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

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Chemotherapy Strategies to Improve the Control of Hodgkin's Disease: the Richard and Hinda Rosenthal Foundation Award Lecture1 [CANCER RESEARCH 42, 4309-4320, November 1982] 0008-5472/82/0042-0000$02.00 Chemotherapy Strategies to Improve the Control of Hodgkin's Disease: The Richard and Hinda Rosenthal Foundation Award Lecture1 Gianni Bonadonna2 Istituto Nazionale Tumori, Via Venez/an 1, Milan 20133, Italy Abstract ogy by David A. Karnofsky and his associates at the Memorial Sloan-Kettering Cancer Center. The cultural atmosphere, per The paper reviews new chemotherapy strategies for inter mediate and advanced stages of Hodgkin's disease as well as meated with pioneering enthusiasm as well as scientific skep the implications of recent biological concepts and mathematical ticism, in which I spent my early American years left on me an models which appear useful in the interpretation and design of indelible professional and psychological mark that has greatly new treatments. The development and the application of the influenced my successive research activity. Adriamycin-bleomycin-vinblastine-dacarbazine (ABVD) combi The theme of my lecture was chosen to present an overview nation was based on critical réévaluationofbenefits and limits of the therapeutic research carried out in Milan during the last of the mechlorethamine-vincristine-procarbazine-prednisone 10 years with the intent of further improving the control of Hodgkin's disease. By reviewing treatments conceived and (MOPP) combination. The attempts to develop non-cross-re sistant regimens, such as ABVD, arose intuitively at first from developed in Italy, but which in reality originated from previous the desire to improve salvage treatment in MOPP-refractory studies performed in the United States, I hope to pay in part patients; more recently, a theoretical framework for this ap my cultural debt to all of you. Among the numerous colleagues proach has been proposed by Goldie and Goldman (Cancer I had the privilege to work with, I would like to acknowledge Treat. Rep., 63: 1727-1733, 1979). The 5-year results the help of Armando Santoro and Pinuccia Valagussa, who achieved with different forms of salvage chemotherapy and have contributed their intelligence and professional dedication with the cyclic delivery of non-cross-resistant combinations in the performance and analysis of our recent studies on Hodgkin's disease. (MOPP and ABVD) can be explained largely by the assumption that drug-resistant mutants represent a major limiting factor in MOPP and MOPP-derived Combinations the cure of Hodgkin's disease, as well as of other neoplasms, In 1974, the prognostic outlook for Hodgkin's disease was by chemotherapy. The initial results from a prospective ran domized trial indicate that the administration as front-line ther definitely more favorable than that of the previous decade. apy of non-cross-resistant regimens is a logical and powerful Based on accurate clinical and surgical staging procedures, strategic approach and therefore that it may constitute an the strategy of megavoltage irradiation, as pioneered by the important avenue of clinical research. Recent observations also Stanford group (35), represented the treatment of choice for patients with Pathological Stages I, II, and MIAdisease. MOPP3 emphasized the problem of the quality of life, since the admin istration of multidrug combinations not including alkylating chemotherapy, as developed by the NCI group (26), dominated agents and/or procarbazine appears to be associated with a the field of chemotherapy, and its impressive CR rate was decreased incidence of carcinogenesis and sterility. The de already confirmed by numerous research groups studying pa parture from the standard practice of utilizing a single multidrug tients with Stage MB, MIA, NIB, and IV disease. Taken in toto, regimen for chemotherapy of Hodgkin's disease should be the favorable consequences of intensive megavoltage irradia supported by sound research and controlled studies built on tion and of MOPP chemotherapy consisted of a progressive decline in the mortality rate for Hodgkin's disease, gradual as drug combinations of known efficacy and toxicity. a consequence of radiotherapy and then more abrupt when MOPP became widely used in the community (25). Ladies and gentlemen of the American Association for Can The design and application of MOPP chemotherapy repre cer Research, and guests: I am deeply honored in being sented a masterly condensation of the biological concepts selected for the Richard and Hinda Rosenthal Foundation made available by Skipper ef al. (62) in the mid-1960's from Award for Clinical Research this year. As the first non-American investigator invited to give this prestigious lecture to a large 3 The abbreviations used are: MOPP, mechlorethamine, vincristine, procar audience of qualified colleagues, I wish to say that much of bazine, and prednisone; NCI, National Cancer Institute; CR, complete remission; -What I have accomplished as a research physician is largely a 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-cyclo- consequence of the cultural relationship that I have had for hexyl-1-nitrosourea; cyclophosphamide, vincristine. procarbazine, and predni more than 20 years with many scientific institutions and clinical sone; BCVPP, 1,3-bis(2-chloroethyl)-1 -nitrosourea, cyclophosphamide, vincris tine, procarbazine, and prednisone; ChlVPP, chlorambucil, vinblastine, procar investigators of this country. Driven for the first time to America bazine, and prednisone; ABVD, Adriamycin, bleomycin, vinblastine, and dacar- by "such wind as scatters young men through the world, to bazine; MABOP, mechlorethamine, Adriamycin, bleomycin, vincristine, and pred seek their fortunes farther than at home, where small experi nisone; B-DOPA. bleomycin, dacarbazine, vincristine, prednisone, and Adria ence grows' ' (W. Shakespeare, The Taming of the Shrew), I mycin; B-CAVe, bleomycin, 1-(2-chloroethyl)-3-cyclohexyl-1 -nitrosourea, Adria mycin, and vinblastine; VABCD, vinblastine, Adriamycin, bleomycin, 1-{2-chlo- had the priceless fortune of being initiated into medical oncol- roethyl)-3-cyclohexyl-1-nitrosourea, and decarbazine; CEP, 1-(2-chloroethyl)-3- cyclohexyl-1-nitrosourea, etoposide (VP-16), and prednimustine; SCAB, strep- 1 Presented at the 1982 Meeting of the American Association for Cancer tozotocin, 1-<2-chloroethyl)-3-cyclohexyl-1-nitrosourea; Adriamycin, and bleo Research in St. Louis, Mo. mycin; ABV, Adriamycin, bleomycin, and vinblastine; MVVPP, mechlorethamine, 2 To whom requests for reprints should be addressed. vincristine, vinblastine, procarbazine, and prednisone, CMF, cyclophosphamide, Received July 20, 1982; accepted July 30, 1982. methotrexate, and fluorouracil. NOVEMBER 1982 4309 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1982 American Association for Cancer Research. G. Bonadonna the rodent leukemia L1210 model. The concepts were related Table 1 to fractional tumor-killing effect of drugs, dose-response effect, Limits of MOPP and MOPP-derived combinations and inverse relationship between cure by drugs and number of Selective drug resistance About 20% of patients do not attain first CR, and at least 40% of complete tumor cells present at the time of treatment. The strategy responders fail to achieve durable remission. utilized in the design of the MOPP protocol was for the first CR and RFS are significantly affected by systemic symptoms. time aimed at the cure of Hodgkin's disease by use of effective, Durability of CR is significantly inferior in nodular sclerosis compared to the other histological subtypes. available drugs (24). The strategic concepts concerning full When the duration of first CR is less than 12 mos., retreatment with MOPP drug doses of the clinically active drugs, cyclic drug adminis yields second remission in less than 30%. tration, and prolonged duration of therapy became subse Toxicity from procarbazine and alkylating agents quently the principal guidelines in designing combination regi Increased incidence of second neoplasms (acute non-lymphoblastic leukemia, non-Hodgkin's lymphomas, a variety of solid tumors). The incidence of mens for practically all other forms of cancer. leukemia is markedly increased by chemotherapy plus extensive irradiation. The confirmed evidence that MOPP could render a large Drug-induced sterility, particularly in males. Sterility is related to treatment fraction of patients completely free of all evidence of disease dose, duration, and age. (CR, 80%; 10-year RFS, 63.4%) (25, 27) at the expense of considerable, although transient, acute toxicity led some inves fraction of patients with Hodgkin's disease who are resistant to tigators to modify the original drug combination by deletion, MOPP, even when chemotherapy is administered at full or substitution, or addition of various MOPP components (11, 39). nearly full doses and for an adequate period of time. An The aim was either to develop a more effective drug regimen additional important facet of new drug combinations should be or to reduce some of the immediate side effects. However, the the attempt to decrease the incidence of treatment-related newly derived MOPP regimens failed to improve significantly sterility and carcinogenesis. To improve the results being the incidence of durable CR. Even recent studies (2, 42), in achieved with either radiotherapy or chemotherapy alone, the which nitrosourea derivatives such as carmustine or BCNU and appropriate sequential combination of the 2 modalities also lomustine or CCNU
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