RESUMEN
BACKGROUND: The 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. METHODS: Consecutive 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. RESULTS: 318 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. CONCLUSION: Primary tumor sidedness and grade appear to exert time-varying prognostic effects in CLM patients undergoing curative liver resection.