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

Home , Cancer research

[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 rÃ©Ã©valuationofbenefits 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

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 were utilized, failed to show definitive appears to be worthy of study, at least in given subsets. evidence of the superiority of the new drug regimens over MOPP. In fact, CCVPP and BCVPP yielded a 5-year RFS which Development of ABVD was very close to that reported by De Vita ef al. (25, 27), although in a randomized study the results achieved with By the end of 1972, our research group in Milan had com BCVPP (2) were significantly superior to those achieved with pleted the Phase II study of 2 new anticancer antibiotics, MOPP. Some of the derived MOPP regimens such as BCVPP Adriamycin and bleomycin (3, 4, 6). Since objective tumor and ChlVPP produced less gastrointestinal toxicity and neuro- response in Hodgkin's disease refractory to alkylating agents, toxicity than did MOPP (37). Vinca alkaloids, and procarbazine was documented at 70 and Within a few years of their introduction into the medical 50%, respectively, we thought that it was appropriate to include community, 2 important long-term adverse consequences of these agents in a multidrug combination. This was the reason MOPP and MOPP-derived treatments began to appear. These for designing MABOP chemotherapy, wherein we substituted are the possibilities of carcinogenesis and of sterility because Adriamycin and bleomycin for procarbazine in a combination of intensive prolonged chemotherapy (8, 43). Today, these regimen otherwise very similar to MOPP. Like other MOPP- concerns are well documented. derived regimens, MABOP failed to improve incidence and Thus, at the end of 1974, the effectiveness as well as the duration of CR, both in patients previously untreated and in limits of intensive irradiation and of single multidrug regimens those relapsing after primary irradiation (3, 23). However, the were clearly evident, and the initiation of combined modality experience with MABOP taught us 2 important lessons. The studies represented an attempt to overcome the plateau of first lesson concerned strategy. By utilizing a single multidrug cure rate inherent in the administration of single modalities. regimen and regardless of the type of drugs included in the The failure of optimal radiation therapy to obtain a long-term combination, we realized that there was a plateau in the inci RFS for 25 to 60% of patients with Hodgkin's disease either dence of durable CR. The second lesson concerned toxicity. spread extensively above and below the diaphragm and/or We noticed that a single 25-mg/sq m dose of Adriamycin failed with systemic symptoms is usually ascribed to the presence of to produce a high incidence of severe myelosuppression when occult foci beyond the fields of irradiation. The limits of MOPP this drug was injected with mechlorethamine (6 mg/sq m). and MOPP-like combinations can be ascribed to 2 main factors Furthermore, if the cumulative dose of Adriamycin was kept (Table 1). The first factor concerns selective drug resistance, below 300 mg/sq m, none of our patients developed cardio- which is responsible for the lack of attaining initial CR or myopathy, not even those who had received prior irradiation to durable CR in a fraction of patients. The second factor involves the mediastinum or who were subsequently given radiation chronic toxicity, namely, sterility and carcinogenesis, and ap therapy to the mediastinal region. In contrast, the single i.v. pears to be primarily related to the intensity of treatment, i.e., dose of bleomycin (30 mg/sq m) produced nonfatal pulmonary the cumulative doses of procarbazine and alkylating agents as toxicity in 20% of the first series of patients who received 6 well the association of intensive irradiation with intensive cycles of MABOP chemotherapy (23). polychemotherapy. The rationale for designing ABVD chemotherapy in 1973 (5, For the above-mentioned reasons, the real alternatives to 15) was essentially based on the following considerations: (a) MOPP chemotherapy should involve the design of entirely new the need to treat effectively MOPP-resistant patients utilizing a regimens consisting of effective drugs not included in the combination of regimen drugs which were individually non- original MOPP combination. The main purpose for designing cross-resistant with MOPP components; (6) the therapeutic these new combinations is the management of the considerable and toxicological information achieved with Adriamycin and

4310 CANCER RESEARCH VOL. 42

Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1982 American Association for Cancer Research. Chemotherapy Strategies to Control Hodgkin 's Disease bleomycin given either alone or through MABOP combination; Pathological Stage IMAor NIB and retroperitoneal adenopathy). (c) the effectiveness of dacarbazine in about 50% of previously The radiotherapy doses were 3500 rads to involved lymphoid treated patients with Hodgkin's disease, as reported by Frei ei areas and 3000 rads to adjacent uninvolved areas. About 1 al. (29) and later confirmed by our group (11 ); (d) the little month after the end of radiotherapy, treatment was completed cross-resistance between vinblastine and vincristine in hu with 3 additional cycles of either chemotherapy. The updated mans. Other considerations included the synergistic effect, comparative treatment results in 196 consecutive patients with no additive toxicity, of dacarbazine and Adriamycin in (MOPP group, 100; ABVD group, 96) have indicated that ABVD experimental animal systems, as reported by Skibba ef al. (57). combined with radiotherapy is significantly superior to MOPP We elected not to utilize one of the nitrosourea derivatives such plus radiotherapy in terms of CR, particularly in patients with as BCNU or CCNU because of their characteristic delayed systemic symptoms, and freedom from progression. The best myelosuppression which could prevent treatment recycling at comparative results were observed in Pathological Stage IIIA rather short intervals. To avoid or limit toxicity from new anti where the 5-year RFS was 100% in the ABVD group and biotics, the single dose of Adriamycin remained 25 mg/sq m, 78.4% in the MOPP group (p = 0.03). The analysis of total and that of bleomycin was lowered to 10 mg/sq m. Their survival failed to show a significant difference between the 2 cumulative doses were planned not to exceed 300 and 150 treatment groups, also because of salvage therapy with ABVD mg/sq m, respectively. To limit as much as possible the need in MOPP-resistant patients (Table 3). In both groups, the first for a dose reduction schedule, all drugs were injected i.v. on 3 cycles of combination chemotherapy induced a prompt tumor Days 1 and 15 of each treatment cycle. Thus, the initial dose shrinkage, thus allowing the delivery of subsequent irradiation schedule of dacarbazine (150 mg/sq m from Days 1 to 5) as with lower doses than usual and smaller ports at the leve! of tested by Frei ef al. (29) was soon modified to 375 mg/sq m mediastinal and paraaortic regions. On the basis of these on Days 1 and 15 to limit vomiting which initially occurred for findings and considering that radiotherapy can effectively kill 5 consecutive days. drug-resistant cells, we believe that, when indicated, combined The strategy utilized in the development of ABVD protocols treatment strategy should begin with chemotherapy. consisted of 3 phases (7, 9). First, we planned to compare the A third comparative test between MOPP and ABVD is pro efficacy of ABVD versus MOPP in advanced Hodgkin's disease vided by our recent analysis of patients with nodular sclerosing previously untreated with chemotherapy and, through a cross histology (13). The scope of the study was to retrospectively over design, to test either regimen in resistant patients. In a evaluate the comparative CR and the 5-year survival rates in the subgroup of patients with nodular sclerosing Hodgkin's second phase, we elected to alternate one cycle of MOPP with one cycle of ABVD as first-line treatment in Pathological Stage disease. Since patients belonged to prospective randomized IV Hodgkin's disease in the attempt to increase the percentage studies, they were comparable in terms of age subgroups, of durable CR. The third phase included a combined modality bulky disease, extranodal involvement, systemic symptoms, study with chemotherapy and radiotherapy and was primarily aimed at decreasing the incidence of treatment-induced leu Table 2 kemia. Comparative results with MOPP versus ABVD MOPP -Â»ra- ABVD -> ra diotherapy diotherapy MOPP versus ABVD <41) (35) p Utilizing a fixed number of 6 cycles, the first prospective CRChemotherapy aloneChemotherapy randomized study indicated that the CR induction rate between radiotherapyAtSyrFreedomplus MOPP (63%) and ABVD (71%) was comparable. The study design was actually more complex and consisted of subse progressionRFSSurvivalfrom quent low-dose irradiation to complete and almost complete responders, including patients with Stage IV disease who re respondersOverallof complete survivalSurvival ceived radiotherapy to all previously involved extranodal sites with NEDa63.070.756.778.585.767.067.071.580.066.380.391.872.872.80.270.390.110.340.34 except the bone marrow (10, 14, 15). Since patients were NED, no evidence of disease after first- and second-line chemotherapy. previously stratified for histological subtypes as well as whether or not they had received prior irradiation, this study also Table 3 provided initial information concerning the comparability be Comparative results with MOPP versus ABVD combined with radiotherapy in tween MOPP and ABVD of relapse-free and total survival rates Stage IIB-IIIA-IIIB at 5 years (Table 2). Similar 5-year results, utilizing polychem- MOPP ABVD group otherapy followed by low-dose radiotherapy in advanced Hodg group (100 (96 cases) kin's disease, were independently reported by Prosnitz ef al. cases) (%) (%) p CRNo (45) at Yale University. An additional comparison between the symptomsSystemic 2 regimens is now available from the analysis of a larger series symptomsNodular than that studied previously (7, 9, 52). Patients were randomly sclerosisAtSyrFreedom allocated to receive 3 cycles of either MOPP or ABVD, admin istered according to the classical dose schedules. In the ab progressionRFSSurvivalfrom sence of tumor progression, treatment was continued with respondersTotalof complete high-energy radiotherapy (subtotal nodal irradiation in patients survivalSurvival with NED"79.096.073.381.865.482.077.667.962.890.796.288.790.682.691.391.384.082.10.040.040.0050.070.550.230.08 with Pathological Stage MB, IIISA, or III ;B with no documented paraaortic adenopathy; total nodal irradiation in patients with ' NED, no evidence of disease after first- and second-line chemotherapy.

NOVEMBER 1982 4311

and median follow-up time. There was a comparatively higher Lack of Cross-Resistance CR rate favoring ABVD in all classical prognostic variables, but We have recently published our updated results on ABVD as the differences between the 2 treatment groups were not second-line chemotherapy in 54 adult patients resistant to significant. In patients with nodular sclerosis histology and MOPP (49). Resistant patients were considered those showing bulky disease, the difference between the ABVD group (86.8%) progessive disease during primary chemotherapy administered and the MOPP group (71.4%) was of borderline significance at full or nearly full doses as well as those relapsing within the (p = 0.05). In contrast, the comparative probability of freedom first 12 months after achievement of pathological CR (48, 49). from progression at 5 years from the start of chemotherapy Although the CR rate was influenced by certain prognostic was significantly in favor of ABVD in the entire series (MOPP parameters, such as disease extent (nodal, 74%; extranodal, 55.6% versus ABVD 80.8%, p = 0.0001) as well as in the 44%) and systemic symptoms ("A," 82%; "B," 49%), available subgroup with bulky lymphoma (MOPP 57.5% versus ABVD data indicate that ABVD is a useful salvage regimen to be used 75.8%, p = 0.02). The comparative 5-year RFS and survival as first treatment in MOPP-resistant patients. Besides inducing results in all complete responders with nodular sclerosis his a prompt high frequency of CR (total, 59%) followed by im tology are summarized in Table 4. RFS was significantly su proved 5-year survival, at the expenses of moderate and re perior in the ABVD group compared to the MOPP group, regardless of absence ("A") or presence ("B") of systemic versible toxicity, ABVD can probably cure one-third of complete responders and therefore about 20% of all MOPP-resistant symptoms. The lack of comparative difference in the total patients. In our experience, the delivery of MOPP in ABVD- survival rates was most probably due to salvage ABVD chemo resistant patients yielded less brilliant results (total CR, 25%), therapy in MOPP-resistant patients. Our findings suggest that but the difference should be partly ascribed to the compara ABVD chemotherapy should now be considered in the treat ment plan for nodular sclerosing Hodgkin's disease. tively lower number of Ã©valuablepatients in the MOPP group. However, the observed findings were sufficient to demonstrate The efficacy of Adriamycin-containing regimens (MABOP, absence of cross-resistance between the 2 combinations (Ta ABVD) versus MOPP also emerged from a comparative analysis ble 6). At least in the United States, ABVD as salvage regimen of salvage chemotherapy regimens in patients failing to re has not yet been properly tested in patients refractory to MOPP spond to primary irradiation. In a recent retrospective study of only for a number of reasons (e.g., additional chemotherapy 96 cases (53), CR occurred in 36 of 48 relapsing patients after failing MOPP, significant modification of the treatment given MOPP (75%) and in 44 of 48 patients treated with an Adriamycin combination (91.7%, p = 0.05). Also, the 5-year regimen, prior resistance to either vinblastine or bleomycin). Over the past few years, other MOPP-salvage combinations freedom from progression (51.6 versus 76.8%, p = 0.006), RFS (64.1 versus 84.1%, p = 0.02), survival of complete were designed in the United States and Europe (39, 49), and all regimens but B-DOPA have included a nitrosourea deriva responders (62.8 versus 85.8%, p = 0.02), and total survival tive, either CCNU or streptozotocin, in the combination (Table (53.9 versus 77.2%, p = 0.009) were significantly in favor of 7). All salvage regimens appeared promising, particularly when a regimen containing Adriamycin. Table 5 shows that our B-DOPA and B-CAVe were utilized. In fact, the CR rate ranged findings with salvage MOPP are comparable to those obtained from 50 to 60%, a result similar to that achieved with ABVD by the NCI (16), Stanford (44), and Harvard (41) research (Table 8). At present, the 5-year results in terms of survival and groups. In contrast, our results with Adriamycin-containing toxicity were not reported in detail. More recently, Einhorn et combinations appear comparatively superior and reaffirm the al. (28) have reported the results of a salvage regimen utilizing usefulness of Adriamycin in the treatment of advanced Hodg kin's disease. the drugs in ABVD and adding CCNU. The VABCD regimen was tested in 18 Ã©valuablepatients resistant to MOPP. CR was

Table 4 Table 5 Nodular sclerosing histology: comparative 5-yr results in complete responders Salvage chemotherapy in patients with Hodgkin's disease relapsing after radiotherapy MOPP group (%) ABVD group (%) p (%)RFSUnknownresults TotalRFSSurvival"A"RFSSurvivalâ€¢â€¢B"RFSSurvival71.580.467.071.073.304. of re cases21 sponse(%)76 NCI (16) Stanford (44) MOPP 46 78 45 58 55" 606 Harvard (41) MOPP 58 Unknown Milan (53)RegimenMOPPMOPP 48 75 64 54 77a Adriamycin 48Complete 925-yr 84Survival75" regimensNo. At 3 years. 188.591.295.894.185.590.00.0040.100.030.070.030.48 At 4 years.

Table 6 Evidence for lack of cross-resistance between ABVD and MOPP in MOPP- and in ABVD-resistant patients

sur sur vival of com vival ofnon-complete responseor du plete re re ofcases5416Noprogres re toCR(mos.)33Medianration ofCR(mos.)176.5Mediansponders(mos.)>60>20Mediansponders(mos.)114 sion(%)2863Partialmission(%)1312CR(%)5925Mediantime ABVDMOPPNo.

4312 CANCER RESEARCH VOL. 42

Table 7 of the results of chemotherapy trials along new lines of thought. Examples of MOPP-salvage drug combinations other than ABVD We are now considering new, attractive experimental hy B-DOPAB-CAVeBVDSABDICSCABCVBBleomycinDacarbazineVincristinePrednisoneAdriamycinBleomycinCCNUAdriamycinVinblastineBleomycinVinblastineDoxorubicinStreptozotocinAdriamycinBleomyinDacarbazineCCNUPrednisoneStreptozotocinCCNUAdriamycinBleomycinCCNUVinblastineBleomycinTablepotheses that we can develop into more ambitious treatment strategies. Chart 1 illustrates the influx of new drugs effective against Hodgkin's disease into clinical use over time, as well as the drug combinations developed for first-, second-, and third-line chemotherapy. Vindesine has been recently added to the list of drugs moderately active in advanced refractory Hodgkin's disease. By properly utilizing available agents, we can indeed design more than one non-cross-resistant combi nation which may also be tested in tandem as primary treatment to overcome the limits inherent in a single drug combination.

The Mutation Theory Today, as stressed by Skipper (58, 60), the results of chemo therapy trials in humans are consistent with inferences of the

CIS-PLATINUM CDDP METHYL-GAG. Me-GAG 1981

Drugs available to develop third-line combinations PREONIMUSTINE

CEP

TENOPOSIDE VM-26 ETOPOSIDE VP-16

8Drug patientsRegimenCVB"SCABBVDSB-DOPAB-CAVeABDICABVDVABCDNo.combinations effective in MOPP-refractory sur-CR dura- Median CR(%)+ PRa tion of CR vivai after of pa DACARBAZINE. OTIC Drugs utilized to develop tients3917101522295418CR(%)263530605034.55944Median(mos.)84.5 (mos.) second-line combinations +59 4.5+ 4.5 +50 8 + 16 ADRIAMYCIN ADM ABVD BLEOMYCIN BLM B-DOPA +80 ? 26 B-CAVe ?77 14+ SCAB 2482.5 35+ BVDS 28+72 28+ LOMUSTINE CCNU ABDIC 60+88 17 STREPTOZOTOCIN. STZ CVB 24+ 28 + PR, partial remission. For description of regimens, see Table 7.

CARMUSTINE.BCNU achieved in 8 patients, and partial response was noted in 8 PROCARBAZINE PCZ patients. Five of 8 complete responders remain continuously VINCRISTINE VCR relapse free from 5 to 36 months. In spite of considerable toxicity (severe myelosuppression, stomatitis, reversible pul VINBLASTINE. VLB monary toxicity in 6 patients, vomiting and alopecia in virtually 1961 all patients), the therapeutic results of VABCD confirm that Drugs utilized to develop initial combinations durable CR and potential cure are possible with non-cross- CYCLOPHOSPHAMIDE CTX resistant combination chemotherapy in a fraction of MOPP- MOMP resistant patients. MOPP CHLORAMBUCIL. CHL COPP This year, we have also reported the usefulness of a third- MVPP BOPP line combination consisting of p.o. administration of CEP in 24 BVCPP patients resistant to both MOPP and ABVD chemotherapy (50). METHOTREXATE. MTX The preliminary results of CEP appeared promising in terms of PREDNISONE. PRO 1953 clinical relevance (CR in 33% of patients for a median duration of 10 months, partial response in 21 % of patients for a median MECHLORETHAMINEHN2 duration of 8 months). Toxicity was moderate and reversible. 1948

The important clinical message to be derived from all salvage Chart 1. Influx over time of clinically effective drugs in Hodgkin's disease and programs currently in use is that, in spite of an appreciably drug combinations developed for first-, second-, and third-line chemotherapy. high complete response rate, the incidence of durable remis Methyl GAG + Me GAG, methyl-glyoxal-bis-guanylhydrazone; MOMP, mechlor- sions in MOPP-resistant patients remains, in most instances, ethanine, Vincristine, methotrexate, prednisone; COPP, cyclophosphamide, vincristine, procarbazine. prednisone; MVPP, mechlorethanine, Vinblastine. procar- rather low. Present findings appear therefore more interesting bazine, prednisone; BOPP, 1, 3-bis(2 chloroethylH-nitrosourea, vincristine, from the conceptual viewpoint for they may allow interpretation procarbazine, prednisone.

NOVEMBER 1982 4313

Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1982 American Association for Cancer Research. G. Bonadonna mutation theory of Luria and Delbruck (40), which was originally simultaneous delivery of a combination of non-cross-resistant based on studies of the fluctuation in numbers of phage-resist- drugs or, probably better, the alternating delivery of 2 or more ant Escherichia coli in independent cell populations of the than 2 non-cross-resistant combinations of drugs. same size. Since survival and overgrowth of drug-resistant neoplastic cells are major causes of chemotherapeutic failure The MOPP-ABVD Program in human cancers, as in animal cancers, the clinical findings which are consistent with inferences of the mutation theory The rationale for alternating one cycle of MOPP with one are: (a) the wide fluctuation in the degree and duration of cycle of ABVD in Hodgkin's disease was first based on the response of similarly staged and treated patients bearing a clinical observation that patients resistant to MOPP showed given neoplastic disease; (b) many observations of partial and either progressive disease after the first 2 to 4 cycles or disease complete response followed by tumor regrowth in the presence recurrence within a few months from an initial complete re of continuing undiminished treatment with the same drug or sponse. A second reason for the alternating program was also combination of drugs; (c) the variance in survival time of treat derived from clinical experience. In fact, MOPP and ABVD ment failures. appeared to be equally effective non-cross-resistant combina Based on the early work of Luria and Delbruck (40) on tions, and the median time to CR with either regimen was the mutation to resistance in bacterial populations, in 1979 Goldie third cycle. Today, the mathematical model of Goldie and and Goldman (33) developed a mathematical model "relating Goldman (33) as well as the experimental studies of Skipper, the drug sensitivity of a tumor to its own spontaneous mutation Schabel, and coworkers (54, 58-61) provide a strong support rate toward phenotypic drug resistance." Briefly, the assump for changing treatment at each cycle of therapy, at least for tions underlying the model are the following, (a) Genetic insta exponentially growing tumors in which chemotherapy produces bility is an intrinsic property of growing mammalian cancer log kills. cells. Genetically unstable cells develop somatic mutations that Our first cyclic MOPP-ABVD program versus MOPP alone lead to phenotypic resistance to drugs to which they have was started in 1974 in adults with Pathological Stage IV Hodg never been exposed, (b) No 2 neoplasms of the same histolog- kin's disease (7, 9, 51 ). In the absence of disease progression, ical subtype and stage need have the same mutation rate. a total of 12 cycles of either regimen was planned because we Therefore, a large fluctuation in the proportion and absolute were aware that in a fraction of patients, particularly those with number of drug-resistant tumor cells, a necessary conse nodular sclerosis histology, as many as 12 cycles could be quence of the mutation theory, probably exists in comparably required to achieve CR. The 5-year results of the trial were staged individuals with a given tumor, depending on whether recently published (51). More patients are presently Ã©valuable the first mutation occurred early or late in the history of the for the comparative complete remission rate and the 5-year tumor. This basic tenet of the mutation theory applied to cancer actuarial results (Table 9). No patient was excluded from anal chemotherapy may provide a reasonable explanation for some ysis because of toxicity or refusal to take drugs before com of the problems that have puzzled oncologists for years, pleting 12 cycles. From the strategic point of view, the first namely, wide variations in the incidences of remissions as well interesting finding is the lack of disease progression during the as their degree and duration in individuals bearing tumors of administration of alternating chemotherapy, compared to the the same stage and type, as well as variations in the cure rate 22.5% which occurred during the administration of MOPP of patients who have achieved complete response (58, 60). (c) alone. CR after MOPP was 72.5%, a result very close to that As tumor size increases, the probability of resistant clones reported in Stage IV by NCI investigators (25, 27), compared increases, and thus for reasons quite independent of growth to 92.3% after MOPP alternated with ABVD. The findings kinetics we would expect increasing reistance to treatment with confirm that the systematic switching of effective non-cross- increasing tumor size. These assumptions from the Goldie and resistant combinations after each cycle of therapy can signifi Goldman model fit very well with the known concepts that cantly affect the mix of sensitive and resistant neoplastic cells. tumor heterogeneity increases with the size of cancer cell The alternating regimen was superior to a single multidrug populations and that there is an invariable relationship between regimen in all prognostic subgroups, particularly in patients the neoplastic cell burden at the initiation of chemotherapy and more than 40 years old, with single extranodal site and no prior "curability." irradiation. The lack of statistical significance in various sub The origin of doubly resistant phenotypes usually is thought groups was due to the limited number of patients Ã©valuablein to be a 2-step process (61 ). The drug-resistant cells are totally each category. The comparative 5-year results also confirmed resistant to a given drug or drug combination, and thus it is not the superiority of the MOPP-ABVD program versus MOPP at all necessary for the total tumor cell burden to approach alone. Our comparative 5-year RFS related to disease extent 1012 before we must expect the presence of doubly or multi- was as follows. Single extranodal site: MOPP, 42%; MOPP- drug-resistant tumor cells of different types. Therefore, the ABVD, 77%. Multiple extranodal sites: MOPP, 66%; MOPP- more rapidly the singly resistant cells are eradicated, the lower ABVD, 100%. The difference in the RFS of Stage IV with MOPP is the probability of the emergence of doubly or multidrug- chemotherapy between NCI (65%) and Milan (45.2%) is ac resistant cells. Clinical resistance will be observed when 10 to tually difficult to explain and may be related to the biological 50% of the surviving neoplastic cells are resistant to the drug factors outlined before, namely, the large fluctuation in the or drugs being used (60). Since doubly drug-resistant neoplas proportion and absolute number of drug-resistant cells, affect tic cells will negate the usefulness of 2-drug combinations and ing incidence of remissions as well as their degree and dura markedly reduce the effectiveness of 3- or 4-drug combina tion. However, it is worth mentioning that, also from another tions, the most effective means for preventing the emergence randomized study (2), the 5-year RFS following MOPP chemo of doubly resistant phenotypes during chemotherapy is the therapy was 50%. Our comparative analysis of total survival,

4314 CANCER RESEARCH VOL. 42

Table 9 primary chemotherapy with non-cross-resistant regimens in Results of MOPP versus MOPP/ABVD in Stage IV Stages III and IV. At present, the results of the NCI MOPP- MOPP-ABVD SCAB program versus MOPP alone are premature (24, 39). MOPP (40 (39 cases) In light of the present results, should the delivery of cyclic cases) (%) (%) MOPP-ABVD become the standard form of chemotherapy for ProgressionCRAgeÂ«40 advanced Hodgkin's disease? Although I have little doubt about the superiority of alternating chemotherapy over a single drug combination, I believe we are still in the data-collecting period. yr>40yrSymptoms"A""B"Nodular Therefore, other research groups are invited to mount pro spective randomized studies to independently confirm our re sults before this alternating program becomes the established sclerosisDisease treatment plan in the medical community. To meet the most stringent requirements for the initial assumption to work, we extentÂ«3 sites>3 are now testing, through a prospective randomized study, the sitesSingle efficacy of an alternating regimen which includes monthly extranodalMultiple administration of a half-cycle of MOPP (mechlorethamine and extranodalPrior vincristine on Day 1, procarbazine and prednisone from Day 1 radiotherapyNoYesAtSyrFreedom to 7) followed by one dose of ABVD on Day 15 (Chart 2). Theoretically, this alternating regimen should test more appro priately the validity of the hypothesis of Goldie and Goldman in a larger number of cases since the study is being performed in progressionRFSSurvivaltrom patients with Stages II (bulky mediastinum), III (A and B), and respondersOverallof complete IV (A and B). In complete responders, low-dose radiotherapy survivalSurvival with NED"22.572.576.964.375.071.472.787.568.876.760.067.983.335.445.275.465.650.4092.388.010091.792.695.210090.697.160.093.190.080.985.493.085.185.20.040.050.090.110.060.040.04<0.00010.00010.080.090.02will be delivered only to the mediastinal area if bulky adenopathy (mass/thoracic ratio, >0.33) is present at the start of NED, no evidence of disease after first- and second-line chemotherapy. chemotherapy, since this is a subgroup which can benefit from combined modality treatment, particularly in the presence of although showing a marked trend in favor of alternating chemo nodular sclerosis histology. Otherwise, no further treatment will therapy (85.1 versus 65.6%), failed, at present, to reach sta be administered once CR is achieved by drug therapy. Patients tistical significance (p = 0.09) because the survival difference not achieving CR after 6 cycles of either alternating regimen became evident only after the first 30 months. The results can will receive CEP chemotherapy, with or without irradiation also be ascribed partly to the transient effect of salvage therapy depending on individual clinical situations. Through incorpo with ABVD in MOPP-resistant patients. ration of more stringent requirements in alternating-sequence Aside from marked vomiting, particularly after each ABVD therapies, the present study essentially attempts to increase exposure, toxicity from alternating chemotherapy was moder the 5-year RFS obtained in Stage IV (85%) by alternating one ate. From the viewpoint of bone marrow tolerance, cyclic full cycle of MOPP with one full cycle of ABVD. In other words, MOPP-ABVD was better tolerated than MOPP alone, as indi our goal is to improve the survival rate with no evidence of cated by the percentage of optimal dose administered in pa disease by the first treatment program, since practically all tients who have completed 12 cycles of either regimen (7,51). salvage regimens have limited efficacy in terms of durable Since it has been shown by the Stanford group (17) that the remission. attainment of CR is best for patients who had a higher mean A research program utilizing 2 (MOPP-ABVD) versus 3-drug rate of drug delivery in the first 3 consecutive MOPP cycles, combinations (CCNU-Alkeran-vindesine, or CAD-MOPP-ABV) our mean dose levels (mechlorethamine, 83%, vincristine, is presently in progress at Memorial Hospital (63). In the study 88%; and procarbazine, 80%) are very close to those admin arm, decarbazine was dropped from ABVD to reduce vomiting istered by the NCI group during the first 3 cycles (26). Complete or almost complete alopecia was documented in only about 10% of patients. No patient showed symptoms and signs of Adriamycin cardiomyopathy or of bleomycin pulmonary fibro- A] Â¡M|M||A|A[[MJM][A|A STAGES sis. One patient given MOPP alone following prior extensive II A (Bulky ) irradiation developed fatal acute nonlymphoblastic leukemia IIB-III-IV MINIMUM 6 CYCLES OR CR + 2 CYCLES

37 months from starting chemotherapy. 123456 Altogether, our findings indicate that alternating chemother MAMAMAMAMAMA apy emerges as a logical and powerful strategic approach for advanced Hodgkin's disease, assuming that one postulates drug-resistant mutants as being a major limiting factor in cure. RADIOTHERAPY ( 2500â€¢3000RAO ) IS DELIVERED ONLY Similar results with MOPP-ABVD in Stage III and IV Hodgkin's TO THE MEDIASTINUM IN COMPLETE RESPONDERS WITH INITIAL BULKY LYMPHOMA. disease were achieved at Memorial Hospital in a prospective CEP i R T WILL BE GIVEN TO PATIENTS NOT ATTAINING nonrandomized study which also included consolidation radio C R AFTER Â«CYCLES. Chart 2. Prospective randomized trial ongoing at the Milan Tumor Institute for therapy to the sites of initial bulky disease (64). The NCI group, intermediate and advanced Hodgkin's disease. M, half MOPP cycle; A, half ABVD the Cancer Leukemia Group B, and the Eastern Cooperative cycle; DTIC, 5(4)-(dimethyltriazino)imidazole-4-carboximide; RT, radiotherapy. Group are currently engaged in the therapeutic evaluation of For details, see text.

NOVEMBER 1982 4315

Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1982 American Association for Cancer Research. G. Bonadonna while in both arms low-dose (2000 rads) radiotherapy is deliv treatment complications, both benign and malignant, including ered to initially involved regions. Also, the Yale group is treating 5 patients with hematological or de novo lymphoid cancers, with MOPP-ABVD and low-dose irradiation in a nonrandomized while nonfatal histopathological effects of therapy were com fashion a high-risk subgroup with Hodgkin's disease charac mon and specifically assessed in thyroid, gonads, and pericar terized by patients more than 40 years old and/or with Stage dium. IV disease with multiple sites of involvement. In the above- As mentioned before, late complications which are relevant mentioned subgroup, the treatment program resulted in a 3- to the treatment strategy of Hodgkin's disease are treatment- year survival of 87% compared to 58% for those treated with induced secondary neoplasms, sterility, cardiotoxicity, and MVVPP and radiation in previous years. However, the reported lung fibrosis (43). As far as secondary neoplasms are con results of both research groups (36, 63) as well as those of our cerned, there is general agreement that acute nonlymphoblas- previous multimodal study (10) do not appear to be superior tic leukemia represents the most frequently observed iatro compared to the results achieved with MOPP-ABVD alone. genic cancer followed by diffuse non-Hodgkin's lymphomas Therefore, the real usefulness of involved-field irradiation inter and by a variety of solid tumors. With the objective of comparing spersed with alternating cycles of combination chemotherapy the incidence of treatment-related morbidity, we initiated in remains highly questionable unless patients have initial bulky 1974 a prospective randomized study between MOPP and disease in the mediastinum. ABVD within a combined modality setting in previously un Should alternating chemotherapy alone be tested in early treated patients with pathological Stages MB, IMA, and NIB. Hodgkin's disease in the attempt to replace radiotherapy? In Table 10, I have selected 4 representative series of pa Admittedly, the temptation is great but should be tempered by tients to show that the highest incidence of acute leukemia has a few important considerations dealing with treatment-related occurred after intensive irradiation and intensive multidrug morbidity. Assuming that the delivery of optimal alternating chemotherapy including procarbazine and alkylating agents, chemotherapy will be as effective as and even more effective particularly when given as salvage treatment. Similar results than current megavoltage irradiation programs for Stage IA and have been observed by other investigators utilizing MOPP or IIA Hodgkin's disease, i.e., that effective polychemotherapy MOPP-derived regimens (38). In the experience of Cancer and will cure 20 to 30% of patients who are not cured by primary Leukemia Group B (31), induction chemotherapy with mech- radiation therapy alone, the precise risk of long-term compli lorethamine-containing regimen, followed by chlorambucil cations over the life span following combinations with 6 to 9 maintenance therapy, had the highest relative risk ratio and life drugs remains unknown. Although by rotating drug combina table estimate (26%). Our present findings do not confirm that tions at each cycle of therapy we may expect a decrease of age 340 years at the start of treatment has an important the acute and delayed toxic manifestations as a consequence adverse effect on the incidence (about 20%) of treatment- of less intensive and prolonged drug exposure to the target induced leukemia, as observed by the Southwest Oncology tissues, we should also remember that the administration of an Group (22). Our research group has recently confirmed that adequate chemotherapy program remains today a distressful no secondary cancers were observed in 104 patients given experience for every patient. In fact, "loss of employment, ABVD either alone or combined with radiotherapy at a projected risk 10 years from the diagnosis of Hodgkin's disease (68, 69). disruption of schooling, dislocation from home, change in phys ical appearance, fear of treatment programs, loss of libido, A variety of other secondary tumors was also documented in separation, and divorce are all very important aspects of treat patients given radiotherapy, with or without MOPP or MOPP- ing Hodgkin's disease. These problems are difficult to express like chemotherapy (31, 68). Present comparative results are as actuarial curves, cure rates, and P values, but are important not definitive since the full extent of the expression of the risk considerations in selecting treatment programs." These words of a secondary cancer may not be appreciated for another come from a recent article written by Rosenberg (46), and I am decade (31). However, it is worth emphasizing that, in 191 unable to add anything important to his wise conclusions. Thus, patients randomized to receive MOPP plus radiotherapy versus in my opinion, the evaluation of primary chemotherapy for ABVD plus radiotherapy, acute leukemia (2 cases), non-Hodg Stage I and II Hodgkin's disease should remain restricted to a kin's lymphoma (1 case), and solid tumors (2 cases) developed very few qualified research centers, which will be able to within 5 years, and all patients belonged to the MOPP group manage the entire spectrum of problems; it should not become Table 10 the new treatment approach in a private office or local hospital. Relative frequency of acute leukemia developing among patients treated for Hodgkin 's disease with various forms of therapy

Attempts to Decrease Treatment Complications (25) (22) (68) (438 pa (21) (1096 (659 pa (1032 pa The days of minimizing the potential long-term toxicity of TreatmentRTa tients)0/1490/1310/1104/65Stanfordpatients)0/4173/652/371tients)0/953/1021tients)0/2721/503/1913/3574/580/104 treatment programs for Hodgkin's disease are past, and in alone"No intensivechemotherapy devising therapy for all stage subgroups the increased risk for RTRT or relapse must be weighed against the increased risk of iatro- +198AuMOPP genic morbidity involving single or multiple organs (43). Re orMOPP-likeregimensRT garding the risk of iatrogenic morbidity, the results of a recent +MOPPRt 1/4531/124SWOG1/2837/179Milan Stanford study (20) reviewing the clinical and pathological +MOPP-likeregimensRT features of 80 patients who came to autopsy from 1972 through salvageABVD+ MOPP 1977 are very interesting in that they revealed that nearly one- Â±RTNCI third of the patients died without evidence of Hodgkin's dis RT, radiotherapy. ease. In particular, a significant number of patients died of " Extended field or total nodal irradiation.

4316 CANCER RESEARCH VOL. 42

(68). Thus, to overcome the problem of secondary cancers in than did MOPP. Furthermore, the recovery of spermatogenesis long-term complete responderÃ¡, other effective regimens not in patients in whom the sperm count was repeated was ob including potent carcinogenic drugs warrant careful consider served in all instances in the ABVD-treated group (4 of 4), ation, particularly when chemotherapy is combined with exten compared to 1 of 3 cases treated with MOPP. The comparative sive radiotherapy. difference for drug-induced amenorrhea appears, at present, Although drug-induced azoospermia and amenorrhea were less evident although the trend favors ABVD (Table 11 ). Since known side effects for a number of years, until recently the gonadal function is also related to the intensity of drug treat impact of gonadal toxicity on the quality of life has received ment, it will be useful to document in future evaluations whether little attention (18). Infertility in males is of particular concern the incidence of azoospermia and of permanent amenorrhea because many patients with Hodgkin's disease are young and will be decreased by alternating MOPP with ABVD, particularly the potential for cure is high. When spermatogenesis is im when a half-cycle of either regimen will be delivered within a 1- paired follicle-stimulating hormone blood levels rise, while in month period. Thus, our findings with ABVD are in keeping with complete Leydig cell failure levels of luteinizing hormone rise the results of other investigators who have observed limited and testosterone levels fall. Combination chemotherapy regi and transient germ cell toxicity following the administration of mens including procarbazine and/or alkylating agents have a anticancer drugs other than alkylating agents or procarbazine profound effect on spermatogenesis, as first reported in Hodg (55). Future studies should also be able to determine more kin's disease by the NCI group (56). At least 80% of the men precisely the percentage of patients with Hodgkin's disease in treated with MOPP or MOPP-like regimens become azoosper- whom gonadal dysfunction is impaired before starting treat mic or severely oligospermic. Recovery of spermatogenesis is ment, particularly when systemic fever is present (18). To unpredictable and, through retrospective studies, it has been minimize the psychological and the physical impact of chemical reported to vary from 20 to 40%. This appears to be directly castration, semen cryopreservation prior to therapy in males, related to the length of time off therapy and indirectly related oral contraceptives in premenopausal women (19), and appro to the total dose of chemotherapy (8, 18). The sterility problem priate trials with an analog of gonadotropin-releasing hormone appears to be less common in adult females than in males, (32) are highly recommended. probably because the low germ cell proliferative rate of the Recent observations (1 ) have indicated that we can expect ovary is less sensitive to drugs compared to the testicular long-term cardiac effects from radiotherapy as a consequence epithelium and Leydig cells. When ovarian failure occurs, there of direct damage to cardiac vessels and muscles. Since the are greatly increased levels of follicle-stimulating hormone and factors which may increase a patient's risk for Adriamycin- luteinizing hormone with abnormally low estradici and proges induced cardiomyopathy include total dose, schedule, age, terone levels. Available data would indicate that 40 to 50% of preexisting cardiac disease, prior mediastinal radiotherapy, women treated with drug regimens containing procarbazine and administration of other cytotoxic drugs (e.g., cyclophos- and alkylating agents will become amenorrheic. The premature phamide, dacarbazine) (70), of particular concern are the pos ovarian failure appears related to age (>25 years, about 85%; sible long-term complications of the use of Adriamycin-contain- <25 years, about 20%), is most probably related to the total ing combinations and radiation to the mediastinum. Probably dose of drugs, and is progressive rather than an all-or-none because the cumulative dose of Adriamycin was always less phenomenon (8, 18). The relationship of age to ovarian dys than 300 mg/sq m and the single dose was only 25 mg/sq m, function has been reported in numerous studies of adjuvant thus far no patient in our trials has developed symptoms and chemotherapy for breast cancer involving various alkylating signs consistent with drug-induced cardiomyopathy. Clearly, a agents (12, 47). Reestablishment of menses and the possibility longer follow-up analysis and more sophisticated studies (e.g., of pregnancy in a treated woman is also correlated with age ejection fraction) to determine occult myocardial damage are and cumulative drug exposure. However, pregnancy does not required before firm conclusions can be drawn on this impor prove lack of ovarian damage (18). The ovaries of prepubertÃ ! tant point. Prior or concomitant thoracic radiotherapy increases and pubertal girls are relatively insensitive to anticancer drugs the incidence of severe pulmonary toxicity (30). Preliminary unless high and prolonged doses are administered. findings from our prospective trial with combined modality Our own preliminary findings derived from the randomized therapy would indicate that the incidence of paramediastinal study with MOPP plus radiotherapy versus ABVD plus radio fibrosis was higher in the ABVD group (41 %) compared to the therapy and limited to patients less than 45 years of age and MOPP group (19%) regardless of the size of mediastinal ade- having no pelvic irradiation indicated that ABVD combination nopathy and the total dose of radiotherapy delivered. However, affected spermatogenesis in a considerably lesser percentage thus far, we have not documented episodes of classical pul-

Table 11 Comparative incidence of gonadal failure in patients given MOPP versus ABVD MalesMOPP

time from end of of term age treatment spermato Ã©val age reversi- preg Ã©valuable1612Median(yr)27(1 (mos.)13(1-56) spermia0 mia(%)100 genesis1/3 uable24 (yr)24(12-44) %ble33 nancy2 + RTa-6 4-41 )c ABVD + RT6Total 5/8 26(16-35)Median 10(1-48)Oligo- 1Azoosper 42Recovery 4/4Total 20FemalesMedian25(14-44)AmenorrheaNo.20 3/4Full- 2 a RT, radiotherapy. Pelvic lymph nodes excluded. c Numbers in parentheses, range.

NOVEMBER 1982 4317

monary fibrosis involving the entire lung. Also the problem of apy, is a major cause (not the only cause) of chemotherapeutic pulmonary toxicity will require a long-term analysis. failure in Hodgkin's disease. This type of lymphoma also may In summary, the positive aspects of ABVD chemotherapy well represent in this context a useful human model for other appear numerous (Table 12). In my opinion, they should be human neoplasms (24). The limits of single drug combinations properly utilized in the treatment strategy to improve the control in terms of incidence and duration of remission are already and minimize the toxicity in given subsets with Hodgkin's clearly evident in all solid tumors. For instance, in advanced disease. It is likely that more extensive trials utilizing alternating breast cancer the same response rate was recently reported chemotherapy, with or without irradiation, for patients with by the Southwest Oncology Group regardless of the number of Stage II and bulky disease or nodular sclerosis histology, Stage drugs administered (67) and our group has shown that in an IMA,NIB,and IV, could further increase the chances for a total adjuvant situation 6 cycles of CMF cyclophosphamide, meth- conquest of Hodgkin's disease at the expense of less overt otrexate, and fluorouracil provided the same therapeutic bene and relatively occult morbidity. fit as did 12 cycles (66). When platinum-vinblastine-bleomycin chemotherapy is given in advanced testicular cancer, complete Conclusions remission is not likely to occur by prolonging the same therapy if not achieved by the third cycle (65), while in acute leukemia, The overview of our study protocols in which MOPP was Hodgkin's disease, and high-grade malignancy non-Hodgkin's tested versus ABVD and alternated with ABVD should provide lymphomas all forms of maintenance treatment have proved to the opportunity for broad conclusions. In particular, it should be useless in increasing the duration of CR (24). All these invite research physicians to reconsider current approaches to examples can be related to inferences of the mutation theory. the design of chemotherapy trials not only in Hodgkin's disease Thus, the cyclic or sequential delivery of combinations of non- but also in many other forms of cancer. This line of rethinking cross-resistant drugs, which are frequently less than additive may involve a few important steps. First, many medical oncol in toxicity when administered in an optimal manner, appears ogists should focus more on strategic approaches than on worthy of appropriate controlled Studies in a broad variety of minor changes in drug regimens. Drug combinations should neoplasms, and particularly in an adjuvant situation. now be regarded as medical tools rather than symbols to Goldie and Goldman (34) correctly caution that "not every identify the skill or the imagination of individual investigators or alternating program can be expected to show benefit." They research groups. Since we have to recognize that a plateau have listed the situation in which alternating at every cycle has been reached in the control of various neoplastic diseases might not prove to be the optimal strategy, namely, a situation with current drug regimens and new effective compounds are in which, by chance, one resistant fraction in a given tumor is not readily available, only different strategies which utilize considerably larger than the other, even if the values for their established combinations, such as MOPP and ABVD in Hodg mutation rates are identical. To commence by alternating treat kin's disease, might open important avenues of research and ment courses would permit the larger of the 2 resistant popu improve treatment results. lations to have intervals when it would grow unimpeded by Second, the strategic approaches should be considerate of therapy; therefore, its further increase in size would greatly some of the implications of new biological concepts and increase the probability of mutation to double resistance. Fur models. In reviewing his numerous experimental chemothera- thermore, when the 2 resistant cell compartments will not peutic trials. Skipper (59, 60) has come to the conclusion that exhibit the same kinetic behavior, alternating chemotherapy "we are now at the point that the mutation theory of Luria and will not be superior to a single drug combination. Finally, it Delbruck should be considered as a basic theory or law that should be recognized that, today, 2 generally equivalent and underlies and explains much of what is observed on chemo- non-cross-resistant combinations, such as MOPP and ABVD therapeutic treatment of experimental leukemia and solid tu for Hodgkin's disease, do not appear to be readily available in mors. The model of Goldie and Goldman has helped to simplify clinical practice. Thus, "alternating sequence therapies that do application of inferences of the mutation theory in the area of not incorporate stringent requirements, that are similar muta cancer treatment." I believe that our results achieved with tion rate to single, double, or multidrug resistance, same log- MOPP, ABVD, and CEP greatly support the concept that the kill on the sensitive compartment, same log-kill to the single presence of drug-resistant neoplastic cells prior to the initiation resistant compartment and the same growth curves of the of treatment, or their emergence and overgrowth during ther- single resistant subpopulations, may well fail to show therapeu tic advantage" (34). Theoretically, in solid tumors, less sub stantial deviations from this symmetry are most likely to occur Table 12 in the treatment of micrometastases. Therefore, alternating Positive aspects of ABVD chemotherapy may constitute the optimal therapeutic approach Induces a total CR rate comparable to that of MOPP. in an adjuvant situation. Here, new studies and research efforts Appears to Improve the RFS over MOPP in nodular sclerosis histology. should be concentrated with a reasonable expectation that optimal alternating chemotherapy will emerge as superior strat Lacks cross-resistance in MOPP failures. egy. Alternated with MOPP increases incidence and duration of CR. Regarding the design of new chemotherapy trials with more than one drug combination, research physicians should gain Produces lesser incidence of gonadal failure than do drug regimens containing experience with the new methodology of computer simulations alkylating agents and/or procarbazine. of actual trials in which combinations of drugs are delivered in Does not appear to induce second neoplasms and overt cardiomyopathy or lung different ways. Such simulations should try to improve visual fibrosis. izations of the influence of diverse combination regimens on

4318 CANCER RESEARCH VOL. 42

20. Colby, T. V., Hoppe, R. T., and Warnke, R. A. Hodgkin's disease at autopsy: the surviving neoplastic cells at the nadir and at the end of treatment. "If used with prudence, the retrospective simula 1972-1977. Cancer (Phila.), 47:1852-1862, 1981. 21. Coleman, N. C.. Burke, J. S.. Varghese, A.. Rosenberg, S. A., and Kaplan, tions of past chemotherapeutic trial results obtained in human H. S. Secondary leukemia and non-Hodgkin's lymphoma in patients treated for Hodgkin's disease. In: S. A. Rosenberg and H. S. Kaplan (eds.). Malig cancers (along with prospective simulation of the possible nant Lymphomas. Etiology, Immunology, Pathology, Treatment. Bristol- influence of changing combinations and their methods of deliv Myers Cancer Symposia, Vol. 3, pp. 259-276. New York: Academic Press, ery), should probably play an important role in new protocol Inc.. 1982. 22. Coltman, C. A., Jr., and Dixon. D. O. Second malignancies complicating design. The main reason for changing our current semi-empiric Hodgkin's disease: a Southwest Oncology Group 10-year follow-up. Cancer methodology should be that such efforts already have proven Treat. Rep., 66: 1023-1033, 1982. 23. De Lena, M., Monfardini, S., Beretta. G., Fossati-Bellani. F., and Bonadonna, useful in the design of better therapeutic regimens for treating G. Clinical trials with intensive chemotherapy and radiotherapy in Hodgkin's experimental cancers. Furthermore, simulation exercises al disease. Nati. Cancer Inst. Monogr., 36: 403-420, 1973. most always point to possibilities and limitations that would not 24. De Vita, V. T. Human models of human disease: breast cancer and the be conceived intuitively" (59). lymphomas. Int. J. RadiÃ¢t.Oncol. Biol. Phys., 5: 1555-1567, 1979. 25. De Vita. V. T., Jr. The consequences of the chemotherapy of Hodgkin's disease. The 10th David A. Karnofsky Memorial Lecture. Cancer (Phila.), 47: 1-13, 1981. References 26. De Vita. V. T., Serpick, A. A., and Carbone, P. P. Combination chemotherapy in the treatment of advanced Hodgkin's disease. Ann. Intern. Mod.. 73: 1. Applefeld, M. M., Slawson, R. G., Spicer. K. M., Singleton, R. T.. Wesley, 891-895, 1970. M. N., and Wiernik, P. H. Long-term cardiovascular evaluation in patients 27. De Vita, V. T.. Simon, R. M., Hubbard, S. M., Young, R. C., Berard, C. W., with Hodgkin's disease treated by thoracic mantle radiation therapy. Cancer Moxeley. J. H., Ill, Frei, E., Ill, Carbone, P. P., and Canellos, G. P. Curability Treat. Rep., 66: 1003-1013, 1982. of advanced Hodgkin's disease with chemotherapy. Ann. Intern. Med., 92: 2. Bakemeier, R. F., Anderson, J., Costello, W., Horton. J., HiÃ±es,J. D.. Glick, 587-595, 1980. J., and Gerard, C. W. BCVPP chemotherapy for advanced Hodgkin's dis 28. Einhorn, L. H., Williams. S. D., Stevens, E. E., and Bond, W. H. Combination ease: evidence for increased complete remission duration and less toxicity chemotherapy with vinblastine, adriamycin, bleomycin, CCNU, and DTIC for MOPP-refractory Hodgkin's disease. Proc. Am. Soc. Clin. Oncol., 1: 167. than with MOPP. Proc. Am. Soc. Clin. Oncol.. 1: 164, 1982. 3. Bonadonna, G., Beretta, G., Tancini, G . Brambilla, C., Bajetta, E., De Palo, 1982. M., De Lena, M.. Fossati-Bedani, F., Gasparini, M., Valagussn, P., and 29. Frei, E., Ili, Luce. J. K., Talley. R. W.. Vaitkevicious, V. K., and Wilson, H. E. Veronesi. U.. Adriamycin (NSC-123127) studies at the Istituto Nazionale 5-(3,3-Dimethyl-triazeno)imidazole-4-carboxamide (NSC-45338) in the Tumori. Cancer Chemother. Rep., 6: 231-245, 1975. treatment of lymphoma. Cancer Chemother. Rep., 56. 667-670, 1972. 4. Bonadonna, G . De Lena, M., Monfardini, S . Bartoli, C., Beretta, G., and 30. Ginsberg, S. J.. and Comis, R. L. The pulmonary toxicity of antineoplastic Fossati-Bellani, F. Clinical trials with bleomycin in lymphomas and in solid agents. Semin. Oncol., 9: 34-51. 1982. tumors. Eur. J. Cancer, 8: 205-215, 1972. 31. Glicksman, A. S.. Pajak, F., Gottlieb, A., Nissen, N., Stutzman, L., and 5. Bonadonna, G., De Lena, M., Monfardini, S., Rossi, A., Brambilla, C . Cooper, R. Second malignant neoplasms in patients successfully treated for Uslenghi, C., and Zucali, R. Combination usage of Adriamycin (NSC- Hodgkin's disease: a cancer and Leukemia Group B study. Cancer Treat. 123127) in malignant lymphomas. Cancer Chemother. Rep., 6: 381-388, Rep., 66: 1035-1044, 1982. 1975. 32. Glode, L. M., Robinson, J., and Gould, S. F. Protection from cyclophospha- 6. Bonadonna, G., Monfardini, S., De Lena, M., Fossati-Bedani, F., and Beretta, mide-induced testicular damage with an analogue of gonadotropin-releasing G. Phase I and preliminary Phase II evaluation of Adriamycin (NSC-123127). hormone. Lancet. 1: 1132-1134, 1981. Cancer Res., 30: 2572-2582, 1970. 33. Goldie, J. H., and Goldman, A. J. A mathematical model for relating the drug 7. Bonadonna, G., and Santoro, A. ABVD chemotherapy in the treatment of sensitivity of tumors to their spontaneous mutation rate. Cancer Treat. Rep., Hodgkin's disease. Cancer Treat. Rev., 9: 21 -35, 1982. 63. 1727-1733, 1979. 8. Bonadonna, G.. and Santoro, A. Drug selection in the treatment of Hodgkin's 34. Goldie, J. H., Coldman, A. J., and Gudauskas, G. A. Rationale for the use of disease. J. Haematol. Oncol., /: (in press), 1983. alternating non-cross resistant chemotherapy. Cancer Treat. Rep., 66:439- 9. Bonadonna, G., Santoro, A., Bonfante, V., and Valagussa, P. Cyclic delivery 449, 1982. of MOPP and ABVD combinations in stage IV Hodgkin's disease: rationale, 35. Kaplan, H. S. Hodgkin's disease and other human malignant lymphomas: background studies, and recent results. Cancer Treat. Rep., 66: 881-887, advances and prospectsâ€”G. H. A. Clowes Memorial Lecture. Cancer Res., 1982. 36:3863-3877. 1976. 10. Bonadonna, G., Santoro, A., Zucali, R., and Valagussa, P. Improved 5-year 36. Kapp, D. S., Prosnitz, L. R., Farber, L. R., Berlino, J. R., Cadman, E. C., and survival in advanced Hodgkin's disease by combined modality approach. Fisher, D. B. Improved results in the management of Hodgkin's disease: the Cancer Clin. Trials, 2: 217-226. 1979. Yale experience. Proc. Am. Soc. Clin. Oncol., 1: 166, 1982. 11. Bonadonna. G.. Uslenghi, C.. and Zucali, R. Recent trends in the medical 37. Kaye, S. B., Jurtner, C. A., Smith, I. E., Barret, A., Austin, D. E., Peckham. treatment of Hodgkin's disease. Eur. J. Cancer, 11: 251-266, 1975. M. J., and McElwain, T. J. Three-years' experience with ChlVPP (a combi nation of drugs of low toxicity) for the treatment of Hodgkin's disease. Br. J. 12. Bonadonna, G., Valagussa, P., and De Palo. G. M. The results of adjuvant chemotherapy in breast cancer are predominantly due to the hormonal Cancer, 39: 168-174, 1979. change such therapy induces: the view against. In: M. B. Van Scoy-Mosher 38. Kyle. R. A. Second malignancies associated with chemotherapeutic agents. (ed.). Controversies in Medical Oncology, pp. 100-109. Boston: G. K. Hall, Semin. Oncol.. 9: 131-142, 1982. 1981. 39. Longo, D. L., Young, R. C., and De Vita, V. T. Chemotherapy for Hodgkin's 13. Bonadonna, G., Villarreal, C. J. R., Musumeci, R.. Bonfante. V.. Zucali, R., disease: the remaining challenges. Cancer Treat. Rep., 66:925-936, 1982. Valagussa, P., and Santoro, A. Comparative efficacy of MOPP and ABVD in 40. Luria, S. E., and Delbruck. M. Mutations of bacteria fiom virus sensitivity to nodular sclerosing Hodgkin's disease. Proc. Am. Soc. Clin. Oncol., i: 165, virus resistance. Genetics. 28: 491 -511, 1943. 1982. 41. Mauch, P., Ryback, M. E., Rosenthal, D., Weichselbaum, R., and Hellman, 14. Bonadonna, G., Zucali. R.. De Lena, M., and Valagussa, P. Combined S. The influence of initial pathological stage on survival of patients who relapse from Hodgkin's disease. Blood, 56: 892-897, 1980. chemotherapy (MOPP or ABVDHadiotherapy approach in advanced Hodg kin's disease. Cancer Treat. Rep., 67: 769-777, 1977. 42. Pavlovsky, S., Morgenfeld. M., Somoza, N.. Suckmann Muriel. F.. Cavag- 15. Bonadonna, G., Zucali, R., Monfardini, S., De Lena, M., and Uslenghi, C. naro. F.. Barros. C. A.. Saslavsky, J., Garay, G., and Palau, M. Long term Combination chemotherapy of Hodgkin's disease with Adriamycin, bleomy follow-up of cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP) in previously untreated Hodgkin's disease. Proc. Am. Soc. Clin. cin, vinblastine and imidazole carboxamide versus MOPP. Cancer (Phila.), 36:252-259, 1975. Oncol., 1: 165, 1982. 16. Canellos, G. P., Young, R. C., and De Vita, V. T. Combination chemotherapy 43. Perry, M. C. (ed.). Toxicity of chemotherapy. Semin. Oncol.. 9: 1-149. for advanced Hodgkin's disease in relapse following extensive radiotherapy. 1982. Clin. Pharmacol. Ther., 73: 750-754, 1972. 44. Portlock, C. S., Rosenberg. S. A., Glatstein. E., and Kaplan, H. S. Impact of 17. Carde, P.. MacKintosh, F. R., and Rosenberg, S. A. Influence of MOPP salvage treatment on initial relapse in patients with Hodgkin's disease, doses and timing on treatment outcome in advanced Hodgkin's disease stages l-lll. Blood, 51: 825-833. 1978. (HD). Proc. Am. Assoc. Cancer Res.. 22: 512, 1981. 45. Prosnitz, L. R., Farber, L. R., Fischer, J. J., Bertino, J. R.. and Fischer, D. B. 18. Chapman, R. M. Effect of cytotoxic therapy on sexuality and gonadal Long term remissions with combined modality therapy for advanced Hodg function. Semin. Oncol.. 9: 84-94, 1982. kin's disease. Cancer (Phila.), 37: 2826-2833, 1976. 46. Rosenberg. S. A. Hodgkin's disease: current status and future challenges. 19. Chapman, R. M.. and Sutcliffe, S. B. Protection of ovarian function by oral contraceptives in women receiving chemotherapy for Hodgkin's disease. Semin. Oncol., 7: 212-214, 1982. Blood, 58: 849-851. 1981. 47. Samaan, N. A., De Asis, D. N.. Buzdar, A. U., and Blumenschein, G. R.

NOVEMBER 1982 4319

Pituitary-ovarian function in breast cancer patients on adjuvant chemoim- Known Burdens and Mixes of Sensitive and Drug-resistant Leukemia Cells munotherapy. Cancer (Phila.), 41: 2084-2087, 1978. Were Treated with Single Drugs and Two-Drug Combinations, Booklet 22. 48. Santoro, A., and Bonadonna, G. Prolonged disease-free survival in MOPP- Birmingham, Ala.: Southern Research Institute, 1981. resistant Hodgkin's disease after treatment with Adriamycin, bleomycin. 60. Skipper, H. E. Some Thoughts on the Optimum Number of Drugs in Combi vinblastine and dacarbazine (ABVD). Cancer Chemother. Pharmacol., 2. nation Chemotherapy and the Optimum Method(s) for Their Delivery. Booklet 101-105, 1979. 4. Birmingham, Ala.: Southern Research Institute. 1982. 49. Santoro, A., Benfante, V., and Bonadonna, G. Salvage chemotherapy with 61. Skipper. H. E. On the Origin of Singly and Doubly Drug-resistant Neoplastic ABVD in MOPP-resistant Hodgkin's disease. Ann. Intern. Med., 96: 139- Cells: Cross-resistance. Lack of Cross-resistance, and Occasional Collateral 144, 1982. Sensitivity; and Some Implications, Booklet 8. Birmingham, Ala.: Southern 50. Santoro, A., Bonfante, V., and Bonadonna, G. Third-line chemotherapy with Research Institute. 1982. CCNU, etoposide, and prednimustine (CEP) in Hodgkin's disease resistant 62. Skipper, H. E., Schabel. F. M., Jr., and Wilkox, W. S. Experimental evaluation to MOPP and ABVD. Proc. Am. Soc. Clin. Oncol., 1: 165. 1982. of potential anticancer drugs. XII. On the criteria and kinetics associated with "curability" of experimental leukemia. Cancer Chemother. Rep., 55: 51. Santoro, A., Bonadonna, G., Bonfante, V., and Valagussa, P. Alternating drug combinations in the treatment of advanced Hodgkin's disease. N. Engl. 1-111, 1964. J. Med.. 306. 770-775. 1982. 63. Straus, D. J., Myers, J., Koziner, B., Lee, B. J., Nisce, L., and Clarkson, B. 52. Santoro, A., Bonfante, V.. Bonadonna, G., Zucali, R., Pagnoni, A. M.. D. A randomized trial of two vs. three non-cross resistant drug combinations and local low-dose radiotherapy for untreated advanced Hodgkin's disease. Recchione, C . Valagussa, P., and Banfi, A. Therapeutic and toxicologie effects of MOPP vs ABVD combined with radiotherapy in Hodgkin's disease. Proc. Am. Soc. Clin. Oncol.. ): 160, 1982. In: S. E. Salmon and S. E. Jones (eds.). Adjuvant Therapy of Cancer III, pp. 64. Straus, D. J., Meyers, J., Passe. S.. Young, C. W., Nisce. L. Z., Lee, B. J., 85-91. New York: GruÃ±eand Stratton, 1981. Koziner, B., Arlin, Z.. Kempin, S., Gee, T., and Clarkson, B. C. The eight- 53. Santoro, A., Villarreal, C. J. R., Bonadonna. G.. Delfino, A., Bonfante, V., drug/radiation therapy program (MOPP/ABVD/RT) for advanced Hodgkin's and Valagussa, P. Salvage chemotherapy (CT) in Hodgkin's disease (HD) disease: a follow-up report. Cancer (Phila.), 46: 233-240, 1980. failing to primary radiotherapy (RT): MOPP vs Adriamycin-containing regi 65. Sturgeon, J. F. G., Alison, R. E., Comisarow, R. H., and Bergsagel, D. E. mens (ADM-Reg). Proc. Am. Assoc. Cancer Res., 23. 118, 1982. Advanced non-seminomatous testicular tumours: maintenance chemother 54. Schabel. F. M.. Skipper. H. E.. Trader, N. W . RÃ¼sselLaster, W.. Jr., Corbett, apy is unnecessary. Proc. Am. Assoc. Cancer. Res., 21: 153, 1980. T. H., and Griswold, D. P., Jr. Concepts for controlling drug-resistant tumor 66. Tancini, G., Bonadonna, G., Marchini, S., Bajetta, E., Valagussa, P., and cells. In: H. T. Mouridsen and T. Palshof (eds.). Breast Cancer: Experimental Veronesi, U. Adjuvant CMF in breast cancer: comparative 5-year results of and Clinical Aspects, pp. 129-211. New York: Pergamon Publishing Corp., 12 vs 6 cycles. Proc. Am. Soc. Clin. Oncol., ÃŽ:86, 1982. 1980. 67. Tranum, B. L.. McDonald, B., Thigpen, T., Vaughn, C., Wilson, H., Maloney, 55. Shamberger, R. C., Rosenberg, S. A., Seipp, C. A., and Sherins, R. J. Effect T., Costanzi, J., Bickers, J., Gad el Mawli, N., Palmer, R., Hoogstraten, B., of high-dose methotrexate and vincristine on ovarian and testicular functions Heilburn, L., and Rasmusen, S. Adriamycin combinations in advanced breast in patients undergoing postoperative adjuvant treatment of osteosarcoma. cancer. A Southwest Oncology Group study. Cancer (Phila.), 49: 835-839. Cancer Treat. Rep., 65: 739-746, 1981. 1982. 56. Sherins, R. J.. and De Vita, V. T. Effects of drug treatment for lymphoma on 68. Valagussa, P., Santoro, A., Fossati-Bellani, F., Franchi, F., Banfi, A., and male reproductive capacity. Ann. Intern. Med., 79: 216-220, 1973. Bonadonna, G. Absence of treatment-induced second neoplasms after 57. Skibba, J. L., Beai, D. D., Ramirez, G., and Bryan, G. T. W-Demethylation of ABVD in Hodgkin's disease. Blood, 59: 488-494, 1982. the antineoplastic agent 4(5H3,3-dimethyl-1-triazeno)imidazole-5(4)-car- 69. Valagussa. P., Santoro. A., Kenda, R., Fossati-Bellani, F., Franchi, F., Banfi, boxamideby rats and man. Cancer Res.. 30: 147-150, 1970. A., Rilke, F., and Bonadonna, G. Second malignancies in Hodgkin's disease. 58. Skipper, H. E. On the Remarkable Progress that Has Been Made in Treat A complications of certain forms of treatment. Br. Med. J., 280: 216-219, ment of Hodgkin's Disease, Booklet 13. Birmingham, Ala.: Southern Re 1980. search Institute, 1980. 70. Von Hoff, D. D., Rozencweig, M., and Piccar!, M. The cardiotoxicity of 59. Skipper, H. E. Results and Interpretations of Trials in Which Animals Bearing anticancer drugs. Semin. Oncol., 9: 23-33. 1982.

4320 CANCER RESEARCH VOL. 42

Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1982 American Association for Cancer Research. Chemotherapy Strategies to Improve the Control of Hodgkin's Disease: The Richard and Hinda Rosenthal Foundation Award Lecture

Gianni Bonadonna

Cancer Res 1982;42:4309-4320.

Updated version Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/42/11/4309

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://cancerres.aacrjournals.org/content/42/11/4309. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.