Time-varying prognostic impact of primary tumor grade and sidedness in colorectal liver metastases

Abstract

Introduction: 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 hypothesized that there exist prognostic factors whose impact in CLM patients are not static during the passage of follow-up time. This study sought to critically appraise the existence of prognostic factors with time-dependent effects and to characterize their impact on survival in patients with colorectal liver metastases (CLM). Method: We obtained data on 55 candidate variables including patient-, tumor-, surgical-, and post-surgical-related factors. We evaluated PH of each covariate and parameters with significant departure from proportionality were included in Cox models which account for time-varying effects by incorporating an interaction with the natural logarithmic function of time. Result: 318 consecutive patients treated between Jan 2000 and Nov 2016 were included in this analysis. Only primary CRC grade and sidedness were found to exhibit non-PH. The adverse prognostic impact of both variables diminished over time. Hazard ratios for tumor grade (poorly- versus well-/moderately-differentiated) decreased from 3.135 (95% CI, 1.637-6.003) at 1 year to 2.048 (95% CI, 1.038-4.042) at 2 years, and became non-significant at 26 months. Among patients with colon carcinomas (n=249, 78.3%), log-log survival plots were empirically observed to cross, indicating a reversal in the prognostic impact of tumor sidedness during the course of follow-up. A right-sided tumor location was found to portend statistically worse prognosis for the initial 10 months after resection compared to left-sided tumors, but subsequently confer a survival benefit to patients who survive beyond 129 months. Conclusion: Primary tumor grade and tumor sidedness exhibit time-dependent hazard ratios in patients with colorectal liver metastases.