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Phase III Trial of Carmustine and Cisplatin Compared With Carmustine Alone and Standard Radiation Therapy or Accelerated Radiation Therapy in Patients With Glioblastoma Multiforme: North Central Cancer Treatment Group 93-72-52 and Southwest Oncology Group 9503 Trials

Jan C. Buckner, Karla V. Ballman, John C. Michalak, Gary V. Burton, Terrence L. Cascino, Paula J. Schomberg, Roland B. Hawkins, Bernd W. Scheithauer, Howard M. Sandler, Randolph S. Marks, Judith R. O'Fallon

From the Mayo Clinic and Mayo Foundation, Rochester, MN; Siouxland Hematology-Oncology Associates, Sioux City, IA; Feist Weiller Cancer Center, Louisiana State University, Shreveport; Ochsner Community Clinical Oncology Program, New Orleans, LA; and the Southwest Oncology Group–University of Michigan, Ann Arbor, MI

Address reprint requests to Jan C. Buckner, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: buckner.jan{at}mayo.edu

	ABSTRACT

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PURPOSE: In patients with newly diagnosed glioblastoma multiforme, to determine whether cisplatin plus carmustine (BCNU) administered before and concurrently with radiation therapy (RT) improves survival compared with BCNU and RT and whether survival using accelerated RT (ART) is equivalent to survival using standard RT (SRT).

PATIENTS AND METHODS: After surgery, patients were stratified by age, performance score, extent of surgical resection, and histology (glioblastoma v gliosarcoma) and then randomly assigned to arm A (BCNU plus SRT), arm B (BCNU plus ART), arm C (cisplatin plus BCNU plus SRT), or arm D (cisplatin plus BCNU plus ART).

RESULTS: Four hundred fifty-one patients were randomly assigned, and 401 were eligible. Frequent toxicities included myelosuppression, vomiting, sensory neuropathy, and ototoxicity and were worse with cisplatin. There was no difference in toxicity between SRT and ART. Median survival times and 2-year survival rates for patients who received BCNU plus RT (arms A and B) compared with cisplatin, BCNU, and RT (arms C and D) were 10.1 v 11.5 months, respectively, and 11.5% v 13.7%, respectively (P = .19). Median survival times and 2-year survival rates for patients who received SRT (arms A and C) compared with ART (arms B and D) were 11.2 v 10.5 months, respectively, and 13.8% v 11.4%, respectively (P = .33).

CONCLUSION: Cisplatin administered concurrently with BCNU and RT resulted in more toxicity but provided no significant improvement in survival. SRT and ART produced similar toxicity and survival.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Cisplatin administered concurrently with radiation therapy (RT) has resulted in improved survival in patients with multiple tumor types, including nasopharyngeal,^1-3 head and neck,^4-7 esophageal,⁸ non–small-cell lung,⁹ and cervical carcinomas.^10,11 Previous studies have suggested that cisplatin may also have antitumor effects in a small proportion of patients with recurrent gliomas.^12-17 Cisplatin is a known radiation sensitizer.^18,19 Previous phase I and II trials have demonstrated both the safety and promising clinical results of carmustine (BCNU) plus cisplatin, with or without etoposide, added to radiation.^20-22 Also, at the time of trial implementation, there was no information available that neoadjuvant cisplatin and BCNU chemotherapy would not improve survival. No prior phase III trial had tested concurrent cisplatin with RT in this population of patients. Moreover, given their short duration of survival, shortening the course of RT for patients with glioblastoma multiforme, if equivalent to a standard RT (SRT) dose/fractionation schema, could reduce the number of days patients are required to travel to the treating institution, and the decreased interval between fractions and the associated reduction in overall treatment time could reduce repopulation of tumor cells, potentially resulting in improved local control without increased toxicity. Consequently, we initiated this trial to determine whether the survival of patients treated with cisplatin and BCNU before, during, and after RT (either standard fractionated or accelerated) differs from patients treated with BCNU alone and RT (either standard fractionated or accelerated) and whether survival of patients treated with an accelerated RT (ART) schedule (plus BCNU alone or BCNU and cisplatin) differs from patients treated with an SRT schedule (plus BCNU alone or BCNU and cisplatin).

	PATIENTS AND METHODS

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Eligibility Criteria
Adults with newly diagnosed, histologically confirmed glioblastoma multiforme who possessed satisfactory organ function were eligible. Contraindications to protocol participation included multifocal tumors, active or uncontrolled infections, other coexistent malignancy, prior cranial radiation, chemotherapy or immunotherapy for brain tumor, Eastern Cooperative Oncology Group (ECOG) performance status of 3 or 4, significant history of congestive heart failure (New York Heart Association class III or IV), pregnancy or lactation, or other significant medical or psychiatric illness that would preclude safe administration of protocol therapy. The protocol was approved by the institutional review board of each participating site; each patient provided written informed consent before protocol enrollment.

Treatment Schema
Patients were randomly assigned to one of four treatment arms within 4 weeks of surgery (Fig 1). Treatment arms were as follows: arm A, BCNU plus SRT; arm B, BCNU plus ART; arm C, BCNU plus cisplatin plus SRT; and arm D, BCNU plus cisplatin plus ART. In arms A and B, BCNU was administered intravenously at 200 mg/m²/d on day 1, every 8 weeks for six cycles. RT began with cycle 1. In arms C and D, BCNU was administered intravenously at 50 mg/m²/d on days 1 to 3, every 8 weeks, in cycles 1 and 2, and then intravenously at 200 mg/m²/d on day 1, every 8 weeks, in cycles 3 to 6. Cisplatin (arms C and D) was administered intravenously at 30 mg/m²/d on days 1 to 3 and 29 to 31, in cycles 1 and 2, every 8 weeks for two cycles. RT began with cycle 2. Patients who experienced progression during preirradiation chemotherapy while on stable or increased corticosteroid dose proceeded directly to assigned arm RT without further chemotherapy.

View larger version (6K): [in this window] [in a new window]   Fig 1. Treatment schema. Treatment arms were as follows: arm A, carmustine (BCNU) plus standard radiation therapy (RT); arm B, BCNU plus accelerated RT; arm C, BCNU plus cisplatin (CDDP) plus standard RT; and arm D, BCNU plus CDDP plus accelerated RT. See Patients and Methods for details. fx, fractions; d, day.

Treatment Monitoring
Pretreatment evaluation included clinical history, physical examination, Folstein Mini-Mental State Examination, CBC, blood chemistries, anticonvulsant level, serum pregnancy test, chest x-ray, head computed tomography or magnetic resonance imaging scan, and audiogram (arms C and D). During treatment, laboratory evaluations included audiograms before RT and with cycles 3 and 6 of chemotherapy, chest x-rays before every other treatment, and CBCs weekly (arms C and D, cycles 1 and 2) or beginning 3 weeks after BCNU otherwise. After treatment, patients were evaluated every 3 months for 1 year, every 4 months for year 2, every 6 months for years 3 and 4, and annually thereafter.

Study Design
This was a stratified, randomized, phase III trial with a 2 x 2 design using a dynamic allocation procedure²³ to determine whether there is a different survival distribution among patients treated with ART and chemotherapy versus SRT and chemotherapy or among patients treated with cisplatin plus BCNU before, during, and after RT versus BCNU administered during and after RT. Secondary goals were to compare the distributions of toxicity, overall survival, and progression-free survival and to determine potential prognostic factors. The stratification factors included patient age, extent of surgery, histology, and baseline performance score. In this design, a two-sided log-rank test²⁴ with a P = .05 significance level for comparing two groups (n = 202 each) has approximately 80% power to detect a 25% decrease in median survival and to detect a 35% increase in median survival.

Statistical Analysis
The primary end point analysis was conducted on and reported for all 451 enrolled patients (ie, intent to treat [ITT]). All remaining analyses were performed for two groups of patients to determine the effect of excluding ineligible and cancelled patients (all 451 enrolled patients and the 401 eligible, noncancelled patients). Patients were cancelled if they were enrolled onto the study but received no treatment before withdrawing. There were three patients who had a major protocol violation so severe as to render the results uninterpretable. These three patients are not included in the eligible group. Because there were no substantial clinical or statistical differences in results between the two groups, we only report the results of the ITT analysis for the primary end point. All other analyses are reported for the eligible, noncancelled (n = 401) group.

Overall survival and progression-free survival distributions were estimated with Kaplan-Meier estimators²⁵ and compared with log-rank tests (P = .05 level of significance). Comparisons were made among all four groups (arm A v arm B v arm C v arm D) as well as among combinations of groups.

Univariable and multivariable Cox proportional hazards models were used to identify potential prognostic factors. Candidate prognostic factors included treatment group (arm A v B v C v D; or SRT v ART; or BCNU v BCNU + cisplatin), patient age, sex, baseline Mini-Mental State Examination score, extent of surgery, baseline corticosteroid use, baseline anticonvulsant use, baseline performance score, histology, family history of brain cancer, and tumor location. Backward step variable selection was used to identify a final set of independent prognostic variables. The stability of the final model was assessed using a bootstrapping technique.

	RESULTS

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Patient Characteristics
Preliminary results of this trial were presented at the 37th Annual Meeting of the American Society of Clinical Oncology in 2001.²⁶ Between December 16, 1994 and June 17, 1999, 451 patients were randomly assigned to this trial, and 401 (89%) were eligible, nonexcluded patients. Reasons for exclusion include incorrect histology (n = 36), insufficient tumor specimen (n = 6), major treatment violation (n = 3), and cancellation (n = 5). Patient and tumor characteristics are listed in Table 1.

View larger version (9K): [in this window] [in a new window]   Fig 2. Overall survival by treatment arm (arm A = carmustine [BCNU] + standard radiation therapy [RT]; arm B = BCNU + accelerated RT; arm C = BCNU + cisplatin + standard RT; arm D = BCNU + cisplatin + accelerated RT).

View larger version (8K): [in this window] [in a new window]   Fig 3. Overall survival in all patients receiving carmustine (BCNU) alone (arms A and B) versus BCNU + cisplatin (CDDP; arms C and D).

View larger version (7K): [in this window] [in a new window]   Fig 4. Overall survival in all patients receiving standard radiation therapy (SRT; arms A and C) versus accelerated radiation therapy (ART; arms B and D).

Median progression-free survival times and 1-year progression-free survival rates in arms A, B, C, and D were 5.2, 5.5, 6.2, and 6.6 months, respectively (P = .62), and 20.4%, 16.7%, 15.2%, and 17.3%, respectively. There was no difference in median progression-free survival times and 1-year progression-free survival rates in patients who received BCNU + RT (arms A and B) compared with patients who received cisplatin, BCNU, and RT (arms C and D) (5.4 v 6.3 months, respectively, P = .31; and 18.1% v 15.8%, respectively). Similarly, there was no difference in median progression-free survival times and 1-year progression-free survival rates in patients who received SRT (arms A and C) compared with patients who received ART (arms B and D) (5.6 v 5.6 months, respectively, P = .82; and 17.8% v 17.0%, respectively, P = .82). Similar results were obtained for the 451 enrolled ITT patients.

Toxicity
Treatment-related toxicity is listed in Tables 3 and 4. The primary toxicities were neutropenia, thrombocytopenia, nausea, vomiting, lethargy, neurosensory changes, hearing loss, alopecia, anorexia, headache, and skin reactions or dermatitis in the radiation ports. Pulmonary toxicity and neurocortical deterioration attributed to treatment were uncommon but potentially serious and included one death (arm A) attributed to neurocortical toxicity. We did not observe a difference in neurocortical toxicity between arms A and B versus arms C and D. However, the short survival of most patients and the absence of formal neurocognitive assessment do not permit firm conclusions concerning potential delayed neurocognitive toxicity. In addition, four patients experienced lethal infections related to treatment. More nausea, vomiting, and hearing loss occurred in the cisplatin-containing treatment arms. Hearing loss was mild and generally not clinically significant. Hearing loss subsequent to treatment was more common in older patients. A more detailed evaluation of ototoxicity was reported separately.²⁷

	DISCUSSION

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The addition of platinum-based chemotherapy concurrently with RT has been shown to improve survival in multiple phase III trials in other malignancies. There is evidence that cisplatin accumulates in high-grade gliomas and has modest single-agent activity.^12-17 Given meta-analyses indicating a modest benefit of single-agent BCNU when added to RT, it seemed reasonable to add an active agent with radiosensitizing properties to RT to improve on single-agent activity with BCNU.^28,29 Pilot data demonstrated safety of the regimen chosen and provided preliminary evidence of improved efficacy.²⁰

On the basis of the ITT analysis, it is tempting to conclude that cisplatin, when added to BCNU and RT, produces improvement in survival (P = .042). However, when only eligible patients with glioblastoma multiforme are included, the apparent difference disappears (P = .19). Of the 50 ineligible patients, 36 did not have glioblastoma on central review of pathology. The diagnoses by central review in the 36 patients without glioblastoma included low-grade glioma, anaplastic astrocytoma, anaplastic mixed glioma, and ependymoma. In arms A plus B versus C plus D, 14 and 22 patients did not have confirmed glioblastoma, respectively. These imbalances likely explain the apparent differences in survival based on the ITT analysis. Even if we accept the ITT analysis at face value, we must acknowledge that the magnitude of survival prolongation is short and that the increased toxicity in the cisplatin-containing regimens diminishes enthusiasm for inclusion of cisplatin in addition to BCNU. Similarly, an ECOG phase III trial using continuous-infusion cisplatin plus BCNU before RT demonstrated no improvement in survival compared with RT and BCNU alone.³⁰

The discrepancy between the ITT analysis compared with the analysis of all patients highlights the need for careful pathology review in clinical trials for glioma patients. Relatively small numbers of patients with distinctively different survival outcomes can significantly skew the survival distributions and lead to misinterpretation of trial outcomes.

Why was the addition of cisplatin ineffective in both this trial and in the ECOG trial? Perhaps cisplatin is inactive or insufficiently active to produce significant survival gains. Alternatively, perhaps toxicity precluded sufficient delivery of intended therapy. Cisplatin was delivered at an initial dose of 90 mg/m²/cycle, with protocol-specified dose reductions based on individual patient experience of toxicity. The prescribed dose was consistent with the dose prescribed in other trials demonstrating benefits of concurrent RT and cisplatin-based chemotherapy regimens. Dose reductions as a result of toxicity occurred in only 8% and 15% of patients in arms C and D, respectively, and only 14% of patients in the entire trial discontinued treatment because of patient refusal or toxicity. Consequently, we conclude that we delivered the maximum-tolerated doses of cisplatin to the majority of patients on this trial and cannot explain the lack of efficacy by the lack of delivery of tolerable doses of cisplatin. It is certainly possible that cisplatin did not reach the tumor within the brain because of reduced drug delivery as a consequence of the blood-tumor barrier. However, limited data from previous reports indicate that cisplatin can reach gliomas in cytotoxic concentrations.³¹ It is also possible that, given the limited single-agent activity, insufficient numbers of doses of cisplatin were delivered concurrently with RT. Both daily and weekly schedules have been used successfully in other tumor types, but treatments administered every 3 to 4 weeks have also demonstrated efficacy.¹ Finally, failure to deliver RT after chemotherapy to some patients may have resulted in shortened overall survival time.

Recently, European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC) investigators demonstrated improvement in survival of glioblastoma patients when temozolomide is administered concurrently with RT and for six cycles after RT compared with RT alone.³² This trial was different from ours in that RT alone was the control arm for the EORTC/NCIC trial. Median survival times in the present trial and in the ECOG trial were just under 12 months, which is similar to the median survival time of the RT alone arm in the EORTC trial (12 months), suggesting that neither BCNU alone nor the combination of BCNU plus cisplatin contributes significantly to survival compared with RT alone. It is noteworthy that the EORTC/NCIC study excluded patients greater than 70 years old and that these patients typically have shorter survival than younger patients. Moreover, temozolomide was administered daily during RT. It is of note that the response rate to single-agent temozolomide, as judged by conventional imaging criteria, was only 5% in one trial³³ and 8% in another.³⁴ Although temozolomide may well be a more active agent, this activity may not be apparent using imaging response criteria. Alternatively, the daily schedule of temozolomide concurrently with RT may explain, in part, the observed benefits of treatment. In either case, the clear survival benefit and low toxicity of temozolomide in combination with RT argues against use of the more toxic BCNU plus cisplatin regimens in the future.

Our study also demonstrated that a short course of ART administered over 3 weeks is no worse in terms of survival than SRT administered over 6 weeks. There is no apparent difference in toxicity between the two RT fraction schemes. Hence, the 3-week twice a day schedule is a viable alternative to the 6-week regimen.

Careful statistical analysis of prognostic variables demonstrated that younger age, a better performance score, and more extensive surgical resection are associated with better outcomes. The significance of these clinical variables has been demonstrated previously.³⁵ An abnormal Folstein baseline Mini-Mental State Examination score (a score of < 27 out of a total possible score of 30) and the use of anticonvulsants, although previously identified as potential prognostic variables in prior North Central Cancer Treatment Group trials, were not confirmed as prognostic variables.^35-38 It is of note that previous trials included patients with both glioblastoma multiforme (WHO grade 4) and anaplastic astrocytoma (WHO grade 3). Consequently, baseline Mini-Mental State Examination and the use of anticonvulsants may be of significance mainly in non–glioblastoma multiforme histologies. Indeed, classification and regression tree analysis indicated that baseline Mini-Mental Status Examination score was important only in younger, non–glioblastoma multiforme patients.

In summary, cisplatin and BCNU administered before and during RT, as administered in this protocol, demonstrated no clinically significant improvement in survival compared with BCNU and RT alone in patients with glioblastoma multiforme. ART as administered in this protocol produced similar outcomes compared with SRT delivered as a single daily fraction for 7 weeks. Substantial toxicity associated with use of cisplatin concurrently with alkylating agents argues against future combination trials with this agent.

	Appendix

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The following institutions participated in the study: Duluth Community Clinical Oncology Program (CCOP), Duluth, MN 55805 (Daniel A. Nikcevich, MD); Medcenter One Health Systems, Bismarck, ND 58506 (Edward J. Wos, DO); Carle Cancer Center CCOP, Urbana, IL 60801 (Kendrith M. Rowland, Jr, MD); Cedar Rapids Oncology Project CCOP, Cedar Rapids, IA 52403 (Martin Wiesenfeld, MD); Iowa Oncology Research Association CCOP, Des Moines, IA 50309 (Roscoe F. Morton, MD); Meritcare Hospital CCOP, Fargo, ND 58122 (Preston D. Steen, MD); Geisinger Clinic and Medical Center CCOP, Danville, PA 17822 (Albert Bernath, MD); Altru Health Systems, Grand Forks, ND 58201 (Todor Dentchev, MD); Ochsner CCOP, New Orleans, LA 70121 (Carl G. Kardinal, MD); Illinois Oncology Research Assn., CCOP, Peoria, IL 61615 (John W. Kugler, MD); Rapid City Regional Oncology Group, Rapid City, SD 57709 (Larry P. Ebbert, MD); CentraCare Clinic, St Cloud, MN 56301 (Harold E. Windschitl, MD); Sioux Community Cancer Consortium, Sioux Falls, SD 57105 (Loren K. Tschetter, MD); Toledo Community Hospital Oncology Program CCOP, Toledo, OH 43623 (Paul L. Schaefer, MD); Scottsdale CCOP, Scottsdale, AZ 85259 (Tom R. Fitch, MD); Michigan Cancer Consortium, Ann Arbor, MI 48106 (Philip J. Stella, MD); Missouri Valley Cancer Consortium, Omaha, NE 68106 (James A. Mailliard, MD); Hematology and Oncology of Dayton, Inc, Dayton, OH 45415 (Howard M. Gross, MD); Atlanta Regional CCOP (Thomas E. Seay, MD, PhD); Wichita CCOP, Wichtia, KS 67214 (Shaker R. Dakhil, MD); and Hawaii Minority-Based CCOP, Honolulu, HI 96813 (William S. Loui, MD).

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Jan C. Buckner, Paula J. Schomberg, Bernd W. Scheithauer, Randolph S. Marks, Judith R. O'Fallon Administrative support: Gary V. Burton Provision of study materials or patients: John C. Michalak, Gary V. Burton, Terrence L. Cascino, Paula J. Schomberg, Bernd W. Scheithauer Collection and assembly of data: Jan C. Buckner, Roland B. Hawkins, Bernd W. Scheithauer, Judith R. O'Fallon Data analysis and interpretation: Jan C. Buckner, Karla V. Ballman, Bernd W. Scheithauer, Judith R. O'Fallon Manuscript writing: Jan C. Buckner, Karla V. Ballman, Paula J. Schomberg Final approval of manuscript: Jan C. Buckner, Karla V. Ballman, John C. Michalak, Gary V. Burton, Terrence L. Cascino, Paula J. Schomberg, Roland B. Hawkins, Bernd W. Scheithauer, Howard M. Sandler, Randolph S. Marks, Judith R. O'Fallon

 

	ACKNOWLEDGMENTS

 
We acknowledge the contributions of patients who participated in this trial and their families, as well as North Central Cancer Treatment Group and Southwest Oncology Group participating institutions, their principal investigators, and clinical research associates.

	NOTES

 
Supported in part by Public Health Service Grants No. CA-25224, CA-37404, CA-15083, CA-63826, CA-35103, CA-35272, CA-63848, CA-45450, CA-35195, CA-52352, CA-35090, CA-35101, CA-35269, CA-37417, CA-35448, CA-63844, CA-63849, CA-35113, CA-60276, CA-35415, and CA-35431.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted November 2, 2005; accepted June 16, 2006.

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