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© 2003 American Society for Clinical Oncology Dose-Intense Chemotherapy Every 2 Weeks With Dose-Intense Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone May Improve Survival in Intermediate- and High-Grade Lymphoma: A Phase II Study of the Southwest Oncology Group (SWOG 9349)
From the Wilshire Oncology Medical Group, Inc, Pasadena, CA; Southwest Oncology Group Statistical Center, Seattle, WA; University of Arizona Cancer Center, Tucson, AZ; Loyola University Stritch School of Medicine, Maywood, IL; Henry Ford Hospital, Detroit, MI; Columbus Community Clinical Oncology Program, Columbus, OH; University of Kansas Medical Center, Kansas City, MO; University of Colorado School of Medicine, Denver, CO; and University of Rochester School of Medicine, Rochester, NY. Address reprint requests to Southwest Oncology Group (SWOG 9349), Operations Office, 14980 Omicron Drive, San Antonio, TX 78245-3217.
Purpose: To test the hypothesis that therapy of intermediate- and high-grade (excluding Burkitt lymphoblastic) lymphoma with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) could be safely dose-intensified with routine filgrastim support. Patients and Methods: Eligible patients were those who were previously untreated and who had either bulky stage II, or stage III or IV lymphoma with working formulation histology D, E, F, G, H, or J; performance status ≤ 2; and acceptable end organ function. No upper age limit was specified. Therapy was dose-intensified CHOP (CHOP-DI) with filgrastim support. Each course was repeated every 14 days for six planned courses. Results: Eighty-eight eligible patients were treated with CHOP-DI and had a median follow-up of 5.1 years on this phase II study, designated Southwest Oncology Group (SWOG) 9349. The progression-free survival was 51% at 2 years and 41% at 5 years. The overall survival was 60% at 5 years. Three fatal treatment-related events occurred. One patient with myelodysplastic syndrome was reported. Conclusion: Treatment with CHOP-DI can be safely administered in the cooperative group setting and results in improved survival. Estimated overall survival at 5 years was 14% better than that of patients treated with standard-dose CHOP in an earlier SWOG study, although progression-free survival of 60% at 2 years—the prespecified end point—was not achieved. CHOP-DI, given every 2 weeks at escalated doses, is a strategy that should be tested in a future randomized clinical trial in lymphoma.
LYMPHOMA, A monoclonal, malignant proliferation of lymphocytes, is increasing in incidence in the United States.1 Causes of this phenomenon are not readily understood.2 Until the introduction of monoclonal antibody therapy, treatment of intermediate-grade lymphoma was based on radiation therapy, alkylating chemotherapy agents, and anthracyclines. A combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) given every 3 weeks was introduced in 1976.3 A large randomized study, coordinated by the Southwest Oncology Group (SWOG 8516) through the Intergroup mechanism, showed that CHOP was as effective, with less toxicity, than three other regimens that included additional chemotherapy drugs.4 Dose intensification (escalating drug doses and compressing the administration schedule) of the standard combination of cytotoxic drugs was one method that we hypothesized might improve treatment results. Retrospective analyses indicated that this might be a promising strategy.5–7 Phase II studies showed that a CHOP-like regimen could be dose-intensified with the use of hematopoietic-growth-factor support.8 Other work showed that high doses of a CHOP-like regimen, given on a 21-day schedule with filgrastim and mesna support, could be given for four cycles.9 We had conducted a phase I, dose-escalation study, which showed that CHOP could be given in a compressed schedule at high doses10 (CHOP-DI) and could yield a planned dose-intensity of more than twice that of standard-dose CHOP. Improvement of progression-free survival (PFS) at 2 years to more than 60% would be of interest and deserving of further testing in a phase III clinical trial. We designed a phase II study of a CHOP-DI regimen administered every 2 weeks in patients with intermediate- or high-grade (excluding Burkitt) lymphoma.
Patient Eligibility Inclusion criteria. Patients who were eligible for the study included men or women older than 15 years who were able to give informed consent and who had biopsy-confirmed lymphoma. Patients with working formulation histology D through H and group J lymphoma were eligible.11 Submission of an adequately sized section to determine architectural pattern for central pathology review was required. Additional eligibility criteria included bulky stage II disease, or stage III or IV disease by the Ann Arbor classification.12 Bulky disease was defined as a mediastinal mass greater than one third of the maximum chest diameter or any other mass greater than or equal to 10 cm in maximum diameter. In addition, performance status of 0, 1, or 2 (ie, out of bed more than 50% of the day), normal organ function (serum bilirubin ≤ 1.5 upper limit of laboratory normal, serum creatinine ≤ 2.0 times the upper limit of the clinical laboratory normal or an estimated creatinine clearance ≥ 60 mL/min, and a pulmonary diffusing capacity greater than 50% of corrected normal) were also required. Each study site had to have a current human investigations committee approval for the study, in accordance with an assurance filed with the relevant Department of Health and Human Services agency. Exclusions. Excluded from the study were patients who had received prior chemotherapy (excluding corticosteroids) or prior radiotherapy for lymphoma; had evidence of CNS involvement with lymphoma; had known human immunodeficiency virus infection; were pregnant or nursing; had prior malignancy; or required therapy for coronary artery disease, cardiomyopathy, congestive heart failure, or cardiac dysrhythmia.
Therapeutic Intervention Dose modification for toxicity. Chemotherapy treatment subsequent to cycle one was to be deferred until the ANC was greater than 2,000 cells/mm3 and the platelet count was greater than 100,000 cells/mm3; filgrastim was to be continued to support the neutrophil count but was not to be administered within 1 day of cytotoxic chemotherapy. RBCs could be supported with transfusion, and cytotoxic therapy then could be continued on schedule. Routine erythropoietin support could be used after the first episode of blood transfusion. If the neutrophil count had not recovered by 4 weeks of any cycle, the patient was removed from the study. Toxicity was scored according SWOG criteria. Development of grade 3 or greater neurologic toxicity called for discontinuation of vincristine, and grade 3 or 4 neurocentric toxicity called for the omission of prednisone on subsequent cycles. For grade 2, 3, or 4 hematuria or hemorrhagic cystitis, saline hydration with furosemide-induced diuresis and mesna uroprotection were used in subsequent cycles. For grade 3 cardiac toxicity, doxorubicin was omitted from subsequent cycles. For grade 3 liver toxicity, doxorubicin and vincristine were to be reduced to 50% of the initial dose until recovery, then resumed at the otherwise-specified dose. For grade 3 toxicities of other systems, treatment was to be deferred until resolution of the toxicity. If the therapy was deferred for more than 2 weeks, the patient was to be removed from the study. For grade 4 nonhematologic toxicity, the patient was to be removed from study therapy and given treatment at the discretion of the treating physician-investigator. Conduct of the study. A bone marrow examination was required within 28 days of study entry, and negative-staging computed tomography (CT) scans (to confirm the absence of disease) were required within 42 days of study entry. CT scans that were indicative of lymphoma masses were required to be performed within 28 days of study entry. Eligibility criteria were reviewed at the SWOG statistical center and central pathology review was carried out to determine eligibility for inclusion in results reporting, but patients were entered into the study and treated on the basis of the histologic diagnosis of the treating center’s pathologist. The day 1 chemotherapy was given at the local institution or the oncology center, and patients were instructed in the methods of filgrastim self-administration. Filgrastim was administered either at the local institution or at the patient’s home, depending on patient competence and physician preference. Filgrastim was supplied as Neupogen by the manufacturer. Patients were required to have a complete blood count three times per week, and the filgrastim was administered on days 2 through 11 of the treatment cycle. Responding patients were to receive a maximum of six courses of chemotherapy. Patients could be removed from study at any time if they had documented progression of disease; had, in the opinion of the investigator or the patient, unacceptable toxicity; had a treatment delay of longer than 2 weeks between cycles; or withdrew their consent for participation at any time for any reason. Because of the compressed treatment schedule, no restaging examinations were planned during study therapy. After completion of therapy, response assessment included clinical laboratory examination, repeat CT scans of the abdomen and pelvis, and chest radiograph, as well as repetition of positive pretreatment scans.
Statistical Methods
Patients Entered Onto the Study SWOG investigators entered 103 patients onto the study between September 15, 1994 and January 15, 1997. Data are analyzed as of January 31, 2002.
Table 1
We analyzed the patients who were entered onto the study according to the International Prognostic Index (IPI), which assigns risk categories on the basis of a patient’s pretreatment age, Ann Arbor stage, serum lactate dehydrogenase, number of extranodal sites of disease, and performance status.14 Almost two thirds of the patients were in the intermediate-risk group. Forty-one percent were in the low-intermediate–risk group, 23% were in the high-intermediate–risk group, 23% were in the low-risk group, and 13% were in the high-risk group. We also retrospectively analyzed patients entered into the study using the World Health Organization/Revised European American Lymphoma pathologic classification scheme.15 Forty-three patients had diffuse large B-cell lymphoma (including 34 patients with diffuse large B-cell lymphoma, four patients with the T-cell rich variant, four patients with the immunoblastic variant, one patient with diffuse large-cell lymphoma, and one patient with follicular lymphoma, grade 3A). Ten patients had follicular lymphoma. Seven patients had mantle-cell lymphoma, six patients had Burkitt lymphoma, three patients had anaplastic large-cell lymphoma, two patients had peripheral T-cell lymphoma (unclassified), one patient had atypical CD30-positive cutaneous lymphoproliferative disorder, one patient had mediastinal thymic large B-cell lymphoma, and one patient had angioimmunoblastic T-cell lymphoma. Fourteen patients could not be classified in the World Health Organization/Revised European American Lymphoma scheme when it was applied in 2002 because immunostaining information from the diagnostic pathology material (originally acquired between 1994 and 1997) was not available.
Toxicity of Therapy
Delivered Dose Intensity Of the 103 patients entered into the study, 80 patients (78%) completed six cycles of therapy. The average time taken to complete therapy for these 80 patients was 13.69 weeks. For the dose-intensity calculation, we report on the 88 eligible patients, and the calculated delivered dose-intensity is reported for all cytotoxic drugs. For cyclophosphamide, the mean dose delivered was 656.7 mg/m2/wk (range, 295.6 to 876.0 mg/m2/wk) or a dose intensity of 2.63 times the standard CHOP dose. For doxorubicin, the mean dose delivered was 26.8 mg/m2/wk (range, 12.0 to 35.9 mg/m2/wk), or 1.61 times the standard CHOP dose. For vincristine, the mean dose delivered was 0.54 mg/m2/wk (range, 0.20 to 0.81 mg/m2/wk) or 1.16 times the standard CHOP dose. The mean delivered dose intensity for all cytotoxic drugs was 1.80 compared with the standard CHOP dose.
Progression-free and Overall Survival
The median follow-up is 5.1 years for the 88 eligible patients entered into the study and treated with CHOP-DI. The 2-year progression-free survival (PFS) estimate, as shown in Table 3
We compared the historic experience of patients who were treated with standard-dose CHOP used in SWOG 8516 with the experience of patients treated with CHOP-DI. Comparison of the Kaplan-Meier PFS curves is shown in Figure 3  and the OS curves are compared in Figure 4. The estimates of PFS at 2 years with CHOP-DI are not striking relative to historic data and did not reach the design-specified 60% level. However, 5-year survival estimates seem to be substantially better (60% v 41%), favoring the CHOP-DI patients over the standard-dose CHOP patients.
When an exploratory analysis compared the CHOP-DI patients with the historic CHOP-treated patients on the SWOG 8516 study, the survival consistently favored CHOP-DI treatment (Fig 4  ). The patients treated on the SWOG 8516 study had an IPI risk distribution similar to those enrolled into the current study: 25% of patients in the low-risk group, 40% of patients in the low-intermediate–risk group, 31% of patients in the high-intermediate–risk group, and 10% of patients in the high-risk group. For IPI groups 1 and 2, a 66% 5-year survival rate was observed for CHOP-DI compared with 55% for CHOP; for IPI groups 3 and 4, a 53% 5-year survival was observed for CHOP-DI, compared with 35% for CHOP. For working formulation groups G and H, a 62% 5-year survival rate was observed for CHOP-DI, compared with 47% for CHOP. Salvage therapy was examined for the 35 patients who survived longer than 6 months after experiencing relapse from completed therapy. Of the 35 patients, 17 were alive at last follow-up and account for the difference in the survival curves: five patients received high-dose chemotherapy with autologous stem-cell support, two patients received therapy at relapse containing rituximab, four patients received either no therapy or local radiation therapy, three patients received other standard-dose chemotherapy regimens containing cisplatin, and no details are available for three patients.
We were successful in modestly increasing the PFS duration and significantly increasing the OS rate in study patients using CHOP-DI chemotherapy when compared with the previous SWOG experience. CHOP-DI is one modification of the CHOP regimen to achieve a statistically superior survival rate in comparison with CHOP. The British National Lymphoma Investigation Group, which compared weekly chemotherapy with an etoposide-containing regimen to CHOP, demonstrated improved survival with weekly etoposide-containing therapy.16 The German High-Grade Non-Hodgkin’s Lymphoma Study Group also reported superior results with CHOP-14 (given every 14 days with filgrastim support) when prospectively compared with CHOP given every 21 days.17 In addition, the dynamic dose adjustment scheme, employed in the etoposide, vincristine, doxorubicin for 96 hours, cyclophosphamide and prednisone regimen, has also shown promise in improving survival compared with historic controls, but it is a concept that remains to be prospectively tested in a multi-institutional setting.18 These improved results are in contrast to use of the continuous-infusion technique for doxorubicin and vincristine in SWOG 9240 and addition of the putative chemosensitizers verapamil and quinine in SWOG 9125, neither of which improved survival when compared with CHOP.19 Modification of CHOP with addition of etoposide and filgrastim to permit dose escalation on a schedule every 3 weeks did not result in improved survival when studied by the Cancer and Leukemia Group B.20 Thus, modifying CHOP with a compressed schedule seems to be the common theme that leads to improved survival. Addition of a biologic agent to standard chemotherapy is also a promising strategy for improving survival in patients with lymphoma. The most promising candidate is rituximab, a chimeric anti-CD20 immunoglobulin G1 monoclonal antibody. Rituximab was first used as a single agent in the treatment of relapsed or refractory indolent lymphomas,21,22 and has activity in the treatment of aggressive or large-cell lymphoma.23 Incorporation of rituximab into the CHOP regimen is feasible,24,25 and has demonstrated improved survival in older patients when compared with CHOP.25,26 Dose escalation of chemotherapy to levels requiring stem-cell support remains a controversial strategy to improve survival. A consensus panel, convened in April 1998, was unable to find consistent evidence that first-line high-dose therapy was superior to conventional induction therapy in high-risk patients, and additional definitive studies were recommended.27 The jury reviewed five randomized studies, some of which have been updated since the 1998 publication. The two studies considered by the jury to show an advantage favoring the high-dose therapy arm have been updated: The LNH87-2 study of the French Groupe d’Etude des Lymphomes de l’Adulte (GELA) compared stem-cell transplantation with standard dose consolidation. Although this trial demonstrated a survival advantage for the stem-cell consolidation group in a retrospectively analyzed high-risk cohort, the authors stopped short of recommending high-dose chemotherapy for high-risk patients.28 The Milan study of untreated or relapsed patients compared methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) with high-dose melphalan or mitoxantrone and total-body irradiation with stem-cell support using a cross-over design, and demonstrated a nonsignificant survival advantage.29 Retrospective analyses of the LNH87-2 and Italian study group trials seem to support the use of consolidative high-dose therapy in high-intermediate–risk or high-risk group (IPI) patients who have completed standard-dose induction therapy, although prospectively designed and analyzed data in the high-risk group are not available. Results from other trials included in the 1998 review have been reported: The Italian Non-Hodgkin’s Lymphoma Cooperative Study Group trial,30 the GELA LNH93–3 trial,31 and the German High-Grade Lymphoma Study Group trial32 did not report results favoring the high-dose experimental arm. However, the role of high-dose chemotherapy and autologous stem-cell support as salvage therapy after an initial response may be an important treatment option. Our analysis of patients who experienced relapse demonstrated that such an approach is feasible after primary therapy with CHOP-DI. Treatment with CHOP-DI was toxic and resulted in three therapy-related deaths in the 88 eligible patients (3.4%; 95% CI, 0.7% to 9.6%). Myelosuppression was the proximate or the contributing cause of death in these patients. The rate of toxic deaths is consistent with experience in studies of dose-escalation therapies at single institutions9 and with experience of the Cancer and Leukemia Group B in using CHOP with the addition of etoposide and filgrastim.20 Design of future studies of either CHOP-DI or dose-compressed CHOP as an experimental arm should incorporate measures to reduce risk of morbidity and of death caused by therapy-related toxicity. Fever during periods of neutropenia should be aggressively managed with broad-spectrum antibiotics and close observation, preferably in a hospital setting. Empiric therapy for Pneumocystis carinii should be considered for patients in whom pulmonary infiltrates are present. The pegylated form of filgrastim, which is now approved for clinical use in the United States, makes this supportive compound an attractive option to incorporate. We would consider open wounds an absolute contraindication to the use of CHOP-DI, and percutaneous drainage devices (such as biliary or nephrostomy drainage tubes) are a relative contraindication. Incorporation of early restaging with gallium nuclear medicine scanning33 or positron emission tomography scanning to asses treatment response should be considered. Because some patients with intermediate- or high-grade lymphoma will experience relapse exclusively with the low-grade component, for which either a "watch and wait" strategy, salvage therapy with a monoclonal-antibody–based therapy, local radiation therapy, or other experimental therapy, would be appropriate and should be accounted for in the trial design. We are unable to definitively explain why estimated OS rate of our patients was substantially better, whereas PFS rate was not markedly improved. Salvage therapy was not specified by the experimental protocol and was selected by the treating physician. Our experience is that patients treated with CHOP-DI were able to undergo high-dose chemotherapy and autologous–stem-cell collection. More definitive conclusions await results of randomized clinical trials. Without results from randomized clinical trials, CHOP-DI should not be adopted as the standard of care in intermediate- or high-grade lymphoma. Our results indicate that dose intensification and dose compression with filgrastim support may provide an advantage compared with standard-dose treatment. CHOP-DI is an appropriate control arm for testing against standard-dose CHOP in a randomized trial. Whether CHOP-DI provides greater clinical benefit than standard-dose CHOP, CHOP with rituximab, than dose-compressed CHOP (ie, every 2 weeks), or some combination of these, or with a strategy incorporating autologous stem-cell transplantation, can only be determined by a prospective randomized clinical trial.
Supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, Department of Health and Human Services: CA38926, CA32102, CA13612, CA46282, CA58416, CA35261, CA12644, CA42777, CA11083, CA35119, CA45377, CA35431, CA04920, CA20319, CA22433, CA63845, CA35128, CA35192, CA58861, CA35090, CA35281, CA37981, CA96429, CA76462, CA63844, CA52386, CA14028, CA04919, CA45807, CA45450, CA35262, CA35176, CA46441, CA35178, CA46136, CA12213, CA45560, CA63850, CA74647, and CA52654. Amgen, Inc (Thousand Oaks, CA) provided the filgrastim (Neupogen) supplied to patients in this study.
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31. Gisselbrecht C, Lepage E, Molina T, et al: Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20:2472–2479, 2002 32. Kaiser U, Uebelacker I, Havemann K, et al: High-dose chemotherapy with autologous stem cell transplantation in high grade NHL: First analysis of a randomized multicenter study. Bone Marrow Transplant 21:S177, 1998 (suppl 1) 33. Janicek M, Kaplan W, Neuberg D, et al: Early restaging gallium scans predict outcome in poor-prognosis patients with aggressive non-Hodgkin’s lymphoma treated with high-dose CHOP chemotherapy. J Clin Oncol 15:1631–1637, 1997[Abstract] Submitted June 24, 2002; accepted January 31, 2003.
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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
