Evaluation of Three Definitions of Progression-free Survival in Preoperative Cancer Therapy (JCOG0801-A)

Progression-free survival is an often-used endpoint in clinical trials comparing preoperative therapy and surgery-first therapy. Because the surgery date is always later in the preoperative arm than in the surgery-first arm, it is difficult to define progression-free survival optimally. We evaluated three progression-free survival definitions that used different methods to handle incomplete resection. The three definitions specify the event date of incomplete resection (IR) as follows: oIR event' method, date of surgery; oIR not event' method, date of radiological or clinical progression after incomplete resection; landmark method, landmark time. According to these definitions, the theoretical strengths and weaknesses of the three definitions are investigated. Three patterns of progression-free survival and overall survival were estimated using the data of the Japan Clinical Oncology Group studies. Theoretically, oIR event' inflates alpha error while oIR not event' method and landmark method reduce the statistical power under the alternative hypothesis. In JCOG9907, hazard ratios for the three definitions were: oIR event', 0.80 (95 confidence interval, 0.591.07; P 0.13); oIR not event', 0.81 (95 confidence interval, 0.601.09; P 0.16); landmark, 0.80 (95 confidence interval, 0.591.07; P 0.15). No P value of any methods corresponded with the positive result for overall survival (P 0.03). In the preoperative arms of the four studies, maximum differences in median and percentage of 1 year progression-free survival among the three definitions were 06.4 months and 1.25.2. Progression-free survival sometimes fails as a surrogate of overall survival, and differences among results obtained with various progression-free survival definitions can be large. Overall survival should be used as primary endpoint in studies evaluating preoperative therapy.