LAUSR

Emerging evidence during the last 5 years has shown that right-sided metastatic colorectal cancer has a very different biology and a poorer prognosis than left-sided disease (Table 1). This difference in outcomes by sidedness appears to extend to benefit from systemic therapy as well. Treatment directed against the epidermal growth factor receptor (EGFR) pathway appears to be significantly less effective for right-sided tumors than for left-sided tumors. The study by Shida et al. in this issue is an interesting addition to the literature because it demonstrates that the known association of right-sided metastatic colorectal cancer with a poorer prognosis appears to be independent of treatment strategy. The study included 678 patients with unresectable stage 4 colorectal cancer. Of these 678 patients, 193 (28%) had right-sided primary tumors and 485 (72%) had left-sided primary tumors. The results demonstrated a significant difference in median overall survival between rightand left-sided tumors (16.4 vs 23.4; p\ 0.01). An analysis of 188 propensity score-matched pairs showed a similar difference in median overall survival between rightand left-sided tumors (16.4 vs 21.5 months; p\ 0.01). It should be noted that patient characteristics differed between those with left-sided and those with right-sided tumors. In particular, the patients with right-sided tumors were older, had worse Eastern Cooperative Oncology Group (ECOG) performance status, and had higher percentages of M1b/M1c disease and poorly differentiated tumors. They also were less likely to receive a targeted therapy in addition to chemotherapy. These differences in patient and tumor characteristics and treatment regimen may have confounded the observed differences in survival based on tumor sidedness. However, in a multivariate analysis that adjusted for ECOG performance status, sites of metastatic disease, tumor differentiation, preoperative carcinoembryonic antigen carcinoembryonic antigen (CEA) levels, type of surgery, and type of chemotherapy regimen, right-sided disease remained an independent prognostic factor associated with worse survival [hazard ratio (HR) 1.26, 95% confidence interval (CI) 1.03–1.53]. These results are particularly important because they are independent of both surgical and systemic therapy strategy. The study findings are limited by its single-center, retrospective cohort design. As the authors acknowledge, patients were enrolled during 16 years. During this time, the standard of care changed repeatedly, so earlier patients likely received suboptimal therapy by current standards. Although the results of the multivariate analysis are compelling, the imbalance toward poorer prognostic features in the right-sided tumor group raises the possibility of residual confounding. Screening also might have had a smaller effect for right-sided tumors than for left-sided tumors if more patients in this population had undergone flexible sigmoidoscopy instead of colonoscopy. Nevertheless, this study contributes important and novel findings for the understanding and treatment of metastatic colorectal cancer. The data align well with the retrospective analyses of the phase 3 randomized CALGB/SWOG 80405 and FIRE-3 trials conducted in the United States and Europe, respectively. The CALGB/SWOG 80405 data showed worse overall survival for patients with rightversus left-sided tumors (19.4 vs 34.2 months; HR 1.56; 95% CI 1.32–1.84). The FIRE-3 data also showed significantly worse overall survival for patients with rightversus left-sided tumors that was most pronounced for patients treated with anti-EGFR therapy (16.1 vs Society of Surgical Oncology 2019