Analysis of Clinical End Points of Randomised Trials Including Bevacizumab and Chemotherapy versus Chemotherapy as First-line Treatment of Metastatic Colorectal Cancer.

AIMS: Progression-free survival is recognised as an appropriate end point for randomised clinical trials of chemotherapy of patients with metastatic colorectal cancer, although it is not clear if it is reliable after chemotherapy plus bevacizumab.

MATERIALS AND METHODS: A literature search of randomised trials of systemic treatment including chemotherapy plus bevacizumab versus chemotherapy in patients with metastatic colorectal cancer was undertaken. For each trial the differences in overall survival and in either time-to-event or response-related end points were calculated. A Spearman test was carried out between the difference in each end point and the difference in survival. For the end points with the higher relationships with overall survival a regression analysis was carried out and R(2) (proportion of variability explained) was reported.

RESULTS: Progression-free survival is closely related to overall survival (r=0.817; R(2)=0.706) and this relationship does not seem to be changed by the discontinuation of bevacizumab. The response-related end points have a better overall performance than the other time-to-event end points, even when only phase III trials are considered. In phase III trials, the disease control rate seems to be strongly related to overall survival (r=0.975; R(2)=0.889) and the overall response rate reports a good performance (r=0.866; R(2)=0.484). An open-label design and the timing of disease radiological evaluation do not seem to interfere with the correlation of differences of progression-free survival and overall survival.

CONCLUSIONS: A validation of the disease control rate and the overall response rate as a surrogate end point of survival at a patient level and a standardised definition of the timing for their measurement are strongly recommended in trials of chemotherapy plus bevacizumab.