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© 2003 American Society for Clinical Oncology Phase III Study Comparing Three Cycles of Infusional Carmustine and Cisplatin Followed by Radiation Therapy With Radiation Therapy and Concurrent Carmustine in Patients With Newly Diagnosed Supratentorial Glioblastoma Multiforme: Eastern Cooperative Oncology Group Trial 2394
From the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Dana-Farber Cancer Institute, Boston, MA; University of Connecticut, Farmington; Lawrence and Memorial Hospital, New London, CT; University of Wisconsin, Madison, WI; H. Lee Moffitt Cancer Center, Tampa, FL; M.D. Anderson Cancer Center, Houston, TX; Ohio State University, Columbus, OH. Address reprint requests to Stuart A. Grossman, MD, 1650 Orleans St, Room G93, The Sydney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD 21231; email: grossman{at}jhmi.edu.
Purpose: This phase III Eastern Cooperative Oncology Group-Southwest Oncology Group intergroup study was conducted to determine whether three 72-hour infusions of carmustine (BiCNU) and cisplatin administered monthly before external-beam radiotherapy would improve the survival of patients with newly diagnosed glioblastoma multiforme. The control arm consisted of radiation with standard adjuvant BiCNU. Patients and Methods: A total of 223 patients were accrued from 1996 to 1999. Of these, 219 patients were eligible; 109 were randomly assigned to the experimental arm, and 110 were randomly assigned to the control arm. Randomization was stratified by age, performance status, and extent of resection. Results: The median age of the patients was 55 years; 55% were male, 93% were white, 26% had a biopsy only, and 84% were ambulatory. Treatment arms were well balanced with respect to baseline characteristics. Median follow-up time of the 15 patients still alive at the time of analysis was 3.3 years (range, 2 to 5 years). Median survival times for the standard and experimental arms were 11.2 and 11.0 months (P = .33, two-sided log-rank test), and survival at 1 year was 45% versus 44%, respectively. Fifty-six percent of patients received all three cycles of BiCNU/cisplatin, 12% received two cycles, and 31% received only one cycle. Toxicity was primarily hematologic and was more common in the experimental arm (P < .01). Conclusion: This study demonstrates that 72-hour infusions of BiCNU and cisplatin followed by radiation do not improve median survival, survival at 1 year, or time to progression. Furthermore, this treatment requires more time in the hospital and is associated with more serious toxicities than standard therapy.
THE OUTCOME for patients with newly diagnosed high-grade astrocytomas (HGAs) has changed little during the last three decades. For adults with glioblastoma multiforme, the median survival time remains less than 1 year, survival at 2 years is less than 10%, and long-term survival is rare. The effect of chemotherapy in this disease has been marginal.1,2 A modest benefit to adjuvant chemotherapy is suggested by meta-analyses but is not evident in individual trials.3,4 Few chemotherapeutic agents have documented efficacy. These include the nitrosoureas (carmustine [BiCNU] and lomustine), procarbazine, and temozolomide, which yield response rates of 30% or less in patients with recurrent disease.5–8 Using modern imaging and response criteria, the efficacy of these agents may be less than reported for some of the older agents.9 Other agents that have been studied recently include irinotecan,10,11 cisplatin and carboplatin,12–17 and paclitaxel.18 Responses have been uncommon, modest, and of brief duration. During the past decade, there has been considerable interest in using combinations of BiCNU and cisplatin or carboplatin to increase response rates. Continuous infusions of BiCNU and cisplatin administered before radiation therapy (RT) have been reported by several investigators19–22 to show response rates of over 40%. As a result, the Eastern Cooperative Oncology Group (ECOG) and the Southwest Oncology Group (SWOG) conducted this phase III study comparing infusional pre-RT BiCNU and cisplatin to standard adjuvant BiCNU chemotherapy. The primary objective of this study was to compare survival and time to progression between the two treatments. The secondary objectives were to compare the proportion of patients who survive 1 year and the observed toxicities.
This phase III study was coordinated by ECOG with participation from SWOG. Patients were randomly assigned to one of the following two treatment arms: arm A (standard therapy), which consisted of BiCNU plus concurrent external-beam RT (BiCNU+RT), or arm B (experimental therapy), which consisted of 72-hour intravenous infusions of BiCNU and cisplatin followed by external-beam RT (BiCNU+cisplatin  RT). Treatments were assigned using permuted blocks within strata with dynamic balancing within main institutions and their affiliate networks. Randomization was stratified by ECOG performance status (0 to 1 v 2), age (< 45 years v  45 years), and extent of surgical procedure (biopsy v all other debulking procedures). Institutions obtained treatment assignments by contacting the ECOG operations office, either by telephone or through the ECOG Web registration program. Institutions from SWOG contacted their own operations office, which contacted the ECOG office to obtain the treatment assignment. The National Cancer Institute Cancer Therapy Evaluation Program and the institutional review boards of each participating institution approved this clinical research protocol.
Eligibility
Treatment and Drug Administration
Arm B (BiCNU+cisplatin
Dose Modifications There were no dose reductions for patients on arm B (BiCNU + cisplatin). On day 28 of each chemotherapy cycle, if values were outside of absolute neutrophil count more than 1,500/µL, platelet count more than 100,000/µL, and creatinine less than 1.7 mg/dL, treatment was delayed until the patient’s laboratory values reached levels that permitted continued therapy. Patients discontinued chemotherapy and received RT if laboratory values had not reached the stated minimum levels within 6 weeks of the last cycle.
Supportive Care
Duration of Therapy
End Points
Statistical Considerations
The primary analysis of outcome was an intent-to-treat analysis on the eligible patients from the point of randomization. A secondary analysis of outcome of all randomized patients was also performed. Analyses of baseline characteristics included eligible patients. For the toxicity analysis, all patients who were randomly assigned and who received protocol therapy were included. Fisher’s exact test was used to test for differences between treatment arms with respect to baseline characteristics.23 The Kruskal-Wallis test for ordered data was used to compare maximum toxicity grade between treatment groups.24 The Kaplan-Meier method was used to estimate distributions for survival and progression,25 and the log-rank test was used to assess differences between these distributions with respect to treatment.26 Cox proportional hazards models were used to estimate the effect of treatment after adjustment for baseline covariates.27 The Wald test was used to test for significant covariates in the proportional hazards models.28 The following covariates were considered: age (
RT Oncology Review Process
Two hundred twenty-three patients were randomized between January 1996 and April 1999, from 37 participating ECOG and SWOG institutions. Patients who were randomized (those who were ineligible, those who were eligible, and those who did not receive treatment) are listed in Table 1  . A total of four patients were ineligible. Three of these patients entered the protocol less than 14 days after undergoing surgery, and one had no available pathology for review. Six patients were randomly assigned but did not receive protocol treatment. Four of these patients refused their assigned treatment, one needed emergency surgery for a ruptured bowel, and one lacked the appropriate medical insurance coverage for the therapy. Therefore, 219 patients were assessable (110 and 109 randomly assigned to arms A and B, respectively). There were no significant differences in the baseline characteristics in the eligible patients randomly assigned to arm A or arm B (Table 2). Seventy-four percent of the patients had a partial or total resection of their tumor before study entry. The median age at study entry was 55 years; 55% of patients were male, 93% were white, and 29% were fully active as judged by their ECOG performance status.
The number of cycles of chemotherapy received by patients on arm A and arm B are shown in Fig 1 . Patients on arm A (BiCNU+RT) received a median of two cycles of BiCNU. Only 10% of patients completed the maximum six cycles of BiCNU. Of all the patients who stopped BiCNU because of progression, 57% had evidence of progressive disease after only one or two cycles of chemotherapy. Seven percent of patients on this arm of the study discontinued chemotherapy secondary to toxicities. The median number of cycles completed by patients on arm B (BiCNU+cisplatinRT) was three, and 61 patients (56%) completed all three cycles of chemotherapy before starting RT. Twenty-four percent of patients discontinued therapy because of progressive disease, and 12% discontinued because of toxicity from therapy.
Six patients (6%) on arm A and 20 (18%) on arm B did not receive RT. Six were randomly assigned but did not receive protocol treatment, eight withdrew or refused RT, 10 on arm B died before RT started, one on arm B received surgery after chemotherapy, and one on arm B received radiosurgery after chemotherapy. Of the 20 patients on arm B who never started RT, 13 had received one cycle of chemotherapy, three had received two cycles, three had received three cycles, and one patient was randomly assigned but did not receive treatment. One percent of patients on arm A and 4% of those on arm B were unassessable for this review because either RT was not completed or data was missing. Of the 103 patients on arm A and 85 patients on arm B who received RT and were assessable for review, 63 (61%) on arm A and 62 (73%) on arm B completed protocol-specified RT. Major or minor deviations from the planned RT regimen were noted in 39% of patients on arm A and 27% on arm B.
Toxicities
Outcome Survival. The median survival time was 11.2 months for the patients on arm A (BiCNU+RT) and 11.0 months for the patients on arm B (BiCNU+cisplatin RT) (P = .33 based on a two-sided log-rank test). The proportion of patients surviving at 12 months was 45% (95% confidence interval, 36% to 55%) for BiCNU+RT and 44% (95% confidence interval, 35% to 54%) for BiCNU+cisplatinRT. The Kaplan-Meier survival curves for each treatment group are presented in Fig 2. A total of 15 patients (7%) were alive at the time of this analysis. The median follow-up of these patients was 3.3 years (range, 2 to 5 years). After adjustment for age, sex, surgical procedure, and ECOG performance status, the results were similar (Table 4). No interactions between the baseline covariates and treatment were significant. When all patients, eligible and ineligible, were analyzed, the results were similar. Being less than 45 years of age and having a resection rather than a biopsy were significant predictors of improved outcome either univariately or in the Cox model (all P values  .01).
Time to progression. The median time to progression was 4.0 months for the patients receiving BiCNU+RT and 5.4 months for the patients receiving BiCNU+cisplatin RT (P = .54 based on a two-sided log-rank test). Figure 3 provides Kaplan-Meier curves for time to progression. Eleven patients without response information were censored at zero in the time-to-progression analysis. Six of these patients came from arm A, and five came from arm B. There was no significant treatment effect for survival or time to progression when analyzed by sex or race.
During the last three decades, substantial advances have been made in the field of neuro-oncology. Most of these relate to technological improvements in neuroradiology, neurosurgical techniques, and novel methods to deliver RT therapy. Unfortunately, these have had little effect on the outcome of patients with HGA. The median survival time remains 10 to 12 months, the 2-year survival rate is under 10%, and long-term survivors are rare. The outcome in these patients continues to be more a function of prognostic factors than of the therapy that is administered. As a result, efforts to combine agents with some activity have been a priority for clinical investigators. This therapeutic impasse has also prompted researchers to study new chemotherapy regimens in a pre-RT window design. This permits responses in previously untreated patients to serve as a guide to the activity of a novel chemotherapy regimen. Both BiCNU and cisplatin have modest response rates in patients with recurrent HGA. In addition, each has a different toxicity profile, allowing them to be given in combination. Reports combining these agents in this patient population began to appear in the literature in the early 1990s from several brain tumor centers. Recht et al29 treated 30 newly diagnosed patients with HGA with preirradiation chemotherapy consisting of two courses of intra-arterial cisplatin (90 mg/m2) and intravenous BiCNU (200 mg/m2). The median survival time of the treated patients was 61 weeks, and 24% of patients were progression-free at 1 year. Yung et al30 combined intravenous BiCNU and cisplatin during and after RT therapy in 45 newly diagnosed patients with HGA. The median survival time was 76 weeks, and 55% of the patients were alive at 18 months. Boiardi et al31 studied 84 patients with newly diagnosed glioblastoma multiforme with combinations of BiCNU, cisplatin, carboplatin, and etoposide. The authors noted that over 50% of the platinum-treated patients survived more than 18 months and concluded that "platinum-based chemotherapy has a beneficial effect on glial tumors."31 Kiu et al32 studied 22 newly diagnosed patients with HGA treated with RT and carmustine and cisplatin given before, during, and after RT and noted that this regimen was moderately toxic with a median survival time of 66 weeks. Kiu et al32 concluded that this regimen did not offer much of a survival advantage. A regimen of high-dose BiCNU and intracarotid cisplatin with autologous stem-cell rescue and RT therapy was administered to 34 patients with newly diagnosed HGA.33 Two patients died of toxicity, the median survival time was 15.5 months, and 24% of patients survived 2 to 6 years after treatment. Rajkumar et al34 studied escalating doses of BiCNU, cisplatin, and etoposide with accelerated RT in 16 patients with newly diagnosed HGA. They concluded that this was feasible and deserved further study. A multivariate analysis of 122 Italian patients treated with cisplatin plus BiCNU indicated that this regimen was significantly predictive of survival (P = .01).35 Lassen et al36 used carmustine, cisplatin, and etoposide followed by RT therapy in 29 newly diagnosed patients with glioblastoma multiforme. He noted a partial response rate of 33% after chemotherapy and an overall median survival time of 11.4 months. More recently, the North Central Oncology Group and SWOG, following on earlier work,37 have conducted a phase III trial randomly assigning patients with newly diagnosed glioblastoma multiforme to BiCNU plus cisplatin or to BiCNU alone in combination with RT therapy. A series of clinical studies focused on a regimen developed at Johns Hopkins that used 72-hour continuous infusions of BiCNU (40 mg/m2/d) and cisplatin (40 mg/m2/d) administered monthly for up to 3 months before RT therapy in patients with newly diagnosed HGA. The initial report of this regimen included 52 patients, 88% with glioblastoma multiforme and 12% who were over 45 years of age with anaplastic astrocytoma.19 Forty-two percent of patients had a response to the chemotherapy, which was defined as a 50% or greater reduction in contrast-enhancing volume on stable or reduced doses of dexamethasone. The median survival time of patients on this protocol was 13 months, and survival at 1, 2, 3, and 5 years was 62%, 19%, 12%, and 5%, respectively. In an attempt to intensify this treatment further, RT was administered concurrently with this chemotherapy regimen in another 50 patients.20 This resulted in increased toxicity without improvement in overall survival. This regimen was also studied in 18 patients in an Italian study in which the authors reported a complete and partial response rate of 54% after chemotherapy.21 Another cohort treated in Pittsburgh reported similarly encouraging results.22 The ECOG entered 50 patients onto a pilot study to determine whether it was feasible to conduct a phase III study using this aggressive and toxic regimen in the community setting.38 Overall, 79% of patients were able to complete at least two cycles of treatment, which exceeded the predefined measure of feasibility. The complete and partial response rate in this setting was 21%. The study presented in this article describes the combined efforts of ECOG and SWOG to conduct a phase III study comparing the Johns Hopkins regimen with standard adjuvant BiCNU. The study was powered to detect a substantial (66%) improvement in median survival because the toxicities and costs of this therapy were felt to be prohibitive if the benefits were marginal. The median survival time of 11.0 months for BiCNU plus cisplatin and 11.2 months for BiCNU is not significantly different (P = .33), and the proportion of patients surviving 1 year is virtually identical (44% v 45%, respectively), as are the overall survival curves. The results were unchanged after adjustments for age, sex, surgical procedure, and performance status. Time to progression was also not significantly different in the two treatment arms.
Although the primary toxicity in both treatment arms was myelosuppression, there was significantly more toxicity associated with arm B (BiCNU+cisplatin This phase III study was a natural consequence of four phase II studies involving over 170 patients that produced response rates ranging from 21% to 54% and provocative survival data at 2 (19%), 3 (12%), and 5 years (5%). However, the results of this study indicate that there is no survival benefit to justify the increased costs, hospitalization time, and toxicities associated with this continuous-infusion BiCNU and cisplatin regimen in patients with newly diagnosed glioblastoma multiforme. Given the intensity of the BiCNU and cisplatin in this regimen, these findings make it unlikely that these agents can substantially affect this disease in an adjuvant setting. Furthermore, on the basis of these results, the likelihood of strategies using higher doses of standard chemotherapy regimens with bone marrow or stem-cell rescue yielding positive results in the phase III context would be expected to be low.39–41 Two other observations are noteworthy. First, the results of this study raise concerns about the predictive value of respectable response rates in phase II pre-RT window studies. In this case, the objective response rate of 42% to BiCNU and cisplatin in phase II pre-RT trials has not translated into a difference in survival when tested in the phase III setting. One has to wonder how high the partial or complete response rate will need to be before a survival advantage will be evident in HGA. In addition, the toxicities of standard adjuvant BiCNU are not inconsequential, as noted in the control arm of this study, in which 65% of patients on arm A experienced grade 3 to 5 toxicities. This information, combined with the recent Medical Research Council study indicating that RT plus procarbazine, lomustine, and vincristine is no better than RT alone2 and the long and meager track record with adjuvant BiCNU, suggest that withholding chemotherapy until recurrence or participating in clinical trials are reasonable approaches in patients with newly diagnosed glioblastoma multiforme.
This study was coordinated by the Eastern Cooperative Oncology Group and supported in part by Public Health Service grants CA16116, CA23318, CA21076, CA73590, CA04920, CA32102, CA66636, CA21115 and from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services, Bethesda, MD. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
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2. Medical Research Council Brain Tumor Working Party: Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: A Medical Research Council trial. J Clin Oncol 19:509–518, 2001 3. Huncharek M, Muscat J, Geschwind JF: Multi-drug versus single agent chemotherapy for high grade astrocytoma: Result of a meta-analysis. Anticancer Res 18:4693–4697, 1998[Medline] 4. Fine HA, Dear KB, Loeffler JS, et al: Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 71:2585–2597, 1993[CrossRef][Medline] 5. Dinnes J, Cave C, Huang S, et al: A rapid and systemic review of the effectiveness of temozolomide for the treatment of recurrent malignant glioma. Br J Cancer 86:499–500, 2002[CrossRef][Medline] 6. Trent S, Kong A, Short SC, et al: Temozolomide as second-line chemotherapy for relapsed gliomas. J Neurooncol 57:247–251, 2002[CrossRef][Medline] 7. Brandes AA, Ermani M, Basso U, et al: Temozolomide in patients with glioblastoma at second relapse after first line nitroourea-procarbazine failure: A phase II study. Oncology 63:38–41, 2002[CrossRef][Medline] 8. Yung WK, Albright RE, Olson J, et al: A phase II study of temozolomide vs procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83:588–593, 2000[CrossRef][Medline] 9. Grossman SA, Supko J, Phupanich S, et al: Phase I/II trial of oral procarbazine in the treatment of recurrent high grade astrocytomas. Neuro-oncol 3:358–359, 2001 10. Turner CD, Gururangan S, Eastwood J, et al: Phase II study of irinotecan (CPT-11) in children with high-risk malignant brain tumors: The Duke experience. Neuro-oncol 4:102–108, 2002[Abstract]
11. Friedman HS, Petros WP, Friedman AH, et al: Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol 17:1516–1525, 1999 12. Jeremic B, Shibamoto Y, Grujicic D, et al: Pre-irradiation carboplatin and etoposide and accelerated hyperfractionated radiation therapy in patients with high grade astrocytomas: A phase II study. Radiother Oncol 51:27–33, 1999[CrossRef][Medline] 13. Jeremic B, Shibamoto Y, Grujicic D, et al: Concurrent accelerated hyperfractionated radiation therapy and carboplatin/etoposide in patients with malignant glioma: Long-term results of a phase II study. J Neurooncol 51:133–141, 2001[CrossRef][Medline] 14. Qureshi AI, Suri MF, Khan J, et al: Superselective intra-arterial carboplatin for treatment of intracranial neoplasms: Experience in 100 procedures. J Neurooncol 51:151–158, 2001[CrossRef][Medline] 15. Peterson K, Harsh G, Fisher PG, et al: Daily low-dose carboplatin as a radiation sensitizer for newly diagnosed malignant glioma. J Neurooncol 53:27–32, 2001[CrossRef][Medline] 16. Vinolas N, Gil M, Verger E, et al: Pre-irradiation semi-intensive chemotherapy with carboplatin and cyclophosphamide in malignant glioma: A phase II study. Anticancer Drugs 13:163–167, 2002[CrossRef][Medline] 17. Robins HI, Chang S, Prados MD, et al: A phase II trial of thymidine and carboplatin for recurrent malignant glioma: A North American Brain Tumor Consortium Study. Neuro-oncol 4:109–114, 2002[Abstract] 18. Fetell MR, Grossman SA, Fisher J, et al: Pre-irradiation paclitaxel in glioblastoma multiforme: Efficacy, pharmacology, and drug interactions. J Clin Oncol 15:3121–3128, 1997[Abstract]
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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
