1. IntroductionIn the era of personalized and precise treatment, due to differences in anatomy and histology between right-sided and left-sided colon, increasing studies have begun to explore whether different primary tumor locations for colon cancer have a significant impact on prognosis [1,2,3,4,5]. Most previous studies have shown that patients with right-sided colon cancer (RCC) have a poorer prognosis compared with left-sided colon cancer (LCC) [1,2,3,4,6,7,8,9], but others are inconsistent [10,11,12,13]. Warschkow et al. found a better survival outcome in RCC relative to LCC among patients with stage I–III colon cancer using the propensity score matched (PSM) method [11]. Therefore, there is still a controversy in survival differences between RCC and LCC. Up to now, the definition of RCC has been divided because some studies classified the transverse colon as right-sided colon, but others excluded it directly [1,8,9,10,11,13,14]. In addition, it has been found in some studies that transverse colon cancer has different biological characteristics from RCC [15,16,17,18]. Therefore, the conflicting results may be partly due to the inconsistency of location grouping criteria, and the dichotomy model (right-sided vs. left-sided colon) may be inappropriate for the study of colon cancer [16,17,18,19]. Moreover, the prognostic differences between specific subsites (cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, and sigmoid colon) have also been reported in a few studies [19,20,21]. In order to further explore the effects of tumor locations on prognosis, it is essential to find two parts with the greatest survival differences by comparing different primary tumor locations.

In our study, we collected the data of patients with stage I–III colon cancer from the Surveillance, Epidemiology, and End Results (SEER) Program database. By analyzing colon cancer data in the SEER database, it was found that the survival difference between cecum and sigmoid colon cancer was most significant among different locations. Then the prognostic significance of the two locations was further explored in multivariate survival analyses after PSM.

4. DiscussionRight-sided and left-sided colons deriving from different embryologic origin are clinically and molecularly distinct. However, the influence of primary tumor locations on the prognosis remains controversial [20,22,23,24,25]. In the present study, we found that patients with RCC had worse CSS and OS than LCC, and the two tumor locations with the greatest survival difference were cecum and sigmoid colon. Moreover, multivariate Cox regression analyses further demonstrated the worse prognosis (CSS and OS) of patients with cecum cancer compared with sigmoid colon cancer after PSM, which is helpful to further explore the influence of primary tumor locations on prognosis. To the best of our knowledge, this is the first study to find that the prognostic difference between cecum and sigmoid colon cancer is the greatest between RCC and LCC, which may partly account for the prognostic difference between RCC and LCC.Currently, most of previous studies demonstrated a poorer prognosis in RCC versus LCC, which is consistent with the present study [1,2,3,4,6,7]. A large retrospective study presented a lower five-year survival rate for RCC (70.4%) relative to LCC (74.0%) in Japan [1]. And RCC also showed a significantly worse five-year survival (HR [95% CI]: 1.71 [1.10–2.64], p = 0.017) in a retrospective study of patients with colon cancer present in the Cancer Genome Atlas (TCGA) [14]. By analyzing the prognosis of patients with unresectable colon cancer liver metastasis, Zhao et al. found that the risk of survival deterioration of RCC was significantly higher than that of LCC [26]. A meta-analysis from 66 researches reported that patients with RCC had their risk of death increased by 18% compared to LCC, which was independent of stage [7]. Another recent meta-analysis from 14 studies on metastatic colorectal cancer reported that primary cancer originating from the right-sided colon was significantly related with a worse survival in contrast to left-sided colon [3]. In addition, the present study divided the data into two parts according to the time period so as to reduce the confounding bias caused by the large time span. The difference in the prognosis of patients with RCC and LCC was shown to be consistent in the two time groups, which further confirmed the worse prognosis of RCC over LCC.As a large sample database with longitudinal data, it is very suitable to utilize the data from the SEER database to analyze the prognostic significance of primary tumor locations. Although there have been several studies about the survival difference between RCC and LCC based on the SEER database, few studies further analyzed the prognostic differences of more precise tumor locations [8,9,10,11,19,27]. The study published by Meguid et al. including 77,978 patients who underwent surgical resection for aggressive colon cancer from 1988 to 2003 in the SEER database showed a 4.2% increased mortality risk associated with RCC versus LCC [8]. Furthermore, the subset analyses stratified by AJCC stage revealed that the higher mortality risk of patients with RCC was observed in stages III and IV compared to patients with LCC [8]. Weiss et al. summarized the data of colon cancer from 1992 to 2005. Although there was no statistical difference in the prognosis between patients with RCC and LCC in the overall cohort, further stratified analysis indicated a higher mortality of patients with RCC compared to LCC in stage III [10]. In order to further explore the prognostic significance between RCC and LCC, Warschkow et al. collected the data of patients with stage I–III colon cancer from the SEER database between 2004 and 2012 and performed a PSM analysis to minimize biases between both primary cancer locations [11]. After PSM, the survival prognosis of patients with RCC was found to be superior to those with LCC regarding OS and CSS in overall cohort, which contradicts our study [11]. However, although Warschkow et al. adopted the PSM, they did not adjust for radiotherapy and chemotherapy in baseline characteristics, which obviously has a great impact on the survival analyses [11]. In addition, our study not only summarized more recent data from 2005 to 2015, but also divided the data into two groups (2004–2009 and 2010–2015) based on time intervals for mutual verification between the two time periods, which reduced the bias due to inconsistent previous treatment standards. Wang et al. also made full use of the data from the SEER database to analyze the survival distinction between RCC and LCC by adopting a competing risk model. The results showed that the cancer-specific mortality (CSM) of RCC significantly increased compared with LCC in the overall cohort [9]. Obviously, not only the inclusion and exclusion criteria of these studies based on the SEER database were inconsistent, but also these grouping criteria according to primary tumor locations were different [8,9,10,11]. Moreover, these studies did not further explore the prognostic differences among more precise tumor locations, especially cecum and sigmoid colon [8,9,10,11]. The present study showed that the survival difference between cecum cancers and sigmoid colon cancers is the largest among the six colon sites, which is akin to the results of Shaib et al. [21]. By analyzing the data of patients with non-metastatic, invasive right-sided adenocarcinoma of the colon from 1988 to 2014 who underwent partial colectomy in SEER, Nasseri at al found that cecum cancers were prone to poorer disease-specific survival (median 86.0, 93.0, and 89.0 months, respectively, pp19]. In addition, Ben-Aharon et al. also found that the Oncotype Recurrence Score, a clinically validated predictor of recurrence risk in patients with stage II CRC, gradually decreased across the colon (cecum, highest score; sigmoid, lowest score; p = 0.04) [20]. In the present study, patients with cecum cancer had more poorly differentiated tumor, advanced LNM, and late TNM stage compared with sigmoid colon cancer, which is in line with results of previous studies [1,2,9,28]. The prognosis of cecum cancer was worse than sigmoid colon cancer regardless of 2004–2009 or 2010–2015 group in univariate analyses. It is worth noting that the prognostic difference between cecum cancer and sigmoid colon cancer is still significant after PSM. Moreover, after adjusting for differences in clinicopathological characteristics, the multivariate analyses identified cecum cancer as an independent unfavorable factor of CSS and OS relative to sigmoid colon cancer. All in all, our study further confirmed that the location of primary colon cancer was an important prognostic factor and suggested that the prognosis of cecum is worse than that of sigmoid colon cancer.The reasons might be related to the different embryological origins of colon tissue—proximal colon (right-sided) deriving from mid-gut and distal colon (left-sided) deriving from hind-gut [29]. Meanwhile, different gut microbiota in left and right-sided colon cause differences in colonic mucosal immunology, which theoretically should be the largest between the cecum and the sigmoid colon [30]. From the perspective of clinical symptoms, obstruction and hematochezia due to LCC occurred more frequently than those due to RCC, which is helpful for the early diagnosis and treatment of sigmoid colon cancer [31]. Ward et al. hypothesized three pathways through which tumor site impacts survival differences, including TNM stage, microsatellite instability (MSI), and other genetic drivers [14]. Many previous studies have suggested that the potential molecular mechanism contributing to the different prognosis between RCC and LCC might be associated with differences in gene expression and signaling pathways [14,20,28,32,33,34,35,36]. Some chemotherapy regimens were also found to have different efficacy between LCC and RCC due to different microsatellite status [34]. Anatomically, the difference between cecum and sigmoid colon is the largest, which may suggest that the prognostic difference between cecum and sigmoid colon cancer is also most significant. In addition, the mobility of the sigmoid colon is better than that of the cecum, which helps to improve the curative effect of surgery and survival.

There are several limitations in the present study. First, although this study grouped the cases according to the time interval and analyzed them separately, due to the large time span, it is still difficult to eliminate the influence of inconsistent treatment standards before and after on the study results. Second, a few confounders are not matched perfectly despite adopting PSM method, which may influence the results to some extent. Third, other potential biases from unobserved confounders may be ignored, such as MSI status, socioeconomic status, environmental exposures, and so on.