Extended adjuvant temozolamide as prognostic factor of longer overall and progression-free survival in glioblastoma multiforme

Abstract

Background: Glioblastoma multiforme (GBM), the most common malignant primary central nervous system tumour, has significant morbi-mortality. The aim is to determine prognostic factors (PF) of overall survival (OS) and progression-free survival (PFS) in patients treated with Stupp protocol. Methods: Retrospective analysis of GBM patients ≥18 years, diagnosed from March 2004 to December 2014, treated with radiotherapy (RT) plus concomitant and adjuvant temozolomide (aTMZ). OS and PFS were assessed by Kaplan-Meier method and multivariate analysis (MA) was performed using Cox regression. Results: A total of 213 patients completed concomitant TMZ-RT and were included in final analysis. Majority were males (n = 134), with median age of 61 years old (24-84) and 43.1% ECOG performance status 0. Gross total resection (GTR) was possible in 46.9%, partial resection in 33.3% and stereotactic biopsy (SB) in 19.7%. 197 patients proceeded to aTMZ: 107 suspended <6 cycles; 17 suspended on 6th cycle due to progression; 13 performed 6 cycles of programmed aTMZ; 60 extended until progression (44 did 7-12 cycles and 16 over 12 cycles). Median OS was 15 months (CI 95%, 13.4-16.6) and PFS 8 months (CI 95%, 7.0-9.0). The PF for longer OS were: ECOG 0 (p = 0.001); GTR (p = 0,029); imagiologic response using MacDonald's criteria ( p<0.001); aTMZ >12 cycles (p < 0.001) and 2nd line chemotherapy (CT) (p = 0.002). The PF for longer PFS was extended aTMZ > 6 cycles (p < 0.001). In MA, ECOG 0 (p = 0.011), imagiologic response (p = 0.001) and 2nd line CT (p = 0.046) were prognostic of better OS. Also, aTMZ >12 cycles (p < 0.001, OS and PFS) and aTMZ 7-12 (p = 0.001, OS; p < 001, PFS) vs. 6 had longer OS and PFS. Analysing only patients who did 6 cycles of programmed aTMZ or extended until progression: aTMZ >12 cycles was associated with longer OS (vs. 6, p = 0.04; vs. 7-12, p = 0.037) without impact on PFS. In MA only aTMZ >12 cycles had positive impact on OS (p = 0.032, HR 0.34, CI 95%, 0.13-0.91). Conclusions: Our results suggest an OS and PFS benefit of extended aTMZ beyond standard 6 cycles, with stronger impact in OS with >12 cycles. The retrospective study design limits conclusions and further validation is necessary in prospective randomized studies.