Abstract
Background/Aim: We previously showed that an elevated postoperative serum C-reactive protein (CRP) level has a negative impact on long-term survival outcomes, regardless of the occurrence of infectious complications in colorectal cancer. However, the cause of postoperative inflammation could not be properly evaluated, because patient background factors, such as the surgical approach (open/laparoscopic), were not unified. Patients and Methods: A total of 277 patients who underwent laparoscopic surgery for stage II/III colorectal cancer were enrolled. Results: The high-CRP group had lower relapse-free and overall survival rates in comparison to the low-CRP group. A high postoperative serum CRP level was significantly associated with a larger tumor diameter and longer operation time, and tended to be associated with a higher T stage and larger amount of bleeding. Conclusion: Larger tumor volume, longer operation time and larger amount of bleeding were associated with the promotion of postoperative inflammation, which worsened long-term survival outcomes in colorectal cancer.
- Colorectal cancer
- C-reactive protein
- postoperative inflammation
- prognosis
The negative impact of postoperative infectious complications on long-term survival has been reported in patients with gastroenterological malignancies, including esophageal cancer (1, 2), gastric cancer (3-5) and colorectal cancer (6-9). Furthermore, it has recently been reported that strong postoperative inflammation, which was caused by factors other than postoperative infectious complications, has a negative impact on long-term survival (10). This finding was consistent with the result from our previous report, which showed that inflammation caused by surgical stress has a negative impact on long-term survival in patients with colorectal cancer (11). However, the cause of the increased inflammatory response after surgery could not be properly evaluated in our previous report, because patient background factors, such as the surgical approach (open surgery/laparoscopic surgery) were not unified. The aim of the study was to validate the significance of the postoperative serum C-reactive protein (CRP) level as a predictor of long-term survival and to evaluate the relationships between the postoperative serum CRP level and the clinicopathological factors in patients who underwent laparoscopic surgery for colorectal cancer.
Patients and Methods
A total of 277 patients who underwent laparoscopic surgery for stage II/III colorectal cancer at the Osaka City University Hospital between January 2012 and December 2016 were enrolled in this study. All patients enrolled in this study underwent curative resection. Patients who received preoperative therapy, such as neoadjuvant chemoradiotherapy, underwent emergency surgery for perforation or obstruction, and patients with ulcerative colitis or familial adenomatous polyposis were excluded from this study. This retrospective study was approved by the Ethics Committee of Osaka City University (approval number: 4182) and was conducted in accordance with the Declaration of Helsinki. All patients provided their written informed consent.
The relationships between the postoperative serum CRP level and the relapse-free/overall survival rate were assessed by using the CRPmax level, which was defined as the highest postoperative CRP level during the hospital stay and has been reported to be a marker with extremely accurate prognostic value (10). An appropriate cut-off value for the CRPmax level was determined based on a receiver operating characteristic (ROC) curve analysis, and the patients were then classified into the low CRPmax and high CRPmax groups. Furthermore, the relationships between the postoperative CRPmax level and the clinicopathological factors were assessed in order to identify the factor that promotes postoperative inflammation.
All statistical analyses were performed using the SPSS software package for Windows (SPSS, Chicago, IL, USA). The significance of differences in the CRPmax level and the clinicopathological factors were analyzed using a chi-squared test and Fisher’s exact test. Survival curves were estimated using the Kaplan–Meier method, and the differences in the survival curves were assessed with a log-rank test. A multivariate Cox proportional hazard model was used to evaluate the prognostic factors associated with the survival. p-Values of <0.05 were considered to indicate statistical significance.
Results
Patient characteristics. The patient characteristics are shown in Table I. The study population included 172 patients with colon cancer and 105 patients with rectal cancer. The distribution of the cancer stages was as follows: stage II, n=143; stage III, n=134. Fifty (18.1%) patients developed a postoperative infectious complication. The median duration of follow-up was 48.0 months. Fifty-four patients relapsed, and 54 patients died during the follow-up period.
Classification according to the CRPmax level. The CRPmax level, as a continuous variable, was used as the test variable and 5-year survival was used as the state variable. An ROC curve analysis revealed that the appropriate cut-off value of the CRPmax level was 7.55 (sensitivity=72.6%, specificity=52.5%) (Figure 1).
Survival analysis according to the CRPmax level. The high CRPmax group had significantly lower relapse-free and overall survival rates in comparison to the low CRPmax group (p=0.0001, p=0.0006, respectively) (Figure 2).
Subgroup analyses limited to patients without postoperative infectious complications. Similarly to the results of the analyses for all patients enrolled in this study, the high CRPmax group had significantly lower relapse-free and overall survival rates than the low CRPmax group (p=0.0010, p=0.0035, respectively) (Figure 3). A high CRPmax level was significantly associated with a larger tumor diameter and longer operation time, and tended to be associated with higher T stage and larger amount of intraoperative blood loss (Table II). The correlations between relapse-free survival and various clinicopathological factors are shown in Table III. According to the results of the univariate analysis, relapse-free survival was significantly associated with tumor depth, lymph node metastasis, transfusion and the CRPmax level. The multivariate analysis indicated that higher T stage, positive lymph node metastasis, transfusion and a higher CRPmax level were independent prognostic factors for worse relapse-free survival. The correlations between overall survival and various clinicopathological factors are shown in Table IV. According to the results of the univariate analysis, overall survival was significantly associated with tumor depth and the CRPmax level, and tended to be associated with histological type and transfusion. The multivariate analysis indicated that higher T stage and higher CRPmax level were independent prognostic factors for overall survival.
Discussion
In this study, a high postoperative CRPmax level was revealed to be associated with worse long-term survival outcomes in patients who underwent laparoscopic surgery for colorectal cancer. This is consistent with the results from our previous report, which showed that postoperative inflammation had a negative impact on the long-term survival outcomes in patients who underwent open or laparoscopic surgery for colorectal cancer (11). In this study, we were able to verify the findings obtained in our previous report.
An increase in the level of inflammatory cytokines contributes to immunosuppression, which prompts the proliferation of residual cancer cells (12-15). Thus, postoperative severe inflammation worsens the prognosis, regardless of the cause. Postoperative infectious complications have previously been reported to have a negative impact on long-term survival outcomes (1-9). However, the presence or absence of postoperative infectious complications alone is insufficient to assess the impact of postoperative infectious complications on long-term survival outcomes because there are many types of postoperative infectious complications, and it has been reported that some types of postoperative infectious complications, such as wound infection, are not associated with the long-term survival outcomes (16). In addition, the severity of complication, as classified by the Clavien–Dindo classification, does not always match the severity of inflammation.
Inflammation markers are comprehensive indicators, including the effects of postoperative infectious complications. Thus, recent studies have concluded that postoperative inflammatory markers have greater prognostic value than the occurrence of postoperative infectious complications (10).
Our previous study included both open and laparoscopic surgery cases (11). In addition, there was a tendency to select laparoscopic surgery for early-stage cancer and open surgery for advanced cancer. Thus, the bias, regarding surgical stress, was very large. In this study, we were able to minimize the bias regarding patient background by limiting the cases to those who underwent laparoscopic surgery. As a result, we were able to investigate the causes of the increase in the postoperative serum CRP level, which could not be accurately examined in our previous study. Factors associated with surgical stress, such as larger tumor volume, longer operation time, and larger amount of intraoperative blood loss, were associated with the promotion of postoperative inflammation.
The present study was associated with some limitations. First, this was a retrospective study of a small cohort of patients who were managed in a single center. Second, in this study, we evaluated the maximum level of the inflammatory marker, but not the duration for inflammatory levels remained high. Examining how the duration of high inflammatory levels is associated the survival outcomes is our next task.
Of course, it is important to reduce postoperative complications and perform strict postoperative management. In addition, it is also necessary to minimize surgical stress and postoperative inflammation by reducing the amount of intraoperative blood loss and shortening the operation time, which could improve long-term survival outcomes.
This study is significant in that we could identify the clinicopathological factors which were associated with the promotion of postoperative inflammation.
Conclusion
Larger tumor volume, longer operation time and larger amount of bleeding were associated with the promotion of postoperative inflammation, which worsened long-term survival outcomes in colorectal cancer.
Footnotes
Authors’ Contributions
MS designed the study, performed the statistical analysis and draft the manuscript. WE and YO collected the clinical data and revised the manuscript critically. KM, KH and MO designed the study and critically reviewed the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors declare that they have no competing interests in regard to this study.
- Received January 10, 2021.
- Revision received January 23, 2021.
- Accepted February 8, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.