Abstract
Background/Aim: Postoperative complications are associated with increased recurrence in colorectal cancer (CRC). We investigated the impact of infectious complications on the recurrence of CRC and overall survival after curative surgery in a single study group. Patients and Methods: In total, 1,668 patients who underwent radical resection for CRC in Yokohama City University, Yokohama Minami Kyosai Hospital, and Kanagawa Cancer Center between 2011 and 2019 were reviewed. Patients were classified into those with infectious complications (IC group) and those without infectious complications (Non-IC group). The risk factors for recurrence-free survival (RFS) and overall survival (OS) were analyzed. Results: Postoperative complications were found in 560 of the 1,668 patients (33.5%), and IC, which occurred in 312 patients (18.7%), included pneumonia, anastomotic leakage, and intraperitoneal abscess. The 5-year OS rates in the Non-IC and IC groups were 95.5% and 90.4%, respectively, while the 5-year RFS rates were 74.4% and 68.1%, respectively. The multivariate analysis demonstrated that postoperative IC were significant independent risk factors for OS and RFS. Conclusion: The presence of postoperative IC after CRC resection is associated with decreased long-term survival. The surgical procedure, surgical strategy, and perioperative care should be carefully planned in order to avoid causing IC.
Colorectal cancer (CRC) is the fourth leading cause of cancer-specific death, the second leading cause of death in men, and the third leading cause of death in women (1). The 5-year survival rates of CRC cases are 90.1% in patients with early-stage disease, 69.2% in patients with locally advanced stage disease, and 11.7% in patients with distant metastasis, indicating that early-stage disease is associated with a higher survival rate. In particular, it has been reported that approximately 40% of patients with stage II/III CRC develop recurrent disease, even after complete curative resection (2). Therefore, it is important to identify the prognostic factors for patients with stage II/III CRC and select patients for more aggressive treatment (3, 4).
Postoperative complications are observed in approximately 20% of patients undergoing curative resection of primary CRC (5-7). Postoperative complications have been shown to increase the length of stay and early mortality (8, 9). Recent studies have shown that postoperative complications are associated with decreased survival and an increased risk of disease recurrence (9-17). In addition, some authors have shown that an immune response to postoperative complications increases the survival rate of undetectable residual tumor cells after surgery (18, 19). There are several reports on the association of postoperative infectious complications (IC) with long-term survival (19, 20). However, limited previous studies have shown a correlation between IC and reduced survival in patients with CRC.
This study aimed to determine whether the occurrence of postoperative IC affects recurrence-free survival (RFS) and overall survival (OS) in patients undergoing radical resection of stage II/III CRC in a multicenter, retrospective study.
Patients and Methods
Study design. In this cohort study, we retrospectively reviewed the clinical records and databases of Yokohama City University, Yokohama Minami Kyosai Hospital, and Kanagawa Cancer Center from January 2011 to December 2019. According to these records, a total of 2,205 patients with CRC underwent radical resection. Among these, cases with pathologic stage I or IV, multiple or synchronous cancers, simultaneous surgery of other organs, and non-curative resection were excluded. Finally, 1,668 patients with curable pathologic stage ll or lll disease were enrolled in the study.
Outcomes of interest. The primary outcome of this cohort study was 5-year recurrence-free survival (RFS) of the existence of all grades IC, and the secondary outcomes were 5-year OS and the short-term outcomes (e.g., operative time and the incidence of post-operative complications). The operative time was defined as the time from skin incision for the first port to completion of all surgical incisions.
Postoperative complications that occurred during hospitalization or within 30 days after surgery or both were assessed according to the Clavien–Dindo classification system (21).
Evaluations and statistical analyses. The significance of the correlation between IC and clinicopathological parameters was determined using Fisher’s test or the χ2 test. OS and RFS curves were generated by the Kaplan–Meier method and compared by the log-rank test. OS and RFS were evaluated by univariate and multivariate analyses using a Cox proportional hazards model. p-Values of <0.05 were considered to indicate statistical significance. The SPSS software program (v26.J Win, SPSS, Chicago, IL, USA) was used for all statistical analyses.
All procedures performed in the study were in accordance with the ethical standards of the institutional research committee (Yokohama City University Institutional Review Board; approval no. 170700003) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Results
Patient characteristics. Postoperative complications were found in 560 of the 1,668 patients (33.5%), and IC, which occurred in 312 patients (18.7%), included pneumonia, anastomotic leakage, and intraperitoneal abscess. Patients were classified, according to their clinicopathological features, into patients with IC (IC group) and patients without IC (Non-IC group) (Table I). Significant differences were observed between the two groups in sex, body mass index (BMI), operative approach, tumor remnant, and American Society of Anesthesiologists’ physical status (ASA). The IC group showed higher proportions of males, obese cases (BMI≥30), cases using an open approach, cases treated with laparotomy, and cases with residual tumors.
Comparison between infectious complications and clinicopathological factors between Non-IC group and IC group.
Infectious complications. The IC included wound infection, anastomotic leakage, pneumonia, catheter-related sepsis, cholecystitis, enterocolitis, urinary infection, and intraperitoneal abscess. The details are shown in Table II. The most frequently diagnosed complication was wound infection, followed by anastomotic leakage, pneumonia, and intra-abdominal abscess. The grades of complications were as follows: grade 2 (n=86), grade 3 (n=113), grade 4 (n=4), and grade 5 (n=7). Mortality was caused by pneumonia in 5 cases and sepsis in 2 cases.
Details of postoperative infectious complications evaluated by Clavien-Dindo classification.
Evaluation of the effect of complications on survival. The Non-IC group showed a significant survival benefit [5-year RFS: Non-IC vs. IC, 74.4% vs. 68.1% (p=0.037)] (Figure 1A); an even stronger tendency was observed in patients with grade ≥II IC (Figure 1B). On the other hand, the presence of anastomotic leakage tended to be associated with worse RFS; however, the difference was not statistically significant (Figure 1C). The 5-year OS rate of the Non-IC group was 95.5%, while that of the IC group was 90.4% (p=0.001) (Figure 2). Eight clinicopathological background factors were included in the multivariate analysis, which indicated that both OS and RFS were independently influenced by postoperative IC (Table III and Table IV).
Recurrence-free survival rates in the non-infectious complications (Non-IC) and IC groups (all grades, A), (grade >III, B), (presence or absence of anastomotic leakage, C). The study population consisted of patients who underwent potentially curative surgery for stage II/III colorectal cancer.
Overall survival rates in the non-infectious complications (Non-IC) and IC groups (all grades). The study population consisted of patients who underwent potentially curative surgery for stage II/III colorectal cancer (p=0.001).
Uni- and multi-variate Cox proportional hazards analysis of clinicopathological factors for recurrence-free survival between Non-IC group and IC group.
Uni- and multi-variate Cox proportional hazards analysis of clinicopathological factors for overall survival between Non-IC group and IC group.
Patterns of recurrence. The sites of initial recurrence are shown in Table V. In both groups, liver metastasis was the most frequent type of recurrence. The rates of recurrence in the groups did not differ to a statistically significant extent.
Comparison of initial recurrent site between Non-IC group and IC group.
Discussion
In this study, we showed that the presence of postoperative IC was an independent risk factor for poor OS and RFS in stage II/III CRC patients who underwent curative treatment. Regarding the relationship between postoperative IC and survival, we have demonstrated that the presence of any postoperative IC, including superficial infections, was associated with worse survival after radical resection and that 2) this tendency was especially strong in serious IC of grade II or higher. These results suggest that CD grade ≥II IC seem to cause more inflammation when stimulating tumor cells in comparison to other complications. However, while the presence of anastomotic leakage tended to worsen RFS, the difference was not statistically significant. Considering this result, the grade of complication seems more important than the type of complication in predicting long-term survival. One of the reasons for this is that the patients who had IC may have had factors that reduced the host immunity to micrometastastic tumor cells. After reviewing studies on mouse models, Dunn et al. (22) reported that the adaptive immune system could function by identifying and eliminating budding tumor cells. A second possible reason is that patients with IC had several factors that promoted the growth of remaining micrometastatic tumor cells after surgery (23). Salvans et al. (24) also reported that postoperative peritoneal infection increases the invasive activity of residual tumor cells after colorectal resection. They collected pre- or post-operative serum and intra-abdominal fluid from patients with leakage and intra-abdominal abscesses, and in addition to cancer cells cultured in vitro, they found that post-operative intra-abdominal fluid from the infected group significantly increased cell migration and invasion in vitro, in comparison to intra-abdominal fluid from the control group. These reports suggest that prevention and management of IC is essential for improving the long-term prognosis of these patients.
Several retrospective studies have investigated the effects of IC, especially anastomotic leakage, on the long-term outcomes of CRC (25-27). These studies show that deep and organ-space wound infections can lead to increased rates of local recurrence and diminish long-term survival through this mechanism. This study failed to statistically demonstrate the relationship between the presence of anastomotic leakage and these long-term prognoses. In addition, there was no correlation between the presence of postoperative IC and the form of recurrence, which did not result in an increase in the local recurrence rate. The reasons for this include the low incidence of anastomotic leakage and oversight of small anastomotic insufficiencies that are not visualized as clinical symptoms.
The present study was associated with some limitations. First, this was a retrospective study in a single research group. The results need to be confirmed in another large-scale prospective validation study. Second, physicians may have initiated adjuvant chemotherapy for patients who had sufficient organ function, but not for patients who developed IC. Third, the study included a time bias. The postoperative management changed between 2011 and 2019; thus, changes in the postoperative therapy may have had a confounding effect.
In conclusion, the long-term outcomes of patients with stage II/III CRC who receive curative resection showed significant differences according to the amount of IC. The results of this study suggest that reducing IC by carefully planning the surgical procedure, perioperative care, and surgical strategy (e.g., the extent of dissection or combined organ resection) has the potential to improve the prognosis of patients with stage II/III CRC.
Acknowledgements
The work was supported, in part, by the following non-governmental organizations: Yokohama Surgical Research Group, Association of Healthcare Corporation, Yoshiki Dermatology Clinic Ginza, and Social Health Corporation Foundation Pond Friends Association (Fukuoka Wajiro Hospital, Fukuoka, Japan).
Footnotes
Authors’ Contributions
Hiroshi Tamagawa and Aoyama Toru made substantial contributions to the concept and design. Hiroshi Tamagawa, Aoyama Toru, Masakatsu Numata, Keisuke Kazama, Yosuke Atsumi, Kenta Iguchi, Sho Sawazaki, Sumito Sato, and Kazuki Kano made substantial contributions to the acquisition of data and the analysis and interpretation of data. Takashi Ohshima, Takanobu Yamada, Teni Godai, Akio Higuchi, Hiroyuki Saeki, Norio Yukawa and Yasushi Rino were involved in drafting the article or revising it critically for important intellectual content. Hiroshi Tamagawa and Aoyama Toru gave their final approval of the version to be published.
Conflicts of Interest
The Authors declare no conflicts of interest in association with the present study.
- Received February 19, 2022.
- Revision received March 10, 2022.
- Accepted March 15, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
