Analysis of Response-Related and Time-to-event Endpoints in Randomized Trials of Gemcitabine-Based Treatment Versus Gemcitabine Alone as First-Line Treatment of Patients With Advanced Pancreatic Cancer.

Background: Gemcitabine-based combinations in advanced pancreatic cancer have been reported to have superior activity compared with gemcitabine alone. The results of the commonly used endpoints of clinical trials after chemotherapy or targeted therapy have been poorly reported.

Methods And Materials: We performed a search of randomized trials of systemic treatment that included gemcitabine plus chemotherapy or targeted therapy versus gemcitabine alone. For selected trials, the differences between the treatment arms for every endpoint were calculated, and a correlation analysis between these differences and the differences in overall survival was performed for every intermediate endpoint. Whenever a correlation coefficient was significant, regression analysis was performed. Finally, an analysis was performed to evaluate the factors that could mediate and moderate the effect of progression-free survival on overall survival.

Results: In addition to overall survival, progression-free survival, the overall response rate, and the disease control rate were the most frequently reported endpoints. Of the possible surrogate endpoints of overall survival, progression-free survival appears to be a reliable endpoint to assess chemotherapy (R(2) = 0.646) and chemotherapy plus targeted therapy (R(2) = 0.530) regimens and the disease control rate to assess chemotherapy (R(2) = 0.569). Of the factors that could limit the effect of progression-free survival on overall survival, the interval of radiologic evaluation could play a role.

Conclusion: In the selected trials, progression-free survival and the disease control rate were the most reliable surrogate endpoints of overall survival. Similar to the time-to-event endpoints, a standardization of response-related endpoints is strongly recommended.