In this study, multivariate analysis identified different independent risk factors for tumor recurrence depending on the location of the original tumor. We also found that there was no significant difference in 5-year OS or RFS between patients with right- vs. left-sided stage II colon cancer after curative resection.
Different independent risk factors for recurrence were identified by multivariate analysis between right- and left-sided stage II colon cancer patients. When the tumor is located on the right side of the colon, no independent risk factor was selected, whereas venous invasion and PNI were selected on the left which suggest the difference in prognosis factors between the right and left colon. Although both the right- and left-side of the colon constitute the same organ, their origins are entirely different. The right-side of the colon arises from the midgut and is vascularized by the superior mesenteric artery (SMA). In contrast, the left-sided colon is derived from the hindgut and is vascularized by the inferior mesenteric artery (IMA). From this embryological perspective, it is reasonable to expect that not only the expression of molecular subtypes but also independent risk factors for recurrence are different between right- and left-sided colon cancer patients.
Our study also showed that there was no significant difference in 5-year RFS or OS rates between patients with right- vs. left-sided stage II colon cancer. The influence of the primary tumor location was found to be consistent with previously reported studies of metastatic unresectable colon cancer.[2–4] However, the impact of the primary tumor location on the prognosis of resectable colon cancer is still unclear, and a consensus has not yet been reached.[5–7] We propose that these discrepancies arise from the association between tumor location and expression of biological molecular subtypes. Supporting this, it has been reported that BRAF and RAS mutations are more common in patients with right-sided colon cancer compared to those with left-sided colon cancer.[15] One randomized clinical trial in Europe demonstrated that among patients with stage III colon cancer with a RAS or BRAF mutant phenotype, disease-free survival (DFS) was better in the right- vs. the left-sided group. In contrast, the European study also showed that in those who were wild-type for RAS and BRAF, DFS was better in the left- vs. the right-sided group.[16] Hence, molecular subtypes seem to have a major impact on prognosis and are influenced by the location of the tumor. In addition, clinicopathological parameters such as budding[12], EX[14], venous invasion, and perineural invasion[13] are also known to have an impact on prognosis. We hypothesize that these factors also have some connection with both molecular subtype and tumor location. To achieve a consensus on the impact of tumor location on the prognosis of resectable colon cancer, we should consider not only the location of the primary tumor, but also the molecular subtype and clinicopathological parameters.
According to the guidelines of major groups such as ASCO,[8] NCCN,[17] and ESMO,[18] adjuvant chemotherapy is not considered as standard of care for patients with stage II colon cancer and is used only in patients with high-risk clinicopathological features, regardless of the primary tumor location. Our study demonstrated that these high-risk clinicopathological features depend on the primary tumor location, suggesting that adjuvant chemotherapy for patients with stage II colon cancer should be considered separately for patients with right- vs. left-sided tumors.
This study has some limitations. First, the patients in this study were treated in the 1990s and 2000s. Thus, patients received oral 5-FU as adjuvant chemotherapy according to the assigned physicians’ preference, despite oxaliplatin-based regimens currently being considered the standard regimen. Second, this study had a retrospective observational design, which may have resulted in misclassification of data or selection bias.
Different independent risk factors for recurrence were identified in right- and left-sided stage II colon cancer, although there was no significant difference in the 5-year postoperative prognosis between patients with right- and left-sided stage II colon cancer after curative resection. The right - and left-sided colon should be regarded as different organs, and high-risk clinicopathological features of stage II colon cancer should be assessed separately for each side. These findings could have an impact on indications for adjuvant chemotherapy and therapeutic regimens for patients with stage II colon cancer. Further prospective studies that assess risk factors for recurrence in the right- and left-sided groups, including evaluation of patients receiving modern adjuvant chemotherapy, are warranted.