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© 2001 American Society for Clinical Oncology Infusional CHOP Chemotherapy (CVAD) With or Without Chemosensitizers Offers No Advantage Over Standard CHOP Therapy in the Treatment of Lymphoma: A Southwest Oncology Group StudyFrom the Loyola University Medical Center, Maywood, IL; Southwest Oncology Group Statistical Center, Seattle, WA; University of Arizona Cancer Center, Tucson, AZ; St Louis Community Clinical Oncology Program, St Louis, MO; Louisiana State University, Shreveport, LA; Ohio State University, Columbus, OH; and Wayne State University, Detroit, MI. Address reprint requests to Southwest Oncology Group (SWOG-9125/9240), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217.
PURPOSE: Two phase II studies were conducted to evaluate infusional cyclophosphamide, doxorubicin, vincristine, and dexamethasone chemotherapy, termed the CVAD regimen, alone (Southwest Oncology Group [SWOG] 9240) and with the chemosensitizers verapamil and quinine (SWOG 9125) to assess effects on response, survival, and toxicity in intermediate- and high-grade advanced-stage non-Hodgkin’s lymphoma (NHL). The results were compared with the historic group of patients randomized to CHOP chemotherapy on Intergroup (INT) 0067 (SWOG 8516). PATIENTS AND METHODS: All patients had biopsy-proven intermediate- or high-grade NHL (lymphoblastic histology excluded), were ambulatory and previously untreated, and had bulky stage II, III, or IV disease. One hundred twelve patients were registered on SWOG 9240 and received cyclophosphamide 750 mg/m2 by intravenous bolus day 1, doxorubicin 12.5 mg/m2/d and vincristine 0.5 mg/d delivered as a continuous 96-hour infusion on days 1 through 4, and dexamethasone 40 mg/d orally on days 1 through 4 (CVAD). Cycles were repeated every 21 days for eight cycles. One hundred patients on SWOG 9125 received the same chemotherapy and the chemosensitizers verapamil 240 mg bid and quinine 40 mg tid. Chemosensitizers were begun 24 hours before chemotherapy and continued for a total of 6 days. RESULTS: Eighty-one patients were eligible for each study. The complete response (CR) rates were 39% on SWOG 9125 and 31% on SWOG 9240. With a median follow-up of 5.8 years on SWOG 9125 and 4.5 years on SWOG 9240, the 2-year failure-free survival (FFS) rate was 42% on SWOG 9125 and 41% on SWOG 9240. Two-year overall survival (OS) rate was 64% on SWOG 9125 and 58% on SWOG 9240. These results are comparable to a 44% CR rate, a 2-year FFS of 46%, and 2-year OS of 63% observed in 225 patients treated with CHOP on INT 0067 (SWOG 8516). CONCLUSION: CVAD combination chemotherapy alone or with the chemosensitizers verapamil and quinine is not promising therapy with respect to improved response or OS in intermediate- and high-grade advanced-stage NHL.
ALTHOUGH SOME patients with intermediate- or high-grade lymphoma may be cured with combination chemotherapy, there remain large numbers for whom cure is not possible. Efforts to treat these patients fail because of intrinsic or acquired resistance to the drugs that are used to treat lymphoma. Although the mechanisms of clinical drug resistance are multiple and in many cases poorly understood, overexpression of mdr-1, the multidrug resistance gene, and its protein product, P-glycoprotein (Pgp), has been proposed as a cause of clinical drug resistance.1,2 Pgp functions as a membrane efflux pump that transports drugs out of cells.3,4 Pgp has been shown to be present at low levels in normal lymphocytes and may play a role in determining eventual relapse of patients with malignancies derived from Pgp-containing lymphoid elements.5 In vitro, overexpression of Pgp confers resistance to a number of important cytotoxic drugs used in the treatment of lymphomas, including the drugs doxorubicin and vincristine.6 Both preclinical and clinical data suggest that there may be a schedule-dependent effect in favor of the administration of certain cytotoxic drugs via an infusional rather than a bolus schedule in circumventing drug resistance mechanisms.7 Likewise several classes of drugs, including calcium channel blockers such as verapamil, inhibit the efflux activity of the Pgp pump and increase the intracellular concentration of susceptible cytotoxic agents.2,8 The antimalarial drug quinine also has been shown to function as a chemosensitizer, and in vitro, verapamil and quinine exhibit synergistic chemosensitizing effects on Pgp-expressing mdr-1 myeloma cell lines.9 Both in vitro and early clinical trials indicated that multidrug resistance associated with Pgp can be reversed in some patients by the use of chemosensitizers given concurrently with chemotherapy.2,10-12 In two consecutive phase II trials, the Southwest Oncology Group (SWOG) tested infusional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, termed the CVAD regimen (cyclophosphamide, doxorubicin, vincristine, and dexamethasone), alone (SWOG 9240) and in combination with the chemosensitizers verapamil and quinine (SWOG 9125) to assess effects on survival and toxicity in intermediate- and high-grade advanced-stage non-Hodgkin’s lymphoma (NHL). In addition, we reviewed the historic group of patients who were randomized to CHOP chemotherapy on Intergroup (INT) 0067 (SWOG 8516), the National High Priority Lymphoma Study, which was a randomized comparison of CHOP versus high-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone (M-BACOD) versus prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, and methotrexate (ProMACE-CytaBOM) and methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B).13 The results of the CVAD trials SWOG 9125 and SWOG 9240 and the retrospective review of the CHOP arm of SWOG 8516 are the subject of this article.
Patient Selection To be eligible for SWOG 9125 or SWOG 9240, patients must have had biopsy-proven intermediate- or high-grade NHL (Working Formulation groups D through J); patients with lymphoblastic lymphoma or divergent lymphomas were excluded. Histologic specimens were evaluated by independent expert reviewers. All patients had stage II bulky, stage III, or stage IV disease. Bulky disease was defined as a mediastinal mass exceeding one third of the maximal chest diameter or any other mass 10 cm or more in maximal diameter. Staging evaluation included physical examination, chest radiography, computed tomography (CT) of the abdomen and pelvis, and bone marrow biopsy, measurement of serum AST, total bilirubin, alkaline phosphatase, and lactate dehydrogenase levels, and peripheral blood counts. Assignment of the Ann Arbor stage was based on clinical findings and tumor measurements obtained before excisional biopsy. All patients were ambulatory (SWOG performance status 0 to 2), and no patient had a history of congestive heart disease or other cancer, symptoms, or findings compatible with CNS involvement with lymphoma or any prior treatment of lymphoma. Patients with AIDS- or human immunodeficiency virus–associated complex were ineligible. All patients had adequate hepatic, renal, and bone marrow function. All patients had passed their 15th birthday; there was no upper age limit on these studies. All patients gave written informed consent according to institutional guidelines.
Treatment CVAD is designed to deliver the same planned dose-intensity and total dose of doxorubicin and cyclophosphamide as the standard CHOP regimen, which consists of cyclophosphamide 750 mg/m2 as a 15-minute infusion on day 1, doxorubicin 50 mg/m2 given intravenously in a bolus over 1 to 2 minutes on day 1, vincristine 1.4 mg/m2 given over a period of 1 to 2 minutes on day 1, and prednisone 100 mg daily given orally on days 1 to 5. Cycles are repeated at 21-day intervals. Vincristine doses in the CVAD regimens were identical to those in CHOP for all patients receiving 2.0 mg with each CHOP cycle. Patients on SWOG 9125 received the CVAD regimen as detailed above given with the chemosensitizers verapamil and quinine. Verapamil was given at a dose of 240 mg bid and quinine was given at a dose of 40 mg tid. Both verapamil and quinine were begun 24 hours before the initiation of CVAD and were continued for a total of 6 days. Cycles were repeated every 21 days for eight cycles. The use of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor was not allowed in SWOG 8516. Their use was allowed in both the CVAD and CVAD verapamil quinine trials at the discretion of the investigator after a documented episode of neutropenia. Doses of cyclophosphamide and doxorubicin were decreased to 75% of the last dose received if blood counts did not recover after a 2-week delay before the initiation of the next cycle of treatment or if the patient experienced severe infection related to neutropenia. Vincristine doses were decreased if grade 2 or higher weakness or pain occurred. There was no modification of the vincristine dose based on the presence of paresthesias or the loss of deep tendon reflexes.
Statistical Analysis Standard SWOG criteria were used to evaluate patient response and toxicity. CR was defined as the complete disappearance of all measurable and assessable disease, with no new lesions, no disease-related symptoms, and no evidence of nonassessable disease. Disease progression was defined as a 50% increase in the sum of products of measurable lesions over the smallest sum observed, the reappearance of any lesion that had disappeared, clear worsening of assessable disease, or the appearance of any new disease. FFS was measured from the date of registration to date of disease progression or death. OS was measured from the date of registration to the date of death (from any cause). Patients known to be alive at the most recent follow-up visit were censored in the survival analysis. The rates of FFS and OS were estimated according to Kaplan and Meier.14
Patient Characteristics Between June l991 and February 1993, 100 patients were registered onto SWOG 9125 (CVAD verapamil quinine). Nineteen patients were ineligible; biopsies of 10 patients showed low-grade lymphoma, eight patients had insufficient prestudy documentation, and one patient received protocol treatment before registration. All 81 patients eligible for the study were included in the analyses of OS and FFS. One hundred twelve patients were registered to SWOG 9240 (CVAD) between January 1993 and February 1994. Thirty-one patients were ineligible, due to pathology review (n = 21), incorrect stage (n = 2), and insufficient prestudy documentation (n = 8). There were 81 eligible patients, all of whom have been included in the analysis of OS and FFS. Patients from each of the four International Prognostic Index (IPI)15 risk groups were enrolled onto each of the studies ( Table 1). The distribution of patients by IPI risk group enrolled onto the CHOP arm of SWOG 8516, as previously reported, is also shown for the purpose of comparison. There were no statistically significant differences in the distribution of risk groups among the three studies.
The median age of patients in SWOG 9125 was 55 years, as compared with a median age of 53 years on SWOG 9240 and a median age of 56 years on the CHOP arm of SWOG 8516. Sixty-seven percent of patients on SWOG 9125 and 70% of patients on SWOG 9240 had diffuse large-cell histology.
Response to Treatment
Survival FFS of patients on SWOG 9125, 9240, and the CHOP arm of SWOG 8516 is shown in Fig 1. For the 81 patients on SWOG 9125 treated with CVAD verapamil quinine, the 2-year FFS was 42% (95% CI, 31% to 53%). For the 81 patients on SWOG 9240 treated with CVAD alone, the 2-year FFS was 41% (95% CI, 30% to 52%). This compares with a 2-year FFS of 46% for patients treated on the CHOP arm of SWOG 8516.
FFS was further estimated within IPI risk categories for each study. For SWOG 9125, patients in the low or low-intermediate IPI risk categories (n = 50) had a 2-year FFS of 54%, and patients in the high-intermediate and high IPI risk groups (n = 31) had a 2-year FFS of 23%. For SWOG 9240, patients in the low or low-intermediate IPI risk categories (n = 41) had a 2-year FFS of 56%, and patients in the high-intermediate and high IPI risk categories (n = 40) had a 2-year FFS of 25%. OS for patients on SWOG 9125, SWOG 9240, and the CHOP arm of SWOG 8516 is shown in Fig 2. Two-year survival for SWOG 9125 was 64% (95% CI, 53% to 75%), and for SWOG 9240, it was 58% (95% CI, 47% to 69%). This compares with a 2-year OS of 63% for patients treated on the CHOP arm of SWOG 8516.
OS was also analyzed within IPI risk groups. As was true for FFS, patients in low and low-intermediate IPI risk groups had a better survival rate than those in the high-intermediate and high IPI risk categories. For SWOG 9125, patients in the low or low-intermediate IPI risk categories had a 2-year OS of 76% and patients in the high-intermediate and high IPI risk categories had a 2-year OS of 45%. For SWOG 9240, patients in the low and low-intermediate IPI risk categories had a 2-year OS of 78% and patients in the high-intermediate and high IPI risk categories had a 2-year OS of 38%. Patients with diffuse large-cell lymphoma were analyzed for each study, but there was no significant difference in FFS or OS compared with results for all eligible patients.
Toxicity
Dose-Intensity The relative dose-intensity (RDI), defined as the ratio of received dose-intensity to planned dose-intensity, is listed in Table 3. RDI was lower for all three drugs in the trials that used infusional therapy compared with standard bolus CHOP. The lowest RDI was seen when infusional CHOP (CVAD) was given with the chemosensitizers verapamil and quinine.
Our results indicate that infusion CVAD chemotherapy alone or with the addition of the chemosensitizers verapamil and quinine is not promising with respect to improved OS compared with CHOP therapy, based on a comparison with the CHOP arm of SWOG 8516. We acknowledge, of course, that these nonrandomized comparisons must be viewed with caution, even if the patient pools seem to be similar, because the patients enrolled onto each of these trials may differ on unmeasurable factors. The CR rates achieved in these two pilot trials were lower than the rates on the CHOP arm of SWOG 8516. Forty-four percent of the 225 patients randomized to CHOP achieved CR. CR was defined in all three trials as the complete disappearance of all measurable or assessable disease. None of the studies dealt in a prospective manner with the commonly encountered phenomenon of residual stable abnormalities on CT scan. The variability in CR rates among the studies may reflect a true difference in CR rates or may reflect variability in the interpretation of the significance of stable abnormalities on CT scan after treatment. For example, on SWOG 8516, patients with stable abnormalities of 2.5 cm or less were considered to be in CR. Adherence to the more strict criterion of complete resolution of abnormalities would result in lower CR rates. A more meaningful measure of the efficacy of a treatment is given by the OS of the patients. Two-year survival rates of 64% and 58% on the CVAD alone trial and CVAD with chemosensitizers trial, respectively, are similar to the 63% 2-year survival rate observed on the CHOP arm of SWOG 8516. Twenty-eight percent of patients registered to the CVAD trial were ineligible and 19% of those registered to CVAD plus chemosensitizers were ineligible. It has been the practice of our reviewing pathologists to exclude from trials designed for intermediate- and high-grade lymphomas those patients who have any evidence of nodularity on the pathology specimen, with the exception of patients with follicular large-cell lymphoma. The rate of ineligibility on these trials compares with an ineligibility rate of 23% on SWOG 8516. Several clinical trials have suggested that infusional therapy may have a therapeutic advantage in the treatment of relapsed lymphoma as compared with conventional bolus therapy. Wilson et al16 treated 74 patients with the etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) regimen. In this regimen, etoposide, vincristine, and doxorubicin are given for 96 hours as a continuous infusion. All patients had relapsed or failed to respond to most of the same drugs given on a bolus schedule. An 87% response was observed (27% CR) in 70 assessable patients. Sparano et al17 treated 58 patients with the cyclophosphamide, doxorubicin, and etoposide (CDE) regimen. In this regimen, cyclophosphamide, doxorubicin, and etoposide are given by continuous infusion for 4 days. Objective response occurred in 30 patients (52%) with relapsed NHL, many of whom had been previously exposed to cyclophosphamide and doxorubicin. Although these studies were provocative, neither provided proof that mdr can be reversed, because neither study was restricted to patients with clinical evidence of drug-resistant relapse and neither study reported Pgp status as a laboratory measure of mdr. Our results with infusional CHOP (CVAD) do not demonstrate the superiority of this approach compared with conventional bolus CHOP in previously untreated patients. For clinical trials that attempt to use modulating agents to be successful and for modification to result in cure, several conditions must be met: (1) Pgp must be functional and present in malignant cells, (2) modulators must be given in adequate doses to block Pgp function, (3) modulators must not increase host toxicity in organs that normally express Pgp, and (4) overexpression of Pgp must be the primary mechanism of resistance present in the tumor cells. In our trials, we did not measure Pgp expression before the initiation of treatment. Several investigators have, however, documented either the overexpression of mdr-1 or its protein product, Pgp, in a minority of lymphoma samples from patients who had received no prior treatment. Goldstein et al1 reported overexpression of mdr-1 mRNA in four (22%) of 18 samples tested. Moscow et al18 studied 11 lymphomas and found overexpression of mdr-1 mRNA in four (36%). At the translational level, Miller et al2 detected Pgp in only one patient (2%) of 42 sampled. This rate was much lower than the rate found in 11 patients who had received prior treatment; seven of these previously treated patients had detectable levels of Pgp.1 As is obvious, the prevalence of detectable Pgp in patients with lymphoma at the time of diagnosis varies greatly from study to study. However, the techniques used to assess Pgp likewise varied. In general, it is hard to detect Pgp in the malignant lymphocytes of patients with lymphoma at the time of diagnosis. Pgp is much more easily detected at the time of relapse and thus there seems to be an increased quantity of Pgp over time with treatment for NHL. Our inability to detect an advantage to infusional therapy, with or without chemosensitizers, might reflect the fact that Pgp was not a significant mechanism of resistance in this patient population. Both verapamil and quinine may be considered first-generation chemosensitizers, ie, these are mdr-modulating agents that were selected from pharmacologic agents already in medical usage. Although verapamil has been shown to have mdr-reversing capabilities, it is also associated with formidable side effects, including hypotension and heart block, when given in doses higher than those recommended in current clinical usage. Using verapamil as a continuous infusion in doses associated with significant cardiac toxicity, Miller et al19 found that peak serum levels ranged from 307 ng/mL to 1,810 ng/mL. These levels were lower than the maximally effective in vitro concentration of 3,000 ng/mL. Our inability to detect an improvement in outcome with chemosensitizers given in conjunction with infusional therapy may well reflect the fact that efficacious levels of chemosensitizers could not be achieved with the doses of chemosensitizers given. An alternative explanation for our inability to detect an improvement in outcome with infusional therapy alone or in combination with chemosensitizers may relate to the lower relative dose-intensity of cyclophosphamide, doxorubicin, and vincristine in the CVAD trials as compared with the RDI of these drugs on the CHOP arm of 8516. The difference in RDI was particularly striking for CVAD given with chemosensitizers. This decrease in RDI occurred despite the use of G-CSF at the discretion of the treating physician on the infusional chemotherapy trials. The use of G-CSF resulted in comparable toxicities between bolus and infusional CHOP given without chemosensitizers. Because these drugs have been used extensively by SWOG investigators for the treatment of lymphoma, the decrease in RDI on the CVAD trials reflects the increased toxicity that was encountered with infusional therapy as compared with standard bolus CHOP therapy. It is now well recognized that the concurrent use of chemosensitizers requires an approximately 30% decrease in dose intensity to achieve an equitoxic regimen. Our decrease in dose intensity was less than that and our resultant toxicity seems higher. Because the use of G-CSF was allowed on the pilot trials at the discretion of the treating physician, it is difficult to compare precisely the incidence of granulocytopenia with CVAD given alone versus CVAD given with chemosensitizers. It should be noted that G-CSF use was not allowed on SWOG 8516 and the incidence of neutropenia on the CHOP arm of that study was only 23%. Some, but not all, studies have shown Pgp expression in normal granulocytes.5 The increased incidence of severe neutropenia seen in our study of CVAD plus verapamil and quinine might be explained by the toxic effect of the chemosensitizers on normal granulocytes. The clinical impact of this increased toxicity was the inability to deliver as much cytotoxic therapy in conjunction with the chemosensitizers as could be delivered with infusional therapy alone or with standard bolus CHOP. However, we clearly administered the MTD of CVAD with verapamil and quinine. It should be noted, however, that despite the fact that the dose-intensity of cyclophosphamide, doxorubicin, and vincristine were all lower on the study using chemosensitizers (SWOG 9125), the outcomes in terms of FFS and OS were similar to those observed when CHOP (SWOG 8516) or CVAD alone (SWOG 9240) were used. Due to the inadequacy of currently available chemosensitizers, the contribution of the mdr phenomenon to the overall problem of drug resistance has probably not yet been adequately assessed. Future trials using more effective chemosensitizers may more adequately define the relevance of mdr reversal in the treatment of cancer. Given the results of our studies, there does not seem to be justification for the use of infusional CVAD either alone or in combination with verapamil and quinine as first-line therapy for advanced-stage intermediate- and high-grade NHL.
Supported in part by Public Health Service Cooperative Agreement grants no. CA38926, CA32102, CA46282, CA13612, CA35128, CA58658, CA04920, and CA14028 awarded by the National Cancer Institute, Department of Health and Human Services, Bethesda, MD.
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Miller TP, Grogan TM, Dalton WS, et al: P-glycoprotein in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high dose verapamil. J Clin Oncol 9: 17-24, 1991 3. Pastan I, Gottesman M: Multiple drug resistance in human cancer. N Engl J Med 316: 1388-1393, 1987[Medline] 4. Kartner N, Everden-Porelle D, Bradley G, et al: Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies. Nature 316: 820-823, 1985[Medline]
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Klimecki WT, Futscher BW, Grogan TM, et al: P-glycoprotein expression and function in circulating blood cells from normal volunteers. Blood 83: 2451-2458, 1994 6. Pastan I, Gottesman MM: Multidrug resistance. Ann Rev Med 42: 277-286, 1991[Medline] 7. Lai G-M, Chen Y-N, Mickley LA, et al: P-glycoprotein expression and schedule dependence of Adriamycin cytotoxicity in human colon carcinoma cell lines. Int J Cancer 49: 696-703, 1991[Medline]
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Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328: 1002-1006, 1993 14. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 451-481, 1958 15. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 329:987-993, 1993
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Pennock GD, Dalton WS, Roeski WR, et al: Systemic toxic effects associated with high dose verapamil infusion and chemotherapy administration. J Natl Cancer Inst 83: 105-110, 1991 Submitted June 18, 1999; accepted October 2, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
