Clinical characteristics and prognosis of different primary tumor location in colorectal cancer: a population-based cohort study

In this study, we evaluated the clinical characteristics and prognostic relevance of PTL in CRC. We further confirmed through historical data that patients with right-sided cancers were more likely to be old, female and mucinous adenocarcinoma or signet ring cell histology than those with left-sided cancers [14‐16]. Our data were consistent with the growing body of evidence showing that those with left-sided cancers have better prognosis than patients with right-sided cancers among patients with metastatic CRC (stage IV) [5‐8]. Our analysis further showed that patients with left-sided cancers exhibited better prognosis than patients with right-sided cancers in all stages (including localized CRC). When grouped based on tumor stage, all patients with left-sided cancers showed significantly better prognosis than those with right-sided cancers regardless of stage. This difference was not apparent between patients with metastatic CRC and those with localized CRC. However, the reason for the different survival rates of patients with different PTL in CRC remains unclear. We speculate that differences in embryological origin and detection time may contribute to this discrepancy. The embryological junction between the midgut and hindgut leads to a potential watershed area in the area of the splenic flexure, and it is supplied by the superior and inferior mesenteric arteries. The rectum also arises from the hindgut and the blood supply from the inferior mesenteric artery. So, we included it in the left half colon analysis. Due to the larger diameter of the right-sided colon tube, all patients with right-sided cancers had later onset of clinical symptoms, such as abdominal pain and intestinal obstruction. Right-sided tumors were more likely to develop into advanced cancers (stage III and IV). After controlling for tumor stage and histology, the patients’ prognosis in left-sided cancers remained better than those of right-sided cancers. This result also suggested that the difference in prognosis between the two groups may be related to genetic and environmental factors. Right-sided cancers are more likely to involve genome-wide hypermethylation and hypermutations than left-sided cancers [17‐20]. Gene analyses elucidated four biological consensus molecular subtypes (CMSs) in CRC [21]. Notably, the differential CMSs were distributed between the left-sided and right-sided cancers, and “microsatellite unstable/immune” CMS1 and “metabolic” CMS3 were more prevalent in right-sided cancers than in left-sided cancers [21]. The different PTLs also exhibited varied microbiota and histories of exposure to potential carcinogenic toxins [22, 23]. In stage IV, patients with left-sided cancers have a higher rate of liver metastases and lung metastases was found when compared with those of right-sided cancers, whereas patients with right-sided cancers were associated with a higher rate of peritoneal metastases and metastases at other sites [24]. In fact, several recent studies have exhibited that PTL may be prognostic and predictive of the response to antiepidermal growth factor receptor (EGFR) therapy in mCRC. Trials using cetuximab as an anti-EGFR therapy, including CRYSTAL and FIRE-3, showed that the prognosis of patients with left-sided cancers were superior to those of patients with right-sided cancers [25]. In terms of treatment, compared to right-sided cancers, some patients with rectal cancers received preoperative or postoperative radiotherapy. Some studies demonstrated that those treatments could improve local control [26‐29]. However, those studies also demonstrated that OS were not improved [27‐30]. It might not affect the results (OS) of our study that the rectum was incorporated into the left colon for analysis. In addition, it might affect the OS that patients with right-sided tumors were older than those with left-sided tumors. Therefore, the clinical characteristics and prognostic mechanisms of different sites of colorectal cancer require further study, especially on locational cancers. Our results also differed from other study [10]. Such different results might be due to the different definitions for right- and left-sided cancers. Cancers located from the rectum to the splenic flexure colon are commonly defined as left-sided cancers, whereas those from the splenic flexure colon to the cecum are defined as right-sided cancers [8, 17, 31, 32]. By contrast, others employed different definitions of left-sided cancers, which only included the descending and sigmoid colon cancers, and right-sided cancers, which only included the cecum and ascending colon cancers; moreover, they excluded patients with cancers in other colorectal locations [10]. Our study was based on the former definition. Such different definitions may explain the inconsistency between the results of the two studies.