Primary tumour location affects survival after resection of colorectal liver metastases: A two-institutional cohort study with international validation, systematic meta-analysis and a clinical risk score

Background Colorectal cancer (CRC) represents a major cause for cancer death and every third patient develops liver metastases (CRLM). Several factors including number and size of metastases and primary tumour lymph-node status have been linked to survival. The primary tumour location along the colo-rectum continuum (sidedness) was analysed in first-line chemotherapy trials, where right-sided CRCs showed decreased survival. This association has not yet been clearly established in patients undergoing resection for CRLM. Methods Clinicopathological differences in CRLM resections according to sidedness in two Austrian centres (2003-2016) are described and survival is compared through Kaplan-Meier and multivariable analysis. A risk-score is presented with time-dependent receiver operating curve analysis and international validation in two major hepatobiliary centres. Furthermore, a systematic meta-analysis of studies on primary tumour location and survival after CRLM resection was performed. Results 259 patients underwent hepatectomy. Right-sided CRC patients (n = 59) more often had positive primary tumour lymph-nodes (76.3%/61.3%; p = 0.043) and RAS-mutations (60%/34.9%; p = 0.036). The median overall and disease-free survival was 33.5 and 9.1 months in right-sided versus 55.5 (p = 0.051) and 12.1 months (p = 0.078) in left-sided patients. In multivariable analysis nodal-status (HR 1.52), right-sidedness (HR 1.53), extrahepatic disease (HR 1.71) and bilobar hepatic involvement (HR 1.41) were significantly associated with overall survival. Sidedness was not independently associated with disease-free survival (HR 1.33; p = 0.099). A clinical risk score including right-sidedness, nodal-positivity and extrahepatic involvement significantly predicted overall (p = 0.005) and disease-free survival (p = 0.027), which was confirmed by international validation in 527 patients (p = 0.001 and p = 0.011). Meta-analysis including 10 studies (n = 4312) showed a significant association of right-sidedness with overall survival after resection (HR 1.55; p< 0.001). There was no significant association with disease-free survival (HR 1.22; p = 0.077), except when rectal-cancers were excluded (HR 1.39; p = 0.006). Conclusions Patients with liver metastases from right-sided CRC experience worse survival after hepatic resection. Sidedness is a simple yet effective factor to predict outcome.