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© 2000 American Society for Clinical Oncology Interferon Alfa Consolidation After Intensive Chemotherapy Does Not Prolong the Progression-Free Survival of Patients With Low-Grade Non-Hodgkin’s Lymphoma: Results of the Southwest Oncology Group Randomized Phase III Study 8809From the Loyola University Stritch School of Medicine, Maywood, IL; Columbia River CCOP, Portland, OR; Southwest Oncology Group Statistical Center, Seattle, WA; University of Utah Medical Center, Salt lake City, UT; Wayne State University, Karmanos Cancer Center, Detroit, MI; Ohio State University Health Center, Columbus, OH; University of Oklahoma Health Science Center, Oklahoma City, OK; and University of Arizona Cancer Center, Tucson, AZ. Address reprint requests to Southwest Oncology Group (SWOG-8809), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217.
PURPOSE: S8809 is a randomized phase III trial determining whether intensive cytoreductive treatment, followed by interferon consolidation at the time of minimal residual disease, prolongs the progression-free survival (PFS) or overall survival (OS) of indolent lymphoma patients. PATIENTS AND METHODS: Five hundred seventy-one patients with previously untreated stage III or IV low-grade non-Hodgkin’s lymphoma were registered. Patients received six to eight cycles of prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide/mechlorethamine, vincristine, procarbazine, and prednisone (ProMACE[day 1]-MOPP[day 8]) chemotherapy or chemotherapy plus radiotherapy. Responding patients were randomized to observation alone or to interferon consolidation. Interferon alfa-2b 2 mU/m2 was given subcutaneously three times weekly for 2 years. RESULTS: Two hundred sixty-eight eligible patients were randomized to interferon alfa consolidation (n = 144) or observation alone (n = 124). With a median follow-up time from randomization among patients still alive of 6.2 years, the median PFS time was 4.1 years for patients who received interferon consolidation therapy and 3.2 years for patients who were observed after ProMACE-MOPP induction (P = .25). The adjusted hazard ratio for relapse for observation to interferon was 0.83 (95% confidence interval [CI], 0.61 to 1.13). The median OS has not been reached in either group. At 5 years, OS is 78% for the interferon group and 77% for the observation group (P = .65). The adjusted hazard ratio for survival for observation to interferon is 1.11 (95% CI, 0.69 to 1.79). CONCLUSION: Interferon alfa consolidation therapy after intensive treatment with anthracycline-containing combination chemotherapy and involved-field radiation therapy does not prolong the PFS or OS of patients with low-grade non-Hodgkin’s lymphoma.
PATIENTS WITH ADVANCED stages of the low-grade or indolent non-Hodgkin’s lymphoma have been treated for many years with various approaches ranging from deferred initial therapy (watch and wait) to single-agent alkylating agents, to radiation therapy, to combination chemotherapy. Although each approach can be effective, none is curative. Unfortunately, the prognosis for these patients has not significantly changed in more than 20 years. Median survival times of only 5 to 10 years with no evident plateau in the survival curves cannot be considered good.1-3 Clearly, innovative treatment strategies are needed. Recombinant interferon alfa was demonstrated to have moderate single-agent activity in relapsed patients with indolent lymphoma during the 1970s to 1980s.4,5 Subsequently, several investigators attempted to combine interferon alfa with chemotherapy in an attempt to prolong remissions and potentially overall survival (OS) for these patients.6-12 However, enormous variation in study design occurred. These included variations in types of patients entered (poor prognosis v all patients); timing of interferon administration (before chemotherapy, during chemotherapy, or after chemotherapy); type of chemotherapy (single-agent v anthracycline-containing combination chemotherapy); type of interferon (alfa-2b v alfa-2a); as well as variations in dose, duration, and schedule of interferon administration. Not surprisingly the results of these studies differ greatly. In 1988, the Lymphoma Committee of the Southwest Oncology Group (SWOG) initiated S8809, a phase III study of interferon alfa consolidation after intensive chemotherapy with prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide/mechlorethamine, vincristine, procarbazine, and prednisone (ProMACE-MOPP) (day 1 to 8) and radiation therapy to all sites of residual disease in patients with low-grade malignant lymphoma. Unfortunately, as shown in this report, neither progression-free survival (PFS) nor OS were improved by this strategy.
Eligibility Criteria Patients were eligible for S8809 if they were at least 16 years of age and had previously untreated, biopsy-proven, and measurable stage III or IV low-grade non-Hodgkin’s lymphoma. Working formulation (WF) groups A through C13 were included but patients with chronic lymphocytic leukemia were excluded. Procedures for determining stage and measurable disease were required within 14 days of registration and included a complete history and physical examination, routine blood counts and chemistry panel, and chest radiograph and abdominal computed tomography scans. A unilateral bone marrow biopsy and an actual or calculated serum creatinine clearance of more than 60 mL/min were required. All patients needed to have a SWOG performance status of 0, 1, or 2. Patients with known HIV infection, known CNS involvement, or known cardiac impairment were excluded. Consultation with both a medical oncologist and a radiation oncologist were also required before study registration. Diagnostic material was submitted for expert central pathology review by the Pathology Subcommittee of the SWOG Lymphoma Committee. In case of discordant findings between the submitting and reviewing pathologists, the diagnosis of the pathology subcommittee was used. The study was approved by the institutional review boards at each participating institution, and all patients gave written informed consent in accordance with institutional and federal guidelines.
Treatment Plan
After six cycles of treatment, all initially abnormal imaging studies were repeated. Patients with less than a partial response were taken off study. Patients with a complete response moved on to the randomized part of the study (see below). Patients with a partial response and negative bone marrow biopsy were given involved-field radiotherapy (see below) before moving to the randomized arms. Patients with a partial response and a positive bone marrow biopsy after six cycles of chemotherapy were given two additional cycles and reevaluated. If the bone marrow remained positive, they were removed from the study. If the bone marrow had been converted to negative or was borderline, these patients were referred for involved-field radiotherapy before randomization. Bone marrow biopsy reports were considered borderline, questionable, atypical, or minimal if they contained small patches of less than 25 atypical lymphoid cells, which suggested lymphoma but were not definitive. These marrows were submitted for central review. In this manner, an attempt was made to randomize all responding patients (complete or partial response) unless the bone marrow restaging remained positive. As noted previously, partial responders with a negative bone marrow after initial chemotherapy were given radiation therapy to residual disease only, beginning 6 weeks after day 1 of the last chemotherapy cycle. Nodal masses more than 2 cm at restaging were considered residual disease and radiated. A minimum dose of 25 Gy was planned for the tumor volume, though a small boost volume could be treated to a maximum of 40 Gy. A minimum margin of 1 to 1.5 cm of normal tissue was required. Daily radiation fractions of 1.5 to 1.8 Gy were standard. All radiation therapy port films and flow sheets were reviewed by a central coordinator. One month after completion of induction treatment (chemotherapy or chemotherapy plus radiotherapy), responding patients were randomized to observation alone or to interferon consolidation. Interferon alfa-2b 2 mU/m2 was given subcutaneously three times weekly for 2 years, initially by clinic nurses. Eventually, most patients self-administered the interferon injections. Follow-up observations while on protocol treatment (including observation) included monthly clinic visits for history, physical examination, and screening laboratories, with chest x-rays and abdominal computed tomography scans, at quarterly intervals. After completion of protocol treatment, follow-up evaluations were performed semi-annually for 2 years, then annually until death. Bone marrow biopsies were not routinely performed in the follow-up period but were repeated at the investigator’s discretion.
Statistical Considerations
Patient Demographics Five hundred seventy-one patients were registered for the ProMACE-MOPP induction chemotherapy phase of this study by 124 institutions from October 1, 1988, until November 15, 1994. Seventy-one patients (12%) were later found to be ineligible and were excluded from further analysis. The reasons for ineligibility included ineligible histology (59 patients), insufficient documentation (five patients), insufficient pathology material submitted (six patients), and ineligible disease stage (one patient).
Demographic and clinical characteristics of the 500 eligible patients are listed in Table 1. The median age was 49 years, with a range of 20 to 79 years. Sixty-two percent of patients were men. Eighty-six percent had follicular lymphomas, and only 14% had WF A. B symptoms were present in only 29% of patients. Seventy-four percent had stage IV disease. The bone marrow was involved in 71% of all patients. Bulky disease, defined as any mass
Response to Induction Chemotherapy The overall response rate of patients for the ProMACE-MOPP induction therapy was 83% (416 of 500 patients), with 235 complete responders (47%) and 181 partial responders (36%). Thus, 17%84 of patients went off study after the failure to achieve an objective response with the initial induction chemotherapy.
Toxicity of Induction Chemotherapy
Radiation Therapy
Interferon Consolidation Therapy
PFS and OS of patients randomized to interferon alfa consolidation therapy or to observation alone are presented in Figs 2 and 3, respectively. With a median follow-up time from randomization among patients still alive of 6.2 years, the median PFS time was 4.1 years for patients who received interferon consolidation therapy and 3.2 years for patients who were observed after ProMACE-MOPP induction (P = .25). The adjusted hazard ratio for relapse for observation to interferon was 0.83 (95% confidence interval, 0.61 to 1.13). The median OS has not been reached in either group. At 5 years, OS is 78% for the interferon group and 77% for the observation group (P = .65). The adjusted hazard ratio for survival for observation to interferon is 1.11 (95% confidence interval, 0.69 to 1.79).
Although this study was not designed solely for patients with clinically aggressive follicular lymphoma, some of these patients are included in the trial. Eighty-six percent of the patients had follicular lymphoma, and only 14% had WF A. However, patients with WF D, ie, follicular large-cell were excluded. No uniform consensus on appropriate prognostic factors for indolent lymphomas has yet been reached. We have selected elements from the Groupe d’Etude des Lymphomes de l’Adulte prognostic factor index that were available in our S8809 database in an attempt to address this issue.7 We identified 133 randomized patients who were less than 70 years of age with bulky disease, B symptoms, or splenic involvement. There was still no difference in PFS between the groups receiving interferon and the controls (P = .35). Of 144 patients randomized to receive interferon treatment, five failed to receive any therapy and were considered major protocol violations. Among the 139 treated patients, one fatal toxicity, a case of acute myelogenous leukemia, occurred and was felt to be treatment-related by the treating physician. Grade 4 toxicities attributed to interferon were one patient each with exfoliative dermatitis, thrombocytopenia, and reactive airway disease. Three ineligible patients had grade 4 toxicities, including one case each of thrombocytopenia, leukopenia, lymphopenia, and depression. Grade 3 toxicities occurred in 46 patients (33%) and were predominantly leukopenia.
During the 1970s and 1980s, several studies demonstrated that various forms of recombinant interferon alfa had moderate single-agent activity in patients with relapsed indolent lymphoma.4 Overall response rates averaged approximately 45%, with 10% complete response rates. The median duration of response was approximately 6 to 8 months. Doses ranged from 2 to 3 mU/m2 to 50 mU/m2, and there was little evidence of a dose response effect until the highest doses were achieved. Similar studies in the aggressive lymphomas yielded only 15% objective response rates, with only 2% complete response rates. Multiple studies were subsequently designed to determine the effectiveness of interferon alfa as a component of the initial treatment of patients with indolent lymphoma. In 1992, Smalley et al6 reported the results of a randomized trial comparing cyclophosphamide, doxorubicin, vincristine, and prednisone (COPA) chemotherapy, a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like regimen with reduced dose-intensity, with COPA plus interferon alfa-2a at a dose of 6 mU/m2 immediately before each cycle of chemotherapy. Patients were eligible if they had low-grade lymphoma with poor prognostic features defined as B symptoms, large nodes, or liver or lung involvement. Patients with intermediate-grade follicular large-cell lymphoma were also eligible. Interferon plus COPA resulted in increased time to treatment failure of approximately 1 year but did not significantly prolong survival. In 1993, Solal-Celigny et al7 reported the results of a randomized trial comparing cyclophosphamide, doxorubicin, teniposide, and prednisone, a CHOP-like regimen with reduced dose-intensity, to cyclophosphamide, doxorubicin, teniposide, and prednisone plus interferon alfa-2b at a dose of 5 mU three times a week (tiw) for 18 months. Patients were eligible if they had follicular lymphoma with a high tumor burden defined as large tumor size, B symptoms, splenic enlargement, effusions, orbital or epidural involvement, ureteral compression, or leukemia. Patients receiving interferon were found to have not only prolonged event-free survival but also prolonged OS. These results were confirmed with longer follow-up.17 Although a meta-analysis of interferon studies has been reported to show a survival advantage for all patients,18 this study represents the only published large randomized trial demonstrating a statistically significant survival advantage for interferon treatment. Several other studies have attempted to combine interferon with anthracycline-based combination chemotherapy; however, these studies have either been only reported in abstracts or have extremely small numbers. Aviles et al9 reported that interferon alfa-2b maintenance therapy prolonged duration of remission and survival of low-grade lymphoma patients who had previously achieved a complete remission after treatment with anthracycline-based combination chemotherapy. The dose of interferon was 5 mU tiw for 1 year. Unfortunately, the study included only 50 patients in each arm. Finally, the German Low-Grade Non-Hodgkin’s Lymphoma Study Group reported in an abstract that interferon alfa-2b, administered at a dose of 5 mU tiw until relapse or intolerable side effects, prolonged the disease-free survival of low-grade lymphoma patients treated with combination chemotherapy.11 Survival data were too preliminary to report. In contrast, multiple studies combining interferon alfa with non–anthracycline-based chemotherapy have shown inconsistent benefit to low-grade lymphoma patients. None have yet shown a survival advantage. Rohatiner et al10 randomized untreated follicular lymphoma patients to receive induction therapy consisting of chlorambucil with or without interferon alfa-2b at a dose of 3 mU/m2 tiw. There was no benefit from the interferon. However, the good responders were then randomized again to receive maintenance interferon or no further therapy. Patients receiving interferon maintenance had a lower recurrence rate but no survival benefit. The European Organization for Research and Treatment of Cancer treated low-grade lymphoma patients with non–anthracycline-based combination chemotherapy followed by extensive radiation therapy and then randomized the patients to receive either interferon alfa-2b at a dose of 3 mU/m2 tiw for 1 year or no further therapy.12 Interferon-treated patients had a trend for improved time to progression that did not reach statistical significance. Finally Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group randomized follicular low-grade lymphoma patients to receive cyclophosphamide with or without interferon alfa-2b at a dose of 2 mU/m2 tiw until 3 months after a complete response or partial response was achieved. A preliminary analysis demonstrated no benefit of interferon-induction treatment.8 S8809 was designed to determine whether a combination of intensive cytoreduction with combination chemotherapy, radiation therapy to sites of residual disease, and then interferon consolidation at the point of minimal residual disease would prolong the failure-free survival or OS of patients with indolent lymphoma. The results reported here demonstrate that this objective was not achieved. At the time of initiation of S8809, there was preliminary data suggesting that the seven- or eight-drug combination chemotherapy regimens might be superior to the standard three- or four-drug regimens, at least in aggressive lymphomas. The ProMACE-MOPP flexible induction regimen had resulted in excellent early results for diffuse aggressive lymphomas19 and was being used with aggressive radiation therapy for indolent lymphomas at the National Cancer Institute. A subsequent modification of that chemotherapy regimen, termed the ProMACE-MOPP (administered day 1 [ProMACE] and day 8 [MOPP]),14 had been piloted with conventional radiation therapy at Loyola University Medical Center. Ultimately, these seven- or eight-drug combination chemotherapy regimens have not been demonstrated to be superior to standard CHOP chemotherapy in aggressive lymphomas.20 Furthermore, the current results do not suggest any improvement over CHOP in indolent lymphomas either. The overall response rates (83%) and complete remission rates (50%) are similar to those reported by the Lymphoma Committee of SWOG in several other studies using CHOP.2 With obviously shorter follow-up, the PFS and OS curves of S8809 also currently overlap those of the historical CHOP studies (data not shown). Involved-field radiation therapy as administered in this study did not seem to significantly increase the complete remission rate. Thus, although the chemotherapy/radiation induction program may be as effective as any other treatment, it’s increased cost and toxicity do not seem to warrant further use. The major finding of this study is that interferon alfa consolidation after intensive chemotherapy and involved-field radiation therapy does not significantly prolong the PFS or OS of patients with low-grade non-Hodgkin’s lymphoma. This conclusion is obviously only relevant to the patient population studied in this clinical trial and to the treatment programs used here. It does not speak to the role of interferon in other schedules, doses, durations, and so on. As noted previously, essentially all of the published studies on this topic differ greatly in their study design. None of the studies duplicate a previously published positive result. Nevertheless, the United States Food and Drug Administration did approve the use of interferon alfa-2b in previously untreated patients with clinically aggressive follicular non-Hodgkin’s lymphoma in conjunction with anthracycline-containing combination chemotherapy. A uniform consensus on appropriate prognostic factors for indolent lymphomas has not yet been reached, although such analyses are currently in progress. As noted previously, using selected elements from the Groupe d’Etude des Lymphomes de l’Adulte prognostic factor index, we identified 133 randomized patients who were less than 70 years of age with bulky disease, B symptoms, or splenic involvement. There was still no difference in PFS between the groups receiving interferon and the controls (P = .35). Thus, although the benefit of interferon therapy in some or all indolent lymphomas continues to be debated, the use of interferon alfa-2b in the manner administered in this large prospective randomized trial cannot be recommended for any known subset of patients.
Supported in part by the following National Cancer Institute Department of Health and Human Services Public Health Service Cooperative Agreement grant nos. CA38926, CA32102, CA46282, CA45377, CA58861, CA14028, CA04920, CA58686, CA13612, CA58416, CA46441, CA46136, CA35281, CA35261, CA35090, CA37981, CA45807, CA20319, CA42777, CA35176, CA22433, CA45450, CA35431, CA04919, CA46113, CA12644, CA45560, CA35128, CA76447, CA35192, CA35178, CA76462, CA27057, CA16385, CA58882, CA96429, CA46368, CA58723, CA12213, CA58415, CA35262, and CA76132.
1. Anderson T, Bender RA, Fisher RI, et al: Combination chemotherapy in non-Hodgkin’s lymphoma: Results of long-term follow-up. Cancer Treat Rep 61:1057-1066, 1977[Medline] 2. Dana BW, Dahlberg S, Nathwani BN, et al: Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. J Clin Oncol 11:644-651, 1993[Abstract]
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The Non-Hodgkin’s Lymphoma Classification Project: A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood 89:3909-3918, 1997
4.
Goldstein D, Laszlo J: Interferon therapy in cancer: From imaginon to interferon. Cancer Res 46:4315-4329, 1986 5. Horning SJ, Merigan TC, Krown SE, et al: Human interferon alpha in malignant lymphoma and Hodgkin’s disease. Cancer 56:1305-1310, 1985[Medline] 6. Smalley RV, Andersen JW, Hawkins MJ, et al: Interferon alpha combined with cytotoxic chemotherapy for patients with non-Hodgkin’s lymphoma. N Engl J Med 327:1336-1341, 1992[Abstract]
7.
Solal-Celigny P, Lepage E, Brousse N, et al: Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. N Engl J Med 329:1608-1614, 1993 8. Peterson BA, Petroni G, Oken MM, et al: Cyclophosphamide versus cyclophosphamide plus interferon alfa-2b in follicular low grade lymphomas: A preliminary report of an intergroup trial (CALGB 8691 and EST 7486). Proc Am Soc Clin Oncol 12:366, 1993 (abstr 1240) 9. Aviles A, Duque G, Talavera A, et al: Interferon alpha 2b as maintenance therapy in low grade malignant lymphoma improves duration of remission and survival. Leuk Lymphoma 20:495-499, 1996[Medline] 10. Rohatiner AZS, Crowther D, Radford JA, et al: The role of interferon in follicular lymphoma. Proc Am Soc Clin Oncol 15:418, 1996 (abstr 1285) 11. Unterhalt M, Herrmann R, Nahler M, et al: Significant prolongation of disease free survival in advanced low grade non Hodgkin lymphomas by interferon alpha maintenance. Blood 86:439, 1995 (abstr 1744)
12.
Hagenbeek A, Carde P, Meerwaldt JH, et al: Maintenance of remission with human recombinant interferon alfa-2a in patients with stage III and IV low-grade malignant non-Hodgkin’s lymphoma. J Clin Oncol 16:41-47, 1998 13. The Non-Hodgkin’s Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: Summary and description of a working formulation for clinical usage. Cancer 49:2112-2135, 1982[Medline]
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Longo DL, DeVita VT, Duffey PL, et al: Superiority of ProMACE-CytaBOM over ProMACE-MOPP in the treatment of advanced diffuse aggressive lymphoma: Results of a prospective randomized trial. J Clin Oncol 9:25-38, 1991
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The International Non-Hodgkin’s Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 329:987-994, 1993 16. Lopez-Guillermo A, Montserrat E, Bosch F, et al: Applicability of the international index for aggressive lymphomas to patients with low-grade lymphoma. J Clin Oncol 12:1343-1348, 1994[Abstract] 17. Solal-Celigny P, Lepage E, Brousse N, et al: Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: Final analysis of survival and toxicity in the Groupe d’Etude des Lymphomes Folliculaires 86 Trial. J Clin Oncol 16:2332-2338, 1998[Abstract] 18. Rohatiner AZS, Gregory WM, Peterson BA, et al: A meta-analysis of randomized trials evaluating the role of interferon as treatment for follicular lymphoma. Proc Am Soc Clin Oncol 17:4, 1998 (abstr 11) 19. Fisher RI, DeVita VT, Hubbard SM, et al: Diffuse aggressive lymphomas: Increased survival after alternating flexible sequences of ProMACE and MOPP chemotherapy. Ann Intern Med 98:304-309, 1983
20.
Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002-1006, 1993 Submitted September 21, 1999; accepted February 9, 2000.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10 cm in diameter or a mediastinal mass 
