Oct 15, 2019
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.
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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.
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.
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.
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.
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, 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.
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.
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.
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.
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