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Randomized Comparison of ABVD and MOPP/ABV Hybrid for the Treatment of Advanced Hodgkin’s Disease: Report of an Intergroup Trial

David B. Duggan, Gina R. Petroni, Jeffrey L. Johnson, John H. Glick, Richard I. Fisher, Joseph M. Connors, George P. Canellos, Bruce A. Peterson

From the Department of Medicine, State University of New York Upstate Medical University, Syracuse, and James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, NY; Cancer and Leukemia Group B Statistical Center, Duke University, Durham, NC; Division of Oncology, University of Minnesota School of Medicine, Minneapolis, MN; University of Pennsylvania Cancer Center and Abramson Family Cancer Research Institute, Philadelphia, PA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; and British Columbia Cancer Agency-Vancouver Cancer Center, Vancouver, British Columbia, Canada.

Address reprint requests to David Duggan, MD, Department of Medicine, State University of New York Upstate Medical University, 750 East Adams St, Syracuse, NY 13210; email: duggand{at}upstate.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Purpose: In a series of trials, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP/ABV) have been identified as effective treatments for Hodgkin’s disease. We compared these regimens as initial chemotherapy for Hodgkin’s disease.

Patients and Methods: Adult patients (N = 856) with advanced Hodgkin’s disease were randomly assigned to treatment with ABVD or MOPP/ABV. The major end points were failure-free and overall survival, life-threatening acute toxicities, and serious long-term toxicities, including cardiomyopathy, pulmonary toxicity, myelodysplastic syndromes (MDS), and secondary malignancies.

Results: The rates of complete remission (76% v 80%, P = .16), failure-free survival at 5 years (63% v 66%, P = .42), and overall survival at 5 years (82% v 81%, P = .82) were similar for ABVD and MOPP/ABV, respectively. Clinically significant acute pulmonary and hematologic toxicity were more common with MOPP/ABV (P = .060 and .001, respectively). There was no difference in cardiac toxicity. There were 24 deaths attributed to initial treatment: nine with ABVD and 15 with MOPP/ABV (P = .057). There have been 18 second malignancies associated with ABVD and 28 associated with MOPP/ABV (P = .13). Thirteen patients have developed MDS or acute leukemia: 11 were initially treated with MOPP/ABV, and two were initially treated with ABVD but subsequently received MOPP-containing regimens and radiotherapy before developing leukemia (P = .011).

Conclusion: ABVD and the MOPP/ABV hybrid are effective therapies for Hodgkin’s disease. MOPP/ABV is associated with a greater incidence of acute toxicity, MDS, and leukemia. ABVD should be considered the standard regimen for treatment of advanced Hodgkin’s disease.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
THE TREATMENT OF Hodgkin’s disease was revolutionized with the development of a regimen containing mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), which was the first drug regimen that produced a high proportion of complete remissions (CRs) and cure.¹ Bonadonna et al² subsequently introduced doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as a potentially curative salvage regimen for patients experiencing relapse after MOPP.

In 1992, the Cancer and Leukemia Group B (CALGB) reported a trial comparing MOPP, ABVD, or alternating MOPP/ABVD for advanced Hodgkin’s disease.³ ABVD and MOPP/ABVD produced similar CR (81% and 82%, respectively) and failure-free survival (FFS) rates (64% for both at 3 years). Furthermore, both ABVD regimens were superior to MOPP (69% CR and 48% FFS at 3 years). There were no differences in overall survival (OS).

In 1985, Klimo and Connors⁴ reported results of the MOPP/ABV hybrid, which produced an 83% CR rate to the chemotherapy and a 73% 5-year FFS rate, including those who received adjuvant radiotherapy (RT). At the time the current trial was planned, randomized trials comparing MOPP/ABV hybrid with both sequential (MOPP ABVD) and alternating (MOPP/ABVD) therapy had recently begun. The results of these trials demonstrate that MOPP/ABV hybrid is equally effective as alternating MOPP/ABVD and more effective than sequential MOPP ABVD.^5,6 Therefore, the current trial comparing MOPP/ABV hybrid and ABVD can be seen as a conclusion to a sequence of comparisons over nearly two decades.

The risk-to-benefit ratio of therapy for Hodgkin’s disease must be assessed over a long time because serious treatment-related toxicity may develop many years after therapy. MOPP causes myelodysplasia (MDS), acute leukemia, sterility, and neuropathy.^3,7 Doxorubicin and bleomycin, components of ABVD, may cause cardiomyopathy and pulmonary fibrosis.^3,7 All of these are of concern with the MOPP/ABV hybrid. Because the MOPP/ABV hybrid was effective and widely used despite the absence of controlled trials comparing it with a less toxic regimen, this trial was designed to compare both the therapeutic benefit and toxicity of the hybrid regimen with that of ABVD alone.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Selection
Adult patients with histologically confirmed stage III₂A, IIIB, or IV Hodgkin’s disease or who had experienced relapse after definitive RT were eligible. Entry requirements included at least one measurable lesion, granulocytes 1,800/µL, platelets 100,000/µL, hemoglobin 10 g/dL, creatinine 2 mg/dL, and bilirubin 1.5 times the upper limit of normal. Patients with laboratory abnormalities ascribed to Hodgkin’s disease were considered eligible. Left ventricular ejection fraction (LVEF) of at least 50%, a diffusing capacity for carbon monoxide (DLCO) and forced expiratory volume in 1 second of at least 50% of predicted, and a performance status of 0 to 2 (CALGB scale) were required. Central pathology review of all diagnostic biopsies was required.

Staging included a history and examination; computed tomography (CT) scan of the chest, abdomen, and pelvis; and a lymphangiogram if the CT scan of the abdomen was equivocal. Laparotomy was required if the CT scan and lymphangiogram were not definitive. Bone marrow aspirate and biopsy were required. A gallium scan was recommended but not required. Patients who had received prior cytotoxic chemotherapy, had a history of a malignancy, were pregnant, or had serious illness that would limit survival or prevent informed consent were excluded. All patients were required to give written informed consent, and the protocol was approved by the institutional review board at each institution.

A chest x-ray and CT scan measurements of tumor response were taken at least every three cycles. LVEF and spirometry with DLCO were repeated after four cycles. RT was not permitted. The use of prophylactic hematopoietic growth factors was not permitted.

Study Administration, Treatment, and Monitoring
The study was coordinated by the CALGB with participation of the Eastern Cooperative Oncology Group, Southwest Oncology Group, and the National Cancer Institute of Canada Clinical Trials Group. Patients were stratified by age (< 40 or 40 years), stage, and whether they had previously received RT. Randomization was performed using a block design within the 12 strata. ABVD or MOPP/ABV hybrid was given with doses and dose modifications as previously described.^3,4 Responding patients received treatment to the attainment of clinical complete response (CCR) plus an additional two cycles, for a minimum of eight cycles and a maximum of 10 cycles. Protocol therapy was discontinued if LVEF decreased by 15% from baseline or to less than 45%, if congestive heart failure or cardiomegaly appeared, or if a persistent new arrhythmia developed. Bleomycin was discontinued if the forced expiratory volume in 1 second or DLCO decreased to less than 50% of predicted or if clinical signs of pulmonary toxicity appeared.

The trial was designed to enroll 900 patients, and an independent Data and Safety Monitoring Board evaluated interim analyses of treatment efficacy and toxicity twice each year. Early closure of the study was planned if statistically significant differences between treatment regimens appeared at any interim analysis,⁸ using group sequential methodology with a continuous use function to determine the rate at which type I error was spent.⁹ The Lan and DeMets¹⁰ analog to the O’Brien and Fleming¹¹ boundaries was used.¹²

In November 1995, the Data and Safety Monitoring Board observed an increased number of treatment-related deaths and secondary malignancies on the MOPP/ABV arm. The trial was then closed, after accruing 856 of a planned sample of 900 patients. Investigators received notification that increased toxicity for patients on the MOPP/ABV arm had been observed, but no OS difference was demonstrated, and it was left to their discretion how to proceed with patients currently receiving therapy.

Statistical Analysis
The results are presented from an analysis based on intention to treat. Of the 856 patients who were registered, all are included in the analysis, with the exception of four patients (two on each arm) who were withdrawn from the study before any treatment was given (we have no data for these patients). Six patients were switched from MOPP/ABV to ABVD when the preliminary results were announced and are analyzed as initially randomized. Twenty-two patients (eight receiving ABVD and 14 receiving MOPP/ABV) were determined to have had non-Hodgkin’s lymphoma after central pathology review. Seventy-six patients (39 receiving ABVD and 37 receiving MOPP/ABV) did not meet all eligibility requirements, but most violations were minor. Analyses that excluded those who switched arms, had non-Hodgkin’s lymphoma, or who did not meet all eligibility criteria were also performed. Similar results were obtained for the two analyses; therefore, the results of the intention-to-treat analysis are reported. Some patients received RT while in partial remission after chemotherapy in violation of the protocol specifications. We did not count as CRs those who improved after RT, nor did we count them as treatment failures caused by additional therapy or censor them at the time of RT. Similarly, we did not exclude patients who received granulocyte colony-stimulating factor, and we ignored those treatment violations in this intention-to-treat analysis.

The sample size was designed to provide 90% confidence of determining a 10% difference in the cure rates (ABVD, 65%; MOPP/ABV, 75%), testing at the one-sided 5% level of statistical significance. Although the study was designed with a one-sided 5% significance level for the major end points, all reported P values correspond to a two-sided test of significance.

Categorical data (toxicity and response) were analyzed using the ² test for contingency tables¹³ using exact significance levels. FFS was measured from registration on study to evidence of first progression, relapse or recurrence, death from any cause, or discontinuation of treatment for nonresponders. Survival was measured from registration to death from any cause. Time to event distributions (FFS and survival) were estimated using the product-limit method of Kaplan and Meier.¹⁴ Formal tests using time-dependent covariables and Schoenfeld residuals were used to test the assumptions of proportional hazards.¹¹ The statistical significance of differences observed in time-to-event distributions was assessed using the log-rank test.¹⁴ Analyses were performed using SAS (Version 8.1; SAS Institute, Inc, Cary, NC) and graphics were generated using S-Plus (Version 4.5; Mathsoft, Seattle, WA).

Response criteria defined a CR as the absence of symptoms, physical findings, or imaging evidence of Hodgkin’s disease. A repeat bone marrow biopsy must have been negative if initially positive. A CCR was defined as the absence of symptoms or physical findings, with CT scans demonstrating a greater than 50% reduction of the product of perpendicular diameters of measurable lesions in the chest and a greater than 80% reduction in the product of perpendicular diameters of measurable lesions in the abdomen persisting over two cycles of treatment. To qualify as a CCR, gallium scans were required to be negative in the mediastinum if they had been initially positive. In the analysis presented here, the patients achieving CR or CCR are pooled into the overall CR category. If a patient did not achieve CR or CCR after eight cycles, they were to be removed from protocol-directed therapy. A partial response was defined as a greater than 50% but less than 80% reduction in the sum of the perpendicular diameters of lesions in the abdomen or a persistently positive gallium scan regardless of tumor measurements. Disease progression was defined as the appearance of new sites of disease or a greater than 25% increase in the sum of the products of the perpendicular directions of measurable disease. Stable disease was defined as a less than 50% reduction in the sum of the products of perpendicular diameters of any site of measurable disease (ie, nonresponder). Patients for whom follow-up measurements are unavailable are considered nonassessable. Toxicity was graded according to the National Cancer Institute common toxicity criteria.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient characteristics are summarized in Table 1. The cohorts were well balanced regarding predefined stratification criteria and important prognostic factors.

View larger version (12K): [in this window] [in a new window]   Fig 1. (A) Overall survival; (B) failure-free survival.

Hasenclever et al¹⁵ identified seven predictive factors for FFS in Hodgkin’s disease: albumin less than 4 g/L, hemoglobin less than 10.5 g/L, male sex, age 45 years, stage IV, WBC count 15,000/mL, and lymphocytopenia (< 600/mL or 8% of WBCs). We did not plan an analysis on the basis of these factors at the time the protocol was written but have abstracted these data on 566 patients and determined their FFS on the basis of their prognostic scores. We excluded patients from our analysis who had received previous RT because the Hasenclever analysis only studied patients who were initially treated with chemotherapy. Furthermore, our protocol excluded patients with a poor performance status, impaired vital organ function, or a hemoglobin level of less than 10.5 g/L, and the Hasenclever analysis included patients treated with many different chemotherapies, including MOPP, such that precise comparisons are not appropriate. Our patients experienced an overall 5-year FFS of 73% (95% CI, 70% to 77%), as compared with 66% reported in the Hasenclever analysis. The FFS at 5 years of our patients on the basis of the number of prognostic factors is listed in Table 3.

Delayed toxicity data, which include all reported toxicity occurring more than 30 days after the completion of chemotherapy, are listed at the bottom of Table 4. Toxicity data for this period have been submitted for 610 patients (300 ABVD patients and 310 MOPP/ABV patients). For this period, pulmonary and cardiac toxicity are defined as the number of patients with any grade 2 to 5 toxicity. During the 6-year interval after cessation of therapy, there has been one additional report of the development of congestive heart failure (patient who received ABVD) and no reports of new pulmonary toxicity, although some toxicity first manifested during treatment did not resolve.

After a median follow-up of 6 years, 46 second malignancies have been recorded, 18 in patients treated with ABVD and 28 in patients treated with MOPP/ABV (P = .13). There have been 11 cases of MDS or acute myelogenous leukemia (AML) in patients randomized to the hybrid arm and two among patients randomized to ABVD (P = .011). There was no relationship between age or the use of previous RT on the rate of development of MDS or AML. The two patients who developed AML or MDS after being randomly assigned to ABVD were subsequently treated with MOPP-containing regimens and RT; one of the two also received additional alkylator-based chemotherapy and autologous bone marrow transplantation before the diagnosis of AML was established. No patient who received only ABVD developed MDS or AML. There were several additional secondary tumors observed; none were significantly more frequent on either arm.

Causes of death are listed in Table 5. Of the 190 deaths observed, 105 (55%) were caused by Hodgkin’s disease and 40 (21%) were caused by complications of initial treatment.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

However, there are statistically significant and clinically important differences in both the toxicity and secondary malignancies observed with these two therapies. The MOPP/ABV hybrid caused significantly more acute hematologic and pulmonary toxicity (Table 4). MOPP/ABV also caused significantly more fatigue, anorexia, and nausea. The MOPP/ABV hybrid was associated with a higher rate of treatment-related deaths, but this was not statistically significant (P = .105). Many of the toxic deaths on the MOPP/ABV arm were due to pulmonary failure, and it is difficult to determine whether infection or drug toxicity was the primary insult; in many patients, both likely contributed to death. Moreover, many patients were neutropenic at the time they developed pulmonary infiltrates. Nevertheless, although the exact pathophysiology may be uncertain, the direct attribution of death to treatment-related toxicity is clear. It is not clear why there is increased pulmonary toxicity on the MOPP/ABV arm, which delivered a lower total dose of bleomycin than did ABVD. There were significantly more patients receiving MOPP/ABV who experienced pulmonary toxicity that necessitated dose adjustment or elimination of bleomycin.

We chose to withdraw bleomycin therapy for any clinical sign or symptom of pulmonary toxicity, or an asymptomatic decrement in DLCO, yet significant rates of serious pulmonary toxicity were observed. It may be that a lower threshold for DLCO decrement would be appropriate for withholding bleomycin, or that bleomycin pulmonary toxicity is unpredictable by standard evaluation methods; nevertheless, careful consideration must be given to future studies to identify better predictive tools and alternative regimens that do not contain bleomycin, and physicians must maintain a high degree of vigilance when monitoring patients receiving bleomycin for the development of pulmonary toxicity.

In sum, MOPP/ABV caused more life-threatening side effects than ABVD during the initial treatment phase. ABVD did not cause any acute toxicity more frequently than MOPP/ABV.

Most striking is the increased incidence of second malignancies seen with the MOPP/ABV hybrid, especially the increased incidence of MDS and secondary acute leukemia. Several studies have linked the use of chemotherapy, notably alkylator-based regimens, to the development of MDS or acute leukemia, especially when used in combination with RT.^16–19 These reports describe an overall risk of 2.5% to 9% of developing acute leukemia or MDS, which becomes apparent within 1 year of diagnosis and remains elevated for at least 9 years before declining. Our data are quite consistent with these studies, demonstrating an increased incidence of MDS or leukemia after MOPP and a substantially smaller or nonexistent risk with ABVD.^20,21 Because this report is based on an average follow-up period of only 7 years, it is likely that additional cases of MDS or leukemia will be reported. However, it is noteworthy that a previous intergroup trial comparing sequential MOPP ABVD to the MOPP/ABV hybrid reported one case of AML among the 367 patients treated with MOPP/ABV hybrid after a median follow-up period of 7.3 years.⁵ This important discrepancy in the rate of AML or MDS associated with the MOPP/ABV hybrid is unexplained.

One of the great concerns regarding the ABVD regimen has been the potential for development of doxorubicin cardiomyopathy. In this trial, the rate of drug discontinuation for cardiac toxicity during the treatment phase was not different in either arm, nor was there a difference in the rate of development of congestive heart failure after 6 years of follow-up.

This trial specified that patients receive a minimum of eight cycles of chemotherapy to recapitulate the duration of treatment described in the original study of MOPP/ABV. The appropriate duration of therapy cannot be ascertained from this trial.

A series of randomized clinical trials in North America have compared ABVD versus MOPP/ABV (current trial), alternating MOPP/ABVD versus MOPP or ABVD alone, sequential MOPP ABVD (three cycles each) versus the MOPP/ABV hybrid program, and alternating MOPP/ABVD versus MOPP/ABV hybrid (Table 6). The MOPP/ABV hybrid has been equal or superior to the alternating MOPP/ABVD and sequential MOPP ABVD regimens. ABVD has been demonstrably superior to MOPP in two randomized trials, the CALGB trial and in a comparison of MOPP versus ABVD, each given with RT, for patients with bulky stage II disease.⁶ The MOPP/ABV hybrid has also been demonstrated to be equal or superior to MOPP ABVD and MOPP/ABVD. In the current trial, ABVD has been shown to be as effective as MOPP/ABV, but less toxic. The natural conclusion of this series of randomized trials is that ABVD alone is at least as effective, and less toxic, than any of the MOPP-containing regimens or hybrids noted above.

In summary, we conducted a randomized clinical trial comparing ABVD with the MOPP/ABV hybrid and demonstrated that the FFS and OS of these regimens are similar, yet there is increased acute toxicity with the MOPP/ABV hybrid, as well as an increased risk of secondary hematologic malignancies and solid tumors. We conclude that ABVD should be considered the standard regimen for the treatment of advanced Hodgkin’s disease and should be the regimen against which new treatments are evaluated.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The following institutions participated in the study: CALGB Statistical Office, Stephen George, PhD (CA33601), Duke University Medical Center, Jeffrey Crawford, MD (CA47577), Durham, Southeast Cancer Control Consortium, Inc, James N Atkins, MD (CA45808), Goldsboro, University of North Carolina at Chapel Hill, Thomas C. Shea, MD (CA47559), Chapel Hill, and Wake Forest University School of Medicine, David D. Hurd, MD (CA03927), Winston-Salem, NC; Christiana Care Health Services, Inc., CCOP, Irving M. Berkowitz, DO (CA45418), Wilmington, DE; Dana-Farber Cancer Institute, George P. Canellos, MD (CA32291), Massachusetts General Hospital, Michael L. Grossbard, MD (CA12449), Boston, and University of Massachusetts Medical Center, Mary Ellen Taplin, MD (CA37135), Worcester, MA; Dartmouth Medical School-Norris Cotton Cancer Center, Marc Ernstoff, MD (CA04326), Lebanon, NH; Finsen Institute, Copenhagen, Denmark; Massey Cancer Center, John D. Roberts, MD (CA52784), Richmond, VA; Memorial Sloan-Kettering Cancer Center, George Bosl, MD (CA77651), Mount Sinai School of Medicine, Lewis Silverman, MD (CA04457), Weill Medical College of Cornell University, Michael Schuster, MD (CA07968), New York, North Shore–Long Island Jewish Medical Center, Daniel R. Budman, MD (CA35279), Manhasset, Roswell Park Cancer Institute, Ellis Levine, MD (CA02599), Buffalo, State University of New York Upstate Medical University, Stephen L. Graziano, MD (CA21060), and Syracuse Hematology-Oncology Assoc, CCOP, Jeffrey Kirshner, MD (CA45389), Syracuse, NY; Mount Sinai Medical Center, Enrique Davila, MD (CA45564), Miami, FL; Rhode Island Hospital, William Sikov, MD (CA08025), Providence, RI; Southern Nevada Cancer Research Foundation, John Ellerton, MD (CA35421), Las Vegas, NV; The Ohio State University, Clara D. Bloomfield, MD (CA77658), Columbus, OH;University of California at San Diego, Stephen Seagren, MD (CA11789), San Diego, and University of California at San Francisco, Alan Venook, MD (CA60138), San Francisco, CA; University of Chicago Medical Center, Gini Fleming, MD (CA41287), Chicago, IL; University of Iowa, Gerald Clamon, MD (CA47642), Iowa City, IA; University of Maryland Cancer Center, David Van Echo, MD (CA31983), Baltimore, MD; University of Minnesota, Bruce A. Peterson, MD (CA16450), Minneapolis, MN; University of Missouri/Ellis Fischel Cancer Center, Michael C. Perry, MD (CA12046), Columbia and Washington University School of Medicine, Nancy Bartlett, MD (CA77440), St. Louis, MO; University of Tennessee Memphis, Harvey B. Niell, MD (CA47555), Memphis, TN; and Walter Reed Army Medical Center, Joseph J. Drabeck, MD (CA26806), Washington, DC.

	ACKNOWLEDGMENTS

 
We thank the patients, nurses, data management staff, and physicians who contributed to this trial. This study was conducted in memory of Arlan Gottlieb, MD.

	NOTES

 
Research for CALGB 8952 was supported in part by grants from the National Cancer Institute, Bethesda, MD (CA31946), to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, Chair). Additional grants to participating institutions are listed in the Appendix (available online at www.jco.org).

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

	REFERENCES

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Submitted December 17, 2001; accepted November 15, 2002.

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