Brain and Central Nervous System Tumors
Conditions
Keywords
adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma
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.
Interventions
Daily oral temozolomide (75 mg/m2) up to 49 doses.
RADIATIONConcurrent radiation therapy
60 Gy in 2 Gy fractions
DRUG100mg/m2 adjuvant temozolomide days 1 to 5 of 28 day cycle
Oral temozolomide on days 1-5 of a 28-day cycle. Dose starts at 150mg/m2 for first cycle, increases to 200mg/m2 for subsequent cycles if no unacceptable toxicity. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding disease may receive up to 6 more courses of temozolomide.
DRUG75mg/m2 adjuvant temozolomide days 1-21 of 28 day cycle
Oral temozolomide on days 1-21 of a 28-day cycle. Dose starts at 75mg/m2 for first cycle, increases to 100mg/m2 for subsequent cycles if no unacceptable toxicity. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding disease may receive up to 6 more courses of temozolomide.
Sponsors
National Cancer Institute (NCI)
European Organisation for Research and Treatment of Cancer - EORTC
NRG Oncology
Radiation Therapy Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
1. Histopathologically proven diagnosis of glioblastoma. Since gliosarcoma is a variant of glioblastoma, gliosarcoma is also an eligible diagnosis. 2. Patients must have at least 1 block of tissue available for analysis of MGMT status; fresh frozen tumor tissue acquisition is encouraged. 3. Diagnosis must be established by open biopsy or tumor resection. Patients who have only had a stereotactic biopsy are not eligible. 4. The tumor must have a supratentorial component. 5. Patients must have recovered from the effects of surgery, postoperative infection, and other complications before study registration. 6. A diagnostic contrast-enhanced magnetic resonance imaging (MRI) or computerized tomography (CT) scan (if MRI is not available) of the brain must be performed preoperatively and postoperatively. The postoperative scan must be done within 28 days of registration and prior to the initiation of radiotherapy. Preoperative and postoperative scans must be the same type. If CT scans were performed perioperatively, a CT and an MRI should be performed before randomization. 6.1. Patients unable to undergo MRI imaging because of non-compatible devices can be enrolled, provided pre- and post-operative contrast-enhanced CT scans are obtained and are of sufficient quality. 7. Therapy must begin ≤ 5 weeks after the most recent brain tumor surgery. 8. History/physical examination within 14 days prior to study registration. 9. Neurologic examination within 14 days prior to study registration. 10. Documentation of steroid doses within 14 days prior to study registration and stable or decreasing steroid dose within 5 days prior to registration. 11. Karnofsky performance status of ≥ 60. 12. Age ≥ 18 years. 13. Complete blood count (CBC)/differential obtained within 14 days prior to study registration, with adequate bone marrow function as defined below: 13.1 Absolute neutrophil count (ANC) ≥ 1500 cells/mm3. 13.2 Platelets ≥ 100,000 cells/mm3. 13.3 Hemoglobin ≥ 10 g/dl. (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10 g/dl is acceptable.) 14. Adequate renal function, as defined below: 14.1 Blood urea nitrogen (BUN) ≤ 25 mg/dl within 14 days prior to study registration 14.2 Creatinine ≤ 1.7 mg/dl within 14 days prior to study registration 15. Adequate hepatic function, as defined below: 15.1 Bilirubin ≤ 2.0 mg/dl within 14 days prior to study registration 15.2 Alanine aminotransferase (ALT) ≤ 3 x normal range within 14 days prior to study registration 15.3 Aspartate aminotransferase (AST) ≤ 3 x normal range within 14 days prior to study registration 16. Patients must sign a study-specific informed consent prior to study registration. If the patient's mental status precludes his/her giving informed consent, written informed consent may be given by the responsible family member. 17. For females of child-bearing potential, negative serum pregnancy test within 72 hours prior to starting temozolomide. 18. Women of childbearing potential and male participants must practice adequate
Exclusion criteria
1. Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease free for ≥ 3 years. (For example, carcinoma in situ of the breast, oral cavity, and cervix are all permissible). 2. Recurrent or multifocal malignant gliomas 3. Metastases detected below the tentorium or beyond the cranial vault. 4. Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable. Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted. See Section 1. 5. Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields. 6. Severe, active co-morbidity, defined as follows: * 6.1. Unstable angina and/or congestive heart failure requiring hospitalization. * 6.2. Transmural myocardial infarction within the last 6 months. * 6.3. Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration. * 6.4. Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration. * 6.5. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol. * 6.6. Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. * 6.7. Major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy. * 6.8. Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity. 7. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic. 8. Pregnant or lactating women, due to possible adverse effects on the developing fetus or infant due to study drug; 9. Prior allergic reaction to temozolomide. 10. Patients treated on any other therapeutic clinical protocols within 30 days prior to study entry or during participation in the study. 11. No tissue provided for histopathologic central review and MGMT status. 12. Tissue provided by stereotactic biopsy method.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 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. |
| 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. |
| 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. |
| 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. |
| 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 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. |
| 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. |
| 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. |
Countries
Canada, United States
Participant flow
Pre-assignment details
Sites were required to submit participant tumor tissue for central histologic review and MGMT (O-6-methylguanine-DNA methyltransferase) status determination in order for registered participants to continue on the study. Of 1173 participants initially registered, 1125 participants met these requirements and started protocol treatment.
Participants by arm
| Arm | Count |
|---|---|
| No Adjuvant TMZ (Not Randomized ) Concurrent radiation therapy (RT) with concurrent temozolomide (75 mg/m2) up to 49 doses. Not randomized to either adjuvant TMZ arm. | 292 |
| Conventional Adjuvant TMZ 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. | 411 |
| Dose-dense Adjuvant TMZ 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. | 422 |
| Total | 1,125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Concomitant RT+TMZ (Pre-randomization) | Death | 18 | 0 | 0 |
| Concomitant RT+TMZ (Pre-randomization) | Disease progression | 48 | 0 | 0 |
| Concomitant RT+TMZ (Pre-randomization) | Ineligible due to insufficient tissue | 144 | 0 | 0 |
| Concomitant RT+TMZ (Pre-randomization) | Other complicating disease | 1 | 0 | 0 |
| Concomitant RT+TMZ (Pre-randomization) | Other, not otherwise specified | 37 | 0 | 0 |
| Concomitant RT+TMZ (Pre-randomization) | Patient refusal | 19 | 0 | 0 |
| Concomitant RT+TMZ (Pre-randomization) | Physician preference | 15 | 0 | 0 |
| Concomitant RT+TMZ (Pre-randomization) | Toxicity | 10 | 0 | 0 |
| Randomization to Adjuvant TMZ Arm | No follow-up collected | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | No Adjuvant TMZ (Not Randomized ) | Conventional Adjuvant TMZ | Dose-dense Adjuvant TMZ | Total |
|---|---|---|---|---|
| Age, Continuous | 60.5 years | 57 years | 58 years | 58 years |
| Sex: Female, Male Female | 126 Participants | 172 Participants | 185 Participants | 483 Participants |
| Sex: Female, Male Male | 166 Participants | 239 Participants | 237 Participants | 642 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 216 / 285 | 376 / 409 | 392 / 420 |
| serious Total, serious adverse events | 105 / 285 | 131 / 409 | 142 / 420 |
Outcome results
Primary
Median Overall Survival Time
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.
Time frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.
Population: Randomized eligible patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Conventional Adjuvant TMZ | Median Overall Survival Time | 16.6 months |
| Dose-dense Adjuvant TMZ | Median Overall Survival Time | 14.9 months |
Comparison: This study was looking for a 20% reduction in hazard rate: null hypothesis (conventional arm): Median survival time (MST) = 14.0 mo.; alternative hypothesis (dose-dense arm): MST= 17.5 mo. A one-sided log-rank test at a significance level of 0.025 would have 80% power to detect this difference with a sample size of 750 patients (647 deaths were required for the final analysis).p-value: 0.6395% CI: [0.88, 1.2]Log Rank
Secondary
Best Treatment Response by MGMT Status
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.
Time frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.
Population: Per the protocol, both arms are combined to compare between MGMT status. MGMT status and treatment response was not available for all randomized eligible participants. Therefore, data was only available for 748/831 randomized eligible patients (arms combined).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Conventional Adjuvant TMZ | Best Treatment Response by MGMT Status | Partial Response | 34 Participants |
| Conventional Adjuvant TMZ | Best Treatment Response by MGMT Status | Stable Response | 110 Participants |
| Conventional Adjuvant TMZ | Best Treatment Response by MGMT Status | Complete Response | 47 Participants |
| Conventional Adjuvant TMZ | Best Treatment Response by MGMT Status | Progressive Disease | 18 Participants |
| Conventional Adjuvant TMZ | Best Treatment Response by MGMT Status | Minor Response | 31 Participants |
| Dose-dense Adjuvant TMZ | Best Treatment Response by MGMT Status | Progressive Disease | 77 Participants |
| Dose-dense Adjuvant TMZ | Best Treatment Response by MGMT Status | Complete Response | 67 Participants |
| Dose-dense Adjuvant TMZ | Best Treatment Response by MGMT Status | Partial Response | 66 Participants |
| Dose-dense Adjuvant TMZ | Best Treatment Response by MGMT Status | Minor Response | 55 Participants |
| Dose-dense Adjuvant TMZ | Best Treatment Response by MGMT Status | Stable Response | 243 Participants |
p-value: 0.012Chi-squared
Secondary
Change From Baseline in Mean EORTC QLQ-C30 Global Health Status
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.
Time frame: Baseline, 10,12, 22, 24, and 46 weeks
Population: Questionnaires were not completed by all QOL population participants. Therefore, the number of participants reported below are the number with the relevant questions answered at baseline and the given time point on each arm.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Conventional Adjuvant TMZ | Change From Baseline in Mean EORTC QLQ-C30 Global Health Status | Week 22 (Cycle 4) | 3.9 score on a scale |
| Conventional Adjuvant TMZ | Change From Baseline in Mean EORTC QLQ-C30 Global Health Status | Week 24 (Cycle 4.5) | -2.8 score on a scale |
| Conventional Adjuvant TMZ | Change From Baseline in Mean EORTC QLQ-C30 Global Health Status | Week 12 (Cycle 1.5) | -4.6 score on a scale |
| Conventional Adjuvant TMZ | Change From Baseline in Mean EORTC QLQ-C30 Global Health Status | Week 46 (Cycle 10) | 5.4 score on a scale |
| Conventional Adjuvant TMZ | Change From Baseline in Mean EORTC QLQ-C30 Global Health Status | Week 10 (Cycle 1) | 0.0 score on a scale |
| Dose-dense Adjuvant TMZ | Change From Baseline in Mean EORTC QLQ-C30 Global Health Status | Week 46 (Cycle 10) | -1.9 score on a scale |
| Dose-dense Adjuvant TMZ | Change From Baseline in Mean EORTC QLQ-C30 Global Health Status | Week 10 (Cycle 1) | -2.9 score on a scale |
| Dose-dense Adjuvant TMZ | Change From Baseline in Mean EORTC QLQ-C30 Global Health Status | Week 12 (Cycle 1.5) | -2.7 score on a scale |
| Dose-dense Adjuvant TMZ | Change From Baseline in Mean EORTC QLQ-C30 Global Health Status | Week 24 (Cycle 4.5) | -0.7 score on a scale |
| Dose-dense Adjuvant TMZ | Change From Baseline in Mean EORTC QLQ-C30 Global Health Status | Week 22 (Cycle 4) | -4.4 score on a scale |
Comparison: A mixed effects model was run with EORTC QLQ-C30 Global Health Status Score (baseline, 10,12, 22, 24, and 46 weeks) as the outcome of interest. Treatment arm, recursive partitioning analysis (RPA) class, MGMT status, and time were included in the model. Treatment arm is reported here.p-value: 0.2184Mixed Models Analysis
Comparison: A mixed effects model was run with EORTC QLQ-C30 Global Health Status Score (baseline, 10,12, 22, 24, and 46 weeks) as the outcome of interest. Treatment arm, RPA class, MGMT status, and time were included in the model. RPA class is reported here.p-value: 0.0763Mixed Models Analysis
Comparison: A mixed effects model was run with EORTC QLQ-C30 Global Health Status Score (baseline, 10,12, 22, 24, and 46 weeks) as the outcome of interest. Treatment arm, RPA class, MGMT status, and time were included in the model. MGMT status is reported here.p-value: 0.5235Mixed Models Analysis
Secondary
Determination of Impactful Baseline Instruments on Overall Survival
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.
Time frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.
Population: Both arms are combined per the protocol. Questionnaires/assessments were not completed by all QOL population participants. Therefore, only 154/191 have COWA, EORTC QLQ-C30, and HVLT-R baseline assessments (final model covariates)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Conventional Adjuvant TMZ | Determination of Impactful Baseline Instruments on Overall Survival | 17.5 months |
Comparison: A Cox proportional hazards model was run with overall survival as the outcome of interest and baseline scores as continuous covariates. The final model was determined from stepwise selection. EORTC physical functioning, EORTC role functioning, standardized HVLT-R recognition, standardized HVLT-R recall, and standardized COWA were included in the initial model. EORTC physical functioning is reported here.p-value: 0.023Regression, Cox
Comparison: A Cox proportional hazards model was run with overall survival as the outcome of interest and baseline scores as continuous covariates. The final model was determined from stepwise selection. EORTC physical functioning, EORTC role functioning, standardized HVLT-R recognition, standardized HVLT-R recall, and standardized COWA were included in the initial model. Standardized HVLT-R recognition is reported here.p-value: 0.043Regression, Cox
Comparison: A Cox proportional hazards model was run with overall survival as the outcome of interest and baseline scores as continuous covariates. The final model was determined from stepwise selection. EORTC physical functioning, EORTC role functioning, standardized HVLT-R recognition, standardized HVLT-R recall, and standardized COWA were included in the initial model. Standardized COWA is reported here.p-value: 0.021Regression, Cox
Secondary
Distribution of Highest Grade AE Reported as Possibly/Probably/Definitely Related to Protocol Treatment
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.
Time frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.
Population: Randomized eligible patients with any adverse events reported as possibly/probably/definitely related to protocol treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Conventional Adjuvant TMZ | Distribution of Highest Grade AE Reported as Possibly/Probably/Definitely Related to Protocol Treatment | Grade 0,1,2 | 231 Participants |
| Conventional Adjuvant TMZ | Distribution of Highest Grade AE Reported as Possibly/Probably/Definitely Related to Protocol Treatment | Grade 3,4,5 | 120 Participants |
| Dose-dense Adjuvant TMZ | Distribution of Highest Grade AE Reported as Possibly/Probably/Definitely Related to Protocol Treatment | Grade 0,1,2 | 175 Participants |
| Dose-dense Adjuvant TMZ | Distribution of Highest Grade AE Reported as Possibly/Probably/Definitely Related to Protocol Treatment | Grade 3,4,5 | 194 Participants |
p-value: <0.001Chi-squared
Secondary
Mean Change From Baseline in EORTC QLQ-C30 Global Health Status Score at Mid-cyle for Cycle 1
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.
Time frame: Baseline and mid-cycle 1 (approximately 12 weeks)
Population: Questionnaires were not completed by all QOL population participants. Therefore, only 40/96 on the conventional arm and 38/95 on the dose-dense arm have both baseline and mid-cycle 1 data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Conventional Adjuvant TMZ | Mean Change From Baseline in EORTC QLQ-C30 Global Health Status Score at Mid-cyle for Cycle 1 | -4.58 score on a scale |
| Dose-dense Adjuvant TMZ | Mean Change From Baseline in EORTC QLQ-C30 Global Health Status Score at Mid-cyle for Cycle 1 | -2.63 score on a scale |
p-value: 0.74t-test, 2 sided
Secondary
Mean Change From Baseline in EORTC QLQ-C30 Global Health Status Score at Mid-cyle for Cycle 4
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.
Time frame: Baseline and mid-cycle 4 (approximately 24 weeks)
Population: Questionnaires were not completed by all QOL population participants. Therefore, only 30/96 on the conventional arm and 23/95 on the dose-dense arm have both baseline and mid-cycle 4 data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Conventional Adjuvant TMZ | Mean Change From Baseline in EORTC QLQ-C30 Global Health Status Score at Mid-cyle for Cycle 4 | -2.78 score on a scale |
| Dose-dense Adjuvant TMZ | Mean Change From Baseline in EORTC QLQ-C30 Global Health Status Score at Mid-cyle for Cycle 4 | -0.72 score on a scale |
p-value: 0.79t-test, 2 sided
Secondary
Mean Change From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score at Mid-cyle for Cycle 1
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.
Time frame: Baseline and mid-cycle 1 (approximately 12 weeks)
Population: Questionnaires were not completed by all QOL population participants. Therefore, only 41/96 on the conventional arm and 35/95 on the dose-dense arm have both baseline and mid-cycle 1 data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Conventional Adjuvant TMZ | Mean Change From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score at Mid-cyle for Cycle 1 | 0.48 score on a scale |
| Dose-dense Adjuvant TMZ | Mean Change From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score at Mid-cyle for Cycle 1 | 0.39 score on a scale |
p-value: 0.78t-test, 2 sided
Secondary
Mean Change From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score at Mid-cyle for Cycle 4
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.
Time frame: Baseline and mid-cycle 4 (approximately 24 weeks)
Population: Questionnaires were not completed by all QOL population participants. Therefore, only 32/96 on the conventional arm and 24/95 on the dose-dense arm have both baseline and mid-cycle 4 data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Conventional Adjuvant TMZ | Mean Change From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score at Mid-cyle for Cycle 4 | -0.23 score on a scale |
| Dose-dense Adjuvant TMZ | Mean Change From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score at Mid-cyle for Cycle 4 | 0.19 score on a scale |
p-value: 0.24t-test, 2 sided
Secondary
Mean EORTC QLQ-C30 Global Health Status Score at Cycle 10 for Participants Without Progression After 6 Months of Adjuvant Therapy
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).
Time frame: Baseline and cycle 10 (approximately 46 weeks)
Population: Cycle 10 questionnaires were not completed by all QOL population participants progression-free at 6 months. Therefore, only 24/96 on the conventional arm and 22/95 on the dose-dense arm had data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Conventional Adjuvant TMZ | Mean EORTC QLQ-C30 Global Health Status Score at Cycle 10 for Participants Without Progression After 6 Months of Adjuvant Therapy | 73.3 score on a scale |
| Dose-dense Adjuvant TMZ | Mean EORTC QLQ-C30 Global Health Status Score at Cycle 10 for Participants Without Progression After 6 Months of Adjuvant Therapy | 69.7 score on a scale |
p-value: 0.57t-test, 2 sided
Secondary
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
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.
Time frame: Baseline and cycle 10 (approximately 46 weeks)
Population: Cycle 10 questionnaires were not completed by all quality of life (QOL) population participants progression-free at 6 months. Therefore, only 24/96 on the conventional arm and 20/95 on the dose-dense arm had data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Conventional Adjuvant TMZ | 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 | 1.17 score on a scale |
| Dose-dense Adjuvant TMZ | 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 | 1.18 score on a scale |
p-value: 0.96t-test, 2 sided
Secondary
Mean MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score Over Time
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.
Time frame: Baseline, 10, 12, 22, 24, and 46 weeks
Population: Questionnaires were not completed by all QOL population participants. Therefore, the number of participants reported below are the number with the relevant questions answered at baseline and the given time point on each arm.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Conventional Adjuvant TMZ | Mean MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score Over Time | Week 10 (Cycle 1) | 1.4 score on a scale |
| Conventional Adjuvant TMZ | Mean MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score Over Time | Week 22 (Cycle 4) | 1.0 score on a scale |
| Conventional Adjuvant TMZ | Mean MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score Over Time | Baseline | 1.3 score on a scale |
| Conventional Adjuvant TMZ | Mean MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score Over Time | Week 24 (Cycle 4.5) | 1.0 score on a scale |
| Conventional Adjuvant TMZ | Mean MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score Over Time | Week 12 (Cycle 1.5) | 1.6 score on a scale |
| Conventional Adjuvant TMZ | Mean MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score Over Time | Week 46 (Cycle 10) | 1.2 score on a scale |
| Dose-dense Adjuvant TMZ | Mean MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score Over Time | Week 46 (Cycle 10) | 1.1 score on a scale |
| Dose-dense Adjuvant TMZ | Mean MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score Over Time | Baseline | 1.1 score on a scale |
| Dose-dense Adjuvant TMZ | Mean MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score Over Time | Week 10 (Cycle 1) | 1.4 score on a scale |
| Dose-dense Adjuvant TMZ | Mean MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score Over Time | Week 12 (Cycle 1.5) | 1.5 score on a scale |
| Dose-dense Adjuvant TMZ | Mean MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score Over Time | Week 22 (Cycle 4) | 1.2 score on a scale |
| Dose-dense Adjuvant TMZ | Mean MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score Over Time | Week 24 (Cycle 4.5) | 1.1 score on a scale |
Comparison: A mixed effects model was run with MDASI Symptom Severity Score (baseline, 10, 12, 22, 24, 46 weeks) as the outcome of interest. Treatment arm, recursive partitioning analysis (RPA) class, MGMT status, and time were included in the model. Treatment arm is reported here.p-value: 0.1702Mixed Models Analysis
Comparison: A mixed effects model was run with EORTC QLQ-C30 Global Health Status Score (baseline, 10, 12, 22, 24, 46 weeks) as the outcome of interest. Treatment arm, recursive partitioning analysis (RPA) class, MGMT status, and time were included in the model. RPA is reported here.p-value: 0.8159Mixed Models Analysis
Comparison: A mixed effects model was run with EORTC QLQ-C30 Global Health Status Score (baseline, 10, 12, 22, 24, 46 weeks) as the outcome of interest. Treatment arm, recursive partitioning analysis (RPA) class, MGMT status, and time were included in the model. MGMT status is reported here.p-value: 0.2174Mixed Models Analysis
Secondary
Mean Neurocognitive Function (NCF) Composite Score at Cycle 10 for Participants Without Progression After 6 Months of Adjuvant Therapy
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.
Time frame: Baseline and cycle 10 (approximately 46 weeks)
Population: Cycle 10 questionnaires were not completed by all QOL population participants progression-free at 6 months. Therefore, only 17/96 on the conventional arm and 20/95 on the dose-dense arm had data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Conventional Adjuvant TMZ | Mean Neurocognitive Function (NCF) Composite Score at Cycle 10 for Participants Without Progression After 6 Months of Adjuvant Therapy | -0.95 score on a scale |
| Dose-dense Adjuvant TMZ | Mean Neurocognitive Function (NCF) Composite Score at Cycle 10 for Participants Without Progression After 6 Months of Adjuvant Therapy | -1.19 score on a scale |
p-value: 0.73t-test, 2 sided
Secondary
Mean Neurocognitive Function (NCF) Composite Score Over Time
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.
Time frame: Baseline, 10, 22, and 46 weeks
Population: Questionnaires were not completed by all QOL population participants. Therefore, the number of participants reported below are the number with data at baseline and the given time point on each arm.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Conventional Adjuvant TMZ | Mean Neurocognitive Function (NCF) Composite Score Over Time | Baseline | -1.2 score on a scale |
| Conventional Adjuvant TMZ | Mean Neurocognitive Function (NCF) Composite Score Over Time | Week 10 (Cycle 1) | -1.3 score on a scale |
| Conventional Adjuvant TMZ | Mean Neurocognitive Function (NCF) Composite Score Over Time | Week 22 (Cycle 4) | -1.1 score on a scale |
| Conventional Adjuvant TMZ | Mean Neurocognitive Function (NCF) Composite Score Over Time | Week 46 (Cycle 10) | -1.0 score on a scale |
| Dose-dense Adjuvant TMZ | Mean Neurocognitive Function (NCF) Composite Score Over Time | Week 46 (Cycle 10) | -1.2 score on a scale |
| Dose-dense Adjuvant TMZ | Mean Neurocognitive Function (NCF) Composite Score Over Time | Baseline | -1.5 score on a scale |
| Dose-dense Adjuvant TMZ | Mean Neurocognitive Function (NCF) Composite Score Over Time | Week 22 (Cycle 4) | -1.3 score on a scale |
| Dose-dense Adjuvant TMZ | Mean Neurocognitive Function (NCF) Composite Score Over Time | Week 10 (Cycle 1) | -1.45 score on a scale |
Comparison: A mixed effects model was run with NCF Composite Score (baseline, 10, 22, 46 weeks) as the outcome of interest. Treatment arm, recursive partitioning analysis (RPA) class, MGMT status, and time were included in the model. Treatment arm is reported here.p-value: 0.2357Mixed Models Analysis
Comparison: A mixed effects model was run with NCF Composite Score (baseline, 10, 22, 46 weeks) as the outcome of interest. Treatment arm, recursive partitioning analysis (RPA) class, MGMT status, and time were included in the model. RPA is reported here.p-value: 0.0147Mixed Models Analysis
Comparison: A mixed effects model was run with NCF Composite Score (baseline, 10, 22, 46 weeks) as the outcome of interest. Treatment arm, recursive partitioning analysis (RPA) class, MGMT status, and time were included in the model. MGMT Status is reported here.p-value: 0.457Mixed Models Analysis
Secondary
Median Overall Survival Time by MGMT Status
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.
Time frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.
Population: MGMT status was not available for all randomized eligible participants. Therefore, data was only available from 376/411 on the conventional arm and 384/420 on the dose-dense arm.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Conventional Adjuvant TMZ | Median Overall Survival Time by MGMT Status | Unmethylated MGMT | 14.6 months |
| Conventional Adjuvant TMZ | Median Overall Survival Time by MGMT Status | Methylated MGMT | 21.4 months |
| Dose-dense Adjuvant TMZ | Median Overall Survival Time by MGMT Status | Unmethylated MGMT | 13.3 months |
| Dose-dense Adjuvant TMZ | Median Overall Survival Time by MGMT Status | Methylated MGMT | 20.2 months |
Comparison: Unmethylated MGMTp-value: 0.4495% CI: [0.82, 1.19]Log Rank
Comparison: Methylated MGMTp-value: 0.8695% CI: [0.87, 1.62]Log Rank
Secondary
Median Progression-free Survival (PFS) Time
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.
Time frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.
Population: Randomized eligible patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Conventional Adjuvant TMZ | Median Progression-free Survival (PFS) Time | 5.5 months |
| Dose-dense Adjuvant TMZ | Median Progression-free Survival (PFS) Time | 6.7 months |
p-value: 0.0695% CI: [0.75, 1]Log Rank
Secondary
Median Progression-free Survival Time by MGMT Status
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.
Time frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.
Population: MGMT status was not available for all randomized eligible participants. Therefore, data was only available from 376/411 on the conventional arm and 384/420 on the dose-dense arm.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Conventional Adjuvant TMZ | Median Progression-free Survival Time by MGMT Status | Unmethylated MGMT | 5.1 months |
| Conventional Adjuvant TMZ | Median Progression-free Survival Time by MGMT Status | Methylated MGMT | 6.5 months |
| Dose-dense Adjuvant TMZ | Median Progression-free Survival Time by MGMT Status | Unmethylated MGMT | 6.0 months |
| Dose-dense Adjuvant TMZ | Median Progression-free Survival Time by MGMT Status | Methylated MGMT | 10.1 months |
Comparison: Unmethylated MGMTp-value: 0.1595% CI: [0.73, 1.05]Log Rank
Comparison: Methylated MGMTp-value: 0.3395% CI: [0.66, 1.15]Log Rank
Secondary
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
* 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.
Time frame: baseline and cycle 10 (approximately 46 weeks)
Population: Both arms are combined per the protocol. Questionnaires/assessments were not completed by all QOL population participants. Therefore, only 36/191 have both MDASI-BT and HVLT-R at baseline and cycle 10.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Conventional Adjuvant TMZ | 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 | Cognitive and Delayed Recognition deterioration | 3 Participants |
| Conventional Adjuvant TMZ | 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 | Cognitive deterioration only | 6 Participants |
| Conventional Adjuvant TMZ | 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 | Delayed Recognition deterioration only | 4 Participants |
| Conventional Adjuvant TMZ | 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 | No deterioration | 23 Participants |
p-value: 0.33Fisher Exact
Secondary
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
* 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.
Time frame: baseline and cycle 4 (approximately 22 weeks)
Population: Both arms are combined per the protocol. Questionnaires/assessments were not completed by all QOL population participants. Therefore, only 71/191 have both MDASI-BT and HVLT-R at baseline and cycle 4.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Conventional Adjuvant TMZ | 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 | Cognitive and Delayed Recognition deterioration | 3 Participants |
| Conventional Adjuvant TMZ | 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 | Cognitive deterioration only | 9 Participants |
| Conventional Adjuvant TMZ | 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 | Delayed Recognition deterioration only | 14 Participants |
| Conventional Adjuvant TMZ | 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 | No deterioration | 45 Participants |
p-value: 0.99Fisher Exact
Secondary
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
* 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.
Time frame: baseline and cycle 1 (approximately 10 weeks)
Population: Both arms are combined per the protocol. Questionnaires/assessments were not completed by all QOL population participants. Therefore, only 116/191 have both MDASI-BT and HVLT-R at baseline and cycle 1.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Conventional Adjuvant TMZ | 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 | Cognitive and HVLT-R deterioration | 10 Participants |
| Conventional Adjuvant TMZ | 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 | Cognitive deterioration only | 12 Participants |
| Conventional Adjuvant TMZ | 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 | HVLT-R deterioration only | 20 Participants |
| Conventional Adjuvant TMZ | 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 | No deterioration | 74 Participants |
p-value: 0.02Chi-squared
Secondary
Number of Participants With Deterioration From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score at Cycle 4
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.
Time frame: baseline and cycle 4 (approximately 22 weeks)
Population: Questionnaires were not completed by all QOL population participants. Therefore, only 51/96 on the conventional arm and 40/95 on the dose-dense arm have both baseline and cycle 4 data
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Conventional Adjuvant TMZ | Number of Participants With Deterioration From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score at Cycle 4 | 7 Participants |
| Dose-dense Adjuvant TMZ | Number of Participants With Deterioration From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score at Cycle 4 | 13 Participants |
p-value: 0.03Z-test of two proportions
Secondary
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
* 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.
Time frame: baseline and cycle 1 (approximately 10 weeks)
Population: Per the protocol, both arms are combined. Questionnaires were not completed by all QOL population participants. Therefore, only 136/191 have both MDASI-BT and EORTC QLQ-C30 at baseline and cycle 1.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Conventional Adjuvant TMZ | 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 | Symptom Severity and GHS deterioration | 18 Participants |
| Conventional Adjuvant TMZ | 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 | Symptom Severity deterioration only | 9 Participants |
| Conventional Adjuvant TMZ | 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 | GHS deterioratoin only | 31 Participants |
| Conventional Adjuvant TMZ | 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 | No deterioration | 78 Participants |
p-value: 0.0002Chi-squared
Secondary
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
* 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.
Time frame: baseline and cycle 10 (approximately 46 weeks)
Population: Both arms are combined per the protocol. Questionnaires were not completed by all QOL population participants. Therefore, only 44/191 have both MDASI-BT and EORTC QLQ-C30 at baseline and cycle 10.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Conventional Adjuvant TMZ | 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 | Symptom Severity and GHS deterioration | 5 Participants |
| Conventional Adjuvant TMZ | 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 | Symptom Severity deterioration only | 4 Participants |
| Conventional Adjuvant TMZ | 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 | GHS deterioration only | 5 Participants |
| Conventional Adjuvant TMZ | 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 | No deterioration | 30 Participants |
p-value: 0.018Fisher Exact
Secondary
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
* 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.
Time frame: baseline and cycle 4 (approximately 22 weeks)
Population: Both arms are combined per the protocol. Questionnaires were not completed by all QOL population participants. Therefore, only 86/191 have both MDASI-BT and EORTC QLQ-C30 at baseline and cycle 4.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Conventional Adjuvant TMZ | 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 | Symptom Severity and GHS deterioration | 10 Participants |
| Conventional Adjuvant TMZ | 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 | Symptom Severity deterioration only | 5 Participants |
| Conventional Adjuvant TMZ | 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 | GHS deterioration Only | 18 Participants |
| Conventional Adjuvant TMZ | 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 | No deterioration | 53 Participants |
p-value: 0.005Fisher Exact
Secondary
Number of Participants With Deterioration From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score at Cycle 4
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.
Time frame: baseline and cycle 4 (approximately 22 weeks)
Population: Questionnaires were not completed by all QOL population participants. Therefore, only 51/96 on the conventional arm and 40/95 on the dose-dense arm have both baseline and cycle 4 data
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Conventional Adjuvant TMZ | Number of Participants With Deterioration From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score at Cycle 4 | 5 Participants |
| Dose-dense Adjuvant TMZ | Number of Participants With Deterioration From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score at Cycle 4 | 11 Participants |
p-value: 0.03Z-test of two proportions
Secondary
Overall Survival Status by Progression Status at 6 Months
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.
Time frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 4.4 years.
Population: Per the protocol, both arms are combined to compare between 6-month progression status. Eligible pre-randomization participants with any follow-up data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Conventional Adjuvant TMZ | Overall Survival Status by Progression Status at 6 Months | 20.7 months |
| Dose-dense Adjuvant TMZ | Overall Survival Status by Progression Status at 6 Months | 10.1 months |
p-value: <0.001Log Rank