Progression-free survival and time to progression as surrogate markers of overall survival in patients with advanced gastric cancer: analysis of 36 randomized trials

Abstract

Progression-free survival (PFS) and time to progression (TTP) have been reported to correlate with overall survival (OS) in several types of cancers. To our knowledge, however, their use in the evaluation of new agents for AGC has not been investigated. We evaluated the potential of PFS and TTP to act as surrogates of OS in clinical trial settings. Randomized trials of systemic chemotherapy for advanced gastric cancer were identified by comprehensive electronic and manual search. Correlations between PFS/TTP and OS were evaluated. Thirty-six trials with a total of 83 treatment arms and 10,484 patients were selected for analysis. The nonparametric Spearman rank correlation coefficient (ρ) between median PFS/TTP and OS was 0.70 (95% CI, 0.59 to 0.82) and the correlation coefficient between hazard ratios in PFS/TTP and OS was 0.80 (95% CI, 0.68 to 0.92). Correlation tended to be higher in trials reporting PFS (ρ = 0.85; 0.72-0.97) than in those reporting TTP (ρ = 0.60; 0.24-0.97), trials in Non-Asian countries (ρ = 0.80; 0.61-0.99) than Asia (ρ = 0.67; 0.39-0.94), trials in patients with measurable lesions only (ρ = 0.91; 0.77-1.00) than in those including non-measurable lesions (ρ = 0.71; 0.50-0.93), albeit that none of these differences was significant. Our results indicate that improvements in PFS/TTP in advanced gastric cancer strongly correlate with improvements in OS. Further research is needed to clarify the surrogacy of PFS/TTP for OS or the role of PFS as the true end point in future randomized clinical trials of chemotherapy for AGC.

Correlation between overall survival and other endpoints in clinical trials of second-line chemotherapy for patients with advanced gastric cancer

“…Another meta-analysis called the GASTRIC project (Global Advanced/Adjuvant Stomach Tumor Research through International Collaboration) analyzed data from 4,102 AGC patients included in 20 randomized trials [15]. The correlation between treatment effects on PFS and OS in each trial was only moderate (trial-level decision coefficient R 2 adjusted for estimation errors was 0.61), which is the same strength of relationship seen in the literature-based analysis [14]. Correlations between PFS and PS were lower for AGC than for those in patients with advanced colorectal cancer [10] or for those seen in studies of adjuvant treatment for colorectal cancer or gastric cancer [20,21].…”

“…Against these limitations, we consider that our work could convey important aspects with regard to the trial conduct and data collection for the future trials of second-line therapy for advanced gastric cancers. Previously, two meta-analyses studied whether PFS could be a surrogate endpoint for OS in patients with AGC who underwent first-line chemotherapy [14,15]. According to a literature-based analysis of 36 randomized trials [14], median PFS or TTP moderately correlated with median OS (q = 0.70).…”

“…Previously, two meta-analyses studied whether PFS could be a surrogate endpoint for OS in patients with AGC who underwent first-line chemotherapy [14,15]. According to a literature-based analysis of 36 randomized trials [14], median PFS or TTP moderately correlated with median OS (q = 0.70). The correlation coefficient between HR of PFS or TTP and OS was 0.80.…”

“…Correlations between PFS or other endpoints and OS have been analyzed in an effort to identify surrogate endpoints of OS [10][11][12][13][14][15]. A validated shorter-term surrogate endpoint would likely both reduce drug development costs and facilitate the assessment of efficacy [16].…”

“…A validated shorter-term surrogate endpoint would likely both reduce drug development costs and facilitate the assessment of efficacy [16]. Previously, a literature-based analysis and an individual patient data meta-analysis evaluated PFS as surrogate endpoint for OS in patients with AGC who underwent first-line chemotherapy [14,15]. However, no corresponding analysis had been done in patients who underwent second-line chemotherapy for AGC.…”