Intensive combination chemotherapy and X-irradiation in Hodgkin's disease.

See related article by Moxley et al.,  This article was a pilot study of the first attempt to cure an advanced solid tumor, in this case Hodgkin disease, with combination chemotherapy (1). It was very controversial. Virtually no one at the time believed it was possible to cure cancer with drugs. Furthermore, it was a general tenet ofmedicine then that drugs, for any disease, should not be used in combination. The administration of combinations of cytotoxic anticancer drugs was therefore considered a radical departure from the norm. The conflict and hostility that surrounded these early attempts to cure cancer with chemotherapy are described in detail in a recent book by V.T. DeVita, Jr. and E. DeVita-Raeburn, The Death of Cancer (Farrar Straus Giroux, 2015). There were three circumstances that led coauthors J.H. Moxley and V.T. DeVita, Jr. to design the study. The first was the publication of an article by Easson and Russell entitled "The Cure of Hodgkin's Disease" (2). The article addressed the use of radiotherapy for early disease. But it was the title, more than the content, which helped trigger the thought of doing a similar study using combination chemotherapy. The second was ongoing research at the National Cancer Institute at the time with childhood leukemia. Frei and Freireich were experimenting with a four drug combination called VAMP (vincristine, amethopterin, 6-mercaptopurine, and prednisone), designed with the specific intent to eradicate all leukemia cells in childrenwith leukemia (3). The third was the work of Howard Skipper at the Southern Research Institute. Skipper reported that, with special attention to leukemia cell kinetics, dosing, and scheduling, mice bearing leukemia 1210 could be curedof their disease using combinations of four active drugs (4). The Hodgkin study, called MOMP, after the first initials of the drugs used, needed to take into account that Hodgkin disease was a disease of the lymph nodes and major organ systems, whereas leukemia was a disease of the bone marrow and blood. In leukemia, the bone marrow was the point of attack. In treating Hodgkin disease, the bone marrow needed to be preserved. Another major challenge was the need (based on the work of Frei, Freireich, and Skipper) for a minimum of four drugs active against Hodgkin disease that could be given in full doses. Nitrogen mustard was the standard at the time and was the first drug selected. The new vinca alkaloids, vinblastine and vincristine, were being actively tested against lymphomas and leukemias. Vinblastine was thought to be the preferred agent in Hodgkin disease, but the bone marrow toxicity of vinblastine and nitrogen mustard overlapped. A more detailed analysis of the data by the authors suggested that vincristine, with little or no marrow toxicity, was equally active, so vincristine was selected as the second drug ("O" for Oncovin, the brand name for vincristine; ref. 5). Prednisone was the third drug, but there was no known active fourth drug. Procarbazine, then called ibenzmethazin, was in early trials in Hodgkin disease at NCI, but the data was thought to be insufficient to include at the time. Without a better option, methotrexate, an active antileukemia agent, was selected on the basis of meager data of activity against lymphomas and was used in a schedule that had been derived frommouse models and was used to treat acute childhood leukemia. The number of patients in the study (14) was, at the time, the standard design of a phase II study, the rule of thumb being that if no one responded, the drug or treatment program would be discarded. If two or more responded, then further study was indicated. Because of the influence of the article by Easson andRussell (2), all patients were seen by a radiotherapist in consultation. If they had disease deemed treatable by radiotherapy, they were treated after the first cycle of chemotherapy was completed to allow the assessment of the effects of chemotherapy onmeasurable disease. The second cycle of chemotherapy began after radiotherapy was completed. Nine of the 14 patients received some form of radiotherapy to involved nodes only. Three cycles of MOMP were given. Vincristine and nitrogen mustard were given in full doses on days 1 and 8. Prednisone was given continuously dailyorally for 3months at adoseof 60mgs/sq. meter. Methotrexate was given intramuscularly at a dose of 30 mgs/sq. meter on days 1, 4, 8, and 11 of each of three cycles. After the last dose ofmethotrexate, no therapy except for prednisonewas given for aminimumof10daysoruntil complete recoveryofblood counts. Asaprecaution, all patientswere treated in reverse isolation. Remarkably, 12 of 14 patients achieved a complete remission. All 9 patients treated with radiotherapy went into remission before radiotherapy was given. Nine of 12 patients stayed in complete remission. Two patients were still responding to chemotherapy at the end of three cycles, but therapy was stopped according to protocol nonetheless. Toxicity was severe. There were no drugs available then to treat nausea and vomiting, and all patients suffered from both. All of the patients also developed neurologic toxicity from vincristine, although this was manageable. All 14 patients developed severe mouth ulcers from methotrexate and Cushingoid features from the continuous dosing of prednisone. Some degree of leukopenia was universal, although only one patient developed febrile leucopenia. This patient recovered with antibiotics. The pilot trial was a success. The therapy easily passed the phase II test for responses and the toxicity was manageable. The MOMP study that had begun in the fall of 1963 was presented at the 1965 meeting of the American Association for Cancer Research. Despite its novelty and its relative success, however, it attracted no particular notice, except for the concern Yale Cancer Center, Yale Univeristy School of Medicine, New Haven,  New York, New York. Los Angeles, California.