MOPPEBVCADChemotherapy with Limited and Conditioned Radiotherapy in Advanced Hodgkin ’ s Lymphoma : 10-Year Results , LateToxicity , and SecondTumors

MOPPEBVCAD (mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine) chemotherapy with limited radiotherapy was devised in1987 to reduce late toxicity and second tumor incidence while trying to improve effectiveness through increases of dose intensity and dose density. Late results, toxicity, and second tumor incidence were reviewed in all the patients treated.  The drugs of three previous alternating regimens [CAD (lomustine, melphalan, and vindesine), MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), and ABV (doxorubicin, bleomycin, and vinblastine)] were intensified and hybridized, the cumulative dose of mechlorethamine was lowered, and irradiation was delivered to no more than two sites either bulky or partially responding to chemotherapy.  A total of 307 previously untreated advanced-stage patients underwent MOPPEBVCAD chemotherapy. Radiotherapy was delivered to 118 of 307 patients (38%). Remission was complete in 290 patients (94%).With a median follow-up of114 months,10-year overall, disease-free, and failure-free survival rates were 79%, 84%, and 71%, respectively. Forty-two patients relapsed and 60 died.The causes of death were Hodgkin’s lymphoma in 36 patients, second neoplasms in 12, cardiorespiratory diseases in 4, pulmonary diseases in 2, and unknown in 6. Sixteen second tumors (of whichnine were myelodysplasia and/or acute leukemia) were diagnosed in all. Outside this series of 307 patients, MOPPEBVCADobtained complete responses in12 of15 relapsedand 9 of 9 refractory patients who had previously been treated with other regimens.  Clinical response and long-term results are very satisfactory, whereas the second tumor incidence was lower than would have been expected with MOPP analogues. Given its response/late toxicity balance, MOPPEBVCAD does not undermine the leading role of ABVD as first-line regimen but can be indicated as a very effective second-line conventional therapy. In the last few decades, Hodgkin’s lymphoma has passed from being a fatal disease to being one of the most curable human cancers. However, despite this clinical progress, 20% to 30% of patients progress or relapse. Furthermore, long-term survivors are still at risk of late treatment–related complications, such as cardiac or pulmonary dysfunction, infertility, thyroid-related sequelae, or second tumors. The malignancies most frequently associated with chemotherapy include acute myeloid leukemia and myelodysplastic syndrome (AML/MDS), whereas the use of radiation therapy is related to a constantly increasing risk of second solid tumors. The standard chemotherapy combination for advanced Hodgkin’s disease was MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) in the 1970s and 1980s and for the last 15 years has been ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). A mathematical model devised by Goldie and Coldman (1) relating the drug sensitivity of tumor cells to the spontaneous mutation rate of cells led many Cancer Therapy: Clinical Authors’ Affiliations: Medicina Interna, Oncologia e Gastroenterologia, Universita' di Pavia and Servizio di Radioterapia Oncologica, IRCCS, Policlinico San Matteo, Pavia, Italy; Divisione di Ematologia, Ospedale ‘‘SS Antonio e Biagio,’’ Alessandria, Italy ; Divisione di Ematologia, Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Foggia, Italy; Unita' Operativa di Ematologia, Ospedale Civile SS. Giovanni e Paolo, Venice, Italy; Medicina Interna and Oncologia Medica, Universita' di Modena, Policlinico di Modena, Modena, Italy; Cattedra e Divisione di Ematologia con TMO, Policlinico, Palermo, Italy ; Divisione di Medicina I, Ospedale Civile, Piacenza, Italy ; Cattedra di Ematologia, Universita' di Bari, Policlinico, Bari, Italy; and Oncologia Medica, Ospedale ‘‘A. Pugliese-Ciaccio,’’ Catanzaro, Italy Received 8/4/05; revised10/24/05; accepted11/10/05. Grant support: Ministerodell’Universita' edellaRicercaScientificaeTecnologica(Rome, Italy),theAssociazione‘‘A.Serra’’andtheFondazioneCassadiRisparmiodiModena(Modena, Italy),andtheIRCCSPoliclinicoS.MatteoandtheFerrata-StortiFoundation(Pavia,Italy). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Paolo G. Gobbi, Medicina Interna, Oncologia e Gastroenterologia, Universita' di Pavia, IRCCSPoliclinico S. Matteo, P.le Golgi no. 2, 27100 Pavia, Italy. Phone: 39-382-502954; Fax: 39-382-526223;   American Association for Cancer Research. doi:10.1158/1078-0432.CCR-05-1707 www.aacrjournals.org Clin Cancer Res 2006;12(2) January15, 2006 529 Research. on April 12, 2017. ] or hybridized them by delivering in each cycle all the drugs scheduled in different regimens [MOPP/ABV (7), MA/MA (MOPP on day 1, ABVD on day 15 of each monthly cycle) (8), ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone)/EVA (etoposide, vincristine, and doxorubicin) (9)]. More recently, a statistical model by the German Hodgkin Study Group, which considers tumor growth and chemotherapy effects (10), indicated that intensifying drug doses through considerable dose escalation could be the best choice: The result of this theory was the BEACOPP (bleomycin, etoposide, Adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) schedule (11, 12). However, in 1987, in agreement with the then contemporary, evolving basic criteria of chemotherapy for advanced Hodgkin’s lymphoma, the Italian Lymphoma Study Group [Gruppo Italiano per lo Studio dei Linfomi (GISL)] designed a shortened, hybridized, and intensified version of Straus’ alternating regimen, CAD/MOPP/ABV (13), and combined it with a restricted use of radiotherapy, which was limited to sites of bulky involvement or to areas that had not responded completely to chemotherapy. The basic idea underlying the formulation of the MOPPEBVCAD regimen was to improve an already existing treatment program, widely tested and highly effective, by introducing selected chances. The hybridization of the drugs of alternating CAD/MOPP/ABV into the MOPPEBVCAD schedule complied more closely with Goldie and Coldman’s (1) theory. Moreover, the adopted modification of the original schedule seemed to partially accomplish the improvements indicated by Norton and Simon’s (14) model, at least as far as the dose density was concerned. The contemporary increase of dose intensity and dose density was obtained for the majority of drugs by administering in six cycles approximately the same cumulative drug dosage delivered with the original nine cycles of the alternating CAD/MOPP/ABV and by reducing the cycle length from 35 to 28 days. The total dose of mechlorethamine was reduced by 50%. The delivery of radiotherapy was limited and conditioned to the presence of no more than two areas with either an original bulky mass and/or a lesion incompletely remitting after chemotherapy. The early data on feasibility, toxicity, and short-term results of this modified chemotherapy program, collected in different trials, were encouraging (15–18). We report here the cumulative experience—with particular attention to late results and toxicity—achieved in all the patients evaluated in those original studies.  In this study, we reviewed and updated the clinical information regarding all those patients treated with MOPPEBVCAD chemotherapy plus limited radiotherapy who were enrolled and considered eligible in the three distinct clinical trials that administered this combined therapy in at least one treatment arm. The population of the present study, therefore, comprised the 145 patients enrolled in a controlled, open, nonrandomized study carried out by the GISL (15, 16) between 1988 and 1993, together with 24 patients evaluated in a prior, unpublished pilot study carried out during 1987, the 32 patients randomized to MOPPEBVCAD—with or without radiotherapy—in a second GISL study (17) conducted from 1994 to 1995, and, finally, the 106 subjects randomized to the same treatment in a randomized trial of the Intergruppo Italiano Linfomi (18) between 1996 and 1999. In the second GISL study (17), the MOPPEBVCAD regimen was compared against a variant in which cyclophosphamide substituted lomustine and etoposide substituted melphalan (MOPPEBVCyED). In the Intergruppo Italiano Linfomi trial (18), patients were randomized into three different treatment arms—MOPPEBVCAD, ABVD, and Stanford V chemotherapy. In all these studies, the criteria adopted for administration of radiation therapy did not differ. Enrollment requirements, staging procedures, and treatment criteria were the same in the three trials and were detailed in each study report. Synthetically, unequivocal histology of Hodgkin’s lymphoma, age between 15 years and an upper limit varying from 65 to 75 years according to the trial, no previous treatment and clinical stage IIB, III, or IV were necessary for entry to the study. Staging was evaluated according to the recommendations of the Cotswolds Meeting (19); in particular, all patients underwent computed tomography of the thorax, abdomen, and pelvis and had