Outcomes of right-sided and left-sided colon cancer after curative resection

The right and left side of the colon derived from the midgut and hindgut, respectively. Previous studies have reported different characteristics of right-sided colon cancer (RCC) and left-sided colon cancer (LCC), but oncological outcomes remain unclear. This study compared the outcomes of RCC and LCC. This retrospective study included 1017 patients who received curative colectomy for stage I-III colon cancer at a single institute between August 2008 and December 2019. Overall survival (OS) and time to recurrence (TTR) were analyzed as outcome measurements. No significant difference in the OS or TTR of patients with RCC and LCC were observed. In subgroup analysis, RCC was associated with shorter TTR than LCC in stage II colon cancer (HR 2.36, 95% confidence interval 1.24–4.48, p < 0.01). Multivariate analysis demonstrated that right sidedness, R1 resection, low body mass index (BMI) and adjuvant chemotherapy were independent factors for poor prognosis for stage II colon cancer. Low BMI, perineural invasion, higher T stage and N2 stage were independent factors for poor prognosis for stage III colon cancer. The results were confirmed by multivariate analysis after propensity score matching. Our study revealed that RCC was an independent risk factor for recurrence in stage II colon cancer.

Statistical analysis. Both K-S and S-W tests were used to confirmed the normal distribution of continuous variables. Variables normally distributed were presented as mean ± standard deviation, otherwise presented as median (Q1-Q3). Comparisons were made using independent-t test or Mann-Whitney test for analysis of continuous variables. Chi-square test was used for comparisons of categorical variables. Kaplan-Meier curves were calculated for all patients and patients with stage I, II, and III colon cancer separately to compare OS and TTR between patients with RCC and LCC. Univariate and multivariate survival analyses were performed with a Cox proportional hazards function; HRs and 95% confidence intervals (CIs) were used to estimate the impact of primary tumor location on survival outcomes. Propensity score matching (PSM) was performed with greedy nearest neighbor matching method, using 14 variables (age, sex, BMI, patient origin, operation method, CEA, LVI, PNI, tumor grade, T stage, N stage, tumor size, chemotherapy and R1 resection) that could potentially influence outcomes. The number of lymph node harvested was not included due to native difference of mesocolon taken during operation between RCC and LCC. The caliper requirement was ignored. A p value of < 0.05 was considered statistically significant.
Ethics approval. This study was approved by the Ethics Committee of Taipei Medical University (approval number: N201912114) and was performed in accordance with the Declaration of Helsinki and its subsequent amendments or comparable ethical standards.
Informed consent. Informed consent was not applicable due to the retrospective nature of this study.

Discussion
This study was a large-scale retrospective study. We followed more than 1000 patients who underwent curative resection for stage I, II, and III colon cancer, with the longest follow-up time more than 10 years. This study demonstrated that the sidedness of colon cancer did not influence OS but influenced TTR in stage II colon cancer. We also observed that RCC, lower BMI, R1 resection and chemotherapy were risk factors for shorter TTR in stage II colon cancer, whereas lower BMI, perineurial invasion, advanced T and N stage were risk factors for shorter TTR in stage III colon cancer. To compensate for the possible bias in this retrospective study, we performed www.nature.com/scientificreports/ propensity score matching. The results of multivariate analysis were mostly compatible with the results before PSM, which makes this study more reliable. In previous population-based studies, the OS rate was highly different between stage I, II, and III RCC and LCC. A study of 91,416 patients demonstrated that OS in stage I and II RCC was longer than in stage I and II LCC 14 . In a study of 77,978 patients, Meguid et al. reported that OS in stage II and III RCC was worse than in stage II and III LCC 6 . However, in a study of 53,801 patients over 65 years of age, Weiss et al. reported that RCC had longer OS than LCC in stage II but worse OS in stage III 16 . The age at diagnosis of RCC is approximately 3.0 to 4.6 years older than that for LCC 6,17,18 , and only one-third of patients with stage I-III colon cancer die from the cancer 19 . Therefore, OS does not truly reflect the difference in prognosis between RCC and LCC 20 ; hence, we used TTR to compare the risk factors of RCC and LCC.
This study also noted differences between RCC and LCC and reinforced the consensus that RCC and LCC can be regarded as distinct cancers. However, our results contradicted previous studies regarding their specific www.nature.com/scientificreports/ differences. First, many previous population-based studies have reported a higher proportion of women with RCC than LCC 6,14,16 ; this was also true in our study. However, in our results, women only composed a higher proportion of patients with stage I and II RCC, not stage III. Second, several studies have noted that RCC has a larger tumor size and presents as a later stage than LCC 6,21 . In our study, tumor size was significantly larger in   www.nature.com/scientificreports/ may be the typical representation of LCC at the time of diagnosis. Third, lymphovascular invasion and tumor grade are powerful prognostic factors in colon cancer 23 , and many studies have reported that RCC has a higher rate of lymphovascular invasion and a higher tumor grade than LCC 12,20,21,24 . However, we observed that tumor grade and the incidence of lymphovascular invasion are significantly higher in stage II RCC than in stage II LCC but not in stage III RCC. The high rate of lymphovascular invasion and the presence of grade 3-4 tumor cells shortened TTR in stage II RCC compared with that for stage II LCC. In our study, although stage III RCC had a larger tumor size and more advanced T stage than stage III LCC, cancer recurrence did not differ if patients underwent appropriate radical resection and adjuvant chemotherapy; moreover, we observed no difference in tumor size between stage II RCC and LCC. However, RCC had a shorter TTR because of a higher proportion of lymphovascular invasion and tumor grade. Therefore, we believe that stage II RCC can be regarded as a unique category of colorectal cancer, and postoperative treatment and follow-up strategies need to be accordingly tailored. Several studies have also suggested that colon cancer heterogeneity is different between RCC and LCC. Microsatellite instability (MSI) and dMMR are more common in RCC. Patients with stage II colon cancer and MSI or dMMR tumors had a better prognosis in RCC than LCC, but in patients with stage III colon cancer, MSI or dMMR provided no benefit to prognosis 12,25,26 . A recent study reported that in patients with dMMR stage II colon cancer, 5-FU based chemotherapy did not improve survival and could even worsen prognosis 27 . The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (2017) recommended that MMR status be checked in stage II colon cancer 3 . Our institute follows this treatment guideline and has tested MMR status for colon cancer since 2017. According to the limited MMR test data, nearly half of patients with RCC had dMMR (45.5%), which is 10-20% higher than in previous studies 12,28 . This also explains why chemotherapy was a risk factor for stage II RCC because many patients underwent adjuvant chemotherapy without an MMR status test before 2017.
In previous studies, no differences in BMI were reported between patients with RCC and LCC 23,24,29 . In this study, however, patients with RCC and stage III RCC had significantly lower BMI than did patients with LCC and stage III LCC, respectively. This may be because patients with RCC are predominantly female and older, which are two groups that generally have a lower BMI. We observed increased BMI to be a positive prognostic factor for patients with both stage II and stage III cancer. By contrast, previous studies have reported obesity or a BMI of > 30 kg/m 2 to be risk factors for cancer recurrence and cancer-related mortality in colorectal cancer [30][31][32][33] . In agreement with our study, Sinicrope et al. reported that overweight patients (BMI 25-29.9 kg/m 2 ) had better OS in stage II and III colon cancer 34 ; the authors speculated that relatively healthy patients in this BMI range can tolerate operations and adjuvant chemotherapy 34 . We speculate that patients with a low BMI have too little visceral fat to cover the tumor, and thus, the tumor can easily invade the surrounding organs or spread. Patients with obesity usually have comorbid diseases, and complications often occur during surgery or chemotherapy. Most patients (91%) in this study had a BMI below 30, and we observed that increased BMI was associated with longer TTR.
This study had several limitations. First, this was a retrospective study at a single institution, which makes our study susceptible to bias and confounding factors despite the large study population. Second, only 33 patients (0.3%), 110 patients (11%) and 488 patients (48%) had an MSI status, MMR status or K-RAS mutation test, respectively. Because of the low number of patients with an MSI status, MMR status or K-RAS mutation test, we did not analyze the effect of these variables on prognosis in this study. Third, detailed chemotherapy data were not available in this study. Patients who received oral chemotherapy, intravenous chemotherapy, and incomplete chemotherapy courses were all classified as having received adjuvant chemotherapy. This may underestimate the effects of chemotherapy. Finally, complete mesocolic excision (CME) in RCC increases OS and DFS, and cancer stage may be underdiagnosed in patients without CME [35][36][37] . CME is not routinely performed for RCC at our institute, and CME status is not always recorded in medical records, thus affecting the analysis of prognosis.
In conclusion, sidedness is an independent risk factor for cancer recurrence in stage II colon cancer; patients with stage II RCC had shorter TTR than did those with stage II LCC. Furthermore, stage III RCC had a more advanced T stage, but this did not influence TTR in stage III colon cancer. Further research is needed to evaluate the differences of sidedness by using clinicopathological and genetic factors.

Data availability
The data generated in this study are available on request from the corresponding author. www.nature.com/scientificreports/ Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.