal medicine at Massachusetts General Hospital. But he then trained in oncology at the National Cancer Institute where he stayed until 1974 when he once again returned to Boston to join the faculty of the then Sidney Farber Cancer Institute where he served as the Chief of Medical Oncology until 1995.
He is currently the William Rosenberg Chair at Medicine at the now Dana Farber Cancer Institute and a Professor of Medicine at Harvard Medical School. Dr. Canellos has authored over 300 peer-reviewed papers and too many reviews and chapters to name. Most importantly, he served as the Second Editor in Chief of the Journal of Clinical Oncology, a role he filled from 1987 until 2001. And during that time, he directed the Journal to become the leading journal in our field.
Perhaps even more importantly, he served as ASCO President in 1993 and 1994, and he's been recognized as an ASCO Oncology Luminary, and he's been recognized with the Statesman Award and the Distinguished Service Award for Scientific Achievement from our society. Dr. Canellos, welcome to our program.
Good to talk to you.
Great to talk to you. You know, I spent a lot of time with you at the Sidney Farber and then Dana Farber Cancer Institute, and I've heard you say, and I've also read, that you originally seriously considered becoming a surgeon because of the work you did with Dr. Oliver Cope, one of the leaders in surgery of our last century and especially related to thyroid and other cancers. So what led you to get away from surgery and become a medical oncologist?
Well, I served as a surgical intern at Mass General at that time, which was a lot of exposure to serious illness and surgery. But it dawned on me. Two things dawned on me. One is that if one was interested at all in malignancy that surgery really wasn't the answer, certainly, in any way. And in those days, of course, even radiotherapy was not the answer.
And so the other thing I realized, that I had the manual dexterity of a California fur seal. I didn't really feel, being left-handed, I didn't feel that I really had the dexterity required to do some of the complicated surgery that was going on in those days because I held retractors as an intern for some very long operations that really didn't achieve more than taking out a gallbladder. It took three hours. Now, we can do it with a laparoscope in a half an hour, probably.
So I switched into medicine at Mass General and stayed in medicine at Mass General. And being inspired to really think about other treatments for malignancy in those days, there were very few really textbooks available that talked about chemo. There was some. I would nip up to the library of the hospital rarely and try to read about them. There were new drugs coming out at that time, but there was very little really known about the action of the drugs and the potential of the drugs that might have existed at that time.
Then I went to NCI, as one had to because there was a doctor draft. And two years of residency in medicine, I actually went to the medicine branch of the NCI. And there, under Emil Frei III, another investigator named Freireich, Jay Freireich, who were around at that time and running the program, such as it was, we first were experience-- I was thinking that I would do research there, and I did. But at the same time, the Clinical Associate Program entailed a year of clinical exposure, of clinical care, and I had several colleagues.
The first major colleague was Vincent DeVita who really, at that time, decided to approach a treatable more solid malignancy, as acute leukemia of childhood was being approached, with combination chemotherapy. However, there weren't many drugs that were very active at that time. There were some. An alkylating agent, nitrogen mustard, steroids, a vinca alkaloid that had just been relatively new introduced for adult disease.
And there was no procarbazine. Of course, it hadn't been invented yet, but methotrexate. And so the first combination regimen that came out of that program was MOMP, M-O-M-P, and that had some activity, but it was only given for a relatively short period of time. Eventually, the tolerance of patients to these drugs was considerable, a considerable issue, because we didn't really have granulocyte support. There were a lot of things that we'd take for granted now that were not available then.
So the toxicity of some of these programs, such as the M-O-P-P Program when procarbazine came along, the MOPP program was considerable. But the interesting thing is the patients that we had were generally on the younger side, younger than 45, let's say, and they could tolerate the therapy. And I found that, honestly and subsequently, with testes cancer, that younger people who get a lot of toxicity from these drugs, despite that, if they think there may be a cure around the corner, will tolerate it.
And you don't hear a great deal of complaints about it, about the toxicity, interestingly. But the older patients, of course, are far more vulnerable. Their bone marrow reserve not being great, these regimens were quite toxic. But, fortunately, the first targeted disease was Hodgkin's disease, and it's generally a disease confined to younger people, in general. About 20% of them are in the older group.
But we first tested the aggressive chemotherapy, known as MOPP, in the younger patients, actually. But what was surprising to us, and surprising to everybody, was the fact that they failed to relapse as they were all expected to do at that time. In the single drug agent era, of course, Hodgkin's disease would relapse eventually. As house officers, we just expected that to happen.
Now, the training in the major academic hospitals in those days, oncology was not an important part, or even a desired part, of the program, if you will. And so most who arrived at a place like NIH really didn't have much background at all in the treatment of cancer because they probably didn't see it all that much. I know I didn't. As a surgeon, yes, but not as internal medicine.
I was going to ask you that. When you were at Mass General and you said you noticed that surgery wasn't curing people, there couldn't have been anybody around that was mentoring you or said, why don't you-- how did you even hear about--
No, no, there wasn't. There were some docs there who really cut their teeth on giving hormones to breast cancer patients, and that was about it. But very few people were giving-- I couldn't think of anybody who was giving-- one person who was giving chemotherapy, a lady, a fine lady, fine physician actually, but on the private side, but nobody on the academic side that amounted--
So what made you-- What made you say, I'm going to go to the NCI and learn how to do this? I mean, that seems like that was completely out of the blue.
Well, you weren't given much choice. Of the two institutes, I applied at the Heart Institute and the Cancer Institute. The Cancer Institute accepted me, and the same with Vince DeVita. He applied to the Heart Institute but got into the Cancer Institute. And we were both there, probably you could say, as our second choice at the time. Because--
Yeah, that's interesting.
Yeah. Very little was known about oncology as a field, and there we were. On the other hand, seeing these patients at least respond to these drugs in the way they did, and seemingly not relapsing, made you wonder whether or not, in time-- when I went back to the NIH, I came back to the MGH to be a senior medical resident. I can tell you what was interesting, because there was no oncology Fellow, per se.
They would ask me to see a patient if the patient had a malignancy. And I remember going in and seeing a patient with ovarian cancer. She had a huge belly full of ascites, malignant ascites, and I said that the drug for this disease is thiotepa, an alkylating agent. I wrote out the recipe, if you will, how many milligrams, et cetera. And I wrote in the note, and I will give the first dose, which I did.
The intern covering the service, a surgical intern covering the GYN service, obviously read part of my note but not all of it, or decided he was going to give another dose as well, but somehow the woman was double-dosed. And there was a certain panic by the nursing staff, et cetera. She tolerated the drug surprisingly well. But more surprising, everything went away. She had this dramatic response to therapy. The ascites went away. The abdominal masses went away. And she was discharged.
And I said to myself, at that time, this is a precedent for something, and that era will arrive once-- if it's not the right drug, we'll find the right drug for the disease. But I can tell you, it was very uplifting to me. I had already been to NIH.
That's a great story. When you guys were at the NCI, a similar question is, when did the light bulb come on that it looked like you were actually curing Hodgkin's disease?
Well, you're talking about a two-year appointment. At the end of the two years there, the remissions were already clear. That is to say, the disease had not come back, and the people were being followed. But two years is just two years. I mean, it's not a long time.
And when I went back on the faculty-- see, I went for a year in England to become a hematologist because everybody had to be a hematologist in those days if you were interested in cancer. Anyway, that's what I did. And when I got back, they recruited me to the faculty, and the patients were still in remission, and that was great.
And then we put our attention to the non-Hodgkin's lymphomas and modified the MOP regimen by putting cyclophosphamide instead of nitrogen mustard, which was a horrific drug by the way, nitrogen mustard in the doses that we gave. But like it or not, we put Cytoxan into it and we called it CMOP. It was like MOP but it was with C instead of the M. So we called it CMOP.
And early in the 1970s, we did a randomized trial with the radiotherapists who were throwing radiation at everything that walked in with a non-Hodgkin's lymphomas, and we did a prospective randomized trial stage by stage, histology by histology. And I remember looking at the data for the large cell lymphomas with the CMOP and I said, Vince, you know, if we judged everything by median, the median survival of our patients was what you'd expect historically. But just below the median, the line straightened up, flattened out, and was going out now several years, at least four or five years, flat in a disease that usually recurred very quickly and killed everybody who was affected by it.
And I remember when the Board of Internal Medicine decided to create a specialty called Medical Oncology and have an exam, et cetera, Vince thought it was because of Hodgkin's. And I'm sure it contributed, but I said it must be also the non-Hodgkin's because it's far more common. It's far more common. We helped far more people. And indeed, it probably is.
Can I interrupt you for a moment? I interviewed Saul Rosenberg for this series, and he told me just [INAUDIBLE] the radiation psychologist. So Dr. Kaplan had referred to him from Memorial to come to Stanford and do radiation, and Dr. Rosenberg told Dr. Kaplan, I think we need to give these people chemotherapy, and Kaplan agree. But the Chair of Medicine did not and would not let Rosenberg see patients in his own clinic and give chemotherapy.
So he wrangled a room from a hematologist, and he told me he would see patients in the room. He had a chair in the hallway. If the patient needed chemotherapy, he'd have the patient go sit in the chair in the hallway. Get an IV pole. He'd start the IV himself and then mix up the chemotherapy himself, hang it up. While the patient was getting chemotherapy in the hallway, he'd see the next patient in the room. Those are the kinds of obstacles he had to do.
And the other thing I have to say, I didn't get to interview Dr. Holland before he passed away, but relative to your looking at the Kaplan-Meier curves, I'll never forget his yelling at me one time that, if you need a statistician to see what you've done, you probably haven't done much.
I said that, 'cause I remember saying that as well, but anyway.
Let me ask you another question.
You're know for lymphoma and chronic leukemias but also for breast cancer, and generally you're credited for coming up with the so-called CMF regimen.
Vince and I were called into the director's office. At that time, the director of NCI was [INAUDIBLE]. And they said, all this lymphoma stuff is wonderful, but we want you to do solids. Now, we didn't have a referral pattern for solids at all. The only breast patients we saw were relatives of employees of the NCI. So Vince wanted to do ovarian, and I said ovarian is a good disease because they have malignant cells floating around, and we can do stuff on those. And Vince really wanted to do ovarian.
I chose breast. And, again, we had no mastectomy surgical group or anything. And so what we did was make deals with medical oncologists in the community, two of them who actually trained-- one of them trained at the Brigham Hospital, actually, and they lived in the area. And they liked to come to our conferences and things.
They would refer patients. And what we specified, initially, was that we have patients without isolated bone lesions only, that they had to have measurable lumpy, bumpy disease. And so to design a therapeutic treatment for them, we had to use the principles that we learned from the lymphoma experience. And that's where CMF came. CMFP, we used to have prednisone in some circumstance. And so that was the regimen that-- if you notice, the design of it would be like the MOP program.
Anyway, so we started treating people like that. Suddenly, they did respond and some responded quite well. They had some toxicity, of course. And the very first paper we wrote was on the toxicity of CMFP. It was hard to get things published in medical oncology areas, and the Lancet was wonderful for us. The Lancet was very helpful, and we published a lot of stuff in the Lancet.
But the first one was in the British Medical Journal, the toxicity of CMF program in patients, and we especially cautioned patients who had compromised liver function because they seemed to get worse toxicity at that time in our imagination. But it worked. It did work. We published it in the Annals of Internal Medicine eventually.
But the important thing was, our friend Johnny Bonadonna would come over periodically to find out what we were doing. And he came over with an offer. He said he had all these patients who would get mastectomies and then nothing.
Let me interrupt you for a moment 'cause I was going to ask you about Dr. Bonadonna.
Would you, just for the audience, a lot of them may not know who he is.
Oh. Well, Johnny Bona-- Do you want me to describe him? Well, at that time, he was a young investigator working in Milan at the major hospital there in oncology, and he trained at Memorial before and then went but back to Italy. So he came and he wanted to know what we were doing. We showed him the protocol that we were doing for breast, and he was interested.
And what he offered was the opportunity of doing a randomized trial on patients with a higher risk, if you will, breast cancer, node-positive patients. And he said that in Italy that nothing was done for them and that he could randomize them nothing to chemotherapy, and we offered him a contract. He required money. We gave him a contract. We gave him our protocol, at least the chemotherapy protocol.
He went back to Italy and did that trial. And he left the prednisone out. He made sure it was of just CMF. And the patients, apparently, I guess, knew what they were getting, but I don't know whether they had strict requirements or informed consent and things like that. We didn't ask. We didn't ask. All we wanted was randomized data, and he certainly had it.
And I remember being at the ASCO meeting in 1976, I think it was, '75 or '76, in Toronto when the first data was presented by Bonadonna. And the media people were there. People were barely hanging from the rafters to hear. The room wasn't big enough, really. None of the rooms were big enough because they never expected the attendance, that there were that many young oncologists around or people interested in oncology. And so he gave that first data, and that was a shot in the arm for adjuvant therapy, certainly for breast cancer, but for other things as well.
I think, in general, he and Dr. Fisher, who sadly passed away before I had a chance to interview him, are responsible for thousands and thousands of people.
Yeah. Absolutely. Absolutely. Absolutely. But I'm giving you the NCI side, my personal side of it, and you're right. Bernie was a real pioneer because he had so much opposition from the surgical establishment at the time. I can tell you that. From a surgeon's point of view, they really thought he was the Antichrist. I mean, it was terrible.
I saw him and Jerry Urban get into a verbal argument at a meeting. I thought it was going to be a fistfight, actually, over--
Really? Yes, yes. Yes, they're severe.
But anyway, let me go-- let me go to my next question, which has tended to change gears for a moment. You may or may not remember this, but when you were ASCO President, in your presidential address, I was in the audience and you said something to the effect that the greatest clinical experiment you have conducted are the Fellows you have trained, or something like that.
And I was in tears, of course. But you certainly can claim success on that. The division chiefs, department chairs, cancer center directors, most recently a Nobel Laureate, [INAUDIBLE], all of them came out of the program. But when you returned to Boston, you could not have envisioned all of this. What was the atmosphere, and what was Dr. Farber's vision?
Well, Dr. Farber had died by the time I got there.
Oh, he was already gone? OK.
He was already gone. And when I was leaving, when Tom Frei recruited me, Vince thought I was mad because they made me Clinical Director. At least have a go at acting job as clinical director of the NCI. But really, down the line, it was a bureaucratic evolution. And I said, I don't really want to be an oncocrat at this age, anyway.
What I said was, Vince, I said, the doctor draft is over. The best and the brightest and the youngest and the cheapest are all going to be in these hospitals, and there are a lot of them in Boston because I happen to know Boston, including house staff at the Brigham, house staff at the BI and Mass General. And I said, that's the future, or at least the future challenge.
And I think he accepted it, but he didn't like it. I mean, he thought-- well, we were great buddies and we worked well together, and that goes for Bob Young and Bruce Chabner too. They thought I was very--
Where else-- at that time, there must have only been two or three places to train in oncology in the whole country, I would imagine.
Yes, yes, yes. And people were just starting to set up cancer centers, sometimes without funding. And then there were all these, not many, but job requests for me to go and look at the job at Wisconsin or you name it, but I didn't want to do that. I really wanted to do medical oncology and not be a bureaucrat in any way. And many of the places, Dan, would say come and be a head of our cancer program, and it was also translated in parentheses, come and write a CORE grant. A lot of places who didn't deserve a CORE grant were asking me for people to come and write a CORE grant. You knew forever they would never get one because they really didn't have the makeup for it, yet.
So what were the hurdles in Boston when you got there?
Well, the hurdles in Boston were twofold. One is the fact that oncology had a very slow start in Boston, and that goes at the Brigham and at the MGH. The MGH was even disinterested in oncology at that time, actively disinterested. They didn't think it had any academic merit and therefore didn't put any effort into it.
I have to say that Gene Braunwald, who was Chief of Medicine at the Brigham at the time, was interested because he had been at NIH at the Heart Institute, he knew Tom Frei, and he wasn't sure about it yet because he couldn't swallow it, I guess. And the fact was that it was growing a bit, and one of his very close associates developed large cell lymphoma and he got chemotherapy, he got to see MOP. And he was long-term remission. And I remember telling Braunwald, he was shocked that it was so successful. And I kept telling him, I said, this is not a rare event. This is happening.
But the big challenge, Dan, at Dana Farber was that there was no oncology known, and we had to build the program from the bottom up. We hospitalized our patients at the Brigham before we opened the beds at the Dana Farber, but we needed the volume of patients. And we had all these beds, I think 59 beds, licensed beds, open. And I kept saying, we don't have the patients. But Tom Frei opened the beds. The next thing you know, I was talking to trustees because Tom said, we'll bring George up and we'll grow. The clinical program will grow.
So the trustees thought the program would probably grow the next day. It didn't. It took a lot of effort without the [? scare ?] and myself going around giving talks in every little hospital that existed. And one of the big things I had my mind, because the house staff looked after our patients as well, was to show them what we could do. Now, in those days, other than the large cell lymphomas, of which we did not have many because they were in the hands of hematologists, was testes cancer.
And the head of urology at the Brigham Hospital used to have these Saturday morning urology rounds inviting all of the practicing urologists around to come and they'd present their problem cases, et cetera. But he asked me to come along and give a talk about this new drug called cisplatin, which was having a big effect in testes cancer in other places. And I did. And I would come and talk about the early results in other places in testes cancer and that we were interested in actually starting a program.
Then, they would-- of course, urologists are anything but chemotherapists, and so they would refer the patients in because, A, they couldn't give any chemotherapy. There was nothing oral that would work. What we would do is, if they sent patients in, we would do an early trial and we would publish the series in a, let's say, not spectacular journal and get reprints. We would send them reprints.
And in some instances, I put the name of the referring doctor, if he'd sent us more than one patient, on the paper for, let's say, testing some antineoplastic thing. And we would put their names on the papers and send them reprints. And there's nothing a urologist loves more than to see his name on a scientific paper, a medical paper. And we started getting a ton of testes cases eventually and did trials and wrote papers about them.
And I remember, when we recruited Phil Kantoff, a Fellow of mine, and I thought he was going to go back to the NIH and do gene therapy. And he walked in one day and he said, I'd like to apply for the GU job, and I said, it's yours. And he wrote quite a few papers based on the accumulated testicular data and the [INAUDIBLE].
Yeah. And he was wonderful.
He's Chief of Medicine now at Memorial.
He's Chief of Medicine at Memorial, yes.
I want to bring up one more thing that this segues into, though, and I believe now almost every medical oncologist who has trained in the last 10 years thinks that multispecialty tumor boards have always existed. But I believe that another of your trainees, Dr. Craig Henderson, who was my mentor, frankly, and you really started the first multispecialty clinic perhaps in all of oncology in this country. Do you agree with that?
We called it the BEC, the Breast Evaluation Center. Yes, and we got cooperation but from surgeons. There were surgeons around, more nihilistic surgeons, if you will, not wanting to do radical surgery and radiotherapists, like Sam Hillman. And they were all around and doing those things. And we brought them into this BEC, the Breast Evaluation Center, and your mentor, Craig, was a little rough on the Fellows, I can tell you, in those days. Just his demands. Anyway, whatever it was.
And so I would go to that clinic as well and see breast patients just to calm things down a bit at times. Anyway, it worked. And I know that the breast people elsewhere were recognizing that Craig had a nice thing going there with the multidisciplinary aspects. You know, it was so awful that breast cancer was treated so badly.
I mean, they'd have a radical operation. And God knows, if there was some disease, that they would then get radical radiotherapy to their chest. And they were walking around sort of mutilated. And we had a part-time psychiatrist when I first arrived to see these patients because many of them had body image problems. So the idea of not doing radical mastectomy was revolutionary at that time.
And I remember being called by the local Blue Cross to serve on a committee to decide whether or not Blue Cross should pay for breast reconstruction on these poor patients, and we voted. There was a committee of medical oncologists from MGH, me, and a plastic surgeon, and we voted 3 to 3 to they should pay, and they didn't. Then they said, thank you for serving on this advisory committee, but we're not paying. We've decided not to pay.
Then, I can tell you, a women's agitation group got a hold of the facts. And one of them called me up and she said, I heard you were on this committee that voted not to pay. And I said, absolutely we voted to pay. They told us, thanks very much but we're not going to pay. So within two weeks then the insurance company changed its opinion because they went bananas at the insurance company.
Yeah. The strength of advocacy, that's been something. Anyway, we're running out of time. I'd like to thank you for taking your time with us.
Not at all, Dan. Not at all. It's a pleasure.
And as I have done for every other interview in this series, I want to thank you not just for taking time with us but for all you've done for the field, for those of us who trained with you or are in the field, and most importantly for all the patients who have benefited. You look back over the--
Yeah, I know. I still follow them. My clinic has follow-ups of cured patients. You become the primary care doc for cured patients.
Well, you think of the 60 years of your career and other fine folks that you were with at the NCI and then beyond, and the thousands or millions of people who have benefited, it's pretty remarkable.
Thanks again. I appreciate you being on.
Not at all.
And enjoy the rest of the day.
Thank you very much, Dan.
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