Radiation Therapy Combined With Chemotherapy in Treating Patients With Anaplastic Astrocytoma or Mixed Gliomas

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00004259
• Collaborator: National Cancer Institute (NCI) (NIH), North Central Cancer Treatment Group (Other), Eastern Cooperative Oncology Group (Other), NRG Oncology (Other)
• Enrollment: 230
• Locations: 92
• Arms: 4
• Duration (Months): 215.4
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy, such as temozolomide, carmustine, and lomustine, use different ways to stop tumor cells from dividing so they stop growing or die. Combining radiation therapy with chemotherapy may kill more tumor cells.

PURPOSE: This randomized phase III trial is studying radiation therapy and temozolomide to see how well they work compared to radiation therapy and carmustine or lomustine in treating patients with anaplastic astrocytoma or mixed gliomas.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: BCNU 80mg/m2; Drug: TMZ 200mg/m2; Radiation: radiation therapy; Drug: CCNU; Drug: BCNU 150mg/m2; Drug: BCNU 200mg/m2; Drug: TMZ 150mg/m2 six 6-week cycles; Drug: TMZ 150mg/m2 six 8-week cycles	Phase 3

Detailed Description

OBJECTIVES:

• Compare the overall survival and time to tumor progression in patients with anaplastic astrocytoma or mixed gliomas treated with radiotherapy combined with temozolomide vs carmustine or lomustine vs temozolomide and carmustine (arm discontinued as of 8/15/02).

• Compare the relative toxic effects of these regimens in these patients.

• Correlate molecular analyses with overall survival and time to tumor progression in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (under 50 vs 50 and over), Karnofsky performance status (60-80% vs 90-100%), and prior surgery (biopsy only vs resection).

Phase I

• Pilot Arms I and II: Prior to initiating the randomization to 1 of 3 treatment arms in phase III, Patients are accrued to Arm III regimen to determine tolerability.

Phase III

• Patients are randomized to 1 of 2 treatment arms (3rd arm was dropped).

• Arm I: Patients undergo radiotherapy 5 days a week for 6 weeks. Patients receive oral temozolomide on days 1-5 of the first week of radiotherapy. Chemotherapy repeats every 4 weeks for a total of 12 courses.

• Arm II: Patients undergo radiotherapy as in arm I. Patients receive carmustine IV or lomustine IV over 1-2 hours on days 1-3 of the first week of radiotherapy and a second course on days 56-58. Chemotherapy repeats every 8 weeks for a total of 6 courses.

• Arm III (dropped, did not open): Patients undergo radiotherapy as in arm I. Patients receive carmustine IV or lomustine IV over 3 hours on day 5 and oral temozolomide (2 hours after completion of carmustine or lomustine infusion) on days 1-5 of the first week of radiotherapy. Combination chemotherapy repeats every 8 weeks for 6 courses.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: Phase I: 30 patients; Phase III: 454 patients (227 per treatment arm) within 4 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 230 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Phase I (sequential) followed by phase III (parallel)Phase I (sequential) followed by phase III (parallel)
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized Study (Phase I Closed) of Radiation Therapy and Temozolomide Versus Radiation Therapy and Nitrosourea for Anaplastic Astrocytoma And Mixed Anaplastic Oligoastrocytoma (Astrocytoma Dominant)
• Study Start Date: Jun 1, 2000
• Actual Primary Completion Date: Feb 1, 2015
• Actual Study Completion Date: May 14, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Radiation therapy + temozolomide (TMZ) Radiation therapy (RT) for 6 weeks concurrent with and followed by TMZ 200mg/m2 for twelve 28-day cycles	Drug: TMZ 200mg/m2; 200 mg/m2 orally on days 1-5 of the first week of radiotherapy. Repeat every 28 days for a total of 12 cycles.; Radiation: radiation therapy; 1.8 Gy fractions (to isocenter), 1 fraction per day, 5 days per week to a dose of 59.4 Gy in 33 fractions.
Active Comparator: RT + BCNU/CCNU Radiation therapy for 6 weeks concurrent with and followed by BCNU 80mg/m2 or CCNU 130 mg/m2 for six 8-week cycles	Drug: BCNU 80mg/m2; BCNU 80 mg/m2 will be administered as an intravenous infusion on days 1, 2, and 3 of the first week of radiotherapy and on days 56, 57, and 58, then every eight weeks for four more cycles for a total of 6 cycles (maximum BCNU dose 1440 mg/m2).; Radiation: radiation therapy; 1.8 Gy fractions (to isocenter), 1 fraction per day, 5 days per week to a dose of 59.4 Gy in 33 fractions.; Drug: CCNU; CCNU at 130 mg/m2 orally every 8 weeks for a total of 6 cycles. Administered on day 1 of the first week of radiotherapy and on day 56, then administered every 8 weeks for four more cycles for a total of 6 cycles.
Experimental: Pilot Arm #1: RT+TMZ+BCNU Radiation therapy for 6 weeks concurrent with and followed by BCNU 200mg/m2 and TMZ 150mg/m2 six 6-week cycles	Radiation: radiation therapy; 1.8 Gy fractions (to isocenter), 1 fraction per day, 5 days per week to a dose of 59.4 Gy in 33 fractions.; Drug: BCNU 200mg/m2; BCNU 200 mg/m2 will be administered as an intravenous infusion on day 1 of radiotherapy and will be repeated every six weeks for a total of 6 cycles (maximum BCNU dose 1200 mg/m2).; Drug: TMZ 150mg/m2 six 6-week cycles; 150 mg/m2 orally on days 1-5 of the first week of radiotherapy. Repeat for a total of six 6-week cycles
Experimental: Pilot Arm #2: RT+TMZ+BCNU Radiation therapy for 6 weeks concurrent with and followed by BCNU 150mg/m2 and TMZ 150mg/m2 six 8-week cycles	Radiation: radiation therapy; 1.8 Gy fractions (to isocenter), 1 fraction per day, 5 days per week to a dose of 59.4 Gy in 33 fractions.; Drug: BCNU 150mg/m2; BCNU 150 mg/m2 will be administered as an intravenous infusion on day 5 of radiotherapy, and it will be repeated every eight weeks for a total of six cycles (maximum total BCNU dose 900 mg/m2).; Drug: TMZ 150mg/m2 six 8-week cycles; 150 mg/m2 orally on days 1-5 of the first week of radiotherapy. Repeat for a total of six 8-week cycles

Outcome Measures

Primary Outcome Measures

1. (Phase III) Overall Survival (OS) [From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening.]

   Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Per the protocol, the pilot arms were not included in the Phase III analyses.

2. (Phase I) Number of Subjects With Dose Limiting Toxicities (DLT) on the Two Pilot Arms [From start of treatment to 3 months]

   Adverse events were graded using CTCAE v2.0. Grade refers to the severity of the adverse event (AE). The CTCAE v2.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Dose limiting toxicity (DLT) was defined as grade 3+ pulmonary toxicity, grade 4+ thrombocytopenia (< 25,000 for 5 days), neutropenia (< 500/microl for 7 days), or neutropenia of any duration with fever requiring hospital admission after one dose reduction of 50% in BCNU. A 20% rate of grade 3+ pulmonary toxicities or a 40% rate of grade 4+ thrombocytopenia and neutropenia was considered unacceptable for a treatment arm combining RT, TMZ, and BCNU.

Secondary Outcome Measures

1. (Phase III) Time to Tumor Progression (TTP) [From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening.]

   Three-year rate is reported. Progression is defined as a radiographic increase in size of the lesion by > 25%, recurrence of the study lesion, or the development of new lesions, confirmed by imaging. Time to tumor progression was estimated using the cumulative incidence function (CIF) on tumor progression, with death as a competing risk. Per the protocol, the pilot arms were not included in the Phase III analyses.

2. (Phase III) Number of Patients With Grade 3 or Higher Toxicity [From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening.]

   Adverse events were graded using CTCAE v2.0. Grade refers to the severity of the AE. The CTCAE v2.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. The number of patients with grade or higher toxicity was calculated overall and for non-hematologic toxicity only. Per the protocol, the pilot arms were not included in the Phase III analyses.

3. (Phase III) Survival Time by MGMT Status [From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening.]

   Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Tumor tissue samples were analyzed for methylation status of methyl guanine methyl transferase (MGMT), classified as methylated vs. unmethylated.

4. (Phase III) Progression-free Survival by MGMT Status [From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening.]

   Progression is defined as a radiographic increase in size of the lesion by > 25%, recurrence of the study lesion, or the development of new lesions, confirmed by imaging. Progression-free survival time is defined as time from randomization to date of progression or death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Tumor tissue samples were analyzed for methylation status of methyl guanine methyl transferase (MGMT), classified as methylated vs. unmethylated.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically proven unifocal anaplastic astrocytoma or mixed gliomas, including the following:

• Anaplastic astrocytoma

• Mixed oligodendroglial/astrocytic tumors

• Oligodendroglial component must be no greater than 25%

• No vascular proliferation and necrosis

• Increased cellularity, pleomorphism, and nuclear atypia allowed

• No tumor predominantly located in the posterior fossa (i.e., brainstem or cerebellum)

• Patients with prior biopsy proven low grade astrocytoma who now have anaplastic astrocytoma and have had no prior radiotherapy or chemotherapy also eligible

• Study therapy must begin within 6 weeks of diagnosis

• No spinal cord tumors, spinal drop metastases, or metastases to noncontiguous meninges

• Pathologic evidence of local meningeal infiltration by underlying tumor allowed

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 60-100%

Life expectancy:

• At least 1 year

Hematopoietic:

• Hemoglobin at least 10 g/dL

• Absolute neutrophil count at least 1,500/mm^3

• Platelet count at least 150,000/mm^3

Hepatic:

• Bilirubin less than 2 times upper limit of normal (ULN)

• Aspartate aminotransferase (AST) less than 2 times ULN

• Alkaline phosphatase less than 2 times ULN

Renal:

• Blood urea nitrogen no greater than 25 mg/dL

• Creatinine less than 1.5 times normal

Pulmonary:

• No pre-existing lung disease that, in the investigator's opinion, would preclude administration of carmustine or lomustine or completion of therapy

Other:

• No other major medical illness or psychiatric impairment that would preclude study compliance

• No other malignancy within the past 5 years except nonmelanomatous skin cancer or carcinoma in situ of the cervix

• No known hypersensitivity to 1 of the components of carmustine, lomustine, temozolomide, dacarbazine, or any other nitrosourea

• No active infection

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior biologic therapy

Chemotherapy:

• See Disease Characteristics

• No prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• See Disease Characteristics

• No prior radiotherapy to brain or head and neck

Surgery:

• Not specified

Other:

• No other concurrent anticancer treatment for anaplastic astrocytoma until a recurrence is detected

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mobile Infirmary Medical Center	Mobile	Alabama	United States	36652-2144
2	Arizona Oncology Services Foundation	Phoenix	Arizona	United States	85013
3	Enloe Cancer Center at Enloe Medical Center	Chico	California	United States	95926
4	North Bay Cancer Center	Fairfield	California	United States	94533
5	Solano Radiation Oncology Center	Vacaville	California	United States	95687
6	Lynn Regional Cancer Center at Boca Raton Community Hospital - Main Center	Boca Raton	Florida	United States	33486
7	University of Florida Shands Cancer Center	Gainesville	Florida	United States	32610-0232
8	Integrated Community Oncology Network	Jacksonville Beach	Florida	United States	32250
9	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida	United States	32207
10	Florida Oncology Associates at Southside Cancer Center	Jacksonville	Florida	United States	32207
11	Baptist Medical Center South	Jacksonville	Florida	United States	32258
12	Florida Oncology Associates	Orange Park	Florida	United States	32073
13	Florida Cancer Center - Palatka	Palatka	Florida	United States	32177
14	Flagler Cancer Center	Saint Augustine	Florida	United States	32086
15	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida	Tampa	Florida	United States	33612-9497
16	John B. Amos Cancer Center	Columbus	Georgia	United States	31904
17	St. Joseph Medical Center	Bloomington	Illinois	United States	61701
18	Graham Hospital	Canton	Illinois	United States	61520
19	Memorial Hospital	Carthage	Illinois	United States	62321
20	Eureka Community Hospital	Eureka	Illinois	United States	61530
21	Galesburg Clinic	Galesburg	Illinois	United States	61401
22	Galesburg Cottage Hospital	Galesburg	Illinois	United States	61401
23	InterCommunity Cancer Center of Western Illinois	Galesburg	Illinois	United States	61401
24	Mason District Hospital	Havana	Illinois	United States	62644
25	Hopedale Medical Complex	Hopedale	Illinois	United States	61747
26	Kewanee Hospital	Kewanee	Illinois	United States	61443
27	McDonough District Hospital	Macomb	Illinois	United States	61455
28	BroMenn Regional Medical Center	Normal	Illinois	United States	61761
29	Community Cancer Center	Normal	Illinois	United States	61761
30	Community Hospital of Ottawa	Ottawa	Illinois	United States	61350
31	Oncology Hematology Associates of Central Illinois, PC - Ottawa	Ottawa	Illinois	United States	61350
32	Cancer Treatment Center at Pekin Hospital	Pekin	Illinois	United States	61554
33	Proctor Hospital	Peoria	Illinois	United States	61614
34	OSF St. Francis Medical Center	Peoria	Illinois	United States	61615-7827
35	CCOP - Illinois Oncology Research Association	Peoria	Illinois	United States	61615
36	Oncology Hematology Associates of Central Illinois, PC - Peoria	Peoria	Illinois	United States	61615
37	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61636
38	Illinois Valley Community Hospital	Peru	Illinois	United States	61354
39	Perry Memorial Hospital	Princeton	Illinois	United States	61356
40	St. Margaret's Hospital	Spring Valley	Illinois	United States	61362
41	Valley Cancer Center	Spring Valley	Illinois	United States	61362
42	McFarland Clinic, PC	Ames	Iowa	United States	50010
43	Cancer Center of Kansas, PA - Chanute	Chanute	Kansas	United States	66720
44	Cancer Center of Kansas, PA - Dodge City	Dodge City	Kansas	United States	67801
45	Cancer Center of Kansas, PA - El Dorado	El Dorado	Kansas	United States	67042
46	Cancer Center of Kansas, PA - Kingman	Kingman	Kansas	United States	67068
47	Southwest Medical Center	Liberal	Kansas	United States	67901
48	Cancer Center of Kansas, PA - Newton	Newton	Kansas	United States	67114
49	Cancer Center of Kansas, PA - Parsons	Parsons	Kansas	United States	67357
50	Cancer Center of Kansas, PA - Pratt	Pratt	Kansas	United States	67124
51	Cancer Center of Kansas, PA - Salina	Salina	Kansas	United States	67042
52	Cotton-O'Neil Cancer Center	Topeka	Kansas	United States	66604
53	Cancer Center of Kansas, PA - Wellington	Wellington	Kansas	United States	67152
54	Associates in Womens Health, PA - North Review	Wichita	Kansas	United States	67203
55	Cancer Center of Kansas, PA - Medical Arts Tower	Wichita	Kansas	United States	67208
56	Cancer Center of Kansas, PA - Wichita	Wichita	Kansas	United States	67214
57	CCOP - Wichita	Wichita	Kansas	United States	67214
58	Via Christi Cancer Center at Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
59	Wesley Medical Center	Wichita	Kansas	United States	67214
60	Cancer Center of Kansas, PA - Winfield	Winfield	Kansas	United States	67156
61	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland	United States	21201
62	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007-3731
63	CCOP - Duluth	Duluth	Minnesota	United States	55805
64	St. John's Regional Health Center	Springfield	Missouri	United States	65804
65	CCOP - Montana Cancer Consortium	Billings	Montana	United States	59101
66	Deaconess Billings Clinic - Downtown	Billings	Montana	United States	59107-7000
67	Good Samaritan Cancer Center at Good Samaritan Hospital	Kearney	Nebraska	United States	68848-1990
68	Methodist Cancer Center at Methodist Hospital - Omaha	Omaha	Nebraska	United States	68114
69	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
70	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
71	Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton	Marlton	New Jersey	United States	08053
72	Franklin & Edith Scarpa Regional Cancer Center at South Jersey Healthcare	Vineland	New Jersey	United States	08360
73	Fox Chase Virtua Health Cancer Program at Virtua West Jersey	Voorhees	New Jersey	United States	08043
74	Lipson Cancer and Blood Center at Rochester General Hospital	Rochester	New York	United States	14621
75	Mission Hospitals - Memorial Campus	Asheville	North Carolina	United States	28801
76	Akron City Hospital	Akron	Ohio	United States	44309-2090
77	Charles M. Barrett Cancer Center at University Hospital	Cincinnati	Ohio	United States	45267
78	Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106
79	Cancer Research UK Medical Oncology Unit at Churchill Hospital & Weatherall Institute of Molecular Medicine - Oxford	Salem	Ohio	United States	44460
80	Cancer Treatment Center	Wooster	Ohio	United States	44691
81	Natalie Warren Bryant Cancer Center at St. Francis Hospital	Tulsa	Oklahoma	United States	74136
82	Kimmel Cancer Center at Thomas Jefferson University - Philadelphia	Philadelphia	Pennsylvania	United States	19107-5541
83	Allegheny Cancer Center at Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
84	Reading Hospital and Medical Center	Reading	Pennsylvania	United States	19612-6052
85	Guthrie Cancer Center at Guthrie Clinic Sayre	Sayre	Pennsylvania	United States	18840
86	Rapid City Regional Hospital	Rapid City	South Dakota	United States	57701
87	Latter Day Saints Hospital	Salt Lake City	Utah	United States	84143
88	Theda Care Cancer Institute	Appleton	Wisconsin	United States	54911
89	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54307-3508
90	Bay Area Cancer Care Center at Bay Area Medical Center	Marinette	Wisconsin	United States	54143
91	Community Memorial Hospital Cancer Care Center	Menomonee Falls	Wisconsin	United States	53051
92	University of Wisconcin Cancer Center at Aspirus Wausau Hospital	Wausau	Wisconsin	United States	54401

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)
• North Central Cancer Treatment Group
• Eastern Cooperative Oncology Group
• NRG Oncology

Investigators

• Study Chair: Susan M. Chang, MD, University of California, San Francisco
• Study Chair: Kurt A. Jaeckle, MD, Mayo Clinic
• Study Chair: Peter Bushunow, MD, Lipson Cancer and Blood Center at Rochester General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT00004259
• Other Study ID Numbers: RTOG-9813; CDR0000067512; ECOG-R9813; NCCTG-RTOG-9813
• First Posted: Jan 27, 2003
• Last Update Posted: Sep 12, 2019
• Last Verified: Aug 1, 2019

• Keywords provided by Radiation Therapy Oncology Group: adult anaplastic astrocytoma; adult mixed glioma
• Additional relevant MeSH terms: Astrocytoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Carmustine

Study Results

Participant Flow

Arm/Group Title	Radiation Therapy + Temozolomide (TMZ)	RT + BCNU/CCNU	Pilot Arm #1: RT+TMZ+BCNU	Pilot Arm #2: RT+TMZ+BCNU
Arm/Group Description	Radiation therapy (RT) for 6 weeks concurrent with and followed by TMZ 200mg/m2 for twelve 28-day cycles	Radiation therapy for 6 weeks concurrent with and followed by BCNU 80mg/m2 or CCNU 130 mg/m2 for six 8-week cycles	Radiation therapy for 6 weeks concurrent with and followed by BCNU 200mg/m2 and TMZ 150mg/m2 six 6-week cycles	Radiation therapy for 6 weeks concurrent with and followed by BCNU 150mg/m2 and TMZ 150mg/m2 six 8-week cycles
Period Title: Overall Study
STARTED	98	103	15	14
COMPLETED	97	99	15	14
NOT COMPLETED	1	4	0	0

Baseline Characteristics

Arm/Group Title	Radiation Therapy + Temozolomide (TMZ)	RT + BCNU/CCNU	Pilot Arm #1: RT+TMZ+BCNU	Pilot Arm #2: RT+TMZ+BCNU	Total
Arm/Group Description	Radiation therapy (RT) for 6 weeks concurrent with and followed by TMZ 200mg/m2 for twelve 28-day cycles	Radiation therapy for 6 weeks concurrent with and followed by BCNU 80mg/m2 or CCNU 130 mg/m2 for six 8-week cycles	Radiation therapy for 6 weeks concurrent with and followed by BCNU 200mg/m2 and TMZ 150mg/m2 six 6-week cycles	Radiation therapy for 6 weeks concurrent with and followed by BCNU 150mg/m2 and TMZ 150mg/m2 six 8-week cycles	Total of all reporting groups
Overall Participants	97	99	15	14	225
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	42	43	48	41	43
Sex: Female, Male (Count of Participants)
Female	42 43.3%	47 47.5%	5 33.3%	6 42.9%	100 44.4%
Male	55 56.7%	52 52.5%	10 66.7%	8 57.1%	125 55.6%

Outcome Measures

1. Primary Outcome

Title	(Phase III) Overall Survival (OS)
Description	Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Per the protocol, the pilot arms were not included in the Phase III analyses.
Time Frame	From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening.

Outcome Measure Data

Analysis Population Description

Eligible randomized patients

Arm/Group Title	Radiation Therapy + Temozolomide (TMZ)	RT + BCNU/CCNU
Arm/Group Description	Radiation therapy (RT) for 6 weeks concurrent with and followed by TMZ 200mg/m2 for twelve 28-day cycles	Radiation therapy for 6 weeks concurrent with and followed by BCNU 80mg/m2 or CCNU 130 mg/m2 for six 8-week cycles
Measure Participants	97	99
Median (95% Confidence Interval) [years]	3.9	3.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiation Therapy + Temozolomide (TMZ), RT + BCNU/CCNU
	Comments	The hypothesized median survival time was 36 months for the RT+BCNU/CCNU arm and 54 months for the RT+TMZ arm, corresponding to a hazard ratio (HR) of 0.67. A sample size of 216 evaluable patients per arm would provide 90% power with a one-sided significance level of 0.05. The final analysis was planned after 155 deaths were observed. Interim efficacy analyses were planned after 52 and 104 deaths, with an interim futility analysis planned at 128 deaths.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.67 to 1.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	(Phase I) Number of Subjects With Dose Limiting Toxicities (DLT) on the Two Pilot Arms
Description	Adverse events were graded using CTCAE v2.0. Grade refers to the severity of the adverse event (AE). The CTCAE v2.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Dose limiting toxicity (DLT) was defined as grade 3+ pulmonary toxicity, grade 4+ thrombocytopenia (< 25,000 for 5 days), neutropenia (< 500/microl for 7 days), or neutropenia of any duration with fever requiring hospital admission after one dose reduction of 50% in BCNU. A 20% rate of grade 3+ pulmonary toxicities or a 40% rate of grade 4+ thrombocytopenia and neutropenia was considered unacceptable for a treatment arm combining RT, TMZ, and BCNU.
Time Frame	From start of treatment to 3 months

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment on Pilot Arms 1 and 2

Arm/Group Title	Pilot Arm #1: RT+TMZ+BCNU	Pilot Arm #2: RT+TMZ+BCNU
Arm/Group Description	Radiation therapy for 6 weeks concurrent with and followed by BCNU 200mg/m2 and TMZ 150mg/m2 six 6-week cycles	Radiation therapy for 6 weeks concurrent with and followed by BCNU 150mg/m2 and TMZ 150mg/m2 six 8-week cycles
Measure Participants	15	13
Subjects with Pulmonary DLT	1 1%	0 0%
Subjects with Hematologic DLT	4 4.1%	3 3%

3. Secondary Outcome

Title	(Phase III) Time to Tumor Progression (TTP)
Description	Three-year rate is reported. Progression is defined as a radiographic increase in size of the lesion by > 25%, recurrence of the study lesion, or the development of new lesions, confirmed by imaging. Time to tumor progression was estimated using the cumulative incidence function (CIF) on tumor progression, with death as a competing risk. Per the protocol, the pilot arms were not included in the Phase III analyses.
Time Frame	From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening.

Outcome Measure Data

Analysis Population Description

Eligible randomized patients

Arm/Group Title	Radiation Therapy + Temozolomide (TMZ)	RT + BCNU/CCNU
Arm/Group Description	Radiation therapy (RT) for 6 weeks concurrent with and followed by TMZ 200mg/m2 for twelve 28-day cycles	Radiation therapy for 6 weeks concurrent with and followed by BCNU 80mg/m2 or CCNU 130 mg/m2 for six 8-week cycles
Measure Participants	97	99
Median (95% Confidence Interval) [months]	45.4	54.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiation Therapy + Temozolomide (TMZ), RT + BCNU/CCNU
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments	2-sided
	Method	Gray's test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.55 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reference level = RT + BCNU/CCNU

4. Secondary Outcome

Title	(Phase III) Number of Patients With Grade 3 or Higher Toxicity
Description	Adverse events were graded using CTCAE v2.0. Grade refers to the severity of the AE. The CTCAE v2.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. The number of patients with grade or higher toxicity was calculated overall and for non-hematologic toxicity only. Per the protocol, the pilot arms were not included in the Phase III analyses.
Time Frame	From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening.

Outcome Measure Data

Analysis Population Description

Eligible randomized patients who started study treatment

Arm/Group Title	Radiation Therapy + Temozolomide (TMZ)	RT + BCNU/CCNU
Arm/Group Description	Radiation therapy (RT) for 6 weeks concurrent with and followed by TMZ 200mg/m2 for twelve 28-day cycles	Radiation therapy for 6 weeks concurrent with and followed by BCNU 80mg/m2 or CCNU 130 mg/m2 for six 8-week cycles
Measure Participants	96	99
Overall toxicity	46 47.4%	75 75.8%
Non-hematologic toxicity	31 32%	34 34.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiation Therapy + Temozolomide (TMZ), RT + BCNU/CCNU
	Comments	Overall toxicity
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	2-sided
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Radiation Therapy + Temozolomide (TMZ), RT + BCNU/CCNU
	Comments	Non-hematologic toxicity
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments	2-sided
	Method	Chi-squared
	Comments

5. Secondary Outcome

Title	(Phase III) Survival Time by MGMT Status
Description	Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Tumor tissue samples were analyzed for methylation status of methyl guanine methyl transferase (MGMT), classified as methylated vs. unmethylated.
Time Frame	From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening.

Outcome Measure Data

Analysis Population Description

Eligible patients with MGMT data

Arm/Group Title	Methylated MGMT	Unmthylated MGMT
Arm/Group Description
Measure Participants	36	22
Median (95% Confidence Interval) [years]	7.2	3.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiation Therapy + Temozolomide (TMZ), RT + BCNU/CCNU
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	Log Rank
	Comments	Two-side significance level = 0.05
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.78
	Confidence Interval	(2-Sided) 95%; 0.93 to 3.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reference level = Methylated MGMT

6. Secondary Outcome

Title	(Phase III) Progression-free Survival by MGMT Status
Description	Progression is defined as a radiographic increase in size of the lesion by > 25%, recurrence of the study lesion, or the development of new lesions, confirmed by imaging. Progression-free survival time is defined as time from randomization to date of progression or death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Tumor tissue samples were analyzed for methylation status of methyl guanine methyl transferase (MGMT), classified as methylated vs. unmethylated.
Time Frame	From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening.

Outcome Measure Data

Analysis Population Description

Eligible patients with MGMT data

Arm/Group Title	Methylated MGMT	Unmthylated MGMT
Arm/Group Description	Patients with MGMT menthylated status
Measure Participants	36	22
Median (95% Confidence Interval) [years]	4.0	2.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiation Therapy + Temozolomide (TMZ), RT + BCNU/CCNU
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.41
	Comments
	Method	Log Rank
	Comments	Two-sided confidence interval = 0.5
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95%; 0.70 to 2.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reference level = Methylated

Adverse Events

Adverse Event Reporting Description	Eligible subjects who started study treatment and have toxicity information are included. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Arm/Group Title	Radiation Therapy + Temozolomide (TMZ)		RT + BCNU/CCNU		Pilot Arm #1: RT+TMZ+BCNU		Pilot Arm #2: RT+TMZ+BCNU
Arm/Group Description	Radiation therapy (RT) for 6 weeks concurrent with and followed by TMZ 200mg/m2 for twelve 28-day cycles		Radiation therapy for 6 weeks concurrent with and followed by BCNU 80mg/m2 or CCNU 130 mg/m2 for six 8-week cycles		Radiation therapy for 6 weeks concurrent with and followed by BCNU 200mg/m2 and TMZ 150mg/m2 six 6-week cycles		Radiation therapy for 6 weeks concurrent with and followed by BCNU 150mg/m2 and TMZ 150mg/m2 six 8-week cycles
All Cause Mortality
	Radiation Therapy + Temozolomide (TMZ)		RT + BCNU/CCNU		Pilot Arm #1: RT+TMZ+BCNU		Pilot Arm #2: RT+TMZ+BCNU
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Radiation Therapy + Temozolomide (TMZ)		RT + BCNU/CCNU		Pilot Arm #1: RT+TMZ+BCNU		Pilot Arm #2: RT+TMZ+BCNU
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/96 (44.8%)		72/99 (72.7%)		8/15 (53.3%)		11/13 (84.6%)
Blood and lymphatic system disorders
Febrile neutropenia	1/96 (1%)		4/99 (4%)		1/15 (6.7%)		0/13 (0%)
Hemoglobin decreased	1/96 (1%)		14/99 (14.1%)		3/15 (20%)		0/13 (0%)
Packed red blood cell transfusion	2/96 (2.1%)		2/99 (2%)		2/15 (13.3%)		0/13 (0%)
Platelet transfusion	3/96 (3.1%)		10/99 (10.1%)		2/15 (13.3%)		2/13 (15.4%)
Cardiac disorders
Edema NOS	0/96 (0%)		2/99 (2%)		0/15 (0%)		0/13 (0%)
Myocardial ischaemia	1/96 (1%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Ear and labyrinth disorders
Otitis externa (exc boil of meatus) NOS	0/96 (0%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Otitis media serous NOS	0/96 (0%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Eye disorders
Late RT Toxicity:Eye NOS	1/96 (1%)		0/99 (0%)		0/15 (0%)		0/13 (0%)
Gastrointestinal disorders
Caecitis	1/96 (1%)		0/99 (0%)		0/15 (0%)		0/13 (0%)
Diarrhea NOS	1/96 (1%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Nausea	1/96 (1%)		2/99 (2%)		0/15 (0%)		0/13 (0%)
Vomiting NOS	1/96 (1%)		2/99 (2%)		0/15 (0%)		0/13 (0%)
General disorders
Constitutional symptons-Other	0/96 (0%)		0/99 (0%)		0/15 (0%)		1/13 (7.7%)
Late RT Toxicity:Other NOS	0/96 (0%)		0/99 (0%)		0/15 (0%)		1/13 (7.7%)
Pain-other	1/96 (1%)		0/99 (0%)		0/15 (0%)		0/13 (0%)
Infections and infestations
Infection NOS	0/96 (0%)		2/99 (2%)		1/15 (6.7%)		0/13 (0%)
Infection with grade 3 or 4 neutropenia	2/96 (2.1%)		4/99 (4%)		2/15 (13.3%)		2/13 (15.4%)
Infection, Other	0/96 (0%)		0/99 (0%)		1/15 (6.7%)		0/13 (0%)
Investigations
Alanine aminotransferase increased	2/96 (2.1%)		0/99 (0%)		0/15 (0%)		0/13 (0%)
Bilirbin-graft versus host disease	0/96 (0%)		0/99 (0%)		1/15 (6.7%)		0/13 (0%)
Gamma-glutamyltransferase increased	1/96 (1%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Leukopenia NOS	4/96 (4.2%)		9/99 (9.1%)		3/15 (20%)		4/13 (30.8%)
Lymphopenia	3/96 (3.1%)		7/99 (7.1%)		0/15 (0%)		0/13 (0%)
Neutropenia	13/96 (13.5%)		43/99 (43.4%)		6/15 (40%)		5/13 (38.5%)
Neutrophils/granulocytes for BMT	1/96 (1%)		0/99 (0%)		0/15 (0%)		0/13 (0%)
Platelet count decreased	16/96 (16.7%)		43/99 (43.4%)		6/15 (40%)		9/13 (69.2%)
Pulmonary function test NOS decreased	0/96 (0%)		2/99 (2%)		0/15 (0%)		0/13 (0%)
Weight decreased	0/96 (0%)		0/99 (0%)		0/15 (0%)		1/13 (7.7%)
Metabolism and nutrition disorders
Acidosis NOS	0/96 (0%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Dehydration	1/96 (1%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Hyperglycemia NOS	1/96 (1%)		1/99 (1%)		1/15 (6.7%)		0/13 (0%)
Hyperkalemia	0/96 (0%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Hyperuricemia	1/96 (1%)		0/99 (0%)		0/15 (0%)		0/13 (0%)
Hypokalemia	1/96 (1%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Hyponatremia	1/96 (1%)		2/99 (2%)		0/15 (0%)		0/13 (0%)
Musculoskeletal and connective tissue disorders
Bone pain	0/96 (0%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Nervous system disorders
Amnesia NEC	1/96 (1%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Ataxia NEC	1/96 (1%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Cerebral ischaemia	0/96 (0%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Convulsions NOS	3/96 (3.1%)		4/99 (4%)		0/15 (0%)		1/13 (7.7%)
Depressed level of consciousness	0/96 (0%)		1/99 (1%)		0/15 (0%)		1/13 (7.7%)
Dizziness (exc vertigo)	1/96 (1%)		0/99 (0%)		0/15 (0%)		1/13 (7.7%)
Headache NOS	4/96 (4.2%)		4/99 (4%)		0/15 (0%)		0/13 (0%)
Hemorrhagic stroke	2/96 (2.1%)		0/99 (0%)		0/15 (0%)		0/13 (0%)
Late RT Toxicity:Brain NOS	1/96 (1%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Peripheral motor neuropathy	6/96 (6.3%)		2/99 (2%)		0/15 (0%)		1/13 (7.7%)
Speech disorder NEC	1/96 (1%)		2/99 (2%)		0/15 (0%)		0/13 (0%)
Syncope	2/96 (2.1%)		0/99 (0%)		0/15 (0%)		0/13 (0%)
Vertigo NEC	0/96 (0%)		0/99 (0%)		1/15 (6.7%)		0/13 (0%)
Psychiatric disorders
Depression NEC	0/96 (0%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Euphoric mood	1/96 (1%)		0/99 (0%)		0/15 (0%)		0/13 (0%)
Personality change	1/96 (1%)		0/99 (0%)		0/15 (0%)		0/13 (0%)
Renal and urinary disorders
Renal failure NOS	0/96 (0%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Urinary incontinence	0/96 (0%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	0/96 (0%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Dyspnea NOS	0/96 (0%)		3/99 (3%)		1/15 (6.7%)		0/13 (0%)
Hypoxia	0/96 (0%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Pulmonary-other	0/96 (0%)		2/99 (2%)		0/15 (0%)		0/13 (0%)
Skin and subcutaneous tissue disorders
Culture wound positive	1/96 (1%)		0/99 (0%)		0/15 (0%)		0/13 (0%)
Dermatitis exfoliative NOS	2/96 (2.1%)		0/99 (0%)		1/15 (6.7%)		0/13 (0%)
Erythema multiforme	1/96 (1%)		0/99 (0%)		0/15 (0%)		0/13 (0%)
Petechiae	1/96 (1%)		0/99 (0%)		0/15 (0%)		0/13 (0%)
Vascular disorders
Hypertension NOS	1/96 (1%)		0/99 (0%)		0/15 (0%)		0/13 (0%)
Thrombosis NOS	2/96 (2.1%)		2/99 (2%)		1/15 (6.7%)		2/13 (15.4%)
Other (Not Including Serious) Adverse Events
	Radiation Therapy + Temozolomide (TMZ)		RT + BCNU/CCNU		Pilot Arm #1: RT+TMZ+BCNU		Pilot Arm #2: RT+TMZ+BCNU
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	94/96 (97.9%)		95/99 (96%)		14/15 (93.3%)		13/13 (100%)
Blood and lymphatic system disorders
Hematologic-Other	4/96 (4.2%)		5/99 (5.1%)		0/15 (0%)		1/13 (7.7%)
Hemoglobin decreased	32/96 (33.3%)		59/99 (59.6%)		13/15 (86.7%)		13/13 (100%)
Cardiac disorders
Edema NOS	3/96 (3.1%)		6/99 (6.1%)		0/15 (0%)		2/13 (15.4%)
Ear and labyrinth disorders
Hearing impaired	5/96 (5.2%)		9/99 (9.1%)		0/15 (0%)		1/13 (7.7%)
Hearing-Other	8/96 (8.3%)		6/99 (6.1%)		0/15 (0%)		1/13 (7.7%)
Eye disorders
Vision blurred	12/96 (12.5%)		10/99 (10.1%)		2/15 (13.3%)		1/13 (7.7%)
Gastrointestinal disorders
Constipation	37/96 (38.5%)		8/99 (8.1%)		3/15 (20%)		0/13 (0%)
Diarrhea NOS	13/96 (13.5%)		12/99 (12.1%)		1/15 (6.7%)		1/13 (7.7%)
Dry mouth	5/96 (5.2%)		5/99 (5.1%)		1/15 (6.7%)		0/13 (0%)
Dyspepsia	9/96 (9.4%)		5/99 (5.1%)		0/15 (0%)		1/13 (7.7%)
Esophagitis NOS	5/96 (5.2%)		1/99 (1%)		0/15 (0%)		0/13 (0%)
Nausea	75/96 (78.1%)		42/99 (42.4%)		7/15 (46.7%)		7/13 (53.8%)
Stomatitis	9/96 (9.4%)		3/99 (3%)		1/15 (6.7%)		0/13 (0%)
Vomiting NOS	34/96 (35.4%)		16/99 (16.2%)		3/15 (20%)		1/13 (7.7%)
General disorders
Fatigue	78/96 (81.3%)		73/99 (73.7%)		9/15 (60%)		9/13 (69.2%)
Late RT Toxicity:Other NOS	17/96 (17.7%)		17/99 (17.2%)		4/15 (26.7%)		3/13 (23.1%)
Pain-other	9/96 (9.4%)		11/99 (11.1%)		0/15 (0%)		2/13 (15.4%)
Pyrexia	2/96 (2.1%)		6/99 (6.1%)		0/15 (0%)		0/13 (0%)
Infections and infestations
Infection NOS	10/96 (10.4%)		6/99 (6.1%)		0/15 (0%)		0/13 (0%)
Injury, poisoning and procedural complications
Late RT Toxicity:Skin(within RT field)NOS	13/96 (13.5%)		11/99 (11.1%)		3/15 (20%)		1/13 (7.7%)
Investigations
Alanine aminotransferase increased	22/96 (22.9%)		21/99 (21.2%)		3/15 (20%)		2/13 (15.4%)
Aspartate aminotransferase increased	21/96 (21.9%)		18/99 (18.2%)		5/15 (33.3%)		1/13 (7.7%)
Blood alkaline phosphatase NOS increased	13/96 (13.5%)		18/99 (18.2%)		2/15 (13.3%)		2/13 (15.4%)
Leukopenia NOS	37/96 (38.5%)		70/99 (70.7%)		12/15 (80%)		10/13 (76.9%)
Lymphopenia	15/96 (15.6%)		13/99 (13.1%)		0/15 (0%)		0/13 (0%)
Metabolic-Other	5/96 (5.2%)		4/99 (4%)		0/15 (0%)		1/13 (7.7%)
Neutropenia	17/96 (17.7%)		45/99 (45.5%)		4/15 (26.7%)		2/13 (15.4%)
Platelet count decreased	44/96 (45.8%)		63/99 (63.6%)		9/15 (60%)		11/13 (84.6%)
Pulmonary function test NOS decreased	0/96 (0%)		9/99 (9.1%)		5/15 (33.3%)		3/13 (23.1%)
Weight decreased	10/96 (10.4%)		10/99 (10.1%)		2/15 (13.3%)		3/13 (23.1%)
Metabolism and nutrition disorders
Anorexia	31/96 (32.3%)		23/99 (23.2%)		6/15 (40%)		3/13 (23.1%)
Hyperglycemia NOS	9/96 (9.4%)		7/99 (7.1%)		1/15 (6.7%)		1/13 (7.7%)
Hypocalcemia	7/96 (7.3%)		7/99 (7.1%)		4/15 (26.7%)		2/13 (15.4%)
Hypokalemia	6/96 (6.3%)		5/99 (5.1%)		3/15 (20%)		2/13 (15.4%)
Hyponatremia	3/96 (3.1%)		6/99 (6.1%)		4/15 (26.7%)		1/13 (7.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/96 (5.2%)		2/99 (2%)		1/15 (6.7%)		1/13 (7.7%)
Muscle weakness NOS	12/96 (12.5%)		5/99 (5.1%)		1/15 (6.7%)		3/13 (23.1%)
Myalgia	6/96 (6.3%)		4/99 (4%)		0/15 (0%)		0/13 (0%)
Nervous system disorders
Amnesia NEC	14/96 (14.6%)		13/99 (13.1%)		2/15 (13.3%)		2/13 (15.4%)
Ataxia NEC	4/96 (4.2%)		5/99 (5.1%)		0/15 (0%)		2/13 (15.4%)
Convulsions NOS	13/96 (13.5%)		13/99 (13.1%)		2/15 (13.3%)		3/13 (23.1%)
Dizziness (exc vertigo)	16/96 (16.7%)		13/99 (13.1%)		0/15 (0%)		2/13 (15.4%)
Headache NOS	45/96 (46.9%)		31/99 (31.3%)		2/15 (13.3%)		7/13 (53.8%)
Late RT Toxicity:Brain NOS	11/96 (11.5%)		14/99 (14.1%)		3/15 (20%)		4/13 (30.8%)
Learning disorder NOS	5/96 (5.2%)		3/99 (3%)		0/15 (0%)		0/13 (0%)
Peripheral motor neuropathy	11/96 (11.5%)		7/99 (7.1%)		1/15 (6.7%)		2/13 (15.4%)
Peripheral sensory neuropathy	14/96 (14.6%)		9/99 (9.1%)		1/15 (6.7%)		1/13 (7.7%)
Speech disorder NEC	8/96 (8.3%)		4/99 (4%)		0/15 (0%)		0/13 (0%)
Taste disturbance	14/96 (14.6%)		13/99 (13.1%)		3/15 (20%)		1/13 (7.7%)
Tremor NEC	7/96 (7.3%)		4/99 (4%)		1/15 (6.7%)		2/13 (15.4%)
Psychiatric disorders
Anxiety NEC	12/96 (12.5%)		9/99 (9.1%)		1/15 (6.7%)		1/13 (7.7%)
Confusion	2/96 (2.1%)		10/99 (10.1%)		2/15 (13.3%)		1/13 (7.7%)
Depression NEC	12/96 (12.5%)		6/99 (6.1%)		1/15 (6.7%)		2/13 (15.4%)
Insomnia NEC	18/96 (18.8%)		8/99 (8.1%)		0/15 (0%)		1/13 (7.7%)
Respiratory, thoracic and mediastinal disorders
Cough	9/96 (9.4%)		7/99 (7.1%)		0/15 (0%)		1/13 (7.7%)
Dyspnea NOS	7/96 (7.3%)		13/99 (13.1%)		0/15 (0%)		5/13 (38.5%)
Skin and subcutaneous tissue disorders
Alopecia	56/96 (58.3%)		58/99 (58.6%)		6/15 (40%)		9/13 (69.2%)
Dermatitis exfoliative NOS	13/96 (13.5%)		7/99 (7.1%)		2/15 (13.3%)		0/13 (0%)
Dermatitis radiation NOS	17/96 (17.7%)		16/99 (16.2%)		2/15 (13.3%)		1/13 (7.7%)
Injection site reaction NOS	0/96 (0%)		8/99 (8.1%)		0/15 (0%)		2/13 (15.4%)
Skin-Other	6/96 (6.3%)		2/99 (2%)		0/15 (0%)		0/13 (0%)
Vascular disorders
Phlebitis superficial	0/96 (0%)		5/99 (5.1%)		0/15 (0%)		0/13 (0%)

Limitations/Caveats

Accrual to the TMZ BCNU arm required an acceptable toxicity profile from a pilot arm. Treatment cessation/reduction for toxicity caused the combination arm to be dropped. Per the protocol, the pilot arms were not included in the Phase III analyses.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.