Chemoradiotherapy Versus Chemotherapy for Elderly and Frail GBM Patients

Currently, the optimal treatment regimen for elderly Glioblastoma (GBM) patients with poor performance status (PS) is unknown. Based on data for elderly GBM patients and the limited data for patients with poor PS, hypofractionated RT or a short course of Temozolomide (TMZ) may provide survival benefit without the added toxicity and inconvenience of a more protracted treatment regimen.

In particular, treatment with RT or TMZ monotherapy on the basis of methylated O6 - methyl guanine - DNA methyltransferase (MGMT) promoter methylation status, followed by the alternative therapy at progression, may provide a safe and effective treatment regimen for patients with poor PS.

The hypothesis of this trial is that in elderly GBM patients with poor performance status (age ≥ 65 years and KPS 60-70), a chemotherapy alone (TMZ monotherapy) approach to therapy results in non-inferior overall survival compared to combined TMZ/RT.

It is hypothesized that chemotherapy will result in non-inferior progression-free survival, reduced toxicity and increased cost-effectiveness compared to combined chemoradiotherapy.

Primary objective:

• To compare overall survival of standard therapy vs chemotherapy in elderly and frail patients with newly diagnosed GBM.

Secondary objective:

* To evaluate progression-free survival following treatment in both arms. * To evaluate adverse events according to CTCAE criteria in both arms. * To evaluate health-related quality-of-life as assessed by MoCA and EORTC QLQ-C30/QLQ-BN20 questionnaires in both arms. * To evaluate cost-effectiveness of standard therapy vs chemotherapy

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).