Improvements in the quality of life and increase in the survival of cancer patients have led to several studies evaluating SPCAC (10, 18–20). In comparison to general populations, small intestine and endometrial cancers are most common in individuals with previous CRC, according to this comprehensive assessment of 30 research. The patient's genetic background, lifestyle, cancer-related treatments, and environmental risk factors may all contribute to the higher risk(21, 22).
According to a recently published study, the incidence of colon, breast, prostate, kidney, and bladder cancer will surge in CCSs (22). This contradicts our findings, which showed that SIR of the small intestine, endometrial, colon, and ovary cancer were all higher in CCSs. We pooled data from all across the world, so the discrepancy could be related to different study designs.
CCSs had a threefold increased risk of small intestinal cancer, according to present results (SIR: 3.68). Previous studies have found a link between primary gastrointestinal cancers and subsequent cancers. (23, 24). In prior SEER, an increased risk of certain GI cancers after CRC was observed among CRC patients, although subsites were not investigated (23, 25). In agreement with our results, Yang et al. reported a significantly increased risk for small intestine cancer among CCSs (SIR: 3.09), particularly in those patients who have had prior right-sided colon cancer (26). Broman et al. also confirmed a remarkable increase in the frequency of small intestine cancer in patients with a history of CCSs and significantly greater in right-sided CRC (18). Researchers demonstrated that a reverse relation exists between age at the time of diagnosis of primary CRC and SPC risk, so patients 40 years or younger have a SIR equal to 5 in comparison with patients 50 years with a SIR of 2.6 (27). Given these findings, strict surveillance among CRC survivors specifically at young ages should be established for early detection of SPCs with specific attention to the small intestine cancer (26)
Findings of this meta-analysis indicated that people with a history of CRCs are three times more likely prone to subsequent uterus and endometrial cancers (SIR: 3.03). In line with the present data, Lee et al. found a 3.2 fold increase in the risk of uterine cancer among CRC survivors (27). Other previous research also confirms the susceptibly of CRC survivors to uterine cancer (4, 26). The underlying reasons for these findings are still unclear. Some studies suggest that medical services access and ethnic variations are responsible for different risks of contraction (28, 29). Shin et al. reported a higher prevalence of uterine cancer among CRC survivors younger than 55 years (21). Hence the screening programs for early diagnosis of the uterus and endometrial cancers among CCs will be of importance in particular, at younger ages.
The incidence of SPCs may be attributed to genetic susceptibility, environmental risk factors, as well as hormonal level changes (21). Mutations in the following genes (MLH1, MSH2, PMS1, and MSH6) can lead to both CRC and endometrial cancer, particularly in youth (30). BRCA1 and BRCA2 encode tumor suppressors, therefore any detrimental mutation in these genes increases the risk of gynecological and colorectal cancers (31). Research revealed that genetic disorders on the metabolism of a drug like glutathione transferase predispose patients to develop secondary cancers (32). Given the fact that embryonic endoderm is the origin of the common SPC sites, genetic susceptibility may act as the main mechanism underlying the risk of multiple cancers, so that adopting an approach to develop more accurate and earlier screening tests in cancer survivors could beneficial (26).
Moreover, lifestyle and environmental factors including food habits, excessive alcohol consumption, as well as can prominently influence the development of secondary malignancies (23). However, the association between previous CRC and susceptibility to tobacco-related gynecological carcinogenesis is still unclear (21). Hormones are another probable factor contributing to the occurrence of SPCs, especially gynecological ones (21). Interestingly, previous studies indicated that having no history of childbirth increases the risk of SPCs, so women who bore more than 4 children are less likely to get cancer than nulliparous women (33, 34).
The current findings point to the need for more case-control and cohort studies to clarify the relationships. If the above-mentioned risk variables are found to be valid in future studies, they might be used to develop a new guideline for patient education and counseling on behavior modification, as well as novel surveillance systems for cancer survivors. Because the majority of studies on second primary malignancies in CRC patients were conducted in rich nations, conducting SEER in developing and low-income countries is necessary to get enough data on SPCs in these areas.
One of the inherent drawbacks of this study could be the varying lengths of follow-up in the included research. Unavailable confounding characteristics such as smoking, alcohol intake, physical activity, food, and lifestyle, may restrict the findings. Furthermore, data misclassification must be addressed to some level due to the use of retro-prospective research and the difficulty to evaluate data correctness. We did, however, assess the quality of each included study and report the level of evidence. In comparison to previous studies, our study has the advantage of investigating a larger population-based cohort of CRC patients. Furthermore, because of the precise screening, the risk of misclassifying synchronous metastases, metachronous metastases, and recurrent CRCs as second primaries was eliminated, preventing the risk of second primary CRCs from being overestimated.