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.
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.
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Welcome to JCO's Cancer Stories, The Art of Oncology, brought to
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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.
Yeah.
You're know for lymphoma and chronic leukemias but also for breast
cancer, and generally you're credited for coming up with the
so-called CMF regimen.
Vince and I were called into the director's office. At that time,
the director of NCI was [INAUDIBLE]. And they said, all this
lymphoma stuff is wonderful, but we want you to do solids. Now, we
didn't have a referral pattern for solids at all. The only breast
patients we saw were relatives of employees of the NCI. So Vince
wanted to do ovarian, and I said ovarian is a good disease because
they have malignant cells floating around, and we can do stuff on
those. And Vince really wanted to do ovarian.
I chose breast. And, again, we had no mastectomy surgical group or
anything. And so what we did was make deals with medical
oncologists in the community, two of them who actually trained--
one of them trained at the Brigham Hospital, actually, and they
lived in the area. And they liked to come to our conferences and
things.
They would refer patients. And what we specified, initially, was
that we have patients without isolated bone lesions only, that they
had to have measurable lumpy, bumpy disease. And so to design a
therapeutic treatment for them, we had to use the principles that
we learned from the lymphoma experience. And that's where CMF came.
CMFP, we used to have prednisone in some circumstance. And so that
was the regimen that-- if you notice, the design of it would be
like the MOP program.
Anyway, so we started treating people like that. Suddenly, they did
respond and some responded quite well. They had some toxicity, of
course. And the very first paper we wrote was on the toxicity of
CMFP. It was hard to get things published in medical oncology
areas, and the Lancet was wonderful for us. The Lancet was very
helpful, and we published a lot of stuff in the Lancet.
But the first one was in the British Medical Journal, the toxicity
of CMF program in patients, and we especially cautioned patients
who had compromised liver function because they seemed to get worse
toxicity at that time in our imagination. But it worked. It did
work. We published it in the Annals of Internal Medicine
eventually.
But the important thing was, our friend Johnny Bonadonna would come
over periodically to find out what we were doing. And he came over
with an offer. He said he had all these patients who would get
mastectomies and then nothing.
Let me interrupt you for a moment 'cause I was going to ask you
about Dr. Bonadonna.
Yeah.
Would you, just for the audience, a lot of them may not know who he
is.
Oh. Well, Johnny Bona-- Do you want me to describe him? Well, at
that time, he was a young investigator working in Milan at the
major hospital there in oncology, and he trained at Memorial before
and then went but back to Italy. So he came and he wanted to know
what we were doing. We showed him the protocol that we were doing
for breast, and he was interested.
And what he offered was the opportunity of doing a randomized trial
on patients with a higher risk, if you will, breast cancer,
node-positive patients. And he said that in Italy that nothing was
done for them and that he could randomize them nothing to
chemotherapy, and we offered him a contract. He required money. We
gave him a contract. We gave him our protocol, at least the
chemotherapy protocol.
He went back to Italy and did that trial. And he left the
prednisone out. He made sure it was of just CMF. And the patients,
apparently, I guess, knew what they were getting, but I don't know
whether they had strict requirements or informed consent and things
like that. We didn't ask. We didn't ask. All we wanted was
randomized data, and he certainly had it.
And I remember being at the ASCO meeting in 1976, I think it was,
'75 or '76, in Toronto when the first data was presented by
Bonadonna. And the media people were there. People were barely
hanging from the rafters to hear. The room wasn't big enough,
really. None of the rooms were big enough because they never
expected the attendance, that there were that many young
oncologists around or people interested in oncology. And so he gave
that first data, and that was a shot in the arm for adjuvant
therapy, certainly for breast cancer, but for other things as
well.
I think, in general, he and Dr. Fisher, who sadly passed away
before I had a chance to interview him, are responsible for
thousands and thousands of people.
Yeah. Absolutely. Absolutely. Absolutely. But I'm giving you the
NCI side, my personal side of it, and you're right. Bernie was a
real pioneer because he had so much opposition from the surgical
establishment at the time. I can tell you that. From a surgeon's
point of view, they really thought he was the Antichrist. I mean,
it was terrible.
I saw him and Jerry Urban get into a verbal argument at a meeting.
I thought it was going to be a fistfight, actually, over--
Really? Yes, yes. Yes, they're severe.
But anyway, let me go-- let me go to my next question, which has
tended to change gears for a moment. You may or may not remember
this, but when you were ASCO President, in your presidential
address, I was in the audience and you said something to the effect
that the greatest clinical experiment you have conducted are the
Fellows you have trained, or something like that.
Yes. Yeah.
And I was in tears, of course. But you certainly can claim success
on that. The division chiefs, department chairs, cancer center
directors, most recently a Nobel Laureate, [INAUDIBLE], all of them
came out of the program. But when you returned to Boston, you could
not have envisioned all of this. What was the atmosphere, and what
was Dr. Farber's vision?
Well, Dr. Farber had died by the time I got there.
Oh, he was already gone? OK.
He was already gone. And when I was leaving, when Tom Frei
recruited me, Vince thought I was mad because they made me Clinical
Director. At least have a go at acting job as clinical director of
the NCI. But really, down the line, it was a bureaucratic
evolution. And I said, I don't really want to be an oncocrat at
this age, anyway.
What I said was, Vince, I said, the doctor draft is over. The best
and the brightest and the youngest and the cheapest are all going
to be in these hospitals, and there are a lot of them in Boston
because I happen to know Boston, including house staff at the
Brigham, house staff at the BI and Mass General. And I said, that's
the future, or at least the future challenge.
And I think he accepted it, but he didn't like it. I mean, he
thought-- well, we were great buddies and we worked well together,
and that goes for Bob Young and Bruce Chabner too. They thought I
was very--
Where else-- at that time, there must have only been two or three
places to train in oncology in the whole country, I would
imagine.
Yes, yes, yes. And people were just starting to set up cancer
centers, sometimes without funding. And then there were all these,
not many, but job requests for me to go and look at the job at
Wisconsin or you name it, but I didn't want to do that. I really
wanted to do medical oncology and not be a bureaucrat in any way.
And many of the places, Dan, would say come and be a head of our
cancer program, and it was also translated in parentheses, come and
write a CORE grant. A lot of places who didn't deserve a CORE grant
were asking me for people to come and write a CORE grant. You knew
forever they would never get one because they really didn't have
the makeup for it, yet.
So what were the hurdles in Boston when you got there?
Well, the hurdles in Boston were twofold. One is the fact that
oncology had a very slow start in Boston, and that goes at the
Brigham and at the MGH. The MGH was even disinterested in oncology
at that time, actively disinterested. They didn't think it had any
academic merit and therefore didn't put any effort into it.
I have to say that Gene Braunwald, who was Chief of Medicine at the
Brigham at the time, was interested because he had been at NIH at
the Heart Institute, he knew Tom Frei, and he wasn't sure about it
yet because he couldn't swallow it, I guess. And the fact was that
it was growing a bit, and one of his very close associates
developed large cell lymphoma and he got chemotherapy, he got to
see MOP. And he was long-term remission. And I remember telling
Braunwald, he was shocked that it was so successful. And I kept
telling him, I said, this is not a rare event. This is
happening.
But the big challenge, Dan, at Dana Farber was that there was no
oncology known, and we had to build the program from the bottom up.
We hospitalized our patients at the Brigham before we opened the
beds at the Dana Farber, but we needed the volume of patients. And
we had all these beds, I think 59 beds, licensed beds, open. And I
kept saying, we don't have the patients. But Tom Frei opened the
beds. The next thing you know, I was talking to trustees because
Tom said, we'll bring George up and we'll grow. The clinical
program will grow.
So the trustees thought the program would probably grow the next
day. It didn't. It took a lot of effort without the [? scare ?] and
myself going around giving talks in every little hospital that
existed. And one of the big things I had my mind, because the house
staff looked after our patients as well, was to show them what we
could do. Now, in those days, other than the large cell lymphomas,
of which we did not have many because they were in the hands of
hematologists, was testes cancer.
And the head of urology at the Brigham Hospital used to have these
Saturday morning urology rounds inviting all of the practicing
urologists around to come and they'd present their problem cases,
et cetera. But he asked me to come along and give a talk about this
new drug called cisplatin, which was having a big effect in testes
cancer in other places. And I did. And I would come and talk about
the early results in other places in testes cancer and that we were
interested in actually starting a program.
Then, they would-- of course, urologists are anything but
chemotherapists, and so they would refer the patients in because,
A, they couldn't give any chemotherapy. There was nothing oral that
would work. What we would do is, if they sent patients in, we would
do an early trial and we would publish the series in a, let's say,
not spectacular journal and get reprints. We would send them
reprints.
And in some instances, I put the name of the referring doctor, if
he'd sent us more than one patient, on the paper for, let's say,
testing some antineoplastic thing. And we would put their names on
the papers and send them reprints. And there's nothing a urologist
loves more than to see his name on a scientific paper, a medical
paper. And we started getting a ton of testes cases eventually and
did trials and wrote papers about them.
And I remember, when we recruited Phil Kantoff, a Fellow of mine,
and I thought he was going to go back to the NIH and do gene
therapy. And he walked in one day and he said, I'd like to apply
for the GU job, and I said, it's yours. And he wrote quite a few
papers based on the accumulated testicular data and the
[INAUDIBLE].
Oh yeah.
Yeah. And he was wonderful.
He's Chief of Medicine now at Memorial.
He's Chief of Medicine at Memorial, yes.
I want to bring up one more thing that this segues into, though,
and I believe now almost every medical oncologist who has trained
in the last 10 years thinks that multispecialty tumor boards have
always existed. But I believe that another of your trainees, Dr.
Craig Henderson, who was my mentor, frankly, and you really started
the first multispecialty clinic perhaps in all of oncology in this
country. Do you agree with that?
We called it the BEC, the Breast Evaluation Center. Yes, and we got
cooperation but from surgeons. There were surgeons around, more
nihilistic surgeons, if you will, not wanting to do radical surgery
and radiotherapists, like Sam Hillman. And they were all around and
doing those things. And we brought them into this BEC, the Breast
Evaluation Center, and your mentor, Craig, was a little rough on
the Fellows, I can tell you, in those days. Just his demands.
Anyway, whatever it was.
And so I would go to that clinic as well and see breast patients
just to calm things down a bit at times. Anyway, it worked. And I
know that the breast people elsewhere were recognizing that Craig
had a nice thing going there with the multidisciplinary aspects.
You know, it was so awful that breast cancer was treated so
badly.
I mean, they'd have a radical operation. And God knows, if there
was some disease, that they would then get radical radiotherapy to
their chest. And they were walking around sort of mutilated. And we
had a part-time psychiatrist when I first arrived to see these
patients because many of them had body image problems. So the idea
of not doing radical mastectomy was revolutionary at that time.
And I remember being called by the local Blue Cross to serve on a
committee to decide whether or not Blue Cross should pay for breast
reconstruction on these poor patients, and we voted. There was a
committee of medical oncologists from MGH, me, and a plastic
surgeon, and we voted 3 to 3 to they should pay, and they didn't.
Then they said, thank you for serving on this advisory committee,
but we're not paying. We've decided not to pay.
Then, I can tell you, a women's agitation group got a hold of the
facts. And one of them called me up and she said, I heard you were
on this committee that voted not to pay. And I said, absolutely we
voted to pay. They told us, thanks very much but we're not going to
pay. So within two weeks then the insurance company changed its
opinion because they went bananas at the insurance company.
Yeah. The strength of advocacy, that's been something. Anyway,
we're running out of time. I'd like to thank you for taking your
time with us.
Not at all, Dan. Not at all. It's a pleasure.
And as I have done for every other interview in this series, I want
to thank you not just for taking time with us but for all you've
done for the field, for those of us who trained with you or are in
the field, and most importantly for all the patients who have
benefited. You look back over the--
Yeah, I know. I still follow them. My clinic has follow-ups of
cured patients. You become the primary care doc for cured
patients.
Well, you think of the 60 years of your career and other fine folks
that you were with at the NCI and then beyond, and the thousands or
millions of people who have benefited, it's pretty remarkable.
Yeah, well.
Thanks again. I appreciate you being on.
Not at all.
And enjoy the rest of the day.
Thank you very much, Dan.
Until next time, thank you for listening to this JCO's Cancer
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