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© 2000 American Society for Clinical Oncology Role of a Doxorubicin-Containing Regimen in Relapsed and Resistant Lymphomas: An 8-Year Follow-Up Study of EPOCHFrom the Division of Clinical Sciences, National Cancer Institute, Bethesda, MD; and Massachusetts General Hospital, Boston, MA. Address reprint requests to Wyndham H. Wilson, MD, PhD, Medicine Branch, National Cancer Institute, Bldg 10, Room 12N/226, 9000 Rockville Pike, Bethesda, MD 20892; email wilsonw{at}mail.nih.gov
PURPOSE: Curative up-front regimens for non-Hodgkin’s lymphomas contain doxorubicin, vincristine, and cyclophosphamide, whereas salvage regimens generally contain non–cross-resistant agents. We hypothesized that up-front agents may be highly effective for salvage and developed an infusional regimen based on in vitro evidence of increased efficacy. PATIENTS AND METHODS: A prospective phase II study of etoposide, vincristine, and doxorubicin over 96 hours with bolus cyclophosphamide and oral prednisone (EPOCH) was performed in 131 patients with relapsed or resistant lymphoma. RESULTS: Seventy-nine percent of patients had aggressive histologies, 46% were considered high risk by the International Prognostic Index, and 34% had resistant disease. Eighty-eight percent of patients had received at least four of the agents in EPOCH, and 94% had received doxorubicin. In 125 assessable patients, 29 (24%) achieved complete responses and 60 (50%) achieved partial responses. Among 42 patients with resistant disease, 57% responded, and in 28 patients with relapsed aggressive de novo lymphomas, 89% responded with 54% complete responses. With a median follow-up of 76 months, the overall and event-free survivals (EFS) were 17.5 and 7 months, respectively. In 33 patients with sensitive aggressive disease who did not receive stem-cell transplantation, EFS was 19% at 36 months. Toxicity was primarily hematologic, with an 18% incidence of febrile neutropenia. No clinically significant cardiac toxicity was observed, despite no maximum cumulative doxorubicin dose. CONCLUSION: EPOCH is highly effective in patients who had previously received most/all of the same drugs and produces durable remissions in curable subtypes. Salvage regimens need not contain non–cross-resistant agents, and infusional schedules may partially reverse drug resistance and reduce toxicity.
DESPITE ADVANCES IN the chemotherapy of non-Hodgkin’s lymphomas (NHL), most patients are still incurable and ultimately require salvage treatment. For initial treatment, doxorubicin-based regimens are the most common type, being the mainstay for aggressive lymphomas and often used in indolent lymphomas.1,2 When patients relapse or progress, however, non–doxorubicin-containing regimens are frequently used because of concern over resistance to previously used cytotoxic agents and cardiac toxicity caused by high cumulative doses of doxorubicin. A number of non–doxorubicin-containing salvage regimens developed over the last two decades are now commonly used.3-7 Historically, these regimens were developed during the era of the Goldie-Coldman hypothesis, which related the drug sensitivity of tumors to their spontaneous mutation rate toward a resistant phenotype, thereby explaining the differential sensitivity of cancers to chemotherapy through the acquisition of drug-specific mechanisms such as membrane pumps, free radical scavengers, mutations of intracellular targets, and DNA repair enzymes.8 Clinically, this translated into the development of regimens that contained agents that were generally considered to be non–cross-resistant with those present in doxorubicin-containing regimens. Hence, regimens such as methyl GAG, ifosfamide, methotrexate, and etoposide (MIME); cyclophosphamide, etoposide, procarbazine, and bleomycin (CEPP-B); and etoposide, methylprednisolone, cytarabine, and cisplatin (DHAP/ESHAP) were developed.3-7 We hypothesized it may be possible to develop an effective doxorubicin-containing salvage therapy that contains most or all of the same agents used in up-front treatment regimens. Several clinical reports had suggested that vincristine and etoposide, common up-front agents, were schedule-dependent and more effective when administered over a prolonged time period. Additionally, in vitro studies showed that tumor cells displayed relatively less resistance to prolonged exposure to low concentrations of the natural product class of drugs, including vincristine, etoposide, and doxorubicin, compared with brief higher-concentration exposure.9 More recent evidence also suggested that the apoptotic response to antineoplastic agents may be an important determinant of chemotherapy sensitivity, thereby raising the question of the relative importance of classical drug-specific mechanisms of resistance and the existence of truly non–cross-resistant agents.10-12 Thus, we designed a salvage regimen around the up-front agents of etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH) and incorporated our findings of schedule dependency by administering the natural product components over 96 hours. In this article, we describe the long-term outcome of 131 patients with relapsed and resistant (ie, refractory to last chemotherapy) lymphomas treated with EPOCH chemotherapy. This study also includes follow-up data from a portion of patients who were the subject of a preliminary report of EPOCH in 1993.13 In this study, we demonstrate the efficacy of EPOCH in patients with chemotherapy-resistant disease and the curative potential of EPOCH in patients with relapsed aggressive lymphomas. These results suggest that effective salvage treatments need not contain different drug classes than those used for prior treatment and raise the question of the role of non–cross-resistant regimens as well as the optimal agents for salvage treatment. An analysis of cardiac toxicity also suggests that a patient’s safe cumulative doxorubicin dose may be determined by cardiac ejection fraction and not a predetermined maximum amount.
Patients and Staging From February 1990 to April 1995, 131 consecutive patients were entered onto a study of EPOCH chemotherapy at the National Cancer Institute. Patients had either relapsed or resistant NHL, and all histologic subtypes (reviewed by E.S.J.) were eligible. Eligibility requirements included measurable disease, a nonreactive test for human immunodeficiency virus, written informed consent, serum creatinine  1.5 mg/dL or a creatinine clearance  40 mL/min, serum bilirubin 2.5 mg/dL, absolute neutrophil count (ANC) 1,000 cells/µL, and platelets 100,000/µL unless caused by respective organ involvement by tumor. There was no limit on cumulative doxorubicin dose but cardiac ejection fraction was required to exceed 40%. Patients with indolent lymphoma were eligible for treatment only if they had disease requiring systemic chemotherapy. Patients with aggressive lymphoma were eligible for treatment immediately after relapse or failure to respond to chemotherapy. Initial evaluation included a history and physical examination, standard blood tests (including lactate dehydrogenase [LDH]; normal > 226 U/L), human immunodeficiency virus antibody, cardiac ejection fraction as medically indicated, whole body computed tomography, and bilateral bone marrow biopsies. Sites of disease were restaged every two cycles thereafter. Patients without tumor regression over two treatment cycles or progressive disease received dexverapamil (a blocker of the multidrug resistance-1 pump) and EPOCH on another study.14 Patients who achieved a complete response (CR) received EPOCH for two additional cycles for a minimum of six cycles, unless they were candidates for stem-cell transplantation (SCT). Patients with aggressive lymphoma, adequate organ function, and minimal residual disease after EPOCH were eligible for high-dose ifosfamide, carboplatin, and etoposide (ICE) and SCT.15
Chemotherapy
Studies conducted by the Pharmaceutical Development Service in the Pharmacy Department at National Institutes of Health Clinical Center demonstrated that a solution containing vincristine, doxorubicin, and etoposide could be admixed in 0.9% sodium chloride (normal saline) injection, at concentrations of 1, 25, and 125 µg/mL; 1.4, 35, and 175 µg/mL; or 2, 50, and 250 µg/mL, respectively (United States Pharmacopoeia). The solutions are stable for at least 48 hours at room temperature when protected from light.16 A 24-hour supply of vincristine, doxorubicin, and etoposide can be admixed in 500 mL of 0.9% sodium chloride injection and delivered by a portable infusion pump through a central venous access device. Cyclophosphamide was diluted in 100 mL of normal saline and infused over 15 minutes. Granulocyte colony-stimulating factor (G-CSF), supplied by the Cancer Therapy Evaluation Program of the National Cancer Institute (IND#BB2704), was self-administered by subcutaneous injection beginning on day 6 and continuing until the ANC was 10,000 cells/µL past the nadir. To prevent Pneumocystis carinii, patients received co-trimoxazole twice daily for 3 consecutive days per week.
Dose Modifications
Definition of Response and Statistical Analysis Survival time and time to any event in months were calculated from the date of study entry until death, relapse, progression, or last follow-up, as appropriate. The probability of survival or event-free survival (EFS) was calculated using the Kaplan-Meier method, and the significance of the difference between pairs of Kaplan-Meier curves was calculated using the Mantel-Haenszel procedure.18,19 The Cox proportional hazards model was used to identify which factors were jointly significant in the association of prognostic factors with survival or EFS.20 The factors considered for inclusion in univariate and Cox analyses were age, sex, stage, histology, Eastern Cooperative Oncology Group (ECOG) performance status, constitutional symptoms, number of prior drugs, number of prior regimens, number of prior EPOCH drugs, response (sensitive v resistant) to last chemotherapy, months since last chemotherapy, number of extranodal sites, LDH, and International Prognostic Index (IPI) score. The associations between response (eg, CR, partial response, or none) and various discrete characteristics were evaluated using Lehmann’s version of the Kruskal-Wallis test for ordered columns, if the row variable was not ordered, or by the Mantel test for trend, if both the rows and columns were ordered.21,22 The association between response and continuously measured parameters was determined by the Kruskal-Wallis test. Jonckheere’s trend test was also applied where appropriate.23 The method of Hochberg was used to evaluate whether any individual association with response was significant at the 0.05 level, after accounting for the other results obtained.24 This approach correctly accounts for the multiplicity of evaluations performed without being as overly stringent as the more common Bonferroni procedure. All P values are two-sided.
Patients Characteristics One hundred thirty-one patients were assessable for toxicity, and 125 patients were assessable for response. Among the six patients not assessable for response, five received only one cycle of therapy and were not restaged, and one patient did not have measurable disease. As listed in Table 2, the median patient age was 48 years, 41% were greater than 60 years old, and 40% had an ECOG performance status 2. Other poor prognostic factors included advanced stage III or IV disease in 91% of patients, elevated LDH in 68%, and high-intermediate/high IPI scores in 46% of patients. Most patients (104, 79%) had aggressive histologies of which 68% were de novo and 32% had transformed histologies at the time of study entry. Diffuse large B-cell was the predominant histology, comprising 68% of patients.
All patients were extensively pretreated, having received a median of eight different drugs (range, one to 17 drugs) and one regimen (range, one to five regimens) or two regimens (range, one to seven regimens) if they had aggressive or indolent histologies, respectively. Moreover, 34% of patients were resistant to the last administered chemotherapy, and 44% had never achieved a CR. Of the drugs present in the EPOCH regimen, 57% of patients had received all five and 88% had received at least four of the agents. All but four patients (6%) had previously received doxorubicin, 70% had received prior etoposide, and 69% had received both etoposide and doxorubicin. Five patients had relapsed after high-dose chemotherapy and SCT.
Treatment Outcome
In determining the clinical utility of a salvage regimen, it is important to assess its activity under conditions where other regimens have failed. In this regard, we analyzed the response to EPOCH in patients who failed to achieve a CR with their primary chemotherapy regimen (induction failure) and in those who showed no response to their last combination regimen (ie, resistant disease) (Table 3). A reasonable percentage of patients (65%) who had failed induction responded to EPOCH, although the 9% CR rate was low. Of significance, however, was the 57% response rate in patients with chemotherapy-resistant disease, a group that generally has a low response to subsequent chemotherapy.25 As expected, patients with chemotherapy-sensitive disease had a higher overall response rate of 83%, including 33% CRs. A clinically important role for salvage chemotherapy is to cyto-reduce patients who are candidates for SCT. For this reason, we were specifically interested in the efficacy of EPOCH in patients with relapsed aggressive de novo lymphoma because they are among the most curable patients with SCT, provided they have responsive disease.26 In the 28 patients in the present series with aggressive lymphomas who had relapsed after CR, 89% responded to EPOCH, including 54% CRs, and became potential candidates for SCT. Furthermore, among the subset of 19 patients who had chemotherapy-resistant disease, seven (37%) responded to EPOCH, including one CR. High-dose therapy with stem-cell support is generally believed to provide the best outcome for patients with chemosensitive relapsed aggressive de novo lymphomas.27,28 In accord with this approach, we offered SCT consolidation to all patients with aggressive de novo lymphomas who had at least a partial response to EPOCH (ie, sensitive disease) and had adequate organ function. At the time of this study, patients with an underlying low-grade lymphoma were not offered SCT consolidation. However, among the 47 such patients in the present series, 33 did not receive SCT for a variety of reasons including inadequate organ function, age, and personal preference. To provide some measure of the curative potential of EPOCH as salvage treatment in this group of patients, we analyzed the outcome of patients with EPOCH responsive disease and censored the follow-up data at the time patients received SCT consolidation. As shown in Fig 1, 18% of these patients were event-free and 37% were alive at 5 years, suggesting that EPOCH alone may provide effective salvage for a proportion of patients. Of note, 79% of patients who received SCT consolidation were in CR after EPOCH compared with 39% of patients who did not receive SCT, suggesting that more favorable patients underwent SCT.
The overall survival (OS) and EFS curves for the entire series are shown in Fig 2. Overall, the patients had a median OS of 17.5 months, with 41% and 26% alive at 3 and 6 years, respectively, and a median EFS of 7 months, with 15% and 10% event-free at 3 and 6 years, respectively. With a median potential follow-up of 76 months, there was no significant difference in OS or EFS among the three histologic subgroups.
Prognostic Factors We performed univariate and multivariate analyses to assess the relationship between clinical factors and response, assess EFS and OS with EPOCH, and identify a number of known prognostic factors. Not surprisingly, the univariate analyses showed a significant association between the outcome measures of response (P = .0047), EFS (P = .0012), and OS (P = .0048) and the IPI, as well as significant associations with individual prognostic factors such as performance status, LDH, constitutional symptoms, and last chemotherapy response. A Cox regression analysis showed chemotherapy resistance (P = .0076), ECOG performance status 2 to 3 (P = .0017), and constitutional symptoms (P = .029) to be best associated with OS, and chemotherapy resistance (P = .0001) and ECOG performance status 2 to 3 (P = .0007) to be best associated with EFS. When the Cox analysis was restricted to the subset of aggressive histologies, only chemotherapy resistance and advanced IPI were significantly associated with OS and EFS. It is often assumed that patients with relapsed lymphoma will not be responsive to previously administered agents.8 To address this issue, we assessed whether the clinical outcome with EPOCH was influenced by prior exposure to the EPOCH drugs. The analysis revealed that, although response to EPOCH was best associated with response to the last chemotherapy regimen (P = .00007) and the number of prior regimens (P = .0054), there was no association of response with the number of prior EPOCH drugs (P = .94). Similarly, there was no association between EFS (P = .20) or OS (P = .61) and prior exposure to any of the EPOCH drugs.
Toxicity
Gastrointestinal toxicity was mild. In general, antiemetics were unnecessary, and only 5% of cycles were associated with significant vomiting, primarily after the administration of cyclophosphamide. Most patients were able to eat regular meals during treatment. Clinically significant mucositis (excluding those events associated with oral herpes simplex) was uncommon, occurring in 7% of cycles. Moderate constipation occurred in 2% of cycles. Mild neurologic toxicity was common, occurring in 22% of patients. However, the majority of patients had peripheral neuropathy at the time of entry to the study, and neurologic toxicity with pain and/or motor weakness that necessitated vincristine dose reductions occurred in only 10% of patients.
A major limitation of doxorubicin is the significant incidence of cardiomyopathy at cumulative doses above 550 mg/m2 and at lower doses in patients who have received mediastinal radiation or have cardiac disease.29,30 For this reason, physicians are reluctant to administer doxorubicin-containing regimens to salvage patients who have previously received cyclophosphamide, doxorubicin, vincristine, and prednisone when a full course generally contains 300 to 400 mg/m2 of doxorubicin. An important advantage of infusional doxorubicin, however, is the potential for lower cardiac toxicity and the ability to administer significantly higher cumulative doses than is tolerated on bolus schedules.31 In the present study, 94% of patients had previously received doxorubicin at a median cumulative dose of 200 mg/m2 (range, 45 to 630 mg/m2). There was no limitation on the permissible cumulative doxorubicin dose in our trial, but patients with high cumulative doses and/or risk factors for cardiac disease underwent serial assessment of left ventricular ejection fraction by multiple gated aquisition scan. As graphically demonstrated in Fig 3, there was only a modest and clinically insignificant decline in the median ejection fraction over multiple cycles of EPOCH. A paired t test analysis comparing cycle 0 to 1 versus cycle 2 to 3, cycle 4 to 5, and cycle
Dose-Intensity (DI) The delivered DI (mean ± SD), calculated for all cycles of EPOCH, was as follows: cyclophosphamide 177 ± 67 mg/m2/wk, doxorubicin 12 ± 1.8 mg/m2/wk, vincristine 0.49 ± 0.06 mg/m2/wk, and etoposide 62 ± 6.8 mg/m2/wk, representing 71%, 92%, 92%, and 93%, respectively, of planned DI. An analysis of the association between DI and response, EFS and OS for each agent showed no statistically significant relationship. Although the later patients enrolled onto this study were eligible to receive G-CSF if they developed neutropenia, an analysis showed no relation between DI and administration of G-CSF so that the data from all patients were included.
Therapeutic advances over the past 20 years have yielded only modest improvements in the cure of lymphomas, making it clinically important to have effective and well-tolerated salvage therapy. For patients who are candidates for SCT, the primary role of salvage therapy is cytoreduction. In the present trial, 70% of patients in the aggressive de novo group, a subset with potentially curable disease, responded to EPOCH, including 36% CRs, and became eligible to undergo SCT. Of note was a 54% CR rate in those patients who had relapsed after having achieved a previous CR. The response rate of a regimen in the setting of resistant disease provides potential insight into its ability to overcome drug resistance and its clinical utility. Even in the 42 patients with resistant disease, 57% responded and achieved clinical benefit. Furthermore, in the subset of 20 patients who were resistant to a doxorubicin-containing regimen, 10 responded, indicating that the continuous-infusion schedule of EPOCH may confer benefit over bolus schedules. The median potential follow-up of 76 months increases the confidence of the results regarding the impact of EPOCH salvage treatment and extends the findings from our previous report.13 For patients with aggressive lymphoma who do not receive SCT, salvage treatment has historically produced a low durable CR rate.27,28 We were particularly interested in the long-term efficacy of EPOCH in the chemotherapy-sensitive aggressive de novo lymphomas because of their potential for cure. Treatment results with EPOCH alone in this subset yielded an OS and EFS of 37% and 19%, respectively, at 5 years, suggesting that a proportion of patients were potentially cured. Chemotherapy toxicity is a significant problem in the salvage treatment of patients because of low bone marrow and other tissue reserves and the frequent presence of poorly controlled disease. Severe toxicity from pretransplant salvage chemotherapy may preclude SCT, and in the majority of patients for whom SCT is not indicated, the need for continuous or chronic intermittent treatment requires that a regimen be well tolerated. Indeed, patients with relapsed aggressive lymphomas rarely achieve durable remissions and require continuous palliative treatment. The toxicity profile of EPOCH was primarily hematologic, characterized by a 48% frequency of brief neutropenia, accompanied by fever during 18% of cycles. Of importance, cardiac toxicity was extremely low, and despite no maximum cumulative doxorubicin dose, only four patients required doxorubicin discontinuation for a low ejection fraction. These results indicate that EPOCH can be tolerated over multiple cycles, and in the extreme case of one patient with a persistent aggressive lymphoma after SCT, EPOCH was continuously administered for 62 cycles; currently the patient remains progression-free. Other investigators have reported similar results to our own with doxorubicin-containing infusional chemotherapy for the salvage treatment of lymphomas. In a preliminary report from a community-based multicenter phase II study, EPOCH was administered to 106 patients with relapsed lymphoma, including 14 patients with Hodgkin’s lymphoma.32 The distribution of patient characteristics was similar to the present study, including prior exposure to EPOCH agents, with the exception that patients had an older median age of 59 years. Among 96 assessable patients in this trial, 63% responded, of which 25% were CRs. These results are not dissimilar from those obtained in the present study and suggest that EPOCH can be effectively used in the community setting. Of note was a 14% treatment related mortality in the first 42 patients, but only a 2% mortality in the subsequent 64 patients with the addition of filgrastim support and physician experience. Miller et al33 reported a 72% response rate (28% CR) with verapamil and an infusional regimen of doxorubicin, vincristine and dexamethasone with bolus cyclophosphamide (CVAD). At the time of the report, the investigators hypothesized that the high response rate was a result of inhibition of the multidrug resistance-1 pump, although later work by Wilson et al14 suggested little benefit of verapamil. The efficacy and toxicity profile of EPOCH compare favorably with other commonly used salvage regimens such as MINE, CEPP-B, and DHAP.3-7 Cisplatin-based regimens, such as DHAP and ESHAP, are currently among the most widely used salvage treatments. A formal comparison of these studies with EPOCH is not possible because of potential biases in the distribution of patient characteristics. However, a review of ESHAP results, the most active of the cisplatin-based regimens, suggests the distribution of patient characteristics are similar to the patients in the present series, although there is a higher percentage of heavily pretreated patients and aggressive histologies in the EPOCH trial.7 Overall, the response rate was 64% with ESHAP and 74% with EPOCH. More significant, however, was the difference in response rate in patients with aggressive de novo lymphomas, many of whom would be candidates for SCT if they responded to salvage treatment. In this subset, ESHAP produced a 48% response rate, with 26% CRs; whereas 70% responded to EPOCH, of which 36% were CRs. The DHAP regimen was similar to ESHAP in aggressive de novo lymphomas and had a 54% response rate with 28% CRs. An assessment of OS showed EPOCH to have a somewhat higher survival rate than ESHAP at 3 years (41% v 31%, respectively) and a longer median survival (17.5 v 14 months, respectively). Of clinical importance, the toxicity profile of EPOCH allows it to be administered on a continuous basis, whereas the renal and hematologic side effects of ESHAP make chronic administration more problematic and often restrict its use in this setting. The results from the present trial raise intriguing questions regarding the role of doxorubicin-containing regimens for salvage treatment. The notion that lymphomas are less responsive to previously administered drugs than to new agents has contributed to the widespread use of non–doxorubicin-containing regimens for salvage treatment of aggressive lymphomas. Emerging evidence, however, suggests that the apoptotic response to chemotherapy may be a major mechanism of drug resistance and, unlike classical mechanisms, may not be as drug-specific.10-12 Indeed, we had previously shown that mutation of the p53 gene and low tumor proliferation, events associated with decreased apoptosis, are significant correlates of the drug-resistant phenotype.34 Hence, optimizing the administration of the most active up-front agents is a viable alternative to changing drug classes. Our results show that a doxorubicin-containing regimen such as EPOCH is very active in the salvage setting, including the ability to produce long-term remissions in aggressive lymphomas, and are consistent with the hypothesis that up-front agents remain highly effective. The activity of EPOCH in doxorubicin-resistant lymphomas also raises the question of whether continuous infusion may partially overcome resistance to bolus schedules for the natural product–derived agents.
1. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphomas. N Engl J Med 328: 1002-1006, 1993
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Solar-Celigny P, Lapage E, Brousse N, et al: Recombinant interferon alfa-2b with a regimen containing doxorubicin in patients with advanced follicular lymphoma. N Engl J Med 329: 1608-1614, 1993
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Cabanillas F, Hagemeister FB, Bodey GP, et al: IMVP-16: An effective regimen for patients with lymphoma who have relapsed after initial combination chemotherapy. Blood 60: 693-697, 1982 4. Cabanillas F, Hagemister F, McLaughlin P, et al: Results of MIME salvage regimen for recurrent or refractory lymphoma. J Clin Oncol 5: 407-412, 1987[Abstract]
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Chao NJ, Rosenberg SA, Horning SJ: CEPP(B): An effective and well-tolerated regimen in poor-risk, aggressive non-Hodgkin’s lymphoma. Blood 76: 1293-1298, 1990 7. Valasquez W, McLaughlin P, Tucker S, et al: ESHAP-An effective chemotherapy regimen in refractory and relapsing lymphoma: A 4-year follow-up study. J Clin Onc 12: 1169-1176, 1994 8. Goldie JH, Coldman AJ: A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63: 1727-1733, 1979[Medline] 9. 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: 696-673, 1991[Medline] 10. Kohn KW, Jackman J, O’Connor PM: Cell cycle control and cancer chemotherapy. J Cell Biochem 54: 440-452, 1994[Medline] 11. Oltval ZN, Korsmeyer SJ: Checkpoints of dueling dimers foil death wishes. Cell 79: 189-192, 1994[Medline] 12. Reed JC: Dysregulation of apoptosis in cancer. Cancer J Sci Am. 4: S8-S14, 1999 (suppl 1)
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Wilson WH, Bryant G, Bates S, et al: EPOCH chemotherapy: Toxicity and efficacy in relapsed and refractory non-Hodgkin’s lymphoma. J Clin Oncol 11: 1573-1582, 1993
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Wilson WH, Bates SE, Fojo A, et al: Controlled trial of dexverapamil, a modulator of multidrug resistance, in lymphomas refractory to EPOCH chemotherapy. J Clin Oncol 13: 1995-2004, 1995
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Wilson WH, Jain V, Bryant G, et al: Phase I and II study of high-dose ifosfamide, carboplatin, and etoposide with autologous bone marrow rescue in lymphomas and solid tumors. J Clin Oncol 10: 1712-1722, 1992
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Wolfe JL, Thoma LA, Du C, et al: Compatibility and stability of vincristine sulfate, doxorubicin hydrochloride, and etoposide in 0.9% sodium chloride injection. Am J Health Syst Pharm 56: 985-989, 1999
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Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 17: 1244-1253, 1999 18. Kaplan E, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 19. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50: 163-170, 1966[Medline] 20. Cox D: Regression models and life tables. J R Stat Soc B34: 187-202, 1972 21. Lehmann E: Nonparametrics: Statistical Methods Based on Ranks. San Francisco, CA, Holden-Day, 1975, pp 306-309 22. Mantel N: Chi-square tests with one degree of freedom: Extensions of the Mantel-Haenszel procedure. J Am Stat Assoc 58: 690-700, 1963
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Jonckheere AR: A distribution-free K-sample test against ordered alternatives. Biometrika 41: 133-145, 1954
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Hochberg Y: A sharper Bonferroni procedure for multiple results obtained. Biometrika 75: 800-802, 1988 25. Wilson WH, Little R, Pearson D, et al: Phase II and dose-escalation with or without granulocyte colony-stimulating factor study of 9-aminocamptothecin in relapsed and refractory lymphomas. J Clin Oncol 16: 2345-2351, 1998[Abstract]
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Vose JM, Anderson JR, Kessinger A, et al: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin’s lymphoma. J Clin Oncol 11: 1846-1851, 1993
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Gianni AM, Bregni M, Siena S, et al: High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 336: 1290-1297, 1997 29. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91: 710-717, 1979 30. Billingham ME, Bristow MR, Glatstein E, et al: Adriamycin cardiotoxicity: Endomyocardial biopsy evidence of enhancement by irradiation. Am J Surg Pathol 1: 17-23, 1977[Medline] 31. Legha SS, Benjamin RS, MacKay B, et al: Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 96: 133-139, 1982 32. Jain VK, Ogden J, Mennel R, et al: A phase-II trial of infusional etoposide, vincristine, and doxorubicin with bolus cyclophosphamide (EPOCH) along with filgrastim support in patients with relapsed Hodgkin’s and non-Hodgkin’s lymphomas. Proc Am Soc Hem 90: 850, 1997 (abstr)
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Miller TP, Grogan TM, Dalton WS, et al: P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil. J Clin Oncol 9: 17-24, 1991
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Wilson WH, Teruya-Feldstein J, Fest T, et al: Relationship of p53, bcl-2 and tumor proliferation to clinical drug resistance in non-Hodgkin’s lymphomas. Blood 89: 601-609, 1997 Submitted October 12, 1999; accepted June 12, 2000. This article has been cited by other articles:
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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
) subtypes; (B) OS 13 months for indolent (*), 12.6 months for aggressive de novo (x), and 23.4 months for aggressive transformed (
