Chapter 04: An Important Contribution to Treatment: Eradicating Metastasis with Methotrexate

Chapter 04: An Important Contribution to Treatment: Eradicating Metastasis with Methotrexate

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In this chapter, Dr. Jaffe talks about building upon Dr. Farber’s work with methotrexate to treat pulmonary metastases from osteosarcoma. He first reviews Dr. Farber’s work with Wilms’ Tumor and the discoveries that led him to his own research on treating metastasis. He also reveals that he went into oncology because he had no choice at the time, working with Dr. Farber. Next Dr. Jaffe talks about osteosarcoma. At the time there was no treatment for osteosarcoma but amputation. Dr. Jaffe describes the process of discovering how to eradicate the metastasis with high doses of methotrexate combined with leukovorin to mitigate high-dose toxicity –still a recognized treatment. Dr. Jaffe asserts that this work represents his greatest contribution to the treatment of pediatric cancers.

Identifier

JaffeN_01_20120420_C04

Publication Date

4-20-2012

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; The Researcher; The Clinician; Influences from People and Life Experiences; Professional Path; Formative Experiences; Discovery, Creativity and Innovation; Discovery and Success; Professional Practice; The Professional at Work

Transcript

Tacey Ann Rosolowski, PhD:

I know we have a lot of different positions to cover before you even get to MD Anderson, but you had mentioned that the seven years under Sidney Farber was such good training, and you were able to accomplish certain things. Maybe you could give me a couple of examples of some things that you accomplished that you really learned something from.

Norman Jaffe, MD :

Okay, I’ll tell you. When I was there, I noticed that Farber had a specific way of treating solid tumors, in particular, Wilms’ tumor. He had originally done some work with a person called Guilio J. D’Angio who we called Dan D’Angio. Dan D’Angio was a radiation therapist. And a problem in cancer existed at that particular time in relation to the kidney. Cancer of the kidney in children is generally Wilms’ tumor. That’s the type of tumor that the kidney develops in children. There are others, but that’s the main one, and the kidney metastasizes—the cancer metastasizes to the lungs, and that eventually causes the demise of the child. Experiments and investigations done by Sidney Farber with a substance called actinomycin D, which he acquired from Selwyn Waksman, who was a friend of his, revealed that the combination of actinomycin D and radiation therapy could destroy the metastases in the lungs. You could destroy metastases in the lungs also with radiation therapy [alone], but the amount of radiation therapy that one had to deliver to the lungs to destroy these metastases was such that you not only destroyed the metastases, but you destroyed a major part of the lungs [as well]. When combined in association with actinomycin D, you could reduce the quantity of radiation therapy and not destroy the lungs. Farber did major investigations in this, so much so that he was able to convert the survival rate of children with Wilms’ tumor from --in optimum circumstances-- under approximately forty percent to close to eighty percent. He had doubled the survival rate. I learned that from Farber. He introduced the concept of [delivery of] radiation therapy plus actinomycin D. That [ ] was also exploited further in some of the solid tumors in rhabdomyosarcoma. That was a major saltation in the treatment of solid tumors and cancers, and it was entirely due to Farber’s investigations. So one had to give him great credit for that. He was a brilliant pathologist, incidentally. I enjoyed listening to him describe the tumors. Every Wednesday afternoon when we would have tumor board, Farber would sit and describe the pathology as it was flashed on the board. This information, incidentally, is available in the letter that I sent to Mukherjee, and I will send it to you.

Tacey Ann Rosolowski, PhD:

Yeah, I’d appreciate that.

Norman Jaffe, MD :

And I think you’ll learn about it in greater detail. Farber did a great service to the children by describing an excellent method, which is still used today, incidentally, in the treatment of Wilms’ tumor. That is cancer of the kidney of children, and it has been extended further to other solid tumors as well, particularly rhabdomyosarcoma.

Tacey Ann Rosolowski, PhD:

Along the way, as we’ve been talking, we kind of moved seamlessly from your interest in pediatrics to oncology, and I’m wondering when was the point that you really made the decision that you wanted to focus on oncology?

Norman Jaffe, MD :

Well, it was after Farber told me that I would not get a job elsewhere. I had no option. It was not my decision. And in the United States, after a while, if you do well and you show exceptional talent, things like that, then they’ll push you as well. And Farber pushed me, and I think he knew that he had—as I heard one of my colleagues say, “He knew he had a gem in you, and he wouldn’t let you go.” That was the reason. As I said, originally I was not interested in oncology, but I had no option at that stage. At ’66 I came to this country. I would say it was ’69-’70, particularly after I had made a huge saltation in the treatment of bone tumors, osteosarcoma, that I said, “Listen, this is the way I’ve got to go now.” And Farber wouldn’t let me turn back.

Tacey Ann Rosolowski, PhD:

Can you tell me about that discovery?

Norman Jaffe, MD :

What happened was the most common bone tumor in a human being, and particularly in children, is called osteosarcoma. It particularly affects the pre-teenage and teenage individual, and until the beginning of the 1970s there was no chemotherapeutic agent that could destroy osteosarcoma. Osteosarcoma develops in the bone, and if it is untreated it continues to metastasize to the lungs. Initially the metastases are not visible on x-ray in the lungs, but they are there because we know that since there [was] no major treatment for osteosarcoma except amputation at that particular time, and even if you amputate, nine months later, these micro metastases in the lungs will appear [visibly] and be responsible for the demise of the patient. Now, Farber, as you may or may not know, was responsible for the discovery of methotrexate, which is used in leukemia. I refer you again to the book The Emperor of All Maladies, which discusses his approach to this particular problem. In ’66, there was no effective treatment for osteosarcoma, but a man called Isaac Djerassi was aware of investigations performed in mice by an investigator called Abraham Golden at the National Cancer Institute. Abraham Golden took massive doses of the methotrexate, which Farber had discovered for the treatment of leukemia, and treated mice with leukemia, and after several hours of administering these massive doses—I call them industrial doses—he would give the antidote to methotrexate, and the mice would not die from toxicity. Djerassi used that approach in children with leukemia and found it to be highly successful. Djerassi had trained at one stage with Sidney Farber but then moved to Philadelphia. We invited Djerassi—well, I invited him because I was in charge of the tumor board—to discuss his investigations and his treatment approach to leukemia with these massive doses of methotrexate. I used to have tumor board every Wednesday afternoon with Sidney Farber. Djerassi was invited and presented the information on the treatment of resistant leukemia with massive doses of methotrexate followed by the antidote leucovorin or [ ] citrovorum factor, but it’s called leucovorin [today]. As I described to you, massive doses, and then after an interval, the antidote—and the patient or mice did not succumb, and the patient also responded. And after hearing his presentation, I approached Sidney Farber a day or two later, and I indicated to him, “Dr. Farber, we have no treatment for osteosarcoma. I would like to treat patients with this particular therapeutic branch.” At that stage, there were no surveillance boards. There were no institutional review boards. You simply had to get permission from the chief, and I remember his words so clearly. “Proceed, young man.” I found a patient who had developed pulmonary metastases, osteosarcoma in the lungs, after she had undergone a hemipelvectomy. We removed half her pelvis from the osteosarcoma. I discussed this with the patient and her mother. I said, “Listen, I have nothing really to offer you, but I’ve heard of a treatment that has been highly successful in leukemia, and I would like to investigate this treatment in your particular situation.” And they said, “Since you tell us there is nothing further, by all means, proceed.” [Redacted] Incidentally, just in passing, the chief of Pediatric Hematology at Texas Children’s Hospital is David Poplack, and David Poplack was my house officer at that particular time. I told David Poplack, “We are going to treat this patient in this particular manner.” We gave the patient the treatment. It did not succeed. I telephoned Djerassi, and I remember his words particularly clear. He said, “Double the dose.” I doubled the dose, and indeed, after doubling the dose, complete disappearance of metastases was achieved, and this is a phenomenon that had never before been seen. I continued on this particular approach because I was afraid [that] cancer, being a dishonest disease, it would recur. It did not recur, but she developed severe toxicity, and I give tribute to David Poplack, who as I say, is chief across the road, for looking after this patient and rescuing her from the toxicity.

Tacey Ann Rosolowski, PhD:

What were the symptoms of the toxicity?

Norman Jaffe, MD :

Severe mouth ulcers, kidney failure, liver failure, the works. She had it very, very severely, but we brought her round, and we continued treatment after that, and there were no problems. She completed two years of treatment. To my knowledge, [redacted] is alive and well and kicking, and she gave birth to two normal, healthy children, and that set the ball rolling for the use of high dose methotrexate with leucovorin in osteosarcoma, which is still used today. It is one of the major achievements that I consider to have accomplished in pediatric oncology, high dose methotrexate with leucovorin factor, and if you look at my CV, you’ll see many of the publications in this regard. The point about telling this story is that I would not be able to accomplish this particular approach at the present time. There are so many regulatory agencies. It has to go through this agency and that agency and this committee and this surveillance and so on and so forth that by the time one finishes with the committees the patient is dead, and you are tired. It could not be done now, but it certainly was done then, and all I needed was permission from Sidney Farber, which is a tribute to him, because I say he had confidence in me. I’m not sure that was appropriate, but nonetheless, as I say, “Proceed, young man.” At least he had the confidence in me to go ahead, because I think he realized that I would not approach him had not the circumstances been so dire and had [there] not been the possibility of accomplishing something without severe toxicity, which did occur. We know now some of the reasons why toxicity occurs, and we can avoid it, but not always. Nonetheless, it’s still an established and recognized form of treatment for osteosarcoma, and in passing, the survival of osteosarcoma was at the order of five to ten percent [at that time]. Now it is of the order of sixty-five to seventy-five percent, utilizing this approach and other agents in addition.

Tacey Ann Rosolowski, PhD:

It’s really landmark.

Norman Jaffe, MD :

Tremendous, and I think Farber was very appreciative of it because he had originally discovered methotrexate, although [had] not discovered this approach, but he was very proud of it. And I used to send him memos more or less on a weekly basis. So-and-so has been treated, so-and-so had a response, so-and-so has had this, this, that and the other. Anyone who has access to Farber’s private papers, if they’re still in existence, will find my memos over there, which I had to send him once a week and to tell him and keep him informed of the situation not only of the high dose methotrexate situation but the clinic and things in general.

Conditions Governing Access

Redacted

Chapter 04: An Important Contribution to Treatment: Eradicating Metastasis with Methotrexate

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