Updated systematic review and meta-analysis of extended adjuvant temozolomide in patients with newly diagnosed glioblastoma

Background. Contemporary standard-of-care for newly diagnosed glioblastoma (GBM) is maximal safe resection followed by postoperative focal conformal radiotherapy (RT) plus concurrent temozolomide (TMZ) and 6-cycles of adjuvant TMZ (Stupp regimen). However, many patients continue to receive extended adjuvant TMZ (beyond 6-cycles) without solid scientific evidence. This review pools data from nonrandomized studies and randomized controlled trials (RCTs) comparing extended adjuvant TMZ (>6-cycles) to standard adjuvant TMZ (6-cycles) in patients with newly diagnosed GBM for updated evidence-synthesis. Methods. This systematic review and meta-analysis was carried out in accordance with the Cochrane methodology including quality assessment of primary studies. Primary outcome of interest was comparative efficacy defined as progression-free survival (PFS) and overall survival (OS). Hazard ratios (HRs) for PFS and OS with corresponding 95% confidence interval (CIs) were extracted/computed from individual primary studies and pooled using random-effects model. Any p-value <0.05 was considered statistically significant. Results. Evidence-synthesis was based on pooling of data from 2578 patients enrolled in 16 nonrandomized comparative studies and 5 RCTs. Overall, extended adjuvant TMZ was associated with statistically significant reduction in the risk of progression (HR = 0.72, 95%CI: 0.60-0.87; p = 0.007) and death (HR = 0.71, 95%CI: 0.57-0.90; p = 0.004) compared to standard adjuvant TMZ. However, on subgroup analysis, survival benefit of extended adjuvant TMZ was limited to data synthesized from retrospective nonrandomized comparative studies with no statistically significant difference in outcomes seen after pooling of data from RCTs only. Conclusion. Apparent survival benefit of extended adjuvant TMZ in newly diagnosed GBM is largely driven by nonrandomized comparative studies with high inherent potential for multiple biases.

Automated summary

This article reviews the efficacy of extended adjuvant temozolomide (TMZ) compared to standard adjuvant TMZ in newly diagnosed glioblastoma patients, based on nonrandomized studies and randomized controlled trials (RCTs). The results show that extended adjuvant TMZ is associated with a significant reduction in the risk of progression and death compared to standard adjuvant TMZ. However, the survival benefit of extended adjuvant TMZ is mainly driven by nonrandomized studies and is not observed when only data from RCTs are considered.