Rethinking endpoints for the watch-and-wait strategy in rectal cancer.

INTRODUCTION To enable cross-trial comparisons of the benefit-risk ratio of the watch-and- wait strategy, two endpoints are required: a primary to assess the benefit and a co-primary to assess the main risk, i.e. regrowth.

MATERIAL AND METHODS We performed a literature search to identify and critically analyse endpoints used to evaluate the watch-and-wait strategies.

RESULTS AND DISCUSSION The review identified four watch-and-wait strategy-specific primary endpoints assessing benefit and four methods for calculating regrowth rate across nine prospective studies, indicating the need for standardisation. To initiate a debate on this topic, we discuss shortcomings of the following commonly used endpoints: 1) "The clinical complete response (cCR) rate" is flawed for demonstrating benefit, as it combines patients who ultimately achieve sustained cCR ('winners') with those who eventually experience regrowth ('losers'); 2) "the organ preservation rate" combines two procedures with different outcomes: watch-and-wait strategy and local excision; 3) calculating "the regrowth rate" only among patients achieving cCR-while excluding those with near-cCR who pursue watch-and-wait but later require surgery for persistent or progressive abnormalities-leads to an underestimation of the risk associated with deferring surgery. The following endpoints do not share these limitations and are therefore proposed for consideration in the debate on standardisation: 1) proportion of patients with sustained cCR among those who start radio(chemo)therapy; 2) the calculation of regrowth rate among pooled patients with cCR and all with near-cCR pursuing watch-and-wait surveillance.