Radiation Therapy (RT) and Temozolomide (TMZ) in Treating Patients With Newly Diagnosed Glioblastoma or Gliosarcoma

Phase 3

Completed

Conditions: Brain and Central Nervous System Tumors

Interventions: Drug: Concurrent temozolomide
Radiation: Concurrent radiation therapy
Drug: 100mg/m2 adjuvant temozolomide days 1 to 5 of 28 day cycle
Drug: 75mg/m2 adjuvant temozolomide days 1-21 of 28 day cycle

Registration Number: NCT00304031

Lead Sponsor: Radiation Therapy Oncology Group

Brief Summary: RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with temozolomide may kill more tumor cells. It is not yet known which schedule of temozolomide when given together with radiation therapy is more effective in treating glioblastoma or gliosarcoma.

PURPOSE: This randomized phase III trial is studying two different schedules of temozolomide to compare how well they work when given together with radiation therapy in treating patients with newly diagnosed glioblastoma or gliosarcoma.

Detailed Description: OBJECTIVES:

Primary

* Determine if dose-intensifying (increasing the "dose-density") the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy as measured by overall survival of patients with newly diagnosed glioblastoma or gliosarcoma.

Secondary

* Determine if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy as measured by progression-free survival.

* Determine in patients with unmethylated MGMT (O-6-methylguanine-DNA methyltransferase) if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy (overall and progression-free survival) compared with patients receiving conventional temozolomide dosing.

* Determine in patients with methylated MGMT if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy (overall and progression-free survival) compared with patients receiving conventional temozolomide dosing.

* Determine if there is an association between tumor MGMT gene methylation status and treatment response.

* Compare and record the toxicities of the conventional and dose-intense chemotherapy regimens.

* Evaluate whether 6-month progression-free survival is associated with overall survival.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to recursive partitioning analysis class (III vs IV vs V), MGMT gene methylation status (methylated vs nonmethylated vs indeterminate), and radiotherapy criteria used (standard vs revised European).

After completion of study treatment, patients are followed every 3 months for 1 year, every 4 months for 2 years, and then every 6 months thereafter.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1173

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Conventional adjuvant TMZ	Concurrent radiation therapy	Concurrent radiation therapy with concurrent temozolomide (75 mg/m2) up to 49 doses. Starting four weeks after completion of RT, 100mg/m2 adjuvant temozolomide days 1 to 5 of 28 day cycle.
Conventional adjuvant TMZ	100mg/m2 adjuvant temozolomide days 1 to 5 of 28 day cycle	Concurrent radiation therapy with concurrent temozolomide (75 mg/m2) up to 49 doses. Starting four weeks after completion of RT, 100mg/m2 adjuvant temozolomide days 1 to 5 of 28 day cycle.
Dose-dense adjuvant TMZ	Concurrent temozolomide	Concurrent radiation therapy (RT) with concurrent temozolomide (75 mg/m2) up to 49 doses. Starting four weeks after completion of RT, 75mg/m2 adjuvant temozolomide days 1-21 of 28 day cycle.
Dose-dense adjuvant TMZ	Concurrent radiation therapy	Concurrent radiation therapy (RT) with concurrent temozolomide (75 mg/m2) up to 49 doses. Starting four weeks after completion of RT, 75mg/m2 adjuvant temozolomide days 1-21 of 28 day cycle.
Dose-dense adjuvant TMZ	75mg/m2 adjuvant temozolomide days 1-21 of 28 day cycle	Concurrent radiation therapy (RT) with concurrent temozolomide (75 mg/m2) up to 49 doses. Starting four weeks after completion of RT, 75mg/m2 adjuvant temozolomide days 1-21 of 28 day cycle.
No adjuvant TMZ (not randomized )	Concurrent radiation therapy	Concurrent radiation therapy (RT) with concurrent temozolomide (75 mg/m2) up to 49 doses. Not randomized to either adjuvant TMZ arm.
Conventional adjuvant TMZ	Concurrent temozolomide	Concurrent radiation therapy with concurrent temozolomide (75 mg/m2) up to 49 doses. Starting four weeks after completion of RT, 100mg/m2 adjuvant temozolomide days 1 to 5 of 28 day cycle.
No adjuvant TMZ (not randomized )	Concurrent temozolomide	Concurrent radiation therapy (RT) with concurrent temozolomide (75 mg/m2) up to 49 doses. Not randomized to either adjuvant TMZ arm.

Primary Outcome Measures

Name	Time	Method
Median Overall Survival Time	From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.	Overall survival time is defined as time from registration/randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Analysis occurred after 647 deaths were reported.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Deterioration From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score and EORTC QLQ-C30 Global Health Status Score (GHS) at Cycle 4	baseline and cycle 4 (approximately 22 weeks)	* The MDASI-BT is a 28-item patient-reported outcome measure assessing symptom severity (SS) and resulting interference with daily living in brain cancer patients. All items range from 0 (not present) to 10 (as bad as you can imagine). A SS score is the average of the SS items, given a specified minimum numbers were completed. A score worse than baseline by at least one is considered deterioration. * Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-C30. The question responses range from 1 (very poor) to 7 (excellent) such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). A score worse than baseline by at least 10 is considered deterioration. * The 2x2 frequency table of SS deterioration vs. GHS deterioration is presented as four rows.
Mean MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score Over Time	Baseline, 10, 12, 22, 24, and 46 weeks	The MDASI-BT is a 28-item patient-reported outcome measure assessing symptom severity and resulting interference with daily living in brain cancer patients. All items range from 0 (not present) to 10 (as bad as you can imagine). The symptom severity score is the average of the symptom severity items, given a specified minimum numbers were completed.
Determination of Impactful Baseline Instruments on Overall Survival	From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.	Overall survival time is defined as time from registration/randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-C30 subscales are calculated as the mean of component items, then standardized such that subscale scores range from 0 to 100. A high score for a functional scale represents a healthy level of functioning. Controlled Oral Word Association (COWA) score is the sum of correct responses with a range of 0 to infinity. A higher score indicates better functioning. Hopkins Verbal Learning Test - Revised (HVLT-R) score ranges from 0 to 36 for total recall is 0 to 36, 0 to 12 for delayed recall, and -12 to 12 for recognition. A higher score indicates better functioning.
Number of Participants With Deterioration From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Score and Hopkins Verbal Learning Test - Revised (HVLT-R) Delayed Recognition (DR) Score at Cycle 4	baseline and cycle 4 (approximately 22 weeks)	* The MDASI-BT is a 28-item patient-reported outcome measure assessing symptom severity (SS) and resulting interference with daily living in brain cancer patients. All items range from 0 (not present) to 10 (as bad as you can imagine). A SS score is the average of the SS items, given a specified minimum numbers were completed. A score worse than baseline by at least one is considered deterioration. * The HVLT-R Delayed Recognition raw score is the number of of correctly identified words minus the number of incorrectly identified words from a list of words including 12 nouns memorized 20 minutes prior. The raw score ranges from -12 to 12. with a higher score indicates better functioning. Scores are standardized (mean 0, standard deviation 1), adjusting for age,education, and gender as necessary. A score worse than baseline by at least two is considered deterioration. * The 2x2 frequency table of SS deterioration vs. HVLT-R deterioration is presented as four rows.
Median Progression-free Survival (PFS) Time	From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.	Progression is defined as greater than 25% increase in tumor area (two diameters) provided that the patient has not had his/her dose of steroids decreased since the last evaluation period. Progression-free survival time is defined as time from registration to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. A concomitant decrease in steroid dose will rule out a progression designation during the first 2 months after completion of radiation therapy. Analysis occurred after 647 deaths were reported.
Median Overall Survival Time by MGMT Status	From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.	Overall survival time is defined as time from randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Tumor tissue submitted at baseline was analyzed to determine MGMT (O\[6\]-methylguanine-DNA methyltransferase) promoter methylation status (methylated / unmethylated). Analysis occurred after 647 deaths were reported.
Median Progression-free Survival Time by MGMT Status	From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.	Progression is defined as greater than 25% increase in tumor area (two diameters) provided that the patient has not had his/her dose of steroids decreased since the last evaluation period. Progression-free survival time is defined as time from registration to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. A concomitant decrease in steroid dose will rule out a progression designation during the first 2 months after completion of radiation therapy. Tumor tissue submitted at baseline was analyzed to determine MGMT (O\[6\]-methylguanine-DNA methyltransferase) promoter methylation status (methylated / unmethylated). Analysis occurred after 647 deaths were reported.
Best Treatment Response by MGMT Status	From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.	Response assessed using Response Evaluation Criteria in Solid Tumors (RECIST v1.0): Complete Response (CR), imaging no longer shows enhancing tumor, confirmed by a second scan ≥ 4 weeks later; Partial Response (PR), \>=50% decrease in tumor area (two diameters) with patient off all steroids, or on adrenal maintenance only; Minor Response (MR), \< 50% decrease in tumor area with patient off all steroids, or on adrenal maintenance only; Stable Disease (SD): scan shows no change with patient receiving stable/decreasing doses of steroids; Progression (P): \> 25% increase in tumor area with no decrease in steroid dose since last evaluation. Tumor tissue submitted at baseline was analyzed to determine MGMT (O\[6\]-methylguanine-DNA methyltransferase) promoter methylation status (methylated / unmethylated). Analysis occurred after 647 deaths were reported.
Distribution of Highest Grade AE Reported as Possibly/Probably/Definitely Related to Protocol Treatment	From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.	Highest grade adverse event (AE) per subject was counted. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. Analysis occurred after 647 deaths were reported.
Overall Survival Status by Progression Status at 6 Months	From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.	Overall survival time is defined as time from registration to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. Progression is defined as greater than 25% increase in tumor area (two diameters) provided that the patient has not had his/her dose of steroids decreased since the last evaluation period.
Mean MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score at Cycle 10 for Participants Without Progression After 6 Months of Adjuvant Therapy	Baseline and cycle 10 (approximately 46 weeks)	The MDASI-BT is a 28-item patient-reported outcome measure assessing symptom severity and resulting interference with daily living in brain cancer patients. All items range from 0 (not present) to 10 (as bad as you can imagine). The symptom severity score is the average of the symptom severity items, given a specified minimum numbers were completed.
Mean Neurocognitive Function (NCF) Composite Score at Cycle 10 for Participants Without Progression After 6 Months of Adjuvant Therapy	Baseline and cycle 10 (approximately 46 weeks)	The NCF Composite score is the arithmetic mean of the Hopkins Verbal Learning Test - Revised (HVLT-R) (Free Recall, Delayed Recall, Delayed Recognition), Trail Making Test Part A (TMTA), Trail Making Test Part B (TMTB), and Controlled Oral Word Association (COWA) test scores, all of which are standardized, adjusting for age, education, and gender as necessary, such that mean is 0 and standard deviation is 1. A participant must have at least 5 of the 6 scores. A higher composite score indicates better neurocognitive function.
Mean EORTC QLQ-C30 Global Health Status Score at Cycle 10 for Participants Without Progression After 6 Months of Adjuvant Therapy	Baseline and cycle 10 (approximately 46 weeks)	Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-C30. The question responses range from 1 "very poor" to 7 "excellent" such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best).
Mean Change From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score at Mid-cyle for Cycle 1	Baseline and mid-cycle 1 (approximately 12 weeks)	The MDASI-BT is a 28-item patient-reported outcome measure assessing symptom severity and resulting interference with daily living in brain cancer patients. All items range from 0 (not present) to 10 (as bad as you can imagine). The symptom severity score is the average of the symptom severity items, given a specified minimum numbers were completed. A score worse than baseline by at least one is considered deterioration. Change is calculated as time point - baseline such that a positive change value indicates worse symptoms compared to baseline.
Mean Change From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score at Mid-cyle for Cycle 4	Baseline and mid-cycle 4 (approximately 24 weeks)	The MDASI-BT is a 28-item patient-reported outcome measure assessing symptom severity and resulting interference with daily living in brain cancer patients. All items range from 0 (not present) to 10 (as bad as you can imagine). The symptom severity score is the average of the symptom severity items, given a specified minimum numbers were completed. A score worse than baseline by at least one is considered deterioration. Change is calculated as time point - baseline such that a positive change value indicates worse symptoms compared to baseline.
Mean Change From Baseline in EORTC QLQ-C30 Global Health Status Score at Mid-cyle for Cycle 1	Baseline and mid-cycle 1 (approximately 12 weeks)	Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-C30. The question responses range from 1 "very poor" to 7 "excellent" such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). Change is calculated as time point - baseline such that a positive change value indicates worse symptoms compared to baseline.
Mean Change From Baseline in EORTC QLQ-C30 Global Health Status Score at Mid-cyle for Cycle 4	Baseline and mid-cycle 4 (approximately 24 weeks)	Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-C30. The question responses range from 1 "very poor" to 7 "excellent" such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). Change is calculated as time point - baseline such that a positive change value indicates worse symptoms compared to baseline.
Change From Baseline in Mean EORTC QLQ-C30 Global Health Status	Baseline, 10,12, 22, 24, and 46 weeks	Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-C30. The question responses range from 1 "very poor" to 7 "excellent" such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). Change from baseline was calculated as time point value - baseline value with a positive change value indicating improved QOL from baseline.
Number of Participants With Deterioration From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score at Cycle 4	baseline and cycle 4 (approximately 22 weeks)	The MDASI-BT is a 28-item patient-reported outcome measure assessing symptom severity and resulting interference with daily living in brain cancer patients. All items range from 0 (not present) to 10 (as bad as you can imagine). The symptom severity score is the average of the symptom severity items, given a specified minimum numbers were completed. A score worse than baseline by at least one is considered deterioration.
Number of Participants With Deterioration From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score at Cycle 4	baseline and cycle 4 (approximately 22 weeks)	The MDASI-BT is a 28-item patient-reported outcome measure assessing symptom severity and resulting interference with daily living in brain cancer patients. All items range from 0 (did not interfere) to 10 (interfered completely). The symptom interference score is the average of the symptom interference items, given a specified minimum numbers were completed. A score worse than baseline by at least one is considered deterioration.
Number of Participants With Deterioration From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score and EORTC QLQ-C30 Global Health Status Score (GHS) at Cycle 10	baseline and cycle 10 (approximately 46 weeks)	* The MDASI-BT is a 28-item patient-reported outcome measure assessing symptom severity (SS) and resulting interference with daily living in brain cancer patients. All items range from 0 (not present) to 10 (as bad as you can imagine). A SS score is the average of the SS items, given a specified minimum numbers were completed. A score worse than baseline by at least one is considered deterioration. * Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-C30. The question responses range from 1 (very poor) to 7 (excellent) such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). A score worse than baseline by at least 10 is considered deterioration. * The 2x2 frequency table of SS deterioration vs. GHS deterioration is presented as four rows.
Number of Participants With Deterioration From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score and EORTC QLQ-C30 Global Health Status Score (GHS) at Cycle 1	baseline and cycle 1 (approximately 10 weeks)	* The MDASI-BT is a 28-item patient-reported outcome measure assessing symptom severity (SS) and resulting interference with daily living in brain cancer patients. All items range from 0 (not present) to 10 (as bad as you can imagine). A SS score is the average of the SS items, given a specified minimum numbers were completed. A score worse than baseline by at least one is considered deterioration. * Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire \[EORTC QLQ\]-C30. The question responses range from 1 (very poor) to 7 (excellent) such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). A score worse than baseline by at least 10 is considered deterioration. * The 2x2 frequency table of SS deterioration vs. GHS deterioration is presented as four rows.
Mean Neurocognitive Function (NCF) Composite Score Over Time	Baseline, 10, 22, and 46 weeks	The NCF Composite score is the arithmetic mean of the HVLT-R (Free Recall, Delayed Recall, Delayed Recognition), TMTA, TMTB, and COWA scores, all of which are standardized, adjusting for age, education, and gender as necessary, such that mean is 0 and standard deviation is 1. A participant must have at least 5 of the 6 scores. A higher composite score indicates better neurocognitive function.
Number of Participants With Deterioration From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Score and Hopkins Verbal Learning Test - Revised (HVLT-R) Delayed Recognition Score at Cycle 1	baseline and cycle 1 (approximately 10 weeks)	* The MDASI-BT is a 28-item patient-reported outcome measure assessing symptom severity (SS) and resulting interference with daily living in brain cancer patients. All items range from 0 (not present) to 10 (as bad as you can imagine). A SS score is the average of the SS items, given a specified minimum numbers were completed. A score worse than baseline by at least one is considered deterioration. * The HVLT-R Delayed Recognition raw score is the number of of correctly identified words minus the number of incorrectly identified words from a list of words including 12 nouns memorized 20 minutes prior. The raw score ranges from -12 to 12. with a higher score indicates better functioning. Scores are standardized (mean 0, standard deviation 1), adjusting for age,education, and gender as necessary. A score worse than baseline by at least two is considered deterioration. * The 2x2 frequency table of SS deterioration vs. HVLT-R deterioration is presented as four rows.
Number of Participants With Deterioration From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Score and Hopkins Verbal Learning Test - Revised (HVLT-R) Delayed Recognition (DR) Score at Cycle 10	baseline and cycle 10 (approximately 46 weeks)	* The MDASI-BT is a 28-item patient-reported outcome measure assessing symptom severity (SS) and resulting interference with daily living in brain cancer patients. All items range from 0 (not present) to 10 (as bad as you can imagine). A SS score is the average of the SS items, given a specified minimum numbers were completed. A score worse than baseline by at least one is considered deterioration. * The HVLT-R Delayed Recognition raw score is the number of of correctly identified words minus the number of incorrectly identified words from a list of words including 12 nouns memorized 20 minutes prior. The raw score ranges from -12 to 12. with a higher score indicates better functioning. Scores are standardized (mean 0, standard deviation 1), adjusting for age,education, and gender as necessary. A score worse than baseline by at least two is considered deterioration. * The 2x2 frequency table of SS deterioration vs. HVLT-R deterioration is presented as four rows.

Trial Locations

Locations (347): Fairbanks Cancer Treatment Center at Fairbanks Memorial Hospital
🇺🇸
Fairbanks, Alaska, United States
Arizona Oncology Services Foundation
🇺🇸
Phoenix, Arizona, United States
Mayo Clinic Scottsdale
🇺🇸
Scottsdale, Arizona, United States
Arizona Oncology - Tucson
🇺🇸
Tucson, Arizona, United States
Auburn Radiation Oncology
🇺🇸
Auburn, California, United States
Providence Saint Joseph Medical Center - Burbank
🇺🇸
Burbank, California, United States
Radiation Oncology Centers - Cameron Park
🇺🇸
Cameron Park, California, United States
Mercy Cancer Center at Mercy San Juan Medical Center
🇺🇸
Carmichael, California, United States
City of Hope Comprehensive Cancer Center
🇺🇸
Duarte, California, United States
Kaiser Permanente Medical Center - Los Angeles
🇺🇸
Los Angeles, California, United States
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Fairbanks Cancer Treatment Center at Fairbanks Memorial Hospital
🇺🇸Fairbanks, Alaska, United States