Time-varying prognostic effects of primary tumor sidedness and grade after curative liver resection for colorectal liver metastases

Abstract

BackgroundThe veracity of the proportional hazards (PH) requirement is rarely scrutinized in most areas of cancer research, although fulfilment of this assumption underpins widely-used Cox survival models. We sought to critically appraise the existence of prognostic factors with time-dependent effects and to characterize their impact on survival among CLM patients. MethodsConsecutive patients who underwent liver resection with curative intent for CLM at the Singapore General Hospital were identified from a prospectively-maintained database. We evaluated PH of 55 candidate variables, and parameters which departed significantly from proportionality were included in Cox models that incorporated an interaction term to account for time-dependent effects. As sensitivity analyses, we fitted Weibull mixture ‘cure’ models to handle long plateaus in the tails of survival curves, and also analyzed the restricted mean survival time. Results318 consecutive patients who underwent curative liver resection for CLM between Jan 2000 and Nov 2016 were included in this analysis. Hazard ratios for tumor grade (poorly-versus well- and moderately-differentiated) were found to decrease from 3.135 (95% CI: 1.637–6.003) at 12 months to 2.048 (95% CI: 1.038–4.042) after 24 months, and ceased to be significant at 26 months. Compared to left-sided tumors, a right-sided tumor location was found to portend worse prognosis for the first 10 months after resection but subsequently confer a survival benefit due to a crossing of survival curves. Corroborating this observation, long-term cure fractions were estimated to be 25.5% (95% CI: 17.4%–33.6%) and 34.2% (95% CI: 17.4%–50.9%) among patients with left-sided and right-sided primary disease respectively. ConclusionPrimary tumor sidedness and grade appear to exert time-varying prognostic effects in CLM patients undergoing curative liver resection.