Our study demonstrated that AL impairs long-term outcomes of the patients undergoing surgery for sigmoid and rectal cancer. Severe comorbidities, male sex, and advanced tumor stage are the risk factors for AL.
Several recent studies investigated the risk factors for AL because the identification of high-risk patients and avoidance of anastomosis in these patients could improve treatment outcomes.8–12 Previously studies demonstrated male gender as a risk factor for AL after rectal surgery and our results were consistent with these findings.3,8,9,13,14 Male gender is thought to increase the AL rate because of more technically demanding surgery in the narrow and deeper pelvis of men.13 There is a possibility that hormonal functions may impact anastomotic healing as well.15,16 The advanced stage of tumor also makes surgery more technically challenging and it was confirmed as another risk factor for AL by our study. Interestingly, we did not find a higher AL rate in patients receiving low anastomosis. These findings are conflicting with some previous reports indicating a higher risk for low anastomoses.3,17 Although, in our results, there was a strong tendency for higher AL rate in low anastomoses (≤ 5 cm (10.9%) vs 6–12 cm (13.6%) vs > 12 cm (5.8%), p = 0.137) and it might be that our study was underpowered to detect significant differences because of the relatively small sample size.
Lower anastomoses may be secured by diverting ileostomy. However, the evidence on the impact of ileostomy on preventing the leak or reducing the symptoms is conflicting. Two meta-analyses concluded that stoma reduces the rate of AL following low anterior resection12,18. In contrast, our study did not confirm that ileostomy prevents AL. This finding is consistent with some previous studies.19,20 A temporary ileostomy may not prevent the AL but rather diminish its symptoms and consequences. Further, the true rate of AL in patients receiving ileostomy may be underestimated because usually asymptomatic patients do not undergo testing for anastomosis integrity at the early postoperative period.21,22 Therefore, further studies are required to clarify the role of ileostomy in the prevention of the AL.
The existing data on AL impact on the long-term outcomes are conflicting as well. A recent study from the Mayo clinic revealed similar OS, DFS, and local recurrence rates between patients with or without AL.6 Propensity-score matched analysis by Sueda et al. also demonstrated a similar OS rate in AL and non-AL patients, except the higher rate of local recurrence in case of leakage.23 In contrast, the previous meta-analysis by Bashir et al. concluded that patients with AL have a lower 5-year OS of 58% compared with 73% in non-leaking patients.24 Moreover, the negative impact of AL on OS was indicated by Yang et al. and a large Scandinavian cohort study by Stormark et al.25,26 Our study confirmed the impaired OS and DFS in patients suffering from AL and there is a rationale for such findings. First, AL may lead to an increased rate of local recurrence because of cancer cell implantation and progression at the inflamed leaking anastomotic site.27,28 Despite AL occurs after surgical tumor removal, several viable tumor cells remain intraluminally proximally and distally to cancer sites.29 These cells were identified after the rectal wash-out or were washed-out from histologically tumor-free stapled doughnuts.30,31 The pre-clinical model confirms these intraluminal cancer cells can implant at the anastomotic site and initiate tumor growth in experimental animals.32 Additionally, the leakage results in a local inflammation, which may further contribute to the increased risk of tumor cell implantation and proliferation at the anastomotic site.33 Moreover, the AL is associated with an increased systemic inflammatory response as showed by increased levels of CRP and such condition may be related to the development and progression of the malignancy.34,35 AL is also associated with the delay or omission of the adjuvant chemotherapy. Therefore, AL may have a negative impact on long-term outcomes, especially in patients with the advanced stage of the disease, where adjuvant chemotherapy is necessary.36–39
The present study has some limitations, including the retrospective design of the study. However, a considerable sample size, multicenter approach and significant national registry-based long-term follow-ups increase the power of the study to demonstrate that AL is associated with impaired long-term outcomes in patients undergoing surgery for left-sided CRC. Future research is needed to find strategies to reduce or prevent the rate of AL in such patients.40