Progression-free survival as a surrogate endpoint for overall survival in glioblastoma: a literature-based meta-analysis from 91 trials

Abstract

Background: The aim of this study was to determine correlations between progression-free survival (PFS) and the objective response rate (ORR) with overall survival (OS) in glioblastoma and to evaluate their potential use as surrogates for OS.

Method: Published glioblastoma trials reporting OS and ORR and/or PFS with sufficient detail were included in correlative analyses using weighted linear regression.

Results: Of 274 published unique glioblastoma trials, 91 were included. PFS and OS hazard ratios were strongly correlated; R(2) = 0.92 (95% confidence interval [CI], 0.71-0.99). Linear regression determined that a 10% PFS risk reduction would yield an 8.1% ± 0.8% OS risk reduction. R(2) between median PFS and median OS was 0.70 (95% CI, 0.59-0.79), with a higher value in trials using Response Assessment in Neuro-Oncology (RANO; R(2) = 0.96, n = 8) versus Macdonald criteria (R(2) = 0.70; n = 83). No significant differences were demonstrated between temozolomide- and bevacizumab-containing regimens (P = .10) or between trials using RANO and Macdonald criteria (P = .49). The regression line slope between median PFS and OS was significantly higher in newly diagnosed versus recurrent disease (0.58 vs 0.35, P = .04). R(2) for 6-month PFS with 1-year OS and median OS were 0.60 (95% CI, 0.37-0.77) and 0.64 (95% CI, 0.42-0.77), respectively. Objective response rate and OS were poorly correlated (R(2) = 0.22).

Conclusion: In glioblastoma, PFS and OS are strongly correlated, indicating that PFS may be an appropriate surrogate for OS. Compared with OS, PFS offers earlier assessment and higher statistical power at the time of analysis.

Keywords: glioblastoma; meta-analysis; overall survival; progression-free survival; regression; response rate; surrogate endpoint.

Fig. 1.

Correlation in treatment effects (HR) between PFS and OS. The linear regression shown in this and subsequent figures is all weighted by trial size. The sizes of the symbols are proportional to the number of patients included in the trial for this and subsequent figures. Treatments (year of publication) are: 1. procarbazine vs TMZ (2000); 2. carmustine plus radiotherapy (RT) with or without cisplatin (2003); 3. cis-retinoic acid vs thalidomide, both in combination with TMZ and RT (2005); 4. cilengitide 500 mg vs 2000 mg (2008); 5. TMZ plus RT with or without pegylated liposomal doxorubicin (2009); 6. erlotinib vs thalidomide/cis-retinoic acid, all in combination with TMZ and RT (2009); 7. RT with or without TMZ (2009); 8. procarbazine, lomustine, and vincristine vs TMZ (2010); 9. TMZ 200 mg/m² for 5 days versus 100 mg/m² for 21 days (2010); 10. hydroxyurea with or without imatinib (2010); 11. enzastaurin vs lomustine, modified Levin criterion (2010). All trials used Macdonald or RANO criteria except for number 11.

Fig. 2.

(A) Correlation between mPFS and mOS by study arm. (B) Correlation between mPFS and mOS in trials using Macdonald or RANO criteria for response evaluation. All RANO trials contain BEV test regimens, and the 3 BEV-containing trials using Macdonald criteria are indicated in blue. There are 83 arms using Macdonald criteria (red circle or square) and 8 arms (7 unique trials) using RANO criteria (black circle or square). (C) Correlation between mPFS and mOS separated by treatment (TMZ [red] vs non-TMZ [black]). Trials included used the Macdonald/RANO criteria for tumor assessment. (D) Correlation between mPFS and mOS separated by treatment (BEV [red] vs non-BEV [black]). Trials included used the Macdonald/RANO criteria for tumor assessment. (E) Correlation between mPFS and mOS separated by line settings (newly diagnosed vs recurrent). (F) Correlation between mPFS and mOS separated by histology (glioblastoma only vs mixed histology). Abbreviation: PI, prediction interval.

Fig. 3.

Correlation between ORR and median OS. Abbreviation: PI, prediction interval.

Fig. 4.

(A) Correlation between 6-month PFS and 1-year OS. (B) Correlation between 6-month PFS and median OS. Abbreviation: PI, prediction interval.

Fig. 5.

Lead-time gained by using PFS instead of OS as the endpoint plotted against mOS and mPFS. The lead-time was defined as mOS minus mPFS in each arm.