Prolonged sequential temozolomide in glioblastoma: A systematic review with exploratory quantitative synthesis

In patients with glioblastoma (GBM), the optimal number of adjuvant temozolomide (TMZ) cycles following combined radio-chemotherapy remains uncertain. This study aimed to synthesize the available randomized evidence addressing treatment duration.

Following PRISMA 2020 recommendations, we conducted a systematic review with exploratory quantitative synthesis of prospective randomized trials in newly diagnosed GBM. Studies were critically appraised with particular attention to survivorship bias, post-randomization selection, molecular heterogeneity, and trial design. Quantitative synthesis was based on reported median overall survival (OS) values according to planned TMZ duration (6 vs 12 cycles).

Nine studies met the inclusion criteria, comprising 7 studies with planned 6-cycle TMZ (965 patients) and 5 studies with planned 12-cycle TMZ (504 patients). Across studies, prolonged TMZ was not associated with a clear survival advantage. Pooled median OS was 17.10 months for six cycles and 17.64 months for twelve cycles, however, with no statistically significant difference. Studies reporting apparent benefit were consistently affected by post-six-cycle selection and survivorship bias.

Current evidence does not allow a definitive determination of the optimal duration of adjuvant TMZ in newly diagnosed GBM. Although extended treatment has been associated with numerically longer survival in some studies, these findings are difficult to interpret due to methodological limitations and heterogeneity. Therefore, it remains uncertain whether prolonging TMZ beyond six cycles provides a meaningful clinical benefit, and treatment decisions should be individualized.