Second line treatment of recurrent glioblastoma with sunitinib: results of a phase II study and systematic review of literature.

INTRODUCTION: Second line treatment of recurrent or progressive glioblastoma multiforme (GBM) is not standardized. Anti-angiogenic strategies with tyrosine-kinase inhibitors have been tested with conflicting results. We tested the association of sunitinib (S) plus irinotecan (CPT-11) in a phase II trial in terms of response rate (RR) and 6-months progression-free survival (6-PFS). We also reviewed the clinical evidence from all the trials with S in this setting published to date and summarized it in a meta-analysis.

EVIDENCE ACQUISITION: Patients with GBM recurrent or progressive after surgery and standard chemo-radiotherapy were treated with S 37.5 mg/day for 14 days + CPT-11 125 mg/sqm every 14 days in a Simon's two-stage phase II study. A summary data meta-analysis was performed to establish the 6-PFS in patients with ascertained histological diagnosis of GBM treated with sunitinib.

EVIDENCE SYNTHESIS: Six patients were enrolled in the stage I of the trial and only one had a stable disease. The overall response rate was 17% and 6-PFS was not reached. Therefore, the trial was stopped early for insufficient activity. All toxicities were grade 1-2. Systematic review of the literature identified 9 studies (including the present one) for a total of 221 patients. Pooled 6-PFS was 15.1% (95% CI 9.0-24.4). Subgroup analysis by different schedule revealed a 6-PFS of 17.5% (95% CI 10.3-28.1) in the weekly setting which was consistent across all the studies (I2 0%, p = 0.66) and a pooled 6-PFS of 12.7% (95% CI 4.9-29.1) in the daily setting with a substantial amount of heterogeneity (I2 65%, p = 0.01).

CONCLUSIONS: Results of this trial and those of the systematic review indicate that, compared to conventional chemotherapy or bevacizumab, S has insufficient activity in the setting of recurrent GBM. Better patient's molecular stratification for second-line treatment in GBM is warranted.