Tumor Sidedness Could be a High-risk Factor in Patients with Stage II Colon Cancer

Background : The search for high-risk factors in stage II colon cancer (CC) is ongoing and several high-risk factors for stage II CC have been identified; however, the effects of tumor sidedness on prognosis is not clear. This study aims to determine whether tumor sidedness could be identified as another high-risk factor for stage II CC. Methods : We retrospectively analyzed 189 patients with stage II CC, following consecutive curative resection surgery performed between 2008 and 2014. We compared clinicopathological findings and long-term outcomes between the patients with right colonic cancer (RCC) and patients with left colonic cancer (LCC). Prognostic factors for survival were determined using univariate and Cox proportional regression analyses. Results : A total of 72 patients were diagnosed with RCC and 117 patients were diagnosed with LCC. Patients with RCC were significantly older (p < 0.001) than those with LCC, and the number of harvested lymph nodes (HLNs) was greater in the RCC group (RCC: 25 vs. LCC: 19; p = 0.003). The overall survival (OS) was notably worse in the RCC group than the OS in the LCC group (5 year survival rate—RCC: 81.3% vs. LCC: 90.4%; p = 0.025), whereas no significant difference was observed in disease-free survival (5 year survival rate—RCC: 74.8% vs. LCC: 83.4%; p = 0.065). Cox proportional regression analysis showed that tumor sidedness (hazard ratio (HR): 3.78, 95% confidence interval (CI): 1.61–8.85, p = 0.022), gender (HR: 3.27, 95% CI: 1.27–8.47, p = 0.014), and the number of HLNs (HR: 4.58, 95% CI: 1.95–10.74, p < 0.001) were independent prognostic factors for OS. Conclusion : Patients with a right-sided primary tumor location have more negative prognostic factors and worse long-term outcomes than those with a left-sided primary tumor location in stage II CC. Tumor sidedness is a high-risk CEA: carcinoembryonic acid; CRC: colorectal cancer; DFS: survival; epidermal growth factor receptor; HLN:

malignancy. The selected patients were divided into two groups, based on tumor sidedness (the RCC and LCC groups). RCC was defined as a tumor arising from the cecum, ascending colon, or transverse colon. LCC was defined as a tumor arising from the descending colon, sigmoid colon, or recto-sigmoid colon.

Surgical procedure and follow-up
The all procedures were performed by skilled surgeons (with the patients under epidural and general anesthesia). The method of surgical approach (open surgery or laparoscopic surgery) was determined in each case, depending on the patient's medical history and tumor progression. Laparoscopic surgery was performed using five ports and optimal resection margins and extent of lymph node dissection were determined according to JSCCR guidelines in all cases [8]. All patients were followed up regularly at our institution, including carcinoembryonic acid (CEA) and cancer antigen 19-9 assays every, computed tomography, and colonoscopy. Adjuvant chemotherapy was offered to all high-risk stage II patients having at least one high-risk factor, according to the JSCCR Guidelines for the Treatment of Colorectal Cancer. Treatment was started after pathological evaluation of the tumor specimen, which was performed within 8 weeks of colectomy, under informed consent. In adjuvant chemotherapy, oral 5-fluorouracil prodrug (capecitabine) was taken by the patient for 6 months following the operation.

Evaluation of surgical outcomes and prognostic factors for survival
We retrospectively compared patient characteristics, including age at diagnosis, gender, tumormarker level, high-risk factors, surgical outcomes and pathological findings, between the RCC group and the LCC group. All data were collected from patients' medical records. Tumor histology was determined by using the World Health Organization classification system [17]. Postoperative complications were classified according to the Clavien-Dindo classification system; grade II or higher was defined as a complication in this study [18]. Long-term outcomes between the groups were evaluated by recurrence rate, overall survival (OS), and disease-free survival (DFS).

Discussion
This study investigated the long-term outcomes and prognostic factors for stage II CC, according to the tumor sidedness. It confirmed that tumor sidedness has a major influence on prognosis. The main clinicopathological findings of this study were that stage II RCC was more frequent in more elderly patients and was characterized by a higher number of dissected lymph nodes, when compared with stage II LCC patients. Furthermore, tumor sidedness was an independent prognostic factor for OS, and the number of HLNs and gender were independent factors for both OS and DFS. For decades, there have been many suggestions that tumor location in CC potentially influences prognosis because of clinical and biological differences. Furthermore, it appears that tumors arising in right colonic lesions have different molecular and genetic pathways, when compared with those arising in left colonic lesions[3, 13,19].
In related studies, it was reported that defective mismatch repair genes, high microsatellite instability (MSI-H), BRAF/KRAS mutations, and CpG island methylator phenotype positive were the notable characteristics of RCC, whereas LCC was characterized by frequent NRAS and p53 mutations [4,13,[20][21][22]. In metastatic CRC, these molecular and genetic features of CRC by tumor location have been associated with prognosis, and the treatment, such as 5-fluorouracil-based chemotherapy or anti-EGFR therapy [19,23,24]. Meanwhile, in stage II CC, the efficacy and role of adjuvant chemotherapy is still uncertain [16,25]. In addition, there is an ongoing debate over which factors are high risk in the prognosis for stage II CC. Although tumor sidedness is not included as a stage II high-risk factor in the current guidelines, attention must be paid to tumor location in view of these molecular biological differences. . In the present study, similar results were obtained, and multivariate analysis showed that the number of lymph nodes was a significantly independent factor for both OS and DFS. Furthermore, the number of HLNs was higher in the RCC group than in the LCC group (23.8 vs. 19.2, p = 0.003). Mik et al. also reported that the total number of HLNs was higher in the RCC group (11.7 vs, 8.3 ; p = 0.0001), and these results are similar to our own findings[32]. The reason for this was due to the differences in the resected area, depending on the tumor location. The right-sided colon mesentery may anatomically contain a more complex lymphatic system and a larger area of resection, when compared with the left-sided colon [33,34]. Therefore, the reference value for the number of lymph node dissections may be better considered separately for each tumor location.
In this study, tumor sidedness was not an independent prognostic factor for DFS, although a certain trend was observed (p = 0.065). However, tumor sidedness is an independent factor for OS in stage II CC. We speculate that RCC could have a greater potential for malignancy with poor biological behavior, once it has recurred, when compared with LCC. Therefore, our results strongly indicate that RCC should be considered as a risk factor for stage II CC. In addition, it is necessary to develop multidisciplinary treatment strategies that include tumor sidedness, as well as pathological and genomic factors.
This study has some limitations. First, the small sample size, its retrospective nature, and singleinstitution setting may limit the generalization of results. Second, this study did not include the status of BRAF/KRAS/NRAS mutations, MSI, sporadic mismatch repair deficiency, germline mutationprompted Lynch syndrome, or any family history. These genomic and epigenomic characteristics should be considered, in addition to the tumor location. Therefore, it is necessary to conduct randomized controlled trials with a large sample size, including genomic information, at multiple institutions across different countries, to confirm the prognostic factors in stage II CC.

Conclusions
In conclusion, this study revealed that tumor sidedness was an independent prognostic factor for OS in stage II CC. We strongly suggest that tumor sidedness should be considered as a high-risk factor in stage II CC patients, in addition to the traditional factors.