PFS Not Established as a Surrogate End Point for OS in Treatment of Ovarian Cancer

A large meta-analysis of individual patient data did not establish progression-free survival (PFS) as a surrogate end point for overall survival (OS) in first-line treatment of advanced ovarian cancer, according to a study published in JAMA Network Open. 

However, the researchers indicated that the analysis was limited by the narrow range of treatment effects observed or by poststudy treatment. 

“Our findings support the GCIG (Gynecologic Cancer InterGroup) Fifth Ovarian Cancer Consensus Conference statement that OS is the preferred primary end point for first-line clinical trials with or without a maintenance component, but we recognize the practical challenges and the potential for confounding factors such as crossover and long post-progression survival,” the authors wrote.

Using studies with a minimum cohort of 60 patients published since 2001 that included PFS and OS, the researchers identified 17 unique randomized trials. There were 7 standard, 5 intensification, and 5 maintenance chemotherapies or targeted treatments identified across 11,029 unique patients. Within this study group, a high correlation was found between PFS and OS at the individual level (τ = 0.724; 95% CI, 0.717-0.732), but a low correlation was found at the trial level (R² = 0.24; 95% CI, 0-0.59). 

Subgroup analyses that separately focused on maintenance and non-maintenance trials brought about similar results. In the external validation, 14 of the 16 hazard ratios for OS in the published reports fell within the 95% prediction interval from PFS. 

Each of the trials required a rigorous assessment schedule, with clinical and physical examinations, evaluation of cancer antigen 125 (CA125), and computed tomographic (CT) imaging. At the trial level, PFS assessed by CT scans and CA125 levels following the GCIG guidelines was moderately correlated with OS in a subgroup of 6 trials. However, the researchers noted that the role of CA125 measurements is controversial, nonetheless. Given that no international standard has been established, this leads to variability in calibration, assay design, and reagent specificities, and CA125 levels are not currently considered a stand-alone marker of progression.

“The choice of the best measure to quantify the treatment effect is controversial,” the authors wrote. “Although the HR is probably the most commonly used relative measure, its validity is limited by the requirement to have a proportional hazard (i.e., that the HR is constant over time).” 

These combined criteria have not, to the knowledge of the researchers, been investigated as an OS surrogate using the meta-analytic approach. Moreover, the effect of such different assessment methods on the surrogacy of PHS also has yet to be assessed.

The researchers indicated that the question of surrogacy value of restricted mean survival times should be explored in future studies.

According to the study, about 240,000 women worldwide were diagnosed with an advanced ovarian, epithelial, fallopian tube, or primary peritoneal cancer in 2012. Furthermore, approximately 75% of women are found to have FIGO stage III or IV cancer at the time of their diagnosis.

Reference:

Paoletti X, Lewsley L, Daniele G, et al. Assessment of Progression-Free Survival as a Surrogate End Point of Overall Survival in First-Line Treatment of Ovarian Cancer. JAMA Network Open. doi:10.1001/jamanetworkopen.2019.18939.