Multifocal Glioblastoma Managed With Primary Temozolomide as a Strategy to Delay Radiation Therapy: Clinical and Radiological Outcomes

AIM: To evaluate the clinical and radiological outcomes of upfront temozolomide (TMZ) monotherapy in deferring radiotherapy for multifocal glioblastoma (GBM). METHODS: We analysed 18 consecutive adult patients with newly diagnosed, multifocal GBM treated with upfront TMZ monotherapy between 2016 and 2024. The primary endpoint was a 6-month progression-free survival (PFS). Secondary endpoints were overall survival (OS) and radiological tumor response. RESULTS: The median age of the cohort was 69 years. The median follow-up was 12 months. Thirteen (72.2%) patients had O⁶-methylguanine-DNA methyltransferase (MGMT)-methylated tumors. Bi-hemispheric disease was present in 16 patients (88.9%) at baseline. Patients received a median of six TMZ cycles. Disease relapse occurred in 94.4% (n = 17) of cases, with 47.0% of failures involving distant sites. The 6-month PFS was 61% (95% CI: 42.3%-88.3%), and the median OS was 12.2 months (95% CI: 11.2-31.1). MGMT-methylated tumors demonstrated a significant volumetric reduction at 3 months compared to unmethylated cases (median -34.2% vs. +114.0%; p = 0.007). Survival outcomes trended in favour of the methylated cohort (6-month PFS 69.2% vs. 40.0%; median OS 12.3 vs. 11.2 months), though these associations did not reach statistical significance (p = 0.480). CONCLUSION: This study provides valuable insights into the use of primary TMZ as an exploratory strategy for short-term modulation in highly selected patients with extensive multifocal GBM. Whilst this approach facilitates a strategic delay in large-volume radiation, the high relapse rate underscores that upfront TMZ serves as a temporary window for deferring neurotoxicity rather than achieving durable disease control.