This phase III trial compares temporally-modulated pulsed radiation therapy versus standard radiation therapy in treating patients with newly diagnosed, IDH wildtype, MGMT-unmethylated glioblastoma. After completion of surgery, the standard of care for glioblastoma is radiation therapy. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. For older and frail patients, standard treatment also includes the chemotherapy drug temozolomide. Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill tumor cells and slow down or stop tumor growth. Approximately 70% of glioblastoma patients have MGMT-unmethylated status. MGMT unmethylated tumors are less likely to respond to temozolomide chemotherapy, so there is more reliance on radiation therapy to kill the tumor cells. Recent clinical trials studying new therapies for MGMT-unmethylated glioblastoma have failed to improve outcomes over temozolomide. These recent studies also indicate that 80% of patients experience a decline in memory and thinking function after treatment. TMPRT differs from standard radiation therapy by delivering the same amount of radiation dose in 10-13 "pulses" with 3-minute breaks between pulses. TMPRT with temozolomide may work better than standard radiation therapy with temozolomide in increasing survival, as well as improving memory and thinking function in patients with newly diagnosed, IDH wildtype, MGMT-unmethylated glioblastoma.
No known IDH mutation. (If tested before step 1 registration, patients known to have IDH mutation in the tumor on local or other testing are ineligible and should not be registered).
Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block and hematoxylin and eosin (H&E) stained slide to be sent for central pathology review for confirmation of histology and MGMT promoter methylation status. Surgical resection is required; stereotactic biopsy alone is not allowed because it will not provide sufficient tissue for MGMT analysis. Note that tissue for central pathology review and central MGMT assessment must be shipped to the New York University (NYU) Center for Biospecimen Research and Development (CBRD) on or before postoperative calendar day 30. If tissue cannot be shipped by postoperative calendar day 30, then patients may NOT enroll on this trial as central pathology review will not be complete in time for the patient to start treatment no later than 8 weeks following surgery. Results of central pathology review and central MGMT analysis will generally be completed within 10 business days of receipt of tissue. Results will be entered by the central lab directly into Rave. Note: In the event of an additional tumor resection(s), tissue must be shipped within 30 days of the most recent resection and the latest resection must have been performed within 30 days after the initial resection.
Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to Step 1 registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.
No known leptomeningeal disease or metastatic disease outside the brain.
None
Parallel
Biospecimen Collection
Procedure/SurgeryUndergo collection of blood
Computed Tomography
Procedure/SurgeryUndergo CT
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Questionnaire Administration
Other interventionAncillary studies
Radiation Therapy
RadiationUndergo standard RT
Temozolomide
DrugGiven PO
Temporally-modulated Pulsed Radiation Therapy
RadiationUndergo TMPRT
Neurocognitive function (NCF)
This endpoint will be evaluated using each NCF testing interval. NCF failure is defined as a decline in NCF using the reliable change index (RCI) on at least one of the following tests: Hopkins Verbal Learning Test - Revised (HVLT-R) Total Recall, HVLT-R Delayed Recall, HVLT-R Delayed Recognition, Trail Making Test (TMT) Part A, TMT Part B, or Controlled Oral Word Association (COWA). The cumulative incidence approach will be used to estimate the time to neurocognitive failure to account for the competing risk of death. Gray's test will assess statistically significant differences in the distribution of NCF failure times (Gray 1988).
Time to NCF failure in the subset of older patients (≤ 65 years)
Will be measured by the HVLT-R, COWA, and TMT. A mixed effects model will be used to assess changes of standardized neurocognitive scores across time using all available data while adjusting for stratification variables and other baseline characteristics. Fixed effects will consist of treatment arm, baseline score, Recursive Partitioning Analysis (RPA) class, fractionation, tumor treating fields therapy (TTFields), steroid use, anti-seizure medication use as well as the interaction between time and treatment arm.
NCF across time
Will be measured by the HVLT-R, COWA, and TMT. A mixed effects model will be used to assess changes of standardized neurocognitive scores across time using all available data while adjusting for stratification variables and other baseline characteristics. Fixed effects will consist of treatment arm, baseline score, RPA class, fractionation, TTFields, steroid use, anti-seizure medication use as well as the interaction between time and treatment arm.
Quality of Life (QoL)
The Functional Assessment of Cancer Therapy - Brain (FACT-Br) total score will be used to measure overall QoL. Scores will be analyzed similarly to the individual NCF tests as described above. Briefly, mixed effects models will be performed. If the time by treatment interaction is significant, then tests will be conducted at each timepoint, within the model framework. Missing data will also be assessed and sensitivity analyses performed as needed.
Patient-reported cognitive outcomes (PRCO)
Nine items make up the FACT-Br-Cognitive Index score that will be used to assess PRCO. Scores will be analyzed similarly to the individual NCF tests as described above. Briefly, mixed effects models will be performed. If the time by treatment interaction is significant, then tests will be conducted at each timepoint, within the model framework. Missing data will also be assessed and sensitivity analyses performed as needed.
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