Chapter 08: Solid Tumors and the TIOS Protocols (Treatment and Investigation of Osteosarcoma)

Chapter 08: Solid Tumors and the TIOS Protocols (Treatment and Investigation of Osteosarcoma)

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In this chapter, Dr. Jaffe describes one of his major roles as Chief of the Solid Tumor section in Pediatrics: establish new protocols for treatment of cancers in children. He notes that this was an assignment he was given by the Department, but also one he assigned to himself. His main work was in the treatment of osteosarcoma. He named his series of protocols TIOS (Treatment and Investigation of Osteosarcoma), and developed three protocols before shifting focus to support a colleague’s study of a promising drug. He then goes on to give more details on the TIOS protocols, which used thee three main drugs for treating osteosarcoma. The first protocol used high-dose methotrexate, and Dr. Jaffe explains that the treatment –and its results—were not accepted at first. He says that “it is almost as if doctors couldn’t accept that osteosarcoma could be cured.” With the protocols he has designed, he explains, survivorship has increased from about 20% to 65%, and when his protocols are combined with multidisciplinary interventions the survivorship increases to 75-80%. He explains why no progress has been made beyond that point. Dr. Jaffe gives more detail on his procedure: they rely on intra-arterial drug delivery to destroy the sarcoma at its site –an essential step in limb salvage procedures.

Identifier

JaffeN_02_20120817_C08

Publication Date

8-17-2012

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; The Researcher; Definitions, Explanations, Translations; Understanding Cancer, the History of Science, Cancer Research; Discovery and Success; Healing, Hope, and the Promise of Research

Transcript

Tacey Ann Rosolowski, PhD:

Let’s go back to your arrival at MD Anderson.

Norman Jaffe, MD :

Then when I came here, as I say, I was the chief of the Solid Tumor Section and also I had a major part— In fact, I was also responsible for the Long-Term Survivor Clinic. But I concentrated my efforts particularly as chief of the Solid Tumor Section, and the first thing I did was to develop a new protocol in Pediatric Oncology for osteosarcoma. I called this protocol TIOS. TIOS is the acronym for Treatment and Investigation of Osteosarcoma. I published three protocols on the TIOS research in osteosarcoma, TIOS I, II, and III. I was concentrating on TIOS IV when Dr. Eugenie Kleinerman [Oral History Interview], who was appointed head at that particular time, also began investigations in what is known as liposome MTP-PE, liposome muramyl tripeptide phosphatidylethanolamine in osteosarcoma, and she needed patients to test the efficacy of this particular compound in osteosarcoma. So as a consequence, I aborted my investigations on TIOS IV and concentrated then on entering patients into the 2 x 2 factorial design which was created for the investigation of this liposome MTP-PE. In fact, I entered the largest number of patients [from a single institution] into this trial to determine its efficacy in osteosarcoma. I would say that the drug has shown some promise. It is available throughout Europe and in Mexico, but for some reason or other, it has not been accepted by the FDA in the United States. Further discussion on this is in progress.

Tacey Ann Rosolowski, PhD:

Let me go back for a moment and ask you about the protocol. Why did you feel that new protocol was needed, and what exactly was the TIOS about?

Norman Jaffe, MD :

We had developed protocols with four major chemotherapeutic agents for the treatment of osteosarcoma. Prior to the development of these agents the survival rate in osteosarcoma was in optimum circumstances ten to twenty percent. It was usually of the order of five percent. Eventually it was concluded that the chemotherapeutic agents which we had discovered were in fact active in osteosarcoma and should be administered to all patients with osteosarcoma. One of the first agents, incidentally, was high dose methotrexate with citrovorum factor, or as it is now known, leucovorin factor or leucovorin in osteosarcoma. This, incidentally, was not initially accepted. It went through a lot of trials and tribulations.

Tacey Ann Rosolowski, PhD:

Why?

Norman Jaffe, MD :

I have no idea, but it appeared that many physicians could not accept the concept that there was in fact a possible cure for osteosarcoma. Prior to that, the understanding was that if a diagnosis of osteosarcoma was established, one should simply amputate the limb and do nothing further. In fact, there was a British surgeon, Sir Stanford Cade, who was both a surgeon and radiation therapist, and in one meeting on osteosarcoma he made the following statement, and I’m paraphrasing. He said, “Gentleman, if you operate, they die. If you don’t operate, they die just the same. This meeting should be concluded with prayers,” and he signed off. That was the prevailing attitude at that particular time. Osteosarcoma was in fact a uniformly fatal disease. With the discovery of high dose methotrexate, which went through a tremendous “birth event” in order to be accepted—it was finally accepted through a randomized, controlled trial—the change in outlook for osteosarcoma was tremendous. Not only was high dose methotrexate effective, but Adriamycin, cyclophosphamide and cisplatin, also known as platin, became effective in osteosarcoma, and combinations of these agents utilized before and after the operation to remove the tumor were administered to the effect that the survival rate now changed from approximately ten to twenty percent to close to sixty-five percent. And with additional multidisciplinary intervention, the survival rate could be escalated even to seventy-five or eighty percent, and that has held true. Unfortunately, it has held true for the past thirty years. We’ve made no major impact in survival since the past thirty to forty years, and that’s our greatest challenge now in osteosarcoma. Notwithstanding, that was the assignment, self-imposed by myself, and for that matter, given to me by Dr. van Eys, to develop a protocol for the treatment of osteosarcoma, and I did so utilizing the TIOS protocol. Now, why the TIOS protocol? The TIOS protocol was unusual from the prevailing protocols at that particular time. The protocols extant at that particular time did not use intra-arterial chemotherapy for osteosarcoma. Dr. Robert Benjamin developed intra-arterial cisplatin for the treatment of osteosarcoma. This enhanced the opportunity to destroy the tumor at the presenting site, so much so that the effects were so great that one could convert most of the patients who were destined for amputation into what is known as a limb salvage procedure, and today at least eighty percent of patients with osteosarcoma undergo limb salvage as opposed to amputation. It was a major milestone in osteosarcoma, and that continued. But as I say, unfortunately, there’s been no major improvement in osteosarcoma following these developments approximately thirty to forty years ago.

Tacey Ann Rosolowski, PhD:

What is your perspective on why that’s the case?

Norman Jaffe, MD :

It’s because we do not have an effective new agent. We do not have new tactics and strategies to treat this particular tumor, and that is sorely needed. That’s our major challenge for the new century.

Tacey Ann Rosolowski, PhD:

You said that there were three types of protocols that you developed under—

Norman Jaffe, MD :

The TIOS protocols. That’s correct, and there was TIOS IV, as I say. I aborted it because I wanted to give Dr. Kleinerman the opportunity to investigate the new biological agent which she had developed in osteosarcoma, liposome MTP-PE.

Tacey Ann Rosolowski, PhD:

I wanted to ask you about your collaborators for the TIOS project. Norman Jaffe, MD The collaborators were simply all the individuals in my department. Anyone who did even the minutest amount of work which I thought was significant was put on as a co-author in my publications.

Tacey Ann Rosolowski, PhD:

Who were some of the individuals that you—?

Norman Jaffe, MD :

Alex Wang, John Murray was the surgeon, Pat Cassidy was the—no, Cassidy was from Dana-Farber. But there were quite a number. They were usually my fellows, and I gave the opportunity for the fellows to have their names on it in order to ensure that their academic positions in the future could be promoted and secured.

Tacey Ann Rosolowski, PhD:

What was the next phase of your research? Or would you like to continue with the story of your influence in the department?

Norman Jaffe, MD :

The next phase in my research, because we now were concentrating on liposome MTP-PE, was devoted entirely to that until I retired.

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Chapter 08: Solid Tumors and the TIOS Protocols (Treatment and Investigation of Osteosarcoma)

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