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Survival and Neurologic Outcomes in a Randomized Trial of Motexafin Gadolinium and Whole-Brain Radiation Therapy in Brain Metastases

Minesh P. Mehta, Patrick Rodrigus, C.H.J. Terhaard, Aroor Rao, John Suh, Wilson Roa, Luis Souhami, Andrea Bezjak, Mark Leibenhaut, Ritsuko Komaki, Christopher Schultz, Robert Timmerman, Walter Curran, Jennifer Smith, See-Chun Phan, Richard A. Miller, Markus F. Renschler

From the University of Wisconsin Medical School, Madison; Froedtert Memorial Hospital at Medical College of Wisconsin, Milwaukee, WI; Kaiser Permanente, Los Angeles; Sutter Hospital, Radiological Associates of Sacramento, Sacramento; Pharmacyclics, Inc, Sunnyvale, CA; Cleveland Clinic, Cleveland, OH; University of Texas M.D. Anderson Cancer Center, Houston, TX; Indiana University Medical Center, Indianapolis, IN; Thomas Jefferson University, Philadelphia, PA; Dr Bernard Verbeeten Institut, Tilburg; Academisch Ziekenhuis Utrecht, Utrecht, the Netherlands; Cross Cancer Institute, Alberta; Montreal General Hospital, Quebec; and Princess Margaret Hospital, Toronto, Canada.

Address reprint requests to Minesh Mehta, MD, Department Human Oncology Radiation Oncology, University of Wisconsin—Madison, K4/B100, 600 Highland Ave, Madison, WI 53792; email: mehta{at}mail.humonc.wisc.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Purpose: This phase III randomized trial evaluated survival as well as neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd).

Patients and Methods: Patients were randomly assigned to 30 Gy of WBRT ± 5 mg/kg/d MGd. Survival and time to neurologic progression determined by a blinded events review committee (ERC) were coprimary end points. Standardized investigator neurologic assessment and neurocognitive testing were evaluated.

Results: Four hundred one (251 non–small-cell lung cancer) patients were enrolled. There was no significant difference by treatment arm in survival (median, 5.2 months for MGd v 4.9 months for WBRT; P = .48) or time to neurologic progression (median, 9.5 months for MGd v 8.3 months for WBRT; P = .95). Treatment with MGd improved time to neurologic progression in patients with lung cancer (median, not reached for MGd v 7.4 months for WBRT; P = .048, unadjusted). By investigator, MGd improved time to neurologic progression in all patients (median, 4.3 months for MGd v 3.8 months for WBRT; P = .018) and in lung cancer patients (median, 5.5 months for MGd v 3.7 months for WBRT; P = .025). MGd improved neurocognitive function in lung cancer patients.

Conclusion: The overall results did not demonstrate significant differences by treatment arm for survival and ERC time to neurologic progression. Investigator neurologic assessments demonstrated an MGd treatment benefit in all patients. In lung cancer patients, ERC- and investigator-determined time to neurologic progression demonstrated an MGd treatment benefit. MGd may improve time to neurologic and neurocognitive progression in lung cancer.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
BRAIN METASTASES are a frequent complication of many cancers, occurring in as many as 24% of all cancer patients.¹ In lung cancer, the most common cause of brain metastases, up to 50% of patients develop central nervous system (CNS) involvement.^2,3 Brain metastases occur early in lung cancer, sometimes producing neurologic symptoms at disease presentation, compared with other cancers where CNS spread is usually a later complication.¹ The median survival of patients with brain metastases is approximately 4 months with whole-brain radiation therapy (WBRT). Clinical trials comparing various radiation therapy regimens and radiosensitizers have not demonstrated a survival benefit.^4–10 The majority of patients with brain metastases have neurologic impairment, yet none of these studies performed detailed assessments of neurologic or neurocognitive function. Neurocognitive impairments preventing functional independence have been shown to be more common than physical disability in patients with primary brain tumors.¹¹ Motexafin gadolinium (MGd) is a redox active drug that targets tumor cells and increases radiation response in preclinical models.^12–14 MGd catalyzes the oxidation of intracellular reducing metabolites, such as ascorbate, glutathione, dihydrolipoate, nicotinamide adenine dinucleotide phosphate, and protein thiols, generating reactive oxygen species in a process known as futile redox cycling.¹² MGd is paramagnetic, and previous clinical studies have demonstrated tumor localization using magnetic resonance imaging (MRI).^15,16 A potentially favorable effect on local tumor control was indicated by a phase I/II study in patients with brain metastases from solid tumors treated with MGd and WBRT, which demonstrated a 72% radiologic response rate, with only 12% of patients dying as a result of CNS tumor progression.¹⁷

This randomized phase III study was designed to determine whether MGd, when added to WBRT, would improve outcome for patients with brain metastases as measured by several assessments of neurologic and neurocognitive function and by survival. Because patients with brain metastases frequently die from systemic disease progression, this study used standardized neurologic and neurocognitive evaluation, centralized blinded review, and neurologic assessments by the clinical investigators to evaluate the effect of improved local tumor control.¹⁸ An independent events review committee (ERC) determined the end points of neurologic progression or death with neurologic progression on the basis of prospectively established progression criteria. In this article, we present the results from this randomized trial with MGd and report the first comprehensive evaluation of neurologic and neurocognitive function in patients with brain metastases from solid tumors.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patients
Adult patients were eligible if they had MRI-demonstrated brain metastases from histologically proven solid tumors, required WBRT, and had a Karnofsky performance status ≥ 70. Institutional review board approval was granted from each center, and written informed consent was obtained from all patients.

Patients were excluded if they had small-cell lung cancer, lymphoma, or germ-cell tumors; had brain metastases that had been partially or completely resected; had received prior cranial irradiation; had leptomeningeal metastases; or had two or more sites of extracranial metastases, except when breast was the primary cancer. Patients were excluded if chemotherapy was planned during WBRT or the subsequent 14 days or if radiosurgery was the initial therapy. Patients were grouped by recursive partitioning analysis (RPA) class according to Karnofsky performance status, age, and extent of disease.¹⁹ Minimal laboratory requirements included the following: absolute granulocyte count ≥ 1,500/µL; platelets ≥ 50,000/µL; total bilirubin, ALT, and AST less than two times the upper limit of normal; and serum creatinine less than 2 mg/dL.

Treatments
In this open-label study, patients were randomly assigned to receive 30 Gy of WBRT given in 10 daily fractions, with or without MGd.¹⁸ MGd was injected intravenously at a dose of 5 mg/kg/d, 2 to 5 hours before each fraction of WBRT. Guidelines for the initiation and tapering of corticosteroids were specified by the protocol.

Efficacy
The coprimary end points were survival and time to neurologic progression. Secondary end points were time to neurocognitive progression, time to loss of functional independence, radiologic response rate, time to radiologic progression, time to progression of brain-specific quality of life (Functional Assessment of Cancer Therapy—Brain [FACT-BR]), and safety.

Patients were evaluated at entry, at monthly intervals for the first 6 months, and then every 3 months until their deaths. MRI scans were obtained at baseline, at 2, 4, and 6 months, and then every 3 months and were reviewed in a blinded manner.¹⁸

At each study visit, neurologic symptoms and signs, FACT-BR, Barthel Index of Activities of Daily Living, and neurocognitive function were evaluated. All individuals administering the neurocognitive tests (Hopkins Verbal Learning Tests, Controlled Oral Word Association, Grooved Pegboard test, and Trailmaking tests A and B) underwent thorough training and certification.¹⁸ Adverse events were graded using the National Cancer Institute Common Toxicity Criteria, version 2.

An ERC, blinded to the treatment assignment, reviewed baseline and follow-up neurologic data according to previously reported procedures.¹⁸ The composition, blinding, and procedures for the ERC were developed in consultation with the Food and Drug Administration and were intended to establish objective progression criteria that were measurements of clinical benefit. Confounding factors that might affect patients’ neurologic function, such as corticosteroid use or tapering, narcotic use, metabolic derangements, or treatment of extracranial cancers, were provided to the ERC. Prespecified criteria for ERC-determined progression required a worsening in two or more of the following clinical domains: neurocognitive function, neurologic signs, and neurologic symptoms. Patients were considered to have had significant deterioration in their neurocognitive function if a z-score average increased by 2 or more (indicating a deterioration by greater than 2 SDs) on two consecutive visits or increased by 2 on the last follow-up visit before death. Deterioration of neurologic signs and symptoms was considered significant if it was consistent with the presence of brain metastases, not explained by confounding factors, and the findings were persistent on two consecutive visits. The ERC considered MRI results only if a patient was found to have deterioration in at least two of the three neurologic domains to confirm that the observed deterioration in neurologic domains was related to brain metastases and not to confounding factors. MRI results were used to confirm clinical findings but were not used to determine the neurologic progression end point.

The ERC assigned the date of neurologic progression as the date with the earliest evidence of progression. The ERC assigned the date of neurologic progression as the date of death for patients with evidence of neurologic progression at the time of death. Patients who received additional brain-metastasis–directed treatments and did not have prior evidence of neurologic progression were censored at the time of additional treatment. Patients who died or terminated study follow-up and did not have prior evidence of neurologic progression were censored at the time of death or termination from follow-up. These patients were not censored in the survival analysis.

Neurologic progression also was determined by investigators using predefined criteria. Progression was based on an overall assessment of the patient’s neurologic status at any visit compared with baseline status, incorporating neurologic symptoms, neurologic signs, and radiologic data. In contrast to the ERC, investigator-determined neurologic progression did not require confirmation at the next visit and could be based on MRI progression. These differences provided the investigators with more frequent assessments and more clinical information than was available to the ERC. Investigators also assessed whether the most probable cause of death was related to CNS or systemic tumor progression.

Statistical Methods and Sample Size Calculation
Patients were stratified at randomization by the urn method according to tumor type (lung, breast, or other), RPA class, and study center.²⁰ Sample size was calculated based on a two-sided Type I error rate of 5% and a power of 80% to detect an approximate 1.7-month increase in median survival time in the study group or to detect a 2-month benefit in time to neurologic progression. By design, the database was locked 6 months after the last randomization. The analyses of survival, time to neurologic progression, time to loss of functional independence, deterioration in quality of life, and time to radiologic progression were performed using a log-rank test stratified by tumor type and RPA class, and the results were plotted using the Kaplan-Meier method.²¹ All analyses (except survival) censored patients for nonneurologic deaths. Cox-proportional hazard modeling was used to test for the interaction between treatment effect and tumor type.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Characteristics
Four hundred one patients were randomly assigned to receive either MGd and WBRT or WBRT alone; there were 193 patients in the MGd and WBRT arm and 208 patients in the WBRT arm. No patients were excluded from the analyses. The two groups were balanced with respect to known prognostic features (Table 1). There were 251 patients with lung cancer, 75 patients with breast cancer, and 75 patients with other cancers. Brain was the only site of metastases in 50.8% of patients. The majority of patients enrolled onto the study had non–small-cell lung cancer with the following histologies: adenocarcinoma, 43%; large cell, 15.2%; squamous cell, 16.3%; other, 2.0%; and not specified, 23.5%. The clinical features of lung cancer patients were found to differ significantly from patients with breast or other cancers, as shown in Table 2. At presentation with their primary tumor, 46.6% of lung cancer patients had brain metastases; 61.4% of lung cancer patients had brain as the only site of metastases. Lung cancer patients had less prior systemic therapy and smaller lesion volume (as measured by the sum of indicator lesions) in the brain. The patient characteristics for the lung cancer subgroup were balanced between treatment arms.

View larger version (15K): [in this window] [in a new window]   Fig 1. Overall survival by treatment group. Study time indicates time in days (D) or months (M) since randomization. Median time is in months. P value calculated by stratified log-rank test. WBRT, whole-brain radiation therapy; MGd, motexafin gadolinium.

View larger version (23K): [in this window] [in a new window]   Fig 2. Time to neurologic progression by treatment arm: (A) Overall—Events Review Committee; (B) Overall—Investigator; (C) Lung—Events Review Committee; (D) Lung—Investigator. Abbreviations/symbols: WBRT, whole-brain radiation therapy, - - -; MGd, motexafin gadolinium, —; censored subject, . . .; NR, not reached. Study time is in days (D) or months (M); median is in months. Hazard ratios (HR) were calculated using Cox proportional hazards model.

Time to Neurocognitive Progression, Cause of Death, and Other Secondary End Points
Baseline neurocognitive function was balanced between treatment arms for the overall study population and for each tumor stratum. Baseline impairment in neurocognitive tests was found in more than 65% of patients, with most patients demonstrating multiple abnormalities (Fig 3A and 3B). Time to neurocognitive progression for memory and executive function were improved in lung cancer patients treated with MGd and WBRT compared with WBRT alone (Table 4). No benefit was found in patients with breast cancer or other cancers.

View larger version (15K): [in this window] [in a new window]   Fig 3. (A) Baseline neurocognitive impairment for all patients by test for Controlled Oral Word Association (COWA), Hopkins Verbal Learning Test (HVLT; delayed, recall, and recognition), Pegboard (PEG, dominant and nondominant) and Trailmaking tests (A and B). (B) Baseline neurocognitive function by number of impaired tests.

A favorable trend in time to loss of functional independence measured by the Barthel Index was found only for lung cancer patients receiving MGd and WBRT compared with WBRT alone (P = .18; hazard ratio, 0.73 by Cox model). No significant differences in time to progression of brain-specific quality-of-life (FACT-BR) assessment were observed in any of the treatment groups. No significant difference in corticosteroid use was noted between the treatment arms at entry or during the study period.

Only 68% of patients had follow-up MRI scans (21.2% of patients died before the first follow-up MRI scan), and there was no significant difference in radiologic response (complete and partial response was 46.3% for MGd and WBRT and 50.7% for WBRT alone) or time to radiologic progression between treatment arms.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
This randomized clinical trial was designed to evaluate the safety and efficacy of MGd in combination with WBRT, compared with WBRT alone, for the treatment of patients with brain metastases from solid tumors. There was no improvement in survival seen with the addition of MGd to WBRT. These results are not unexpected in the patient population enrolled onto this trial because most patients had uncontrolled primary tumors, extracranial metastases, or multiple brain metastases. In a study in patients with single brain metastases, Patchell et al²² found no survival benefit in patients treated with surgical resection and radiation compared with surgery alone, despite improvement in local control in the combined-treatment group. Other studies that have examined more aggressive radiation doses and schedules or used WBRT in combination with radiosensitizing drugs also failed to show a survival benefit.^4–10,23,24

Because of the limitations of a survival end point in assessing the value of a treatment aimed at improving tumor control in the brain, this study used several measurements of neurologic and neurocognitive function to determine the potential benefit of MGd when added to WBRT. The neurologic progression end point provided a clinical measure of the impact of brain metastases progression on neurologic function. Patients with brain metastases develop myriad neurologic abnormalities, and these may be confounded by additional complications related to systemic disease and the use of corticosteroids, narcotics, and other treatments. A novel system for scoring neurologic progression by an independent panel of experts, blinded to treatment assignment, was designed to avoid the potential bias of investigator-determined neurologic progression.¹⁸ Although some components of the data provided to the ERC, such as physical examination, were collected by unblinded physicians, ERC scoring of progression required findings of multiple, significant, and persistent abnormalities that could only be attributed to brain metastases progression. One of the three clinical domains considered by the ERC, neurocognitive function, was assessed in a centralized laboratory by blinded scoring. The ERC progression criteria were more stringent than those used in standard clinical practice because they required a worsening in two or more of three neurologic domains and confirmation at the next follow-up visit. Prospectively defined neurologic evaluation by the investigators also was used to determine neurologic progression. Investigator assessment has been the standard in neuro-oncology studies.^22,25,26 Investigator-determined progression could be based on any single neurologic finding, did not require confirmation, allowed use of MRI as sole evidence of progression, and made use of clinical information obtained during nonscheduled study visits. Investigators scored progression more frequently and earlier than the ERC. By investigator assessment, a significant improvement in time to neurologic progression for the intent-to-treat population was observed for patients receiving MGd and WBRT. The difference in findings observed between the ERC and investigators was primarily a result of censoring from deaths before the ERC progression criteria were met. Although there is the potential for bias by investigator assessment of neurologic progression, the benefit was seen only in lung cancer patients.

Although the study did not meet the coprimary end point of time to neurologic progression by ERC for the entire study population, both the ERC and investigator assessment revealed a benefit with MGd treatment in the prespecified lung cancer stratum. A significant interaction between tumor type and MGd treatment effect was found for the ERC neurologic assessments, corroborating this subgroup analysis. As shown in Table 2, patients who had lung cancer differed substantially from patients with breast cancer and other cancers. Lung cancer patients more often presented with brain metastases at their initial primary tumor diagnosis, had brain as the only known site of metastases, had smaller lesion volume, and received less prior therapy. There are several possible causes of the observed benefit in time to neurologic progression seen in the lung cancer subgroup. It is likely that less-extensive intracranial disease, more rapid and reversible development of CNS signs and symptoms, and less exposure to potentially neurotoxic chemotherapies provide a greater opportunity to demonstrate a benefit in this subgroup. Similar findings were recently reported by Sperduto et al²⁷ in a study of WBRT with or without radiosurgery in patients with one to three brain metastases in which a treatment benefit was seen in a lung cancer subgroup.

In contrast to other studies, we found no survival difference between RPA class 1 and 2.^19,28,29 The RPA classification was developed based on retrospective analysis. The lack of prognostic utility of RPA class in our prospective study may question the value of RPA class. Alternatively, our results could have occurred because patient-entry criteria were different from those used in previous studies.

This study establishes that patients with brain metastases have significant neurocognitive impairment before receiving WBRT. Neurocognitive function, one of the secondary end points of this study, is objective and not dependent on self-reporting, which is unreliable because of impairment caused by tumor growth and treatment. Although never previously measured in patients with brain metastases, in glioblastoma multiforme, neurocognitive progression is predictive for survival.³⁰ Performance on neurocognitive tests is related to the patient’s ability to manage finances, recognize safe and unsafe behaviors, and remember and comply with medication regimens.^11,31 Consistent with the results of the ERC and investigator time to neurologic progression, neurocognitive testing revealed a benefit in prolonging time to neurocognitive progression in six tests of memory and executive function for lung cancer patients treated with MGd. There was no benefit seen in testing fine motor skills. Fine motor skills could be irreversibly affected by baseline neurologic impairments and exposure to neurotoxic therapies. Functional independence, measured using the Barthel Index, an activities-of-daily-living scale, also showed a favorable trend for MGd treatment benefit in lung cancer patients. FACT-BR seemed to be an insensitive measurement of quality of life in our study because the median time to progression based on these scores was not reached in either treatment arm. There was no significant difference seen in radiologic response between treatment arms, but follow-up MRI scans were available in only 68% of patients. Grant et al³² also have reported no relationship between radiologic response and time to progression or survival in patients with gliomas. Both our study and the study of Grant et al indicate that radiologic evaluations are not reliable indicators of clinical benefit determined by neurologic progression or survival. No difference in corticosteroid usage was seen between treatment arms. Although corticosteroid usage was considered by the ERC, its use is likely subjective and variable.

Our study demonstrates that most patients experience neurologic progression despite treatment with WBRT and indicates the need for improved therapies for brain metastases. The assessment of neurologic progression using the techniques described in this study may provide improved methods to test the efficacy and clinical benefit of treatments for brain metastases. Our findings indicate that it may be difficult to demonstrate neurologic benefit in patients with brain metastases that develop relatively late in the course of the disease, possibly as a result of prior neurotoxic therapies or irreversibility of fixed neurologic deficits. In breast cancer, for example, prolonged neurocognitive impairment has been demonstrated after adjuvant chemotherapy.³³ Our studies indicate that patients most likely to benefit from therapies aimed at controlling brain metastases are those with limited prior therapy, limited extracranial disease, and development of brain metastases soon after primary cancer diagnosis.

In this study, we show that MGd is well tolerated when used in combination with WBRT and seems to improve neurologic outcomes in the subset of patients with brain metastases from lung cancer. A randomized phase III trial using ERC-determined time to neurologic progression as the study end point is underway in patients with non–small-cell lung cancer to confirm the benefit of MGd in combination with WBRT in this group of patients.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The following investigators and institutions also participated in the study: R. Albright, University of Cincinnati, Cincinnati, OH; T. Batchelor, Massachusetts General Hospital, Boston, MA; H. Brereton, Radiation Medicine Associates of Scranton, Scranton, PA; P. Pickens, Abington Hematology Oncology Associates, Meadowbrook, PA; A. Cmelak, Vanderbilt University, Nashville, TN;S. McCachren, Thompson Cancer Survival Center, Knoxville, TN; C. Collier, Amsterdam Community Cancer Program, Amsterdam, NY; A. Frank, Riverview Cancer Care Medical Associates, Rexford, NY; I. Crocker, Emory University, Atlanta, GA; M. Croghan, Arizona Oncology Associates, Tucson, AZ; P. Eisenberg, Marin Oncology Associates, Greenbrae, CA; J. Ford, University of California Los Angeles Medical Center, Los Angeles, CA; A. Rao, Kaiser Permanente, Los Angeles, CA; Q. Le, Stanford University School of Medicine, Stanford, CA; M. Leibenhaut, Radiological Associates of Sacramento, Sacramento, CA; R. Pezner, City of Hope National Medical Center, Duarte, CA; L. Gaspar, University of Colorado, Denver, CO; M. Katin, Radiation Therapy Services, Inc, Fort Myers, FL; R. Komaki, University of Texas M.D. Anderson Cancer Center, Houston, TX; F. Mott, Scott & White Hospital, Temple, TX; M. Saunders, Tyler Cancer Center, Tyler, TX; P. Kumar, Cancer Institute of New Jersey, New Brunswick, NJ; J. Liebmann, New Mexico Hematology Oncology, Albuquerque, NM; K. Levin, Wayne State University, Detroit, MI; M. Mehta, University of Wisconsin, Madison, WI; C. Schultz, Medical College of Wisconsin, Milwaukee, WI; J. Rieke, Virginia Mason Medical Center, Seattle, WA; A. Schorer, Department of Veterans Affairs Medical Center, Minneapolis, MN; R. Siemers, North Memorial Research Center, Minneapolis, MN; M. Seiler, Hematology Oncology, New Orleans, LA; J. Suh, Cleveland Clinic, Cleveland, OH; R. Timmerman, Indiana University Medical Center, Indianapolis, IN; A. Bezjak, Princess Margaret Hospital, Toronto; Y. Ung, Sunnybrook Regional Cancer Centre, Toronto, Ontario;B. Fisher, London Regional Cancer Centre, London, Ontario; S. Sagar, Hamilton Regional Cancer Centre, Hamilton, Ontario; W. Roa, Cross Cancer Centre Institute, Edmonton, Alberta; L. Souhami, Montreal General Hospital, Montreal, Quebec, Canada; M. Brada, The Royal Marsden National Health Service Trust, Surrey; T. Illidge, Wessex Cancer Centre, Southampton; I. Kunkler, Western General Hospital, Edinburgh; E. Levine, Christie Hospital National Health Service Trust, Manchester, UK; C. Carrie, Centre Régional Léon-Bérard, Lyon; J. Caudrelier, Centre Oscar Lambret, Lille; C. Haie-Meder, Institut Gustave Roussy, Villejuif; J. Mazeron, Hôpital de la Pitié-Salpêtrière, Paris, France; F. Lagerwaard, Daniel den Hoed Kliniek, Rotterdam; C. Terhaard, Academisch Ziekenhuis, Utrecht; J. Meerwaldt, Medisch Spectrum Twente, Enschede; P. Rodrigus, Dr Bernard Verbeeten Instituut, Tilburg; and L. Stalpers, Academisch Medisch Centrum, Amsterdam, Netherlands.

	ACKNOWLEDGMENTS

 
We thank the members of the events review committee (William Shapiro [Chairman], Michael Glantz, Roy Patchell, and Michael Weitzner) and the members of the data safety monitoring board (John MacDonald [Chairman], Paul Jacobsen, David Pistenmaa, and Charles Scott) for their dedication and contributions; we also thank Janet Wittes for biostatistical support.

	NOTES

 
Supported by and study drug provided by Pharmacyclics, Inc, Sunnyvale, CA.

This study has been presented in part at the 2002 Annual Meetings of the American Society of Clinical Oncology, May 18–21, 2002, Orlando, FL; the American Society of Therapeutic Radiology and Oncology, October 6–10, 2002, New Orleans, La; and the Society of Neuro-Oncology, November 21–24, 2002, San Diego, CA.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted December 20, 2002; accepted April 3, 2003.

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