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© 2003 American Society for Clinical Oncology Prolonged Single-Agent Versus Combination Chemotherapy in Indolent Follicular Lymphomas: A Study of the Cancer and Leukemia Group B
From the University of Minnesota Medical School, Division of Hematology, Oncology and Transplantation, Minneapolis, MN; University of Virginia Cancer Center, Charlottesville, VA; New York Presbyterian-Cornell University Medical Center, New York; Mount Sinai Medical Center, New York; Roswell Park Cancer Center, and Veterans Affairs Western New York Healthcare System, Buffalo; and State University of New York Health Science Center at Syracuse, Division of Hematology/Oncology, Syracuse, NY; The Ohio State University Comprehensive Cancer Center, Columbus, OH; Department of Hematology, Finsen Center, Rigshospital, Copenhagen, Denmark; Wake Forest University School of Medicine, Winston-Salem; Salisbury Veterans Affairs Hospital, Salisbury; and CALGB Statistical Center, Duke University, Durham, NC. Address reprint requests to Bruce A. Peterson, MD, Division of Hematology, Oncology and Transplantation, MMC 286, University of Minnesota, Minneapolis, MN 55455; email: peter001{at}umn.edu.
Purpose: The array of options for the initial management of follicular small cleaved lymphoma (FSCL) and follicular mixed lymphoma (FML) ranges from little or no therapy to the use of intensive combinations of drugs. The Cancer and Leukemia Group B (CALGB) compared two contrasting approaches: a single agent, and combination chemotherapy capable of curing diffuse aggressive lymphomas. Patients and Methods: A total of 228 patients with stage III or IV FSCL or FML were randomized to cyclophosphamide or the combination of cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-B). Treatment was continued in responders for 2 years beyond maximal response. The primary end point was survival in the most common subtype, FSCL. Results: Ninety-one percent of all patients responded; complete responses were seen in 66% of those treated with cyclophosphamide and in 60% treated with CHOP-B (P = .36). At 10 years with either cyclophosphamide or CHOP-B, respectively, overall time to failure (25% failure free v 33%; P = .107) and survival (44% alive v 46%; P = .79) were similar by treatment. Outcomes in FSCL also were similar. In 46 patients with FML, at 10 years the combination was associated with better failure-free (9% v 48%; P = .005) and overall (25% v 61%; P = .024) survival. Acute toxic effects were more common with combination chemotherapy. Second malignancies, which might be attributed to treatment, were seen with both approaches. Conclusion: There is no advantage to the initial use of the relatively intensive combination, CHOP-B, for patients with FSCL compared with the less toxic single agent, cyclophosphamide. However, in an unplanned subgroup analysis, patients with FML who received the combination experienced improved disease control and survival.
IN A CLASSIC paper published in 1956, Rappaport et al1 provided criteria for the diagnosis of follicular (nodular) lymphomas and emphasized the potential clinical importance of subclassification based on their marked cytologic variation. Two subtypes were identified as indolent or low-grade malignancies2,3 and were called follicular, predominantly small cleaved cell lymphoma (FSCL) and follicular, mixed small cleaved and large cell lymphoma (FML) in the widely used Working Formulation for Clinical Usage3 and, now, follicular lymphoma, grades 1 and 2, respectively, in the more recently introduced Revised European-American (REAL) Classification of Lymphoid Neoplasms4 and World Health Organization (WHO) Classification.5,6 These subtypes are characterized by a long natural history, with life expectancies extending to several years despite almost always presenting as disseminated malignancies. Therapeutic approaches in current use range from little or no initial treatment7–10 to intensive multidrug combinations.11–13 In addition, newer agents, such as recombinant biologics9,14–16 or monoclonal antibodies,17–19 and newer technologies, such as stem cell transplantation,12,20,21 are being evaluated. A consensus has not emerged as to the best treatment. This situation attests, in part, to the inadequacies of currently available treatments. Much of the dilemma arises from the nature of these malignancies, which are relatively easy to put into remission but are rarely cured. Unlike diffuse aggressive lymphomas, where intensive combinations of effective drugs cure a substantial proportion of patients,22–27 the benefits of such therapies have not been demonstrated in low-grade lymphomas. However, regimens that would be considered potentially curative in diffuse aggressive lymphomas have not been adequately compared with more conservative therapies that also might be sufficient and less toxic. In 1980, the Cancer and Leukemia Group B (CALGB) undertook a prospective study comparing the single agent, cyclophosphamide, with combination chemotherapy in patients with follicular lymphomas. Because there is a consensus that follicular, predominantly large-cell lymphoma (FLCL) or grade 3, a third subtype, is clinically more aggressive and requires combination chemotherapy,28–31 we included only patients with FSCL or FML. The combination of drugs studied was based on a regimen, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP),32 established as curative in diffuse aggressive lymphomas and as the standard of care for those subtypes of lymphoma.22,24 In our study, bleomycin was added to CHOP (CHOP-B) because it is known to be an active drug with only modest myelotoxicity,33,34 and therapy was continued after maximal responses because available evidence indicated prolongation of remissions with maintenance treatment.35–38 Although complete response (CR) rates are an important early indicator of a treatment’s efficacy and a prerequisite for cure in the more aggressive lymphomas, CR is not as meaningful in the indolent lymphomas, where prolongation of time to failure and, especially, survival are the only reliable measures of a superior therapy. Because the clinical course is relatively long in these lymphomas, early results of an intervention may be misleading. We now report the mature results of this study.
CALGB 7951 was open for patient accrual from January 1980 through April 1985. Patients with histologically confirmed and measurable stage III or stage IV39 FSCL or FML were registered no more than 100 days from diagnosis. None had received chemotherapy or irradiation. Protocol eligibility also required that patients spend less than 100% of their waking time in bed (performance score < 4) and have no significant impairment of renal, hepatic, or bone marrow function unless related directly to the lymphoma. If pretreatment cardiac or pulmonary function prohibited the safe use of doxorubicin or bleomycin, respectively, patients were ineligible. All patients were adults and gave informed consent after approval of the study by local human investigations committees. Eligibility on the basis of histopathology was determined by a diagnosis of FSCL or FML at the participating institution, but only those patients for which two expert hematopathologists (G.F. and M.B.) concurred in a diagnosis of either FSCL or FML were included in the subgroup analyses reported by histopathologic subtype. Patients with any degree of an unequivocal follicular (nodular) pattern were included. A case was called FSCL or FML in central review on the basis of the estimated percentage of large versus total neoplastic cells: FSCL, less than 20%; FML, between 20% and 50% large cells.40 The large cells included were the large, transformed lymphoid cells with a fair amount of basophilic cytoplasm that clearly stand out at any power in the examination of the lymph nodes and are referred to as large, noncleaved cells in the Lukes-Collins’ classification41 or centroblasts in the Kiel,42 REAL,4 and WHO5,6 classifications. These cells are morphologically distinct from other, visually less obvious, large cells with paler nuclei and more eosinophilic cytoplasm, referred to as large cleaved cells41 and follicular dendritic cells. The large cells that were estimated are the same that are actually counted in the grading method recommended in the more recent REAL4 and WHO5,6 classifications. Although no direct comparison of results obtained on the same material with these two grading methods is available in the literature, in the experience of the hematopathologists (G.F. and M.B.) involved in this study, there is consistent overlap between FSCL and grade 1, and FML and grade 2, respectively. Before registration, patients were evaluated with tumor measurements by physical examination and radiographic techniques. Computed tomography (CT) scans were performed to assess the chest, abdomen, and pelvis, and lymphograms were required if the abdominal/pelvic scan was normal. A percutaneous liver biopsy was obtained if there was either radiologic or biochemical evidence of hepatic disease. The bone marrow was assessed by aspirate and bilateral trephine biopsies. Before randomization, patients were stratified by age (older or younger than 70 years) and by symptoms, as asymptomatic patients might theoretically be candidates for deferral of initial therapy.7,8 Patients were designated "asymptomatic" if they did not have B symptoms, bulky disease representing a potential physiologic threat (eg, airway or venous obstruction), pleural effusion, ascites, hemoglobin < 10 g/dL, leukopenia or thrombocytopenia, significant abnormalities on tests of hepatic function, or a history of rapidly progressive lymphoma. All patients, however, including those considered asymptomatic, were registered on this study within 100 days of diagnosis and treated immediately.
Patients were randomized to receive either cyclophosphamide as a single agent or the combination of cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-B). Details of drug dosages and schedule are given in Table 1
Patients were monitored at identical intervals while on therapy. The first complete assessment of response was at 18 weeks. Thereafter, patients in partial response (PR) were reassessed for further response every 3 months. A CR was defined as the total disappearance of all signs and symptoms related to the lymphoma lasting at least 4 weeks. Previously involved liver and bone marrow were rebiopsied and proven negative to document a CR. A PR indicated a 50% or greater decrease in the sum of the products of the two longest perpendicular dimensions of all measurable lesions lasting 4 or more weeks without the enlargement of any existing lesion, the appearance of any new lesion, or a deterioration in performance status. Complete resolution of measurable lymph nodes or other masses despite persistent minimal bone marrow or liver involvement was considered a PR. A maximal response was a CR or a PR that remained stable on further treatment for 3 or more months. Any regression less than partial was considered to be no response. For 5 years after completing therapy, patients were examined every 3 months and had CT scans and bone marrow biopsies (if initially positive) every 6 months. Thereafter, such reassessments were routinely scheduled every year. Progressive disease or relapse was signaled by the reappearance of an old lesion, appearance of a new lesion, or a 25% or greater increase over maximal regression in the size of residual lesions.
Statistical Methods
Categorical data (toxicity, response) were analyzed using the appropriate For patients who achieved a CR, remission duration was measured from time of first CR to relapse or death from any cause. Time to treatment failure was measured from registration 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 (duration of remission, time to failure, survival) were estimated using the product limit method of Kaplan and Meier.45 Formal tests using time-dependent covariables and Schoenfeld residuals were used to test the assumptions of proportional hazards.45 The statistical significance of differences observed in time to event distributions was assessed using the log-rank test and the likelihood ratio test (LR) under the assumptions of proportional and nonproportional hazards, respectively.45 Cox proportional hazards regression was used to investigate the simultaneous effects of baseline patient characteristics on time to treatment failure and overall survival.45 Although the study was designed with a one-sided significance level for the major end point (survival), all reported P values correspond to a two-sided test of significance. According to the original study design, the proportional hazards assumption was tested at the two-sided 10% level of significance. Results are presented for an intent-to-treat analysis as well as analyses based on eligible FSCL and FML patients as determined by central pathology review. The intent-to-treat analysis is based on all registered patients regardless of eligibility status or central pathology review. Canceled patients were an exception because no patient data were available for these cases. Analyses were performed using SAS Version 6.12 (SAS Institute, Inc., Cary, NC), and graphics were generated using S-Plus Version 4.5 (MathSoft, Seattle, WA).
Patient Characteristics A total of 234 patients were registered. Three patients registered on each treatment regimen were cancelled and are not included in any of the analyses. Thus, the analyses reported on the basis of intention to treat include 228 patients; 119 patients randomly assigned to receive cyclophosphamide and 109 to receive CHOP-B/COP. Of the 170 cases enrolled with an institutional diagnosis of FSCL, central review found that 76% were FSCL, 15% were FML, and 8% were other. Of 47 cases enrolled as FML, review diagnoses were FML in 43%, FSCL in 34%, and other in 23%. Thirty-nine patients were excluded from the analyses restricted to eligible histopathologic subtypes as centrally determined (five patients were ineligible because of laboratory findings on initial evaluation; 26 patients, mostly with higher grade histologies, were determined to be ineligible after histopathologic review; and material for central histopathologic review was not available for eight). Exclusions based on histopathologic review were by chance disproportionate (18 cases, CHOP-B/COP; eight cases, cyclophosphamide). The remaining 189 patients, including 143 classified centrally as FSCL and 46 as FML (103 patients randomly assigned to cyclophosphamide and 86 to CHOP-B/COP), were analyzed as eligible and reviewed cases. Further details of the study population are described in Table 2  .
Response Ninety-one percent of all patients, including 89% of those treated initially with cyclophosphamide and 93% of those treated with CHOP-B, had objective responses to treatment. Although initial responses were quickly apparent, fully documented CRs occurred more slowly. The median time to CR for those achieving CR was 9 months; 38% of all CRs did not occur until after the first year of treatment. There was no difference in time to CR by treatment. The overall CR rates were 66% with cyclophosphamide and 60% with CHOP-B/COP (  2 P = .36).
Logistic regression models were used to investigate the simultaneous effects of baseline patient characteristics on the probability of attaining a CR. After adjusting for each stratification factor, female sex and a performance status of 0 or 1 were positively associated with the achievement of a CR. With these variables in the model, no other baseline characteristic, including age, assigned treatment, histopathologic subtype by either institutional or central determination, stage, symptom status, serum lactate dehydrogenase level, or number of extranodal sites was found to be a significant predictor of CR. In patients with FSCL as determined by central review, the CR rates were 68% with cyclophosphamide and 62% with CHOP-B (
Time to Failure and Duration of Response
The median time to failure for all patients was 4 years; 29% (95% confidence interval [CI], 23% to 35%) of patients are estimated to remain failure free at 10 years. The time to failure analyzed by intention to treat is similar in both treatment groups (cyclophosphamide; median, 4.2 years, 25% failure free at 10 years; CHOP-B/COP; median, 3.6 years, 33% failure free at 10 years [LR P = .107]; the test for dependence of time on the relative hazard function [proportional hazards v decreasing] was rejected at P = .084, likelihood ratio P = .107, log-rank P = .23; Fig 1a
Despite the absence of detectable differences in time to failure for the overall group, a better outcome was seen in a subgroup analysis of those patients centrally classified as FML who received combination chemotherapy. In these patients, the assigned treatment (P = .03) was the only pretreatment variable that correlated with outcome. Only two (9%; 95% CI, 0% to 20%) of the 23 patients who had FML and were treated with cyclophosphamide remained failure-free at 10 years, but 48% (95% CI, 27% to 68%) of the 23 patients treated with CHOP-B/COP remained failure free 10 years after beginning treatment (log-rank P = .005; Fig 1c  ). The same difference was not apparent in FSCL, where failures routinely occurred over the entire period of observation with either regimen (cyclophosphamide: 32% failure free at 10 years; CHOP-B/COP: 32%; [log-rank P = .96]; Fig 1b)
As noted, the overall duration of CR was better following CHOP-B/COP (Fig 2a
Toxicity
Each of the drugs used in this study can cause unique toxic effects. Eight patients had possible drug-related pulmonary toxicity. Seven were patients on CHOP-B who received total amounts of bleomycin ranging from 30 to 60 units/m2 (median, 60 units/m2). Findings were limited to chest x-ray abnormalities in four patients and varying degrees of dyspnea in three other patients. One patient who received only cyclophosphamide developed dyspnea and a moderate restrictive ventilatory defect. Five patients had possible cardiac toxicity after receiving 100 to 474 mg/m2 of doxorubicin (median, 350 mg/m2). Two patients experienced paroxysmal supraventricular tachycardia, one patient developed moderate congestive heart failure, and another had an asymptomatic decrease in left-ventricular ejection fraction as measured by radionuclide scan. The fifth patient suffered a myocardial infarction while receiving COP in the maintenance phase. Mild to moderate hematuria occurred in a total of 11 patients (11%) on continuous single-agent therapy and five patients (6%) on combination therapy. Chlorambucil was substituted for cyclophosphamide in these patients. Moderate to severe neuropathy in those receiving vincristine was reported in 38% of patients through the maintenance phase compared with only 6% in those receiving cyclophosphamide ( Thirty patients had a total of 32 second malignancies diagnosed while on this study. Twenty-one cancers were common solid tumors, and one was Hodgkin’s lymphoma. These malignancies occurred in 12 patients who had received cyclophosphamide and 10 who had received CHOP-B/COP. Six other patients were diagnosed with carcinoma of the urinary bladder (four with cyclophosphamide, two with CHOP-B/COP) 2 to 15 years (median, 8.5 years) after entering this study. Four patients, three treated with cyclophosphamide and one with CHOP-B/COP, developed acute myeloid leukemia or myelodysplastic syndrome. The interval to the diagnosis of leukemia or myelodysplastic syndrome ranged from 3.9 to 12.7 years (median, 7.5 years).
Dosage of Drugs
Survival and Causes of Death
Although the treatment did not affect survival in the eligible patients with FSCL (log-rank P = .68; Fig 3b ), patients with FML treated with combination chemotherapy have lived substantially longer than those treated with cyclophosphamide (Fig 3c). The median survival time for those diagnosed with FML and treated with cyclophosphamide is 6.7 years compared with 13 years for those treated with CHOP-B/COP. Survival at 10 years in the FML patients is estimated to be 25% (95% CI, 6% to 44%) following cyclophosphamide and 61% (95% CI, 41% to 81%) with CHOP-B/COP (log-rank P = .024). Of pretreatment characteristics in this subgroup, only the use of combination chemotherapy (P = .04) and stage (P = .006) were associated with longer survival.
Since Rappaport et al1,46 characterized the follicular lymphomas more than 40 years ago, the clinical importance of separate histopathologic subtypes or grades, the specific criteria used to identify them, and the best therapy for affected patients have been debated extensively. These lymphomas occupy a clinicopathologic spectrum characterized cytologically by varying proportions of large cells and small cleaved cells within malignant follicles, the defining architectural feature. An increasing proportion of large cells is generally reflected in the degree of clinical aggressiveness, but the morphologic and clinical boundaries between the subtypes are not well demarcated. The Working Formulation for Clinical Usage identifies three subtypes of follicular lymphoma, which correspond to those previously recognized by Rappaport et al.2,3 Two of these, FSCL and FML, are considered to represent indolent or low-grade malignancies and are the subject of this therapeutic trial. The third, FLCL, is clinically more aggressive, and the favorable results reported with combination chemotherapy seemingly justify treatment similar to that commonly used in diffuse aggressive lymphomas.28–31 However, the difference in clinical behavior between the two indolent follicular subtypes is more subtle. Because a wide array of treatments has been followed by relapse in most patients, there is little agreement as to optimal therapy for either subtype. Several studies indicate that the CR rate in indolent follicular lymphomas with a single alkylating agent is approximately 50%10,47,48 and the CR rate with drugs in combination is generally higher (approximately 60% to 80%).13,37,49–54 When single agents, cyclophosphamide or chlorambucil, however, were directly compared with combinations of three drugs (COP), significant differences in long-term outcome, including survival, were not observed.47,48,55,56 Unfortunately, these studies were inconclusive. They were not restricted to follicular lymphomas, the number of patients in each was small, and often the follow-up provided was short. A few larger studies37 evaluated a number of different combinations in low-grade lymphomas, but these regimens were not compared with single agents, and neither COP nor these other combinations have a sustained record of curing any type of lymphoma. Whether chemotherapy, curative in a significant proportion of patients with diffuse aggressive lymphomas, is warranted in patients with low-grade lymphomas had not been directly addressed. Successful treatment in diffuse aggressive lymphoma depends on combining effective agents, most notably CHOP, on which the program used in this study was based. The use of CHOP cures approximately 30% to 35% of patients with advanced, diffuse, large-cell lymphoma.22,24 Other combinations, which include additional drugs and more complex schedules, also are curative in diffuse aggressive lymphomas, but they also are more toxic and no more effective than CHOP.22,24 There has been experience with CHOP and related combinations in follicular lymphomas,1315,20,53,57,58 and it appears in most, but not all,14,20 settings to result in a high CR rate. Several historic analyses even indicated that combinations, such as CHOP, improved the results of treatment.57–60 Two prospective studies52,54 evaluating the addition of doxorubicin to combination chemotherapy were unable to attribute any benefit to the inclusion of the anthracycline. However, follow-up intervals were brief, and CHOP or its variants were being compared with other multidrug combinations, not with single agents. Because it is in the direct comparison of substantially different therapies that treatment-specific benefits, if they exist, are most likely to be demonstrated, we chose to compare two substantially different interventions. Continuous oral cyclophosphamide was selected for study because of extensive experience with it as a single agent and its relative lack of acute side effects.10,47,48,55,56 CHOP was chosen because it was an emerging standard of curative therapy for patients with diffuse, aggressive lymphomas. Bleomycin was added to CHOP because it is known to be active,33,34 has little myelotoxicity, and at the time this study was initiated, was thought to contribute to the apparent success of advanced-generation treatments in diffuse lymphomas. The importance of bleomycin has since not been confirmed in prospective studies.22,24,61 Similarly, although there was a suggestion of benefit from maintenance therapy, and this led us to employ maintenance therapy in the current trial, prospective evaluations of maintenance therapy have demonstrated no survival benefit.35–38 Our overall results with either cyclophosphamide or CHOP-B/COP are nearly identical. In the entire study population, no significant advantages may be attributed to the combination in response rate, time to failure, or survival, with a long interval of follow-up. The similarities in outcome were observed despite the fact that patients given the single agent received substantially less of their target dose of drug than did those given the combination. Dosage reductions were primarily related to myelosuppression caused by continuous therapy but were also appropriate to a philosophy of conservative management. The CR rate we observed for the single agent, 66%, is similar to that seen with the combination, 60%, and higher than that previously reported by others for cyclophosphamide or chlorambucil.10,47,48,55,56 It also is comparable to the highest reported rates in other sizable populations treated with some of the most intensive treatment short of high-dose therapy and stem cell transplantation.13 In part, this CR rate may result from continuing the responding patients on therapy while repetitively reassessing completeness of response and allowing adequate time in which to reach maximal response. Most studies determine response at a single point in time. CR rates as low as 13% to 36% have been reported in patients receiving a variety of single agents or combinations for only 12 to 24 weeks.14,20,55 Others also have noted the relatively long time required by some patients to fully respond and that, as therapy continues, additional patients achieve CR.48 We also found no overall advantage in the time to failure attributable to the combination of drugs. The median time to failure is 4 years from the initiation of either therapy. Although median durations of CR, measured from the date of remission, are slightly longer following CHOP-B/COP, this is primarily related to its effect on patients with FML because no difference is seen in the analysis restricted to patients with FSCL. Most of our patients, even those entering CR, eventually relapsed. This result is not surprising in that the molecular hallmark of follicular lymphomas, the BCL2 gene rearrangement, persists in the bone marrows of patients successfully treated with CHOP.62 In view of the similar outcomes, not unexpectedly, no overall differences in survival have been observed in the two treatment groups. Most deaths in the present study were related directly to lymphoma and the failure of both treatment programs. Although the overall results of the two treatment approaches are similar, the subgroup of patients with FML appeared to benefit more when treated with combination chemotherapy than with the single agent. In patients with FML treated with CHOP-B/COP, a large proportion of CRs were sustained and time to failure was significantly longer than in those who received cyclophosphamide. Although additional relapses may still be seen in this group, the prompt and steady rate of relapses observed following cyclophosphamide has not occurred. The use of CHOP-B/COP in the subgroup of patients with FML, but not FSCL, also led to an improvement in survival. Complete remissions that appear especially durable in patients with FML were first reported from the National Cancer Institute.27,49 In 24 patients with stage III and IV FML treated with cyclophosphamide, vincristine, procarbazine, and prednisone, 79% achieved CR and 57% of responders were projected to remain in CR at 5 years.49 Findings in a follow-up report showed that most remissions were sustained, but occasional relapses were observed as late as 7.5 years.63 Others also have noted the tendency for longer CRs in FML.64 However, investigators51 using a slightly different schedule of the same drugs employed at the NCI and others50 using doxorubicin-based therapy were unable to confirm durable responses in this histopathologic subgroup. Although subclassification of follicular lymphomas has been common practice for many years, a variety of morphologic criteria have been used,3,40,46,65,66 and opinions vary as to which method is preferred.4,42,66–68 There are frequent discrepancies in distinguishing subtypes among expert hematopathologists attempting to apply the same criteria.67,69–71 Recently, in the REAL4 and WHO5,6 classifications, it has been acknowledged that the best method of grading follicular lymphomas is still being debated, but criteria have been recommended in an attempt to increase reproducibility and aid future clinicopathologic studies. These criteria include the actual counting and averaging of the number of large cells within nodules. The criteria identify as grade 1 tumors those showing < 5 large cells and those with 6 to 15 large cells as grade 2. The large cells are the same (centroblasts) that in this study were estimated as a percentage of the total neoplastic cells, using the classic criteria of Warnke et al.40 Although both the terminology and the criteria used in this study long precede the new classifications, in actual practice FSCL and FML largely overlap grade 1 and 2, respectively. The effort to grade follicular lymphomas appears warranted. In the analysis by histopathologic subtype in our study, the diagnoses were assigned by two reference pathologists who agreed in each case on either FSCL or FML.40 In contrast to the patients classified as FSCL, there was a significant advantage to using combination chemotherapy in patients with FML. In the absence of a distinct therapeutic advantage for either treatment in FSCL, the regimen that causes the least toxicity or poses the least risk to a patient should be selected for further use. The combination of drugs used in this study was reasonably well tolerated, and unique problems of cardiac, pulmonary, and neurotoxicity were infrequent and generally mild. However, cyclophosphamide as a single agent produced even less toxicity. A major concern in the use of cytotoxic drugs, particularly the alkylating agents, is the development of secondary malignancies. A total of 32 new malignancies were diagnosed in 30 patients and occurred on both treatment regimens. Twenty-two of the malignancies were common cancers, and it is difficult to implicate the treatment in their etiology. Ten malignancies, four cases of myelodysplasia or acute myeloid leukemia, and six cases of bladder carcinoma, in which the treatment might be causal, occurred in this group of 228 patients. The cumulative incidence was 2.6% and 1.8%, respectively. From published estimates, approximately 5% of our patients would be expected to have developed leukemia at 7 years72 and somewhat fewer to have developed carcinoma of the urinary bladder.73 Although the incidence of secondary malignancies in this study seems low, additional cases may still occur. In summary, we were unable to show in FSCL any advantage for prolonged therapy with a combination of drugs that is curative in diffuse, large-B-cell lymphoma compared with the prolonged use of a single agent at a relatively low dose. With such long-term follow-up, it is unlikely any differences will emerge. Because results of these two divergent approaches to therapy are nearly identical except in the toxicity they cause, it is difficult to justify the routine use of CHOP or CHOP-B/COP in patients with FSCL. However, as the great majority of patients on this study still died of lymphoma, new approaches need to be explored. It is noteworthy that the small number of patients with FML in the unplanned subset analysis appear to benefit from the use of combination chemotherapy as administered on this study.
The following present and past CALGB institutions and prinicipal investigators that participated in this study. Columbia University, Rose Ruth Ellison, MD, CA12011 Dartmouth-Hitchcock Medical Center, L. Herbert Maurer, MD, CA04326 Finsen Center, Rigshospital, Nis I. Nissen, MD, Medical Center of Delaware, Irving Berkowitz, DO, CA28411 North Shore - Long Island Jewish Health System, Daniel Budman, MD, CA11028 Massachusetts General Hospital, Michael L. Grossbard, MD, CA12449 McGill Cancer Center, Brian Leyland-Jones, MD, CA31809 Mount Sinai School of Medicine, James F. Holland, MD, CA04457 Weill Medical College of Cornell University, Michael Schuster, MD, CA07968 Rhode Island Hospital, Louis A. Leone, MD, CA08025 Roswell Park Cancer Institute, Ellis G. Levine, MD, CA02599 University of California at San Diego, Stephen Seagren, MD, CA11789 University of Minnesota, Bruce A. Peterson, MD, CA16450 University of Missouri/Ellis Fischel Cancer Center, Michael C. Perry, MD, CA12046 University of North Carolina at Chapel Hill, Thomas C. Shea, MD, CA47559 SUNY Health Science Center at Syracuse, Stephen L. Graziano, MD, CA21060 Wake Forest University School of Medicine, David D. Hurd, MD, CA03927 Walter Reed Army Medical Center, John C. Byrd, MD, CA26806 CALGB Statistical Office, Durham, NC, Stephen George, PhD, CA33601
We wish to acknowledge the additional statistical assistance of Thomas F. Pajak, PhD, and James R. Anderson, PhD; coordination of data management by Mary Walawander, Linda Faso, Anne Pasco, and Jane Gau, RN; and preparation of the manuscript by Carol Thomas. We also are indebted to George P. Canellos, MD, for reviewing the manuscript and for providing helpful suggestions.
 Deceased. 
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
60 units/m2). Cycles of treatment with the remaining four drugs (CHOP) continued at 3-week intervals until a CR was documented and every 4 weeks thereafter. Doxorubicin was discontinued when the cumulative dose reached 450 mg/m2. Then the dose of cyclophosphamide for subsequent cycles was increased to 1,000 mg/m2, and treatment for both complete and partial responders continued with cyclophosphamide, vincristine, and prednisone (COP) at 4-week intervals. Dosage of drugs was adjusted according to specified guidelines for toxicity. Responders on both treatment regimens continued on their assigned therapy for 2 years following documentation of maximal response. 
