A selective history of the therapy of Hodgkin's disease

This is, for the most part, the history of the development of curative combination chemotherapy for Hodgkin’s disease, and its consequences, from 1963 up to the early 1990s [the MOPP (nitrogen mustard, oncovin, procarbazine, prednisone) programme]. Coupled with radiotherapy, it had a major impact on the management of the disease. It is also heavily weighted towards the description of the events that occurred at the Medicine Branch of the National Cancer Institute (NCI) in Bethesda, MD, USA, between 1963 and the early 1990s. To this is added a brief description of the follow-up development of the ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) treatment drug programme by the group in Milan, Italy. The latter added significantly to the therapeutic armamentarium available to physicians in the 1970s and beyond. This selective history is perhaps justified because, although the focus of the studies discussed below was on Hodgkin’s disease, there was a more important issue involved. A new breed of cancer investigators in the 1960s had been addressing the generic question of whether or not cytotoxic chemotherapy was ever capable of curing patients with any type of advanced malignancies. The answer would turn out to be ‘yes’, and this affirmative answer enabled chemotherapy to be used in many other tumours and, notably, in the adjuvant setting after treatment of apparently localized disease. The question was addressed in two important human models, childhood acute leukaemia (Frei & Freireich, 1965) and Hodgkin’s disease, and used combination chemotherapy, a concept that deviated from the practice of the time. The response in the academic community to this radical departure from dogma was initially quite negative. The protected environment of The Medicine Branch, at the Clinical Center of the NCI, facilitated studies in both diseases, under the inspired leadership of Dr Emil Frei, who was Chief until 1965 (Fig 1). In recounting these events, the novelty of the approaches and study results do not seem so radical in retrospect, but they were. At the time the programmes began at the NCI, radiation therapy was already established for Hodgkin’s disease patients presenting with apparently localized disease. We did not know the aetiology of Hodgkin’s disease or the cellular origin of the Reed–Sternberg cell that characterizes the disease. Medical oncology, as a speciality, had not yet appeared on the scene. Physicians who would become the medical oncologists of the future worked with therapeutic radiologists and pathologists to integrate newer methods of diagnosis, staging and radiotherapy with the newly developed chemotherapy programmes and converted Hodgkin’s disease from a largely fatal to a largely curable disease. For the integration of chemotherapy and radiotherapy in Hodgkin’s disease, we owe a debt of gratitude to the late Henry Kaplan (Fig 2), who was unique in his field in recognizing the value of the new chemotherapy. He set in motion a brilliant series of studies of the use of MOPP and radiotherapy at Stanford University in the late 1960s and 1970s that still serve as a model of clinical investigations (Kaplan, 1962, 1966; Kaplan & Rosenberg, 1966; Kaplan et al, 1973). Curative chemotherapy had provided the missing link in the therapeutic equation. The group of senior faculty members from the Medicine Branch, shown in Fig 3, went on to apply these same principles to other cancers (Bagley et al, 1972; Canellos et al, 1974). The development of the CMF programme (cyclophosphamide, methotrexate and 5-fluorouracil) for breast cancer (Canellos et al, 1974) and the NCI’s contract with the Istituto Tumori in Milan, Italy, to test it in the adjuvant situation helped to set in motion a similar series of events in breast cancer. The author (Fig 4) chose to end this tale in the early 1990s because, at that point, we entered a new era of treatment for Hodgkin’s disease. Investigators began to focus on the problems of curing a minority of patients not cured by the initial programmes and reducing the morbidity of treatment revealed in long-term follow-up studies. A daunting task, but another story entirely.