Document KRXRELpyjv0bYNOB96Gyq673o

COMBINATION CHEMOTHERAPY OF HODGKIN'S DISEASE WITH ADRIAMYCIN, BLEOMYCIN, VINBLASTINE, AND IMIDAZOLE CARBOXAMIDE VERSUS MOPP GIANNBI ONADONNAM, D, * ROBERTOZUCALIM, D,+ SILVIOMONFARDINMI,D , ~ MARIODE LENA,M D , ~AND CARLOUSLENCHIMD,I' This paper reports the preliminary results of a controlled study randomizing MOPP vs. a new four-drug combination (ABVD) in advanced Hodgkin's disease. ABVD consists of 6 cycles of adriamycin, bleomycin, vinblastine, and imidazole carboxamide. The purpose for designing this new combination was two-fold: to compare the efficacy of ABVD with MOPP, and to demonstrate absence of cross-resistance between the two regimens. Of 60 patients entered into the study, 45 (MOPP 25,ABVD 20)are presently evaluable for the analysis of remission induction. No patient was previously treated with chemotherapy; 20W had relapsed after primary radiotherapy. Whenever possible, complete remission was defined also through rebiopsy of known organ involvement. Complete remission occurred in 76% of patients treated with MOPP and in 75% of those given ABVD, with no difference between the two regimens as far as stage (IIIB-IIIs and IV), histologic type, and prior irradiation were concerned. Crossover carried out for progressive disease or for relapse after initial remission showed absence of cross-resistance between MOPP and ABVD. Toxic manifestations after ABVD were in general well tolerated and reversible. T h e percent of optimal dose for each drug was as follows: adriamycin 87%, vinblastine 87%, bleomycin 96%, and imidazole carboxamide 96%. These preliminary results indicate that in terms of complete remission, ABVD could represent a successful alternative to MOPP to be used either in MOPP failures or in sequential combination with MOPP. However, the lack of long-term fol- lowup limits at the present time a n adequate comparison between the two treatments. Cancer 36:252-259, 1975. T HE QUADRUPLE COMBINATION KNOWN AS M O P P (mechloretamine, vincristine, procarbazine, and prednisone) has become in recent years the most widely used form of chemotherapy in advanced Hodgkin's disease. Presented at the 65th Annual Meeting of the American Association for Cancer Kesearch, Houston, TX, March 27-30, 1974. From the Istituto Nazionale Turnori, Milan, Italy. * Associate Ilirector, Division of Clinical Oncology F. ' Clinical Assistant, Division of Radiology, Assistant Professor of Kadioloyy, University of Milan. I Clinical Assistant, Division of Clinical Oncology F. 5 Clinical .\ssistant, Division of Clinical Oncology F. " Assistant Professor of Radiology, University of Milan. Address for reprints: Dr. Gianni Bonadonna, Istituto Nazioriale 'I'urnori, Via Venezian 1, 20133 Milano, Italy. The authors wish to knowledge the useful co-operation of Ilr. Kenato Xlusurneci for critically reviewing all lyrnphograms, and Dr. I'asquale Spinelli for performing peritoneoscopies. Received for publication ,July 17, 1974. The incidence of complete remissions after six to eight cycles in patients untreated and previously treated with either radiotherapy or chemo- therapy is well established.7~1'~1~~1e~zzT~zh'e~ao~*1 long-term results appear most encouraging in about half of complete responders. 10*10*p7*s1 MOPP has become almost the symbol of recent progress made in the control of neo- plastic disease. Several new combinations were subsequently designed with the intent to improve both the in- cidence of complete remission and the duration of response. 18917-21*a8716*80 However, none of the current regimens has shown a definite therapeutic superiority when retrospectively compared to MOPP. The main characteristic of these otherwise effective combinations was that all have included one or more drugs already present in the original MOPP. Therefore, from the point of view of drug combination they could 252 No. 1 NEWCOMBINATIVOSN. M O P P IN HODGKIND'SISEASE Bonadonna et a[. 253 be regarded somehow as MOPP modifications. A multiple drug combination designed to include some of the drugs known to be effective in Hodgkin's disease and not present in the classical M O P P would be very useful. First of all, such a new combination could be effectively employed in MOPP failures. Furthermore, it could be used in appropriate sequence with MOPP to increase the percentage of complete responders and, more important, the number of long-term survivors free of disease. New effective drugs have recently appeared on the horizon of cancer chemotherapy. Among them, adriamycin (ADM), bleomycin (BLM), and nitrosourea derivatives (BCNU, CCNU, Me-CCNU) were all found to produce objective response, through a wide range of treatment schedules, in 40 to 60% of patients with ad- vanced Hodgkin's disease.2-6-10*11M*zo8reover, Frei et al." reported in 1972 that 5-(3,3dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC) administered intravenously in 5-day courses at the initial dose of 250 mg/mz induced complete plus partial remissions in 10/18 (56%) previously treated patients with Hodgkin's disease, with a median duration of 4 months. The therapeutic effects of DTIC in refractory Hodgkin's disease were also confirmed in our Institute, with the observation of objective response in 5/6 patients. DTIC is nonmyelosuppressive in the majority of patients adequately treated, and when combined with ADM is synergistic in experimental systems without producing additive toxicity." The favorable effects of the combination of DTIC with ADM in human sarcomas were reported by Gottlieb et a1.2o O n the base of favorable results obtained in our Institute with a quintuple drug treatment including mechloretamine (HN,), adriamycin (ADM), bleomycin (BLM), vincristine (VCR), and prednisone (MABOP)," a new combination was designed in 1973 with ADM, BLM, vinblastine (VLB), and DTIC (ABVD). ADM, BLM, and DTIC are known to be individually non-cross-resistant to drugs included in MOPP; also, VLB appears to show little cross-resistance with VCR in humans.8 The purpose of combining these four drugs was two-fold: 1) to compare in terms of remission induction the efficacy of ABVD with MOPP; 2) to demonstrate the absence of cross-resistance between the two combinations. This paper reports the preliminary results of this prospective controlled study. PATIENTSAND METHODS Patient Sample A total of 60 patients (30 in each treatment group) was entered into this study between April, 1973 and January, 1974. At the present moment, 45 are considered evaluable for the analysis of remission induction (MOPP 25, ABVD 20). The remaining patients are not considered evaluable since they have not yet completed the induction phase. The distribution of patients by age, sex, histologic type, stage, and previous therapy is presented in Table 1. The TABL1E. Main Features of Evaluable Patients MOPP (25 cases) Mean age (yr) Median time from diagnosis to treatment (rno) Sex Males Females Histology Lymphocyte predominance Nodular sclerosis Mixed cellularity Lymphocyte depletion Stage Clinical Pathologic IIn untreated prior RT IIIB-IIIB (A + B ) untreated +IV (A B) prior RT untreated prior RT 38 (6-60) 2 12 13 1 12 7 5 1 (490) 24 (96%) 2 0 8/11 3/11 8/12 4/12 ABVD (20 cases) 37 (5-67) 2 14 6 1 10 7 2 2 (1090) 18 (90%) 1 0 loft1 1/11 5/8 3/8 254 CANCEJURLY 1975 Vol. 36 Lukes and Butler histopathologic classification was used.*' A total of 11 patients (MOPP 7/25, ABVD 4/20) had received radiotherapy (RT) prior to combination chemotherapy and had relapsed to primary irradiation program. No patient was previously treated with chemotherapy. History, physical examination, complete blood-counts, liver function tests, skin tests, chest roentgenogram with tomography in the presence of mediastinal adenopathies, skeletal survey, bipedal lymphangiography, liver-spleen scans, and bone marrow biopsy with Jamshidi needle were done routinely. Staging was performed in accordance with the Ann Arbor classification.' In 8/42 patients (19%), peritoneoscopy was carried out in place of laparotomy. For the sake of simplicity, patients relapsing after R T were staged as the untreated patients in relation to their lymphatic or extralymphatic involvement. Treatment Program MOPP was administered according to the classical dose schedule as originally described by De Vita et al." In the absence of progressive disease, ABVD was also administered in monthly cycles for a total of six treatments. ABVD consisted of ADM (25 mg/m2, i.v.), BLM (10 mg/ma, i.v.), VLB ( 6 mg/mz, i.v.), and DTIC (150 mg/m2, i.v.). The first three drugs were administered on day 1 and 14, while DTIC was given during the first 5 days of each cycle. No treatment was given from day 15 to 28. In the first three patients (all untreated) of this series, ADM, BLM, and VLB were repeated on day 8 during cycles 1 and 2. Because of consistent leukopenia (WBC 2500-2000/mms) present in all patients on day 8, in subsequent cy- cles as well as in all other patients the second administration of these drugs was always done on day 14. Table 2 presents the dose adjustments used during both treatments. Virtually all patients were treated and managed on an outpatient basis. In the presence of progression during induction or relapse before 8 weeks from the sixth cycle (induction failure), crossover was carried out. Although this report will deal only with remission induction, it is worth mentioning that the subsequent treatment program in responsive patients includes low-dose (3000-3500 rads) high-energy R T delivered to involved as well as to adjacent lymph-node-bearing areas (extended-field R T in Stage IIB and total nodal irradiation in Stage IIIB-IIIB) in patients with lymphatic extension. In these patients no further treatment is given after completion of RT. In those with extralymphatic disease R T is delivered to sites of major pretreatment involvement (including lung, liver, and bone), followed by six more cycles of either MOPP or ABVD administered every 2 months. Assessment of Results Before starting a new cycle, chest roentgenogram and followup films of retroperitoneal nodes were carried out in practically all patients. One month after the end of the sixth cycle or after disappearance of all visible signs of disease for at least 1 month, skeletal survey and liver scan (or liver-spleen scan in non splenectomized patients) were repeated. At the same time needle biopsy of either bone marrow and/or liver (peritoneoscopy with four biopsies) was also performed if these two sites were known to be involved. A patient was considered in a state of com- TABL2E. Dose Reduction Schedule Before Starting Each Course WBC count per mm' >4000 3999-3000 2999-2000 1999-1500 < I500 Platelet count per mm' >130,000 129,000-100,000 99,000-80,000 79,000-50,000 <50,000 Dose adjustment MOPP ABVD 100%of all drugs 100%VCR, DTIC, B LM, PR ED. 50% HN2, ADM, VLB, PROC. 100%BLM, PRED 50% VCR, DTIC 25% HN2,ADM, VLB, PROC. 100%BLM, PRED. 25%VCR, DTIC NO HN,, ADM, VLB, PROC. 100%BLM, PRED all other drugs withheld Pred.-prednisone; PROC-procarbazine. No. 1 NEWCOMBINATIvOsN. M O P P IN HODCKIND'SISEASE Bonadonna et al. 255 plete remission (CR) when all symptoms and signs of disease, including roentgenographic, radioisotopic, and biochemical studies had returned to normal. Furthermore, a second biopsy of accessible extralymphatic sites of known involvement such as liver and bone marrow had to be interpreted as negative. One patient in whom there was a complete disappearance of systemic symptoms and lymphadenopathies after 6 cycles of MOPP, although osteoblastic bone lesions remained unchanged, was judged to be a complete response. Partial remission (PR) was defined a 75% or greater (but not complete) reduction in the product of the longest perpendicular diameters of all evidence of disease. Patients with regression of less than 75% or no change in measured tumors by the end of sixth cycle, or with relapse (regrowth of tumor masses and/or appearance of new lesions) during induction or within 2 months from its completion (i.e. before starting R T ) were all categorized as induction failures (IF). RESULTS Comparison of Response The comparison of response after primary treatment in relation to stage is presented in Table 3. There is no statistical difference in terms of C R , PR, and IF between MOPP and ABVD. All clinical evidence of disease had disappeared in most patients of both treatment groups after the end of the fourth cycle. In the present series ABVD was usually able to produce a more rapid regression of measurable disease than MOPP; in 7/15 complete responsers a complete disappearance of lesions was observed by the end of second cycle. In both treatment groups the last parameter to return to normal was usually the lymphogram. In all patients considered clinically in complete remission, the second biopsy of bone marrow and liver was interpreted as negative. The sites of incomplete or no remission were observed in extra-lymphatic structures in 3/12 patients treated with M O P P (liver 1, lung 2) as compared to 1/8 of those given ABVD (liver 1). These findings occurred at the level of adenopathies in 4/25 M O P P patients and in 4/20 ABVD patients, respectively. In a total of 6/8 patients the incomplete regression was observed in retroperitoneal nodes. The comparison of treatment results in relation to histologic subtypes revealed no significant difference between the two treatment groups. However, it is of note that both patients with lymphocytic depletion achieved CR after ABVD as compared to 2/5 after MOPP. The comparison of response in relation to prior radiotherapy also failed to show a particular difference between MOPP and ABVD, and confirms that the percentage of C R is not influenced by previous irradiation. Data about crossover for remission induction failure are presently available only for five patients (MOPP two, ABVD three). In one patient with Stage IIIB disease, complete clinical remission was achieved with four cycles of ABVD. Then a progressive relapse occurred only in the mediastinurn, despite two more cycles of therapy. One month after the sixth cycle of ABVD, MOPP was started, followed by rapid objective response. A second patient with Stage IV achieved an almost complete clinical remission after six cycles of ABVD. During the time of re-evaluation, there was a relapse of the retroperitoneal adenopathies which showed a prompt objective and subjective response starting from the first cycle of MOPP. As far as results of A B V D as secondary treatment are concerned, one patient with Stage IIB disease initially treated with MOPP, with almost com- plete remission of lymphoadenopathies, showed by the fifth cycle new manifestations of disease, which failed to regress after the sixth cycle. Crossover to A B V D produced a complete remission after only one cycle. A good partial remission is being obtained in a patient with Stage IV not achieving complete regression after 6 cycles of MOPP. In another patient with Stage IV showing only a minimal re- ~ ~~ ~ Stage IIB III IV B-I (A lls + (A B) + B) TOTAL TABL3E. Comparison of Response in Relation to Stage MOPP No CR PR ABVD IF No CR PR 21 1 11 9 2 12 9 1 2 25 19 3 3 (76%) (12%) (12%) 11 11 8 86 20 15 (75%) 1 2 3 (1 590) IF 2 2 (10%) 256 Vol. 36 sponse after two cycles of MOPP followed by rapid progression, a transient tumor regression was observed also after two cycles of ABVD. Since the patient died about 1 month from the last dose of ABVD, he was categorized as an induction failure after both treatments. Three patients died during the induction phase. The cause of death was due to viral hepatitis in one patient while in partial remission after four cycles of MOPP, and to progressive disease in two other cases (one in each treatment group). As already mentioned before, one patient failed to show a consistent response to secondary therapy with ABVD. The second patient died in another hospital with a superim- posed bronchopneumonia, and therefore a crossover to M O PP was not performed. The manifestations of toxicity are reported in Table 4. A various degree of nausea and vomiting occurred in both groups after each drug administration without being significantly relieved by injection of sedatives. In general, patients tolerated fairly well both types of treatments. The prompt disappearance of symptoms and signs of disease was usually followed by improvement in their performance status. Bone marrow suppression represented the main doselimiting factor, and therefore a temporary reduction of myelosuppressive agents was required. The incidence of transient leukopenia, as determined on the day of drug administration, was higher after MOPP than after ABVD. However, only 1 patient given MOPP showed a WBC less than 2000/mma. In both treatments thrombocytopenia occurred in the minority of patients; in no instance was the platelet count determined below 80,000/mms. Incidence and degree of myelosuppression were not statistically different between the groups of splenectomized and nonsplenectomized patients, as well as between previously irradiated and previously nonirradiated patients. No infections or hemorrhagic manifestations related to drug TABL4E. Toxic Manifestations MOPP (25 cases) ABVD (20 cases) Leukopenia. lhrombocytopenia' Paresthesias Loss of hair Skin changes Amenorrhea WBC < 4000. Platelets < 130,000. ' hlenstruating females. 56% 16% 72% 48% 118: 45% 15% 5% 75% 40% 3/ 3' administration were observed. Transient normochromic normocytic anemia developed in 2 patients of each group. In 2 patients of the MOPP group a temporary drastic reduction of the dose of VCR was necessary because of severe paresthesias. The incidence of temporary loss of hair was higher in the group given ABVD as compared to MOPP. Due to the action of ADM, 15 patients developed an almost complete alopecia, while in 5 instances loss of hair was completely absent. Skin changes due to BLM, although noted in a total of 40%, consisted only in few hyperpigmented stria on the back (6 patients) and in a moderate thickening of the skin in both hands (2 patients). Interstitial pulmonary lesions were suspected in 4 patients, and for this reason the administration of BLM was temporarely interrupted. However, the classic signs of pulmonary toxicity'* were in no instance confirmed through repeated chest roentgenograms, and BLM could be resumed without untoward effects. In a total of 4 patients, amenorrhea was observed during the induction phase. All three menstruating females given ABVD showed cessation of menses. At the time of this writing, it is not yet possible to state whether this side effect is temporary or permanent. Table 5 presents the percentage of optimal dose per m2of body surface administered during the six cycles in each treatment group. It appears evident that although some dose reduction was necessary after the first cycle, this was not progressive through the induction phase. Patients, with the exception of those on the sixth cycle of MOPP, received more than 81% of optimal dose. The average total dose fails to show a significant difference in the two treatments as far as highly myelosuppressive agents (HN, and procarbazine vs. ADM and VLB) and moderately myelosuppressive agents (VCR vs. DTIC) are concerned. DISCUSS~ON The results of this study, though based on a limited series of patients, suggest that the quadruple cyclic combination called ABVD is similar to MO P P in terms of remission rate in advanced Hodgkin's disease. Furthermore, there is also a preliminary indication that there is no crossresistance between the two treatments. Complete response after primary treatment was achieved at various levels of metastatic involvement; whenever possible, clinical findings were confirmed through a second Nu. 1 N E W COMBINATIOvsN. MOPP IN HODGKIND'SISEASE Bonadonna et 01. TABL5E. Percentage of Optimal Dose per Cycle +M O P P HN2 PROC: VCK PREL) ABVD ADM + VLB U1'1C B LM Cycles 12345 6 100 90 100 92 100 84 88 100 100 100 100 87 81 84 94 94 89 90 73 93 88 73 100 93 86 85 97 95 92 97 100 87 257 Average total course 89 88 100 87 96 96 biopsy. At the time of writing, it is too early to provide adequate information about the duration of complete remission. For this reason, in the absence of long-term followup, this study remains preliminary in nature, since it provides only comparative remission rates. Furthermore, the duration of CR, which is now the most important parameter of comparability of new combinations with MOPP, is presently not available. Toxicity, as expressed by incidence of side effects and percentage of optimal dose administered per cycle, appears reversible and tolerable in both treatments groups. ABVD also appears fairly simple to administer; virtually all patients were treated on an outpatient basis. Cyclic combination chemotherapy is now accepted as the most successful therapeutic modality to induce a prompt and complete remission in advanced (Stages IIIB-IV) Hodgkin's disease of adults and children." Several studies have recently shown the useful results of combined drug treatment also in earlier stages (IIB-IIIA) when given either a 1 0 n e ' ~ ~o~r' after high-energy irradiation.'" Which is the Combination of choice? So far, as mentioned before, none of the multiple drug treatments designed in various centers throughout the world has yielded better results than those achieved with MOPP. Therefore, this combination should be regarded at the present moment as the most simple and effective drug therapy to be used in clinical practice. However, MOPP has failed to control successfully for long periods of time all patients with advanced Hodgkin's disease. Therefore, there is a need in our opinion for another effective and tolerable drug combination, to be employed especially in MOPP failures. For this reason, this combination should include drugs non-cross-resistant to MOPP. The problem of whether further intensive treatment or maintenance single agent chemotherapy can statistically influence the duration of remission and the long-term survival in complete responders as compared to no further therapy remains open to discussion. Certainly, the definition of complete response through histologic rather than only clinical parameters can be of help in clarifying this controversy. Concerning the sequence of combined treatment modality for advanced Hodgkin's disease with nodal extension, we still prefer to administer chemotherapy before radiotherapy. As outlined in a previous publication," effective chemotherapy can control and possibly destroy distant microscopic foci of disease located outside the irradiation fields. Furthermore, a partial remission in the lymph nodes after chemotherapy can become more easily complete after subsequent radiotherapy, rather than before. Hematosuppression usually recovers more quickly after multiple drug treatment than after total lymphoid irradiation. Our present program includes radiotherapy also in Stage IV patients who were found responsive to induction chemotherapy. Low-dose radiotherapy is delivered primarily to sites of major pretreatment involvement, in accordance with the findings observed by Frei et al." The incidence of secondary neoplasms in occasional patients given combination chemotherapy or chemotherapy plus intensive radiotherapy'." should not prevent, in our opinion, the appropriate use of effective and tolerable combined modalities in good-risk patients with advanced Hodgkin's disease. In conclusion, the results presented in this paper indicate that the development of an effective multiple drug treatment independent from M O P P can be achieved by the association of some of the new compounds known to be active in Hodgkin's disease such as ADM, BLM, and DTIC. Although this multiple drug treatment (as other similar treatments) was designed more 258 C A N C E X 1~9U75~ Y Vol. 36 on an empirical rather than a solid scientific bases, it produced a percentage of complete responders comparable to that observed in a randomized study with the classic MOPP. It should be emphasized once more that ABVD was not designed with the intention to compete with MOPP. Rather, its main purpose is to serve as an effective alternative treatment in MOPP failures. It needs to be emphasized that potentially severe, and to a certain extent unpredictable, side effects occur from both ADM and BLM. The unique toxicities of two of the agents in the ABVD combination would probably render difficult and even hazardous a long-term therapy at full dosage. For this reason, the primary use of this combination in young untreated patients would, at present, not be preferable to MOPP. If the promising results emerging from our preliminary study are confirmed on a larger series of patients, followed for an adequate period of time, the next logical step would be to combine sequentially both MOPP and ABVD in an attempt to increase the percentage of complete responders, as well as to decrease the incidence of patients destined to relapse. REFERENCES Arsenau, J. C., Sponzo, R. W., Schnipper, L. E., Bonner, H., Young, K.C . , Canellos, G. P., Johnson, R. E., and De Vita, V. T.: Non lymphomatous malignancies complicating Hodgkin's disease.-Possible association with intensive therapy. N. Engl. J . M r d . 287:1119-1122,1972. 2. Blurn, R. H., and Carter, S. K.: A clinical review of bleomycin, a new antineoplastic agent. Cancer 31 903-914, 1973. 3. Blum, K.H., and Carter, S. K.: Keview ofadriamycin, a new anticancer drug with significant clinical activity. Ann. Intern. M e d . 8(1:249-259,1974. 4. Bonadonna, G., hlonfardini, S., De Lena, M., Fossati Bellani, F., and Beretta, G.: Clinical trials with adriamycin-Results of three years study. In International Symposium on Adriamycin. Berlin, Springer, 1972; pp. 139-1S2. 5. Honadonna, G., I)e Lena, A l . , hionfardini, S., Bartoli, C., Bajetta. E., Beretta, G . ,and Fossati Bellani, F.: Clinical trials with bleomycin in lymphomas and in solid tumors. Eur. J . Cancer 8:205-215,1072. 6 . Bonadonna, G.. De Lena, hi., Banfi, A,, and Lattuada, A . : Secondary neoplasnis in malignant lymphomas after intensive therapy. N . Engl. J . M r d . 288:1242-1243,1973. 7. ( h e l l o s , G. P.,Young, K. C., and De Vita, V. T.: Combination chemotherapy for advanced Hodgkin's disease in relapse following extensive radiotherapy. Clin. Pharmacol. Thcr. 13:750-755, 1972. 8. Carbone, P. P., Bono, V., Frei, E., 111, and Brindley, C. 0.:Clinical studies with vincristine. Blood 21 :640-647. 1963. 0. Carbone, P.P . , Kaplan, H. S.,hlusshoff, K., Smithers, D. W.<and l`ubiana, hl.: Keport of the Committee on Hodykin's Disease Staging Classification. Canccr Rrs. 31:1860-IHbl,1971. 10. Carter, S. K., Schabel, F. h l . , Brader, L. E., and Johnston, 'I. P.: I ,3 bis-(2-chloroethyl)-l-nitrosourea(BCNU) and other nitrosoureas in cancer treatment-A review. Adu. Cancer Res. 163273-332,1972. I I . De Lena, hl., and Beretta, G.: Comparative toxic and therapeutic effect of adriamycin and bleomycin in malignant lymphoma. Tumori 58:78-88,1972. 12. I)e Lena, h l . , Guzzun, A . , hiunfardini, S., and Bonadonna, G . ; Clinical, radiologic, and histopathologic studies on pulmonary toxicity induced by treatment with bleomycin (NSC-125U66).Canccr Chrmothrr. Rep. 56343-356, 1072. 13. De Lena, hl.,hlonfardini, S., Beretta, G., Fossati Bellani, F . , and Bonadonna, G,:Clinical trials with intensive chemotherapy and radiotherapy in Hodgkin's disease. Nafl. Cancer Insf. Monogr. 36:403-420,1973. 14. De Vita, \:. T., Serpick, A. A., and Carbone, P. P.: Combination chemotherapy in the treatment of advanced Hodgkin`s disease. Ann. I n h n . M e d . 73:881-895,1970. 15. De Vita, V. T., and Carbone, P. P.: Chemo- therapeutic implications of staging in Hodgkin's disease. Cancer Res. 31:1838-1844,1971. 16. De Vita, V. T., Canellos, G . P., and Moxley, J. H. 111: A decade of Combination chemotherapy of advanced Hodgkin's disease. Cancer 30:1495-1504.1972. 17. Lhrant, J. K., and Lessner, H. E.: Development of four-drug B C N U combination chemotherapy regimens. Cancer 32:277-285,1973. 18. Frei. E..111, LuceL,j.K.. Talley, R . W., Vaitkevicius, V. K., and Wilson, H. E.: 5-(3,3-dimethyl-triazeno) imidazole-4-carboxamide (NSC-45388)in the treatment of lymphoma. Cancer Chemofher. Rrp. 56:667-670, 1972. 19. Frei, E., 111, Luce, J. K., Gamble, J. F., Coltman, C. A., Jr., Costanzi,J . J. Talley, R. W., Monto, R. W. Wilson, H. E. Hewlett, J. S. Delaney, F. C., and Gehan, E. G . : Combination chemotherapy in advanced Hodgkin's disease-Induction and maintenance of remission. Ann. Intern. M r d . 79:376-382,1973. 20. Gottlieb, J. A,, Baker, L. H., Quagliana, J. M., et al.: Chemotherapy of sarcomas with a combination of adriamyrin and dimethyl triazeno imidazole carboxamide. Cancer 30:1632-1638,1972. 21. Jacquillat, C., Weil, M . , Desprez-Curely, J. P., et al.: Chimiotherapie de la maladie de Hodgkins par Ies association thirapeutiques. Bull. Cancer (Paris) 58221-234, 1971. 22. Lowenbraun, S.,De Vita, V. T., and Serpick, A . A,: Combination chemotherapy with nitrogen mustard, vincristine, procarbazine, and prednisone in previously treated patients with Hodgkin's disease. Blood 36:704-717, 1970. 23. Luce, J. K., Gamble, J. F., Wilson, H. E., et al.: Combined cyclophosphamide, vincristine and prednisone therapy of malignant lymphoma. Canccr 28:306-317,1971. 24. Lukes, K.J., and Butler, J. J.: The pathology and nomenclature of Hodgkin's disease. Canccr Rcr. 26:1063-108I , I P66. 25. hlcElwain, `r.J., Wrigley, P. F. M., Hunter, A,, Crowther, D., Malpas, J. S., Peckham, M . J. Smithers, D. W., and Fairley, G. H.: Combination chemotherapy in advanced and recurrent Hodgkin's disease. Nafl. Cancrr Inst. Mongr. 36:395-402,1973. 26. Moore, M.L.,Bull, J. M . Jones, S. E. Roscnberg, No. 1 NEWCOMBINATVISO. NMOPP IN HODCKIND'SISEASE Bonadonna et af. 259 S. A, and Kaplan, H. S.: Sequential radiotherapy and chemotherapy i n the treatment of Hodgkin's disease-A progress report. Ann. Intern. Med. 77:l-9, 1972. 27. Moore, M. K., Jones, S . E., Bull, J. M., William, L. A., and Kosenberg, S. A.: M O P P chemotherapy for ad- vanced flodgkin's disease-Prognostic factors in 81 patients. Cancer 32:52-60, 1973. 28. O'Bryan, K. hl., Luce, J. K., Talley, R. W., Gottlieb, J . h . ,Baker, L. H., and Bonadonna, G . : Phase I 1 evaluation of adriamycin in human neoplasia. Cancer 32:l-8, 1973. 29. Skibba, J . L., Beal, L). D., Ramirez, C., et al.: Ndemethylation of antineoplastic agent 4(5)-(3, 3-dirnethyl-l- triazeno) irnidazole-5(4) carboxarnide by rats and man. Cancer Rrs. 30:147-150, 1970. 30. Stutzman, L., and Glidwell, 0.: Multiple chemot herapy agents for Hodgkin's disease-Comparison of three routines: a cooperative study by Acute Leukemia Group B. J A M A 225:1201-1211, 1973. 31. Young, K. C., Chabner, B. A., Canellos, G. P., Schein, P. S., a n d De Vita, V. T.: Maintenance chemotherapy for advanced Hodgkin's disease in remission. Lancet i:1339-1343, 1973. 32. i'oung, K. C., De Vita, V. T., and Johnson, K. E.: Hodgkin's disease in childhood. Blood 42~163-173, 1973.