Surrogacy of progression-free survival (PFS) for overall survival (OS) in esophageal cancer trials with preoperative therapy: Literature-based meta-analysis.

BACKGROUND: There have been no reports evaluating progression-free survival (PFS) as a surrogate endpoint in resectable esophageal cancer. This study was conducted to evaluate the trial level correlations between PFS and overall survival (OS) in resectable esophageal cancer with preoperative therapy and to explore the potential benefit of PFS as a surrogate endpoint for OS. METHODS: A systematic literature search of randomized trials with preoperative chemotherapy or preoperative chemoradiotherapy for esophageal cancer reported from January 1990 to September 2014 was conducted using PubMed and the Cochrane Library. Weighted linear regression using sample size of each trial as a weight was used to estimate coefficient of determination (R2) within PFS and OS. The primary analysis included trials in which the HR for both PFS and OS was reported. The sensitivity analysis included trials in which either HR or median survival time of PFS and OS was reported. In the sensitivity analysis, HR was estimated from the median survival time of PFS and OS, assuming exponential distribution. RESULTS: Of 614 articles, 10 trials were selected for the primary analysis and 15 for the sensitivity analysis. The primary analysis did not show a correlation between treatment effects on PFS and OS (R2 0.283, 95% CI [0.00-0.90]). The sensitivity analysis did not show an association between PFS and OS (R2 0.084, 95% CI [0.00-0.70]). CONCLUSION: Although the number of randomized controlled trials evaluating preoperative therapy for esophageal cancer is limited at the moment, PFS is not suitable for primary endpoint as a surrogate endpoint for OS.

Effect site concentrations of remifentanil and pupil response to noxious stimulation.

BACKGROUND: Opioid drugs block reflex pupillary dilatation in response to noxious stimulation. The relationship between the target effect site concentration (Ce(T)) of remifentanil and the pupil diameter and reactivity in response to a standard noxious stimulus were evaluated. METHODS: Anaesthesia was induced with propofol TCI to obtain loss of consciousness (LOC) in 12 ASA I/II patients. Thereafter, remifentanil Ce(T) was titrated by increments of 1 up to 5 ng ml(-1). In the awake state, at LOC and at each plateau level of remifentanil Ce(T), arterial pressure, heart rate, and BIS (A2000) were recorded. Pupil size and dilatation after a 100 Hz tetanic stimulation (T100) were measured at LOC and at each plateau level of remifentanil Ce(T). RESULTS: LOC was observed at a mean propofol Ce(T) of 3.53 (SD 0.43) microg ml(-1). Arterial pressure and heart rate decreased progressively from LOC to 5 ng ml(-1) remifentanil Ce(T) without any statistical difference between each incremental dose of remifentanil. Mean BIS values decreased from 96 (2) in the awake state, to 46 (12) at LOC (P<0.05) and then remained unchanged at all remifentanil Ce(T). Pupil dilatation in response to 100 Hz tetanic stimulation decreased progressively from 1.55 (0.72) to 0.01 (0.03) mm and was more sensitive than pupil diameter measured before and after 100 Hz tetanus. An inverse correlation between pupil dilatation in response to 100 Hz tetanus and an increase in remifentanil Ce(T) from 0 to 5 ng ml(-1) was found (R(2)=0.68). CONCLUSIONS: During propofol TCI in healthy patients, the decrease in pupil response to a painful stimulus is a better measurement of the progressive increase of remifentanil Ce(T) up to 5 ng ml(-1) than haemodynamic or BIS measurements.