Chemotherapy Strategies to Improve the Control of Hodgkin's Disease: The Richard and Hinda Rosenthal Foundation Award Lecture1

The paper reviews new chemotherapy strategies for inter mediate and advanced stages of Hodgkin's disease as well as the implications of recent biological concepts and mathematical models which appear useful in the interpretation and design of new treatments. The development and the application of the Adriamycin-bleomycin-vinblastine-dacarbazine (ABVD) combi nation was based on critical réévaluation of benefits and limits of the mechlorethamine-vincristine-procarbazine-prednisone (MOPP) combination. The attempts to develop non-cross-re sistant regimens, such as ABVD, arose intuitively at first from the desire to improve salvage treatment in MOPP-refractory patients; more recently, a theoretical framework for this ap proach has been proposed by Goldie and Goldman (Cancer Treat. Rep., 63: 1727-1733, 1979). The 5-year results achieved with different forms of salvage chemotherapy and with the cyclic delivery of non-cross-resistant combinations (MOPP and ABVD) can be explained largely by the assumption that drug-resistant mutants represent a major limiting factor in the cure of Hodgkin's disease, as well as of other neoplasms, by chemotherapy. The initial results from a prospective ran domized trial indicate that the administration as front-line ther apy of non-cross-resistant regimens is a logical and powerful strategic approach and therefore that it may constitute an important avenue of clinical research. Recent observations also emphasized the problem of the quality of life, since the admin istration of multidrug combinations not including alkylating agents and/or procarbazine appears to be associated with a decreased incidence of carcinogenesis and sterility. The de parture from the standard practice of utilizing a single multidrug regimen for chemotherapy of Hodgkin's disease should be supported by sound research and controlled studies built on drug combinations of known efficacy and toxicity. Ladies and gentlemen of the American Association for Can cer Research, and guests: I am deeply honored in being selected for the Richard and Hinda Rosenthal Foundation Award for Clinical Research this year. As the first non-American investigator invited to give this prestigious lecture to a large audience of qualified colleagues, I wish to say that much of -What I have accomplished as a research physician is largely a consequence of the cultural relationship that I have had for more than 20 years with many scientific institutions and clinical investigators of this country. Driven for the first time to America by "such wind as scatters young men through the world, to seek their fortunes farther than at home, where small experi ence grows' ' (W. Shakespeare, The Taming of the Shrew), I had the priceless fortune of being initiated into medical oncol1 Presented at the 1982 Meeting of the American Association for Cancer Research in St. Louis, Mo. 2 To whom requests for reprints should be addressed. Received July 20, 1982; accepted July 30, 1982. ogy by David A. Karnofsky and his associates at the Memorial Sloan-Kettering Cancer Center. The cultural atmosphere, per meated with pioneering enthusiasm as well as scientific skep ticism, in which I spent my early American years left on me an indelible professional and psychological mark that has greatly influenced my successive research activity. The theme of my lecture was chosen to present an overview of the therapeutic research carried out in Milan during the last 10 years with the intent of further improving the control of Hodgkin's disease. By reviewing treatments conceived and developed in Italy, but which in reality originated from previous studies performed in the United States, I hope to pay in part my cultural debt to all of you. Among the numerous colleagues I had the privilege to work with, I would like to acknowledge the help of Armando Santoro and Pinuccia Valagussa, who have contributed their intelligence and professional dedication in the performance and analysis of our recent studies on Hodgkin's disease. MOPP and MOPP-derived Combinations In 1974, the prognostic outlook for Hodgkin's disease was definitely more favorable than that of the previous decade. Based on accurate clinical and surgical staging procedures, the strategy of megavoltage irradiation, as pioneered by the Stanford group (35), represented the treatment of choice for patients with Pathological Stages I, II, and MIAdisease. MOPP3 chemotherapy, as developed by the NCI group (26), dominated the field of chemotherapy, and its impressive CR rate was already confirmed by numerous research groups studying pa tients with Stage MB, MIA, NIB, and IV disease. Taken in toto, the favorable consequences of intensive megavoltage irradia tion and of MOPP chemotherapy consisted of a progressive decline in the mortality rate for Hodgkin's disease, gradual as a consequence of radiotherapy and then more abrupt when MOPP became widely used in the community (25). The design and application of MOPP chemotherapy repre sented a masterly condensation of the biological concepts made available by Skipper ef al. (62) in the mid-1960's from 3 The abbreviations used are: MOPP, mechlorethamine, vincristine, procar bazine, and prednisone; NCI, National Cancer Institute; CR, complete remission; RFS, relapse-free survival; BCNU, 1,3-bis(2-chloroethyl)-1-nitrosourea; CCNU. 1-(2-chloroethyl)-3-cyclohexyl-1 -nitrosourea; CCVPP, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; cyclophosphamide, vincristine. procarbazine, and predni sone; BCVPP, 1,3-bis(2-chloroethyl)-1 -nitrosourea, cyclophosphamide, vincris tine, procarbazine, and prednisone; ChlVPP, chlorambucil, vinblastine, procar bazine, and prednisone; ABVD, Adriamycin, bleomycin, vinblastine, and dacarbazine; MABOP, mechlorethamine, Adriamycin, bleomycin, vincristine, and pred nisone; B-DOPA. bleomycin, dacarbazine, vincristine, prednisone, and Adria mycin; B-CAVe, bleomycin, 1-(2-chloroethyl)-3-cyclohexyl-1 -nitrosourea, Adria mycin, and vinblastine; VABCD, vinblastine, Adriamycin, bleomycin, 1-{2-chloroethyl)-3-cyclohexyl-1-nitrosourea, and decarbazine; CEP, 1-(2-chloroethyl)-3cyclohexyl-1-nitrosourea, etoposide (VP-16), and prednimustine; SCAB, streptozotocin, 1-<2-chloroethyl)-3-cyclohexyl-1-nitrosourea; Adriamycin, and bleo mycin; ABV, Adriamycin, bleomycin, and vinblastine; MVVPP, mechlorethamine, vincristine, vinblastine, procarbazine, and prednisone, CMF, cyclophosphamide, methotrexate, and fluorouracil.