Brain and Central Nervous System Tumors
Conditions
Keywords
adult diffuse astrocytoma, adult oligodendroglioma, adult mixed glioma
Brief summary
RATIONALE: 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. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving temozolomide together with radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving temozolomide together with radiation therapy works in treating patients with low-grade gliomas.
Detailed description
OBJECTIVES: * Compare the 3-year survival of patients with high-risk low-grade gliomas treated with temozolomide and radiotherapy followed by temozolomide alone with that of patients enrolled on European Organization for Research and Treatment of Cancer (EORTC)clinical trials EORTC-22844 and EORTC-22845. * Determine the toxicity of this regimen in these patients. * Determine the association between progression-free survival and O6-methylguanine-DNA methyltransferase (MGMT) methylation status in patients treated with this regimen. * Determine the association between survival and MGMT methylation status in patients treated with this regimen. * Determine the quality of life (QOL) of patients treated with this regimen. * Determine the neurocognitive function of patients treated with this regimen. * Evaluate the feasibility of collecting patient-reported QOL and neurocognitive assessments over 3 years. OUTLINE: This is a non-randomized, multicenter study. Patients receive oral temozolomide once daily on days 1-42 and undergo radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40, one hour before RT weekdays, in the evening weekends. Beginning 28 days after completion of chemoradiotherapy, patients receive oral temozolomide once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline, 6 months, 12 months. After completion of study treatment, patients are followed at 4 months, every 6 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 135 patients will be accrued for this study within 44 months.
Interventions
DRUGTemozolomide
Concurrent chemoradiotherapy temozolomide given 75 mg/m\^2 daily during radiotherapy for 6 weeks. Post-Radiation Temozolomide given 150 mg/m2 daily on days 1-5 every 28 days with cycle one beginning 28 days post-radiotherapy. In the absence of grade 3 or 4 adverse events, a single dose escalation to 200 mg/m2/day could be attempted for cycle 2 and, if tolerated, that dose should continue for all subsequent cycles. Cycles were repeated every 28 days (+/- 2 days) for a total of 12 cycles.
RADIATIONRadiation therapy
One treatment of 1.8 Gy given daily, 5 days per week (over 6 weeks) for a total dose of 54.0 Gy.
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Radiation Therapy Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed\* supratentorial glioma of 1 of the following histologies: * Astrocytoma (diffuse fibrillary, protoplasmic, or gemistocytic) * Oligodendroglioma * Oligoastrocytoma Note: \*Histologic atypia allowed provided no other histologic features (i.e., frequent mitoses, endothelial proliferation, and/or acute necrosis) that would result in a designation of anaplastic astrocytoma, anaplastic mixed oligodendroglioma or oligoastrocytoma, or glioblastoma multiforme are present * Unifocal or multifocal disease * World Health Organization (WHO) grade II disease * Neurofibromatosis allowed * Surgical biopsy or resection for tumor tissue sampling required within the past 12 weeks * Tissue block or core biopsy available for O6-methylguanine-DNA methyltransferase analysis and tissue banking * Patients who have only had a stereotactic biopsy are not eligible * Must have ≥ 3 of the following risk factors: * Age 40 and over * Largest preoperative tumor diameter ≥ 6 cm * Tumor crosses the midline * Astrocytoma-dominant tumor subtype * Preoperative Neurological Function Status \> 1 * No other low-grade glioma histologies, including any of the following: * Pilocytic astrocytoma * Subependymal giant cell astrocytoma of tuberous sclerosis * Subependymoma * Pleomorphic xanthoastrocytoma * Presence of a neuronal element, such as ganglioglioma * Dysneuroembryoplastic epithelial tumor * No high-grade glioma, including any of the following: * Anaplastic astrocytoma * Glioblastoma multiforme * Anaplastic oligodendroglioma * Anaplastic oligoastrocytoma * No tumors in any non-supratentorial location, including any of the following: * Optic chiasm * Optic nerve(s) * Pons * Medulla * Cerebellum * Spinal cord * No evidence of disease progression to spinal meninges or noncontiguous cranial meninges (i.e., leptomeningeal gliomatosis) by MRI of the spine or cerebrospinal fluid (CSF) cytology * MRI of the spine or CSF cytology are not required for patients without symptoms of spinal/cranial meningeal disease progression PATIENT CHARACTERISTICS: Age * 18 and over Performance status * Zubrod 0-2 Life expectancy * Not specified Hematopoietic * Absolute neutrophil count ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 Hepatic * Total bilirubin ≤ 1.5 mg/dL * Serum glutamate oxaloacetate transaminase (SGOT) or Serum glutamate pyruvate transaminase (SGPT) ≤ 2 times normal * Alkaline phosphatase ≤ 2 times normal Renal * Serum creatinine ≤ 1.5 mg/dL Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No known HIV positivity * No other malignancy within the past 5 years except carcinoma in situ of the cervix or nonmelanoma skin cancer * No active infection PRIOR CONCURRENT THERAPY: Biologic therapy * No concurrent immunotherapy or biologic therapy Chemotherapy * No prior chemotherapy * No other concurrent chemotherapy Endocrine therapy * Not specified Radiotherapy * No prior radiotherapy to the head and neck unless head and neck radiotherapy clearly excluded the brain (e.g., localized radiotherapy to the vocal cords) * No prior radiotherapy to the brain * No concurrent intensity modulated radiotherapy * No concurrent stereotactic boost radiotherapy Surgery * See Disease Characteristics Other * No other concurrent investigational agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival Rate at 3 Years | Registration to 3 years | Survival time is defined as time from registration to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. This analysis was planned to occur when all patients had been potentially followed for at least 3 years. |
| Progression-free Survival | From registration to last follow-up, up to 7.1 years. Analysis occurs after all patients have been on study for at least 3 years. | Progressive Disease (PD) is defined as 25% or \> increase in the cross-sectional area of enhancing or non-enhancing tumor on consecutive MRI scans, or any new area(s) of tumor. Under exceptional circumstances, disease progression may be declared in the absence of an increase in tumor size based on clinical deterioration including the need for increasing doses of steroid and/or a worsening Karnofsky Performance Status(KPS) / Neurologic Function Score(NFS). Progression-free survival time is defined as time from registration to date of progressive disease or death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Median survival time is reported. |
| Survival and Progression-free Survival by O(6)-Methylguanine-DNA Methyltransferase (MGMT) Methylation Status | Registration to 3 years | Survival time is defined as time from registration to date of death from any cause. Progressive Disease (PD) is defined as 25% or \> increase in the cross-sectional area of enhancing or non-enhancing tumor on consecutive MRI scans, or any new area(s) of tumor. Under exceptional circumstances, disease progression may be declared in the absence of an increase in tumor size based on clinical deterioration including the need for increasing doses of steroid and/or a worsening Karnofsky Performance Status(KPS) / Neurologic Function Score(NFS). Survival and progression-free survival are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. |
| Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Baseline, 6 months, and 12 months. | Functional Assessment of Cancer Therapy Scale with brain module (FACT-BR): a 50-question self-report questionnaire contains the following domains (scales): Physical well-being (7 questions totalling 0-28), social/family well-being (7 questions totalling 0-28), emotional well-being (6 questions totalling 0-24), functional well-being (7 questions totalling 0-28) and brain cancer subscale which contains concerns relevant to patients with brain tumors (19 questions totalling 0-76). Each question has a value 0-4. For some questions a higher indicates better outcome and others are the opposite. The former are summed as is, the latter are reversed in value before adding, such that each domain ranges from 0 to 4 multiplied by the number of questions in the domain, with 0 indicating worst and the highest possible value indicating best outcome. The FACT-Br total (0-184) is obtained by adding all domains together if the overall question response rate is greater than 80%. |
| Neurocognitive Function | Baseline, 6 months, and 12 months. | Hopkins Verbal Learning Test (HVLT) is a test measuring learning memory retrieval, and memory consolidation processes.; Controlled Oral Word Association Test (COWAT) is a test of phonemic verbal fluency. The patient produces as many words as possible in 1 min. (each) for a specific letter (C, F, L or P, R, W).; Trail Making Test (TMT) is a measure of visuospatial scanning, attention, sequencing, and speed in Part A (TMT A) and executive function in Part B (TMT B). Patients must connect the dots either in a numbered sequence or alternating letters and numbers. Difference between pre-treatment baseline and follow-up assessment scores determined by the reliable change (RC) index, using a 90% confidence interval to designate statistically significant change. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Temozolomide + Radiation Therapy (RT) Daily temozolomide plus concurrent radiotherapy followed by temozolomide | 129 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 7 |
Baseline characteristics
| Characteristic | Temozolomide + Radiation Therapy (RT) |
|---|---|
| Age, Continuous | 49 years |
| Sex: Female, Male Female | 54 Participants |
| Sex: Female, Male Male | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 129 / 129 |
| serious Total, serious adverse events | 37 / 129 |
Outcome results
Primary
Neurocognitive Function
Hopkins Verbal Learning Test (HVLT) is a test measuring learning memory retrieval, and memory consolidation processes.; Controlled Oral Word Association Test (COWAT) is a test of phonemic verbal fluency. The patient produces as many words as possible in 1 min. (each) for a specific letter (C, F, L or P, R, W).; Trail Making Test (TMT) is a measure of visuospatial scanning, attention, sequencing, and speed in Part A (TMT A) and executive function in Part B (TMT B). Patients must connect the dots either in a numbered sequence or alternating letters and numbers. Difference between pre-treatment baseline and follow-up assessment scores determined by the reliable change (RC) index, using a 90% confidence interval to designate statistically significant change.
Time frame: Baseline, 6 months, and 12 months.
Population: Eligible patients entered after QOL component amendment with baseline score and alive at 6 and 12 months for respective timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Temozolomide + Radiation Therapy (RT) | Neurocognitive Function | TMT A Status: Deterioration | 15 participants |
| Temozolomide + Radiation Therapy (RT) | Neurocognitive Function | HVLT Recall Status: Improvement | 13 participants |
| Temozolomide + Radiation Therapy (RT) | Neurocognitive Function | TMT A Status: Improvement | 11 participants |
| Temozolomide + Radiation Therapy (RT) | Neurocognitive Function | COWA Status: Deterioration | 1 participants |
| Temozolomide + Radiation Therapy (RT) | Neurocognitive Function | COWA Status: Improvement | 6 participants |
| Temozolomide + Radiation Therapy (RT) | Neurocognitive Function | COWA Status: No change | 42 participants |
| Temozolomide + Radiation Therapy (RT) | Neurocognitive Function | TMT B Status: Deterioration | 11 participants |
| Temozolomide + Radiation Therapy (RT) | Neurocognitive Function | HVLT Recall Status: Deterioration | 11 participants |
| Temozolomide + Radiation Therapy (RT) | Neurocognitive Function | TMT B Status: No change | 27 participants |
| Temozolomide + Radiation Therapy (RT) | Neurocognitive Function | TMT A Status: No change | 24 participants |
| Temozolomide + Radiation Therapy (RT) | Neurocognitive Function | TMT B Status: Improvement | 11 participants |
| Temozolomide + Radiation Therapy (RT) | Neurocognitive Function | HVLT Recall Status: No change | 26 participants |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Neurocognitive Function | TMT B Status: Improvement | 15 participants |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Neurocognitive Function | COWA Status: Improvement | 12 participants |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Neurocognitive Function | TMT A Status: Deterioration | 7 participants |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Neurocognitive Function | TMT A Status: No change | 24 participants |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Neurocognitive Function | TMT A Status: Improvement | 14 participants |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Neurocognitive Function | HVLT Recall Status: Deterioration | 8 participants |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Neurocognitive Function | HVLT Recall Status: No change | 22 participants |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Neurocognitive Function | HVLT Recall Status: Improvement | 15 participants |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Neurocognitive Function | COWA Status: Deterioration | 3 participants |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Neurocognitive Function | TMT B Status: Deterioration | 7 participants |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Neurocognitive Function | TMT B Status: No change | 22 participants |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Neurocognitive Function | COWA Status: No change | 28 participants |
Primary
Overall Survival Rate at 3 Years
Survival time is defined as time from registration to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. This analysis was planned to occur when all patients had been potentially followed for at least 3 years.
Time frame: Registration to 3 years
Population: Eligible patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temozolomide + Radiation Therapy (RT) | Overall Survival Rate at 3 Years | 73.1 percentage of participants |
Comparison: Assuming exponential distribution of survival times, the null hypothesis was a 43% increase in median survival time (40.5 mo. to 57.9 mo.) and a 21% increase in 3-year survival rate (54% to 65%). Assuming 5% ineligibility, 72 patients were required to be accrued over 3 years with 3-years of follow-up resulting in 80% power and 1-sided 0.10 significance level. (N later increased to 135 to accommodate an additional separate analysis of O-6-Methylguanine-DNA Methyltransferase (MGMT) status.)p-value: <0.001Z-test
Primary
Progression-free Survival
Progressive Disease (PD) is defined as 25% or \> increase in the cross-sectional area of enhancing or non-enhancing tumor on consecutive MRI scans, or any new area(s) of tumor. Under exceptional circumstances, disease progression may be declared in the absence of an increase in tumor size based on clinical deterioration including the need for increasing doses of steroid and/or a worsening Karnofsky Performance Status(KPS) / Neurologic Function Score(NFS). Progression-free survival time is defined as time from registration to date of progressive disease or death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Median survival time is reported.
Time frame: From registration to last follow-up, up to 7.1 years. Analysis occurs after all patients have been on study for at least 3 years.
Population: Eligible patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temozolomide + Radiation Therapy (RT) | Progression-free Survival | 4.5 years |
Primary
Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR)
Functional Assessment of Cancer Therapy Scale with brain module (FACT-BR): a 50-question self-report questionnaire contains the following domains (scales): Physical well-being (7 questions totalling 0-28), social/family well-being (7 questions totalling 0-28), emotional well-being (6 questions totalling 0-24), functional well-being (7 questions totalling 0-28) and brain cancer subscale which contains concerns relevant to patients with brain tumors (19 questions totalling 0-76). Each question has a value 0-4. For some questions a higher indicates better outcome and others are the opposite. The former are summed as is, the latter are reversed in value before adding, such that each domain ranges from 0 to 4 multiplied by the number of questions in the domain, with 0 indicating worst and the highest possible value indicating best outcome. The FACT-Br total (0-184) is obtained by adding all domains together if the overall question response rate is greater than 80%.
Time frame: Baseline, 6 months, and 12 months.
Population: Eligible patients entered after QOL component amendment and alive at 6 and 12 months for respective post-baseline endpoints.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Temozolomide + Radiation Therapy (RT) | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Physical Well-Being | 23 units on a scale |
| Temozolomide + Radiation Therapy (RT) | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Social/Family Well-Being | 24.5 units on a scale |
| Temozolomide + Radiation Therapy (RT) | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Emotional Well-Being | 18.5 units on a scale |
| Temozolomide + Radiation Therapy (RT) | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Functional Well-Being | 17.0 units on a scale |
| Temozolomide + Radiation Therapy (RT) | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Brain Cancer Subscale | 54.0 units on a scale |
| Temozolomide + Radiation Therapy (RT) | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | FACT-Br Total | 135.3 units on a scale |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | FACT-Br Total | 129.9 units on a scale |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Physical Well-Being | 22 units on a scale |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Functional Well-Being | 18.0 units on a scale |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Brain Cancer Subscale | 52.0 units on a scale |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Social/Family Well-Being | 24.0 units on a scale |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Emotional Well-Being | 20.0 units on a scale |
| Temozolomide + Radiation Therapy (RT) at 12 Months | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Social/Family Well-Being | 24.3 units on a scale |
| Temozolomide + Radiation Therapy (RT) at 12 Months | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Emotional Well-Being | 23.0 units on a scale |
| Temozolomide + Radiation Therapy (RT) at 12 Months | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | FACT-Br Total | 140.0 units on a scale |
| Temozolomide + Radiation Therapy (RT) at 12 Months | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Functional Well-Being | 19.5 units on a scale |
| Temozolomide + Radiation Therapy (RT) at 12 Months | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Physical Well-Being | 23 units on a scale |
| Temozolomide + Radiation Therapy (RT) at 12 Months | Quality of Life as Measured by the Functional Assessment of Cancer Therapy Scale With Brain Module (FACT-BR) | Brain Cancer Subscale | 59.0 units on a scale |
Primary
Survival and Progression-free Survival by O(6)-Methylguanine-DNA Methyltransferase (MGMT) Methylation Status
Survival time is defined as time from registration to date of death from any cause. Progressive Disease (PD) is defined as 25% or \> increase in the cross-sectional area of enhancing or non-enhancing tumor on consecutive MRI scans, or any new area(s) of tumor. Under exceptional circumstances, disease progression may be declared in the absence of an increase in tumor size based on clinical deterioration including the need for increasing doses of steroid and/or a worsening Karnofsky Performance Status(KPS) / Neurologic Function Score(NFS). Survival and progression-free survival are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact.
Time frame: Registration to 3 years
Population: Eligible patients with O(6)-methylguanine-DNA methyltransferase (MGMT) status
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Temozolomide + Radiation Therapy (RT) | Survival and Progression-free Survival by O(6)-Methylguanine-DNA Methyltransferase (MGMT) Methylation Status | Overall Survival | NA years |
| Temozolomide + Radiation Therapy (RT) | Survival and Progression-free Survival by O(6)-Methylguanine-DNA Methyltransferase (MGMT) Methylation Status | Progression-free Survival | NA years |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Survival and Progression-free Survival by O(6)-Methylguanine-DNA Methyltransferase (MGMT) Methylation Status | Overall Survival | 3.0 years |
| Temozolomide + Radiation Therapy (RT) - Unmethylated | Survival and Progression-free Survival by O(6)-Methylguanine-DNA Methyltransferase (MGMT) Methylation Status | Progression-free Survival | 2.0 years |
Comparison: Overall survival: The sample size was increased to 135 to ensure adequate power to detect a hazard ratio (HR) of 2.5 for MGMT status, at a 2-sided significance level of 0.05 with an MGMT prevalence rate of at least 30%p-value: 0.000695% CI: [1.64, 7.56]Log Rank
Comparison: Progression-free survivalp-value: 0.000795% CI: [1.55, 6.04]Log Rank