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© 2000 American Society for Clinical Oncology Assessment of the Stanford V Regimen and Consolidative Radiotherapy for Bulky and Advanced Hodgkin’s Disease: Eastern Cooperative Oncology Group Pilot Study E1492From the Department of Medicine, Stanford University Medical Center, Stanford, CA; Eastern Cooperative Oncology Group Statistical Center, Boston, MA; Washington University, St Louis, MO; University of Rochester, Rochester, NY; and University of Miami, Miami, FL. Address reprint requests to Sandra J. Horning, MD, Department of Medicine, Division of Medical Oncology, Stanford University Medical Center, 1000 Welch Rd, Suite 202, Palo Alto, CA 94304-5756; email ml.xsh{at}forsythe.stanford.edu
PURPOSE: This study was performed, in a multi-institutional setting, to evaluate the efficacy and feasibility of the Stanford V chemotherapy regimen plus radiotherapy to bulky Hodgkin’s disease sites.
PATIENTS AND METHODS: A two-stage design was implemented in a phase II study involving 47 patients with bulky mediastinal stage I/II or stage III/IV Hodgkin’s disease. Twelve weeks of the Stanford V chemotherapy regimen were given with consolidative radiotherapy (36 Gy) to lymph nodes RESULTS: With a median follow-up of 4.8 years, 45 patients are alive and 40 have been continuously disease-free. The estimated freedom from progression was 87% at 2 years and 85% at 5 years. Overall survival was 96% at 2 and 5 years. There was one death from Hodgkin’s disease and one death from an M5 acute leukemia. Six of seven relapsed patients received high-dose therapy and autologous stem-cell transplantation. The freedom from second progression for the seven relapsed patients was estimated at 98% at 3 years. CONCLUSION: Stanford V chemotherapy and consolidative radiotherapy to bulky disease is effective in bulky and advanced Hodgkin’s disease in a multi-institutional setting. On this basis, an Intergroup study comparing doxorubicin, bleomycin, vinblastine, and dacarbazine with the Stanford V regimen has been initiated.
MODERN COMBINATION chemotherapy yields cure rates of 60% to 80% in advanced-stage and bulky Hodgkin’s disease.1-7 A series of randomized controlled trials has demonstrated that six to 10 courses of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or mustard, vincristine, procarbazine, and prednisone (MOPP) plus ABVD combinations are more effective than MOPP alone in advanced Hodgkin’s disease.1,2,6 The most recent Intergroup trial was closed prematurely because there was significantly more toxicity associated with MOPP/ABV hybrid than with ABVD, whereas no difference was noted in efficacy.3 Although late effects related to ABVD have been modest, fatal pulmonary complications attributed to bleomycin have been reported, and severe cardiac abnormalities have been observed in children after treatment.2,8,9 Because most complications are a function of total drug dose, the Stanford group developed an abbreviated regimen that maintained the dose-intensity of active agents but reduced the cumulative doses of doxorubicin, bleomycin, and mustard.10,11 In addition, the 12-week Stanford V regimen offered the advantage of a shorter duration of administration compared with conventional treatment. A key component of the Stanford V program, facilitating its brevity, was the incorporation of radiotherapy in therapeutic doses to sites of bulky disease. However, because radiotherapy is associated with its own serious late effects, such as second cancers and cardiopulmonary toxicity, the volume was limited to the anatomic regions with the highest probability of relapse.12 Previously, the Stanford investigators had reported an estimated freedom from progression (FFP) of 89% and overall survival of 96% at 3 years in bulky and advanced-stage Hodgkin’s disease.10,11 The current Eastern Cooperative Oncology Group (ECOG) study, E1492, was undertaken to evaluate the efficacy and feasibility of Stanford V chemotherapy plus radiotherapy to bulky sites in a cooperative group study for several reasons. First, the eligibility, case report forms, treatment delivery, evaluation of response, and toxicity would be subject to the scrutiny of centralized review. Second, the acceptability of the safety profile for the chemotherapy regimen would be tested at multiple institutions. Finally, adherence to protocol guidelines for radiotherapy would be evaluated for patients from each of the participating institutions. In discussions with the National Cancer Institute, ECOG investigators undertook this pilot study with the understanding that encouraging results would support a group-wide phase III trial in which the Stanford V regimen would serve as the investigational arm.
Study Design A conservative study design was used because untreated Hodgkin’s disease presenting in any stage is potentially curable and because the concept of abbreviated therapy was novel and relatively untested when the study was activated in 1992. Thus, we implemented a two-stage design that would allow early study closure if the response rate was disappointing relative to the expected response rate. The plan was to accrue approximately 50 patients over 20 months. Twenty-two patients were to be entered initially, with the assumption that 20 would be eligible. If 16 or more complete responses (CRs) or complete clinical responses (CCRs) were seen, an additional 28 patients would be entered, with the assumption that 25 of them would be eligible. If 39 or more CRs were seen among the 45 eligible patients, the conclusion would be that the response rate with the Stanford V regimen ± radiotherapy was consistent with a response rate of 90%, and immediate consideration would be given for an enlarged successor study. With this design, if the true response rate was 90%, the probability (P) of stopping early and rejecting Stanford V was .04, and the probability of declaring it promising was .83.
Eligibility
Statistical Methods
Administrative Information
Chemotherapy
During the entire 12 weeks of chemotherapy, ancillary treatment to prevent complications consisted of ranitidine 150 mg orally (PO) twice a day; trimethoprim/sulfamethoxazole double-strength PO twice a day, ketoconazole 200 mg PO every day, and acyclovir 200 mg PO three times a day. If dose reduction or delay occurred at any time during chemotherapy, filgrastim was incorporated into all subsequent treatment at 5 µg/kg subcutaneously, starting 48 hours after myelosuppressive chemotherapy given on weeks 3, 5, 7, 9, and 11. Doses of mechlorethamine, doxorubicin, vinblastine, and etoposide were reduced to 65% of the full dose if the ANC on the day of treatment was 500 to 1000/µL. If the ANC was less than 500/µL on the day of treatment, therapy was delayed for 1 week and resumed at the level indicated by the complete blood cell count. Filgrastim was started 48 hours after the new day of treatment and incorporated into all subsequent cycles to prevent dose reduction or delay.
Radiotherapy Consolidative radiotherapy commenced 2 to 4 weeks after the completion of chemotherapy, when the WBC was > 3,000/µL and the platelet count exceeded 100,000/µL. A radiation oncology review of assessable cases was undertaken by Linda Martin, Director of the ECOG Radiation Therapy Quality Assurance Center, and Dr Richard T. Hoppe, the radiation oncology cochairman for E1492.
Patients Characteristics Table 2 lists the characteristics of the 47 assessable patients. As anticipated with advanced disease, there was a male predominance. Forty-one of the 47 patients were white. The median age was 32 years, with a range of 20 to 56 years. Three patients had an ECOG performance status greater than 1 at study entry. As detailed in Table 2, histologic subtype of Hodgkin’s disease was recorded as nodular sclerosis in 40 cases, mixed cellularity in five cases, and lymphocyte predominance in two cases. Central pathologic review was conducted in 39 cases. Thirty-one of 34 cases of nodular sclerosis were confirmed, with one reclassified as mixed cellularity and two reclassified as other (eg, interfollicular or unclassified) histologic subtypes of Hodgkin’s disease. Three of five cases of mixed cellularity were confirmed, with one reclassified as nodular sclerosis and the other as unspecified non-Hodgkin’s lymphoma. One of two cases of lymphocyte predominance was confirmed, with the other reclassified as nodular sclerosis. As noted below, in retrospect, the case of lymphocyte predominance may have been a composite lymphoma also containing diffuse large-cell lymphoma (DLCL).
According to the Ann Arbor Conference classification, 21 patients had stage I or II disease with a massive mediastinal component. Fourteen patients had stage III disease, and 12 patients had stage IV disease. Constitutional symptoms were present in 26 patients (55%). Twenty patients (43%) had night sweats, 10 (21%) had fever, and 13 (28%) reported a significant weight loss. The majority of patients (89%) had mediastinal disease. Extranodal extension of disease was present in 16 patients with stage I to III disease and the 12 patients with stage IV disease (61% of the total population). Extranodal sites included lung (n = 10), pleura (n = 9), bone marrow (n = 3), liver (n = 3), bone (n = 1), and other (n = 10). Several patients had multiple extranodal lesions. Disseminated (stage IV) sites of disease included the lung (defined as involvement of > one lobe), liver, bone marrow, and bone.
Radiotherapy Quality Control
Toxicity
One patient developed a second malignancy after the completion of therapy. A 43-year-old woman developed an M5 acute leukemia bearing a balanced 9;11 chromosomal translocation and a trisomy 8 at 16 months after registration. Although she underwent a successful induction, her leukemia ultimately relapsed, and she died 24 months after study entry. Fertility was not consistently monitored on this study. Anecdotally, eight patients (four men and four women) treated on E1492 at Stanford successfully conceived 11 children subsequent to treatment.
Efficacy and Survival Data Duration of follow-up was calculated based on the last time the patient was examined, and the results were sent to the ECOG Coordinating Center. Patients have been observed for a median of 4.8 years (range, 3.4 to 6.2). Forty-five of 47 patients are alive, and 40 of these patients have been continuously disease-free. The characteristics of the seven patients who failed treatment are listed in Table 4. Five patients experienced relapses shortly after the completion of treatment. Patient no. 14004 presented with a markedly elevated lactate dehydrogenase, pancytopenia, marked splenomegaly, extensive pelvic adenopathy, and biopsy-proven hepatic and bone marrow disease. An axillary lymph node was diagnosed as lymphocyte-predominant Hodgkin’s disease, confirmed by central review. At relapse, the surgically excised spleen demonstrated both lymphocyte-predominant Hodgkin’s disease and DLCL. In retrospect, this patient may have had a composite lymphoma at study entry. Two patients who relapsed early did so immediately after radiotherapy, and one patient relapsed during radiotherapy. Each relapse was outside of the irradiated field. Of note, four relapses involved subdiaphragmatic sites, and three occurred in bone marrow or bone. Patient no. 14041 had disease staged as IIA, with a 13 x 14-cm mediastinal mass and an erythrocyte sedimentation rate of 81. He relapsed in subdiaphragmatic lymph nodes. This man, who had a body-surface area of 2.63 m2, received full doses of chemotherapy as prescribed per protocol, capped at 2 m2.
The remaining two relapses occurred at 19 and 45 months. Both of these patients had massive mediastinal disease and recurred adjacent to the irradiated field, one in an infraclavicular node and the other in a hilar node. In retrospect, the latter was considered to be a marginal miss of the radiotherapy treatment field. Fig 1 describes the FFP for the 47 patients. The estimated FFP was 87% at 2 years and 85% (95% CI, 81% to 88%) at 5 years. The patient with lymphocyte-predominant Hodgkin’s disease and DLCL was scored as a treatment failure, although this might have been categorized as a new malignancy. Failure-free survival, which scores the late treatment-related death as well, was estimated at 85% at 2 years and 83% (95% CI, 80% to 84%) at 5 years.
Overall survival for the 47 patients was estimated at 96% at both 2 and 5 years (Fig 2). These data reflect one death caused by Hodgkin’s disease and one death caused by secondary leukemia. As described in Fig 2, the estimated tumor mortality, which scores death caused by disease only, was 98% with no events after 2 years.
Management of Treatment Failure Six of the seven relapsed patients received high-dose therapy and autologous transplantation. Five are alive and without evident disease from 26 to 61 months after transplant. One patient relapsed shortly after transplant and subsequently committed suicide. Patient no. 14043 completed combination chemotherapy and radiotherapy 3 months ago. Figure 3 demonstrates the freedom from second progression for these seven patients, estimated at 98% at 3 years.
This study was undertaken to confirm the efficacy of the Stanford V regimen and consolidative radiotherapy in bulky and advanced-stage Hodgkin’s disease in a multi-institutional setting. The survival data compare favorably with those published by Bartlett et al10 and updated by Horning et al11 from Stanford University. The design of the study demonstrated the difficulties in using degree of response as a surrogate for efficacy in Hodgkin’s disease. Despite the definition of CR, which allows for stable residual radiographic abnormalities with more than 50% response, 12 patients were scored as partial responders after chemotherapy. Ten of these patients remained disease-free for 2 to 6 years compared with 30 of 34 patients scored as CR or CCR. The treatment program used in this study was based on the hypothesis that abbreviated chemotherapy, which was dose-intense but delivered lower cumulative doses of drugs, would maintain or improve cure rates in bulky and advanced Hodgkin’s disease when combined with radiotherapy delivered to bulky disease sites. The survival data in the current study compare favorably with other multidrug regimens, including ABVD, which is currently the standard combination chemotherapy program for similar patients. In successive, randomized Intergroup trials led by the Cancer and Leukemia Group B, six to 10 cycles of ABVD resulted in failure-free survival rates of 65% at 3 years and 55% at 10 years.2,3 Comparison of treatment results between studies is always hazardous, however, and demands prospective phase III clinical trials. The importance of radiotherapy in the Stanford V program and the ability to deliver the prescribed radiotherapy in a multi-institutional setting have been debated. In the quality control analysis of E1492, 64% of patients received radiotherapy per protocol. Excluding patients who received appropriate radiotherapy but in a non-ECOG institution, there were only five major protocol violations, and 90% of patients received treatment to appropriate regions at greater than or equal to the prescribed doses. Several studies have failed to demonstrate a benefit to low-dose consolidative radiotherapy in advanced Hodgkin’s disease.16–18 It is important to note that radiotherapy was delivered in this study only to bulky disease sites and the dose was 36 Gy, a full therapeutic dose. Overall, 41 patients (87%) were scheduled to receive radiotherapy per the E1492 protocol. By comparison, 67% of patients were treated with 36 Gy consolidative radiotherapy to bulky sites and residual disease in the recent study of the German Hodgkin Study Group (GHSG) in which the standard and escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimens were introduced.19 Analysis of relapses provides a potential method to determine the impact of chemotherapy and radiotherapy and consider future treatment modifications. No patient in the current study relapsed in an irradiated site, although two patients with massive mediastinal disease failed at the treatment margins. Two patients with advanced disease failed in subdiaphragmatic sites during or shortly after completing radiation to supradiaphragmatic regions. Because the majority of relapses occurred in the setting of advanced and symptomatic Hodgkin’s disease, it would seem that the chemotherapy program was inadequate in these cases. Capping of drug doses may have contributed to relapse in one patient. The relapse with DLCL might have been scored in other studies as a second cancer. As noted above, the presenting features in this case were more consistent with DLCL than lymphocyte-predominant Hodgkin’s disease. The recent reporting of a high incidence of secondary non-Hodgkin’s lymphoma by the GHSG in their HD-9 study is remarkable.20 This may reflect greater sophistication in pathologic diagnosis, a factor which could also influence the incidence of reported relapses of Hodgkin’s disease. One of the major objectives of the Stanford V program was to lessen the incidence of serious late effects. Thus, it was disturbing that one patient developed a secondary leukemia. The M5 subtype of acute leukemia has been reported in patients receiving topoisomerase inhibitors.21 The relationship of this form of secondary leukemia to total etoposide dose, schedule, and drug interactions is uncertain.22 A balanced translocation involving 11q23 is characteristic, and this secondary leukemia occurs with a shorter latency than that which is attributed to alkylating agents. Although the frequency of secondary leukemia cannot be assessed from this study, it seems to be a relatively infrequent event. No cases of leukemia have been seen among 170 patients treated with Stanford V at Stanford University and followed a median of 5 years (S.J. Horning, personal communication, January, 2000). On another note, the Stanford V chemotherapy regimen has significantly less reproductive toxicity than alkylating agent–based regimens, and a number of patients in the current study were able to conceive. Recently, an international group has described a prognostic score for advanced Hodgkin’s disease that may be used to describe study results and facilitate comparisons among studies.23 Unfortunately, data for all the described prognostic factors were not available for the E1492 patients. Subsequent to the standard combination chemotherapy used in cases included in the prognostic factor model, treatment programs have been described that may have greater efficacy and may be able to overcome adverse prognostic factors. For instance, the GHSG has reported outstanding results with standard and escalated BEACOPP in a large multi-institutional study.19 Freedom from relapse was significantly superior with BEACOPP compared with cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP/ABVD). High-dose therapy and autologous stem-cell transplantation, which is effective in refractory and recurrent Hodgkin’s disease, has been investigated as primary treatment for high-risk patients.24 Based on encouraging phase II data with transplantation, a randomized trial is in progress in Europe and an Intergroup trial is planned in poor-risk patients in the United States.25,26 Intensive, high-dose chemotherapy programs increase the risk of gonadal toxicity and generate a theoretical concern about the incidence of late effects, such as secondary cancers. Further, although intensive regimens have reported improved freedom from relapse, no survival benefits are apparent to date.19,20 Thus, it becomes important to evaluate the success of second-line therapy after relapse with less toxic combination chemotherapy programs such as the Stanford V regimen. As summarized in Table 5 and Fig 3, six of seven patients were successfully treated with second-line treatment after failing Stanford V and radiotherapy. Although the numbers are small, this degree of success is even greater than expected based on the published results with autotransplantation in refractory and recurrent disease.25,26 It is possible that some failures on the Stanford V program are related to an inadequate duration of treatment rather than absolute drug resistance.
In conclusion, in this ECOG pilot study, Stanford V chemotherapy with radiotherapy to bulky disease sites proved to be effective, safe, and deserving of further study in a multi-institutional study. Based on these data, ECOG and the Southwest Oncology Group have initiated a randomized phase III trial comparing Stanford V chemotherapy plus radiotherapy to bulky sites with ABVD combination chemotherapy in patients with bulky and advanced Hodgkin’s disease with zero to two adverse risk factors according to the International Prognostic Factors.23 End points for this study include failure-free survival, FFP, overall survival, and toxicity.
Supported in part by Public Service grants no. CA23318, CA11083, CA66636, and CA2115 from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services.
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.
1. Bonadonna G, Valagussa P, Santoro A: Alternating non-cross-resistant combination chemotherapy or MOPP in stage IV Hodgkin’s disease: A report of 8-year results. Ann Intern Med 104:739-746, 1986 2. Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327:1478-1484, 1992[Abstract] 3. Duggan D, Petroni G, Johnson J, et al: MOPP/ABV vs ABVD for advanced Hodgkin’s disease: A preliminary report of CALGB 8952 (with SWOG, ECOG, NCIC). Soc Clin Oncol 16:12a, 1997 (abstr 43) 4. Connors JM, Klimo P, Adams G, et al: Treatment of advanced Hodgkin’s disease with chemotherapy: Comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD—A report from the National Cancer Institute of Canada clinical trials group. J Clin Oncol 15:1638-1645, 1997[Abstract]
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Viviani S, Bonadonna G, Santoro A, et al: Alternating versus hybrid MOPP and ABVD combinations in advanced Hodgkin’s disease: Ten-year results. J Clin Oncol 14:1421-1430, 1996 6. Somers R, Carde P, Henry-Amar M, et al: A randomized study in stage IIIB and IV Hodgkin’s disease comparing eight courses of MOPP versus an alteration of MOPP with ABVD: A European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group and Groupe Pierre-et-Marie-Curie controlled clinical trial. J Clin Oncol 12:279-287, 1994[Abstract]
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Glick JH, Young ML, Harrington D, et al: MOPP/ABV hybrid chemotherapy for advanced Hodgkin’s disease significantly improves failure-free and overall survival: The 8-year results of the intergroup trial. J Clin Oncol 16:19-26, 1998 8. Mefferd JM, Donaldson SS, Link MP: Pediatric Hodgkin’s disease: Pulmonary, cardiac, and thyroid function following combined modality therapy. Rad Oncol Biol Phys 16:679-685, 1989 9. Fryer CJ, Hutchinson RJ, Krailo M, et al: Efficacy and toxicity of 12 courses of ABVD chemotherapy followed by low-dose regional radiation in advanced Hodgkin’s disease in children: A report from the Children’s Cancer Study Group. Clin Oncol 8:1971-1980, 1990 10. Bartlett NL, Rosenberg SA, Hoppe RT, et al: Brief chemotherapy, Stanford V, and adjuvant radiotherapy for bulky or advanced-stage Hodgkin’s disease: A preliminary report. J Clin Oncol 13:1080-1088, 1995[Abstract]
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Horning SJ, Rosenberg SA, Hoppe RT: Brief chemotherapy (Stanford V) and adjuvant radiotherapy for bulky or advanced Hodgkin’s disease: An update. Ann Oncol 7:105-108, 1996 (suppl 4) 12. Hancock SL, Hoppe RT: Long term complications of treatment and causes of mortality after Hodgkin’s disease. Semin Radiat Oncol 6:225-242, 1996[Medline] 13. Carbone P, Kaplan H, Musshoff K: Report of the committee on the Hodgkin’s disease staging. Res 31:1860-1865, 1971 14. Atkinson EN, Brown BW: Confidence limits for probability of response in multistage phase II clinical trials. Biometrics 41:741-744, 1985[Medline] 15. Kaplan EL, Meier P: Non-parametric estimation of incomplete observations. J Am Stat Assoc 53:270-283, 1958
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Fabian CJ, Mansfield CM, Dahlberg S, et al: Low-dose involved field radiation after chemotherapy in advanced Hodgkin disease: A Southwest Oncology Group randomized study. Ann Intern Med 120:903-912, 1994
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Diehl V, Loeffler M, Pfreundschuh M, et al: Further chemotherapy versus low-dose involved-field radiotherapy as consolidation of complete remission after six cycles of alternating chemotherapy in patients with advance Hodgkin’s disease: German Hodgkin’s Study Group (GHSG). Ann Oncol 6:901-910, 1995 18. Weiner MA, Leventhal B, Brecher ML, et al: Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin’s disease in pediatric patients: A Pediatric Oncology Group study. J Clin Oncol 15:2769-2779, 1997[Abstract]
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Diehl V, Franklin J, Hasenclever D, et al: BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin’s lymphoma: Interim report from a trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 16:3810-3821, 1998
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Tesch H, Diehl V, Lathan B, et al: Moderate dose escalation for advanced stage Hodgkin’s disease using the bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone scheme and adjuvant radiotherapy: A study of the German Hodgkin’s Lymphoma Study Group. Blood 92:4560-4567, 1998
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Smith MA, Rubinstein L, Cazenave L, et al: Report of the Cancer Therapy Evaluation Program monitoring plan for secondary acute myeloid leukemia following treatment with epipodophyllotoxins. Cancer Inst 85:554-558, 1993 22. Stine KC, Saylors RL, Sawyer JR, et al: Secondary acute myelogenous leukemia following safe exposure to etoposide. Oncol 15:1583-1586, 1997
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Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin’s disease: International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 339:1506-1514, 1998 24. Carella AM, Carlier P, Congiu A, et al: Autologous bone marrow transplantation as adjuvant treatment for high-risk Hodgkin’s disease in first complete remission after MOPP/ABVD protocol. Transplant 8:99-103, 1991
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Horning SJ, Chao NJ, Negrin RS, et al: High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin’s disease: Analysis of the Stanford University results and prognostic indices. Blood 89:801-813, 1997
26.
Yuen AR, Rosenberg SA, Hoppe RT, et al: Comparison between conventional salvage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin’s disease. Blood 89:814-822, 1997 Submitted June 30, 1999; accepted October 19, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
5 cm and/or macroscopic splenic disease. Treatment was administered in one of five institutions participating in the Eastern Cooperative Oncology Group. 
