A Randomized Controlled Trial of Chemo-Radiotherapy Versus Chemotherapy for Elderly and Frail Patients With Newly Diagnosed Glioblastoma
Methods: Patients will be randomized to two treatment groups in a 1:1 ratio. Standard Arm: Combined modality arm Chemo-radiotherapy consisting of 40 Gy in 15 daily fractions with concurrent TMZ. TMZ will be delivered at a dose of 75 mg/m2 daily for 21 days. TMZ will be administered 1 hour before each session of RT. After a 4-week break, patients will receive adjuvant TMZ according to the standard 5-day schedule (days 1-5) every 28 days, up to 6 cycles as tolerated by the patient. The dose will be 150 mg/m2 for the first cycle and increased to 200 mg/m2 beginning with the second cycle, so long as there are no hematologic adverse events, intractable nausea or fatigue. If tolerated, additional cycles of adjuvant TMZ may be administered at the treating investigator's discretion according to site practice. Investigational Arm: TMZ monotherapy Patients will receive TMZ at a dose of 75 mg/m2 daily for 21 days, followed by adjuvant TMZ according to the standard 5-day schedule (days 1-5) every 28 days, up to 6 cycles as tolerated by the patient. The dose will be 150 mg/m2 for the first cycle and increased to 200 mg/m2 beginning with the second cycle, so long as there are no hematologic adverse events, intractable nausea or fatigue. If tolerated, additional cycles of adjuvant TMZ may be administered at the treating investigator's discretion according to site practice. Upon treatment completion, participants will be followed by every 2 and 3 months for 2 years. Response and progression will be evaluated using the new international criteria proposed by the Response Assessment in Neuro-Oncology working group (RANO).
• Newly-diagnosed, histologically proven, intracranial glioblastoma with maximal safe resection. Biopsy alone is expected if resection is not possible. MGMT promoter methylation status must be tested and the results positive (defined as all non-negative MGMT status, including intermediate or indeterminate status (i.e., with cutoff higher than the MGMT negative threshold).
• History and physical examination, including neurological examination, within 14 days prior to randomization.
• Age ≥ 65 \& KPS of 60 - 70
• Stable or decreasing dose of corticosteroids for at least 14 days prior to randomization.
• Laboratory evaluation within 7 days prior to randomization, with adequate function as defined below:
‣ ANC ≥ 1.5 x 109/L
⁃ Platelets ≥ 100 x 109/L
⁃ Serum creatinine ≤ 1.5 times ULN or estimated Glomerular Filtration Rate (eGFR) \> 59
⁃ Total serum bilirubin ≤ 30 umol/L (ie ≤ 1.5 times ULN)
⁃ ALT \< 150 U/L (ie \< 3 times ULN)
⁃ AST \< 120 U/L (ie \< 3 times ULN)
⁃ Alkaline phosphatase \< 390 U/L (ie \< 3 times ULN)
• Patients must sign a study-specific informed consent prior to study registration.
• Patients of childbearing / reproductive potential should use highly effective birth control methods, as defined by the investigator, during the study treatment period and for a period of 6 months after the last dose of study drug. A highly effective method of birth control is defined as those that result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
• Note: abstinence is acceptable if this is established and preferred contraception for the patient and is accepted as a local standard.
⁃ This will apply for male patients only and their female partner if of child bearing potential.
⁃ Effective contraception should also be used by male patients taking temozolomide. Men being treated with temozolomide are advised not to father a child during or up to 6 months after discontinuation of treatment (male patients).
• Male patients should agree to not donate sperm during the study treatment and for six months post treatment completion.