Impact of postoperative complications after primary tumor resection on survival in patients with incurable stage IV colorectal cancer: A multicenter retrospective cohort study

Abstract Aims Primary tumor resection for patients with incurable stage IV colorectal cancer can prevent tumor‐related complications but may cause postoperative complications. Postoperative complications delay the administration of chemotherapy and can lead to the spread of malignancy. However, the impact of postoperative complications after primary tumor resection on survival in patients with incurable stage IV colorectal cancer remains unclear. Therefore, this study aimed to investigate how postoperative complications after primary tumor resection affect survival in this patient group. Methods We reviewed data on 966 patients with stage IV colorectal cancer who underwent palliative primary tumor resection between January 2006 and December 2007. We examined the association between major complications (National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 grade 3 or more) and overall survival using Cox proportional hazard model and explored risk factors associated with major complications using multivariable logistic regression analysis. Results Ninety‐three patients (9.6%) had major complications. The 2‐year overall survival rate was 32.7% in the group with major complications and 50.3% in the group with no major complications. Patients with major complications had a significantly poorer prognosis than those without major complications (hazard ratio: 1.62; 95% confidence interval: 1.21‐2.18; P < .01). Male, rectal tumor, and open surgery were identified to be risk factors for major complications. Conclusions Postoperative complications after primary tumor resection was associated with decreased long‐term survival in patients with incurable stage IV colorectal cancer.


| INTRODUC TI ON
Colorectal cancer is the fourth most commonly diagnosed cancer and the second leading cause of cancer deaths worldwide. 1 Approximately 20% of all patients with colorectal cancer are diagnosed with stage IV cancer, and approximately 80% of those patients cannot undergo curative resection of the distant metastasis. 2,3 The effectiveness of palliative primary tumor resection (PTR) for incurable stage IV patients is still controversial. 4-6 PTR could prevent tumor-related complications, such as intestinal obstruction, perforation, bleeding, or fistula. [7][8][9] Conversely, PTR may cause postoperative complications that requires time for the patients to recover from, which subsequently delays the administration of systemic chemotherapy and these delays can lead to the systemic spread of malignancy. [10][11][12] Postoperative complications can worsen the long-term survival as well as short-term outcomes. Previous studies reported that postoperative complications decrease survival after curative surgery; however, only a few reports have focused on PTR for patients with incurable stage IV colorectal cancer. [13][14][15] This study aimed to investigate the impact of postoperative complications after PTR on survival in patients with incurable stage IV colorectal cancer.

| Study design and setting
This is a retrospective cohort study using data from the Japan

| Eligibility
Patients with stage IV disease were included in this study. From them, we excluded patients with postoperative 30-day or in-hospital death.

| Postoperative complications
Postoperative complications were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 (CTCAE). 16

| Statistical analysis
Continuous variables were compared using the Mann-Whitney U test.
Categorical valuables were compared using the Fisher's exact test.
Overall survival (OS) was defined as the time between the date of primary tumor resection and the date of death. Survival curves were created by Kaplan-Meier estimates, and they were compared by the log-rank test. Multivariable cox regression models were used to examine the association between major complications and OS, adjusting for all variables. Subgroup analyses were performed to explore the differences in impact of major complications on OS according to age, American Society of Anesthesiologists -Physical Status (ASA-PS), and the number of organs with residual tumor.
Multivariable logistic regression models were performed to explore factors associated with major complications. Of all the variables assessed, other than postoperative treatments, we selected variables that had a P value of <.1 in the univariable analysis or clinically relevant factors such as age, ASA-PS, emergency operation, tumor depth, and lymph node metastasis.
All P values were two-sided, and P values <.05 were considered statistically significant. All statistical analyses were performed using JMP Statistical Software Version 14 (SAS-Institute Inc, Cary, NC, USA).

| Details of postoperative complications
The characteristics of postoperative complications are described in Table 2. There was a total of 246 complications, including 92 grade 3 complications and 11 grade 4 complications.
Anastomotic leak, ileus/obstruction, and wound infection were the most common complications. Infectious major complications were found in 53 patients and non-infectious major complications were found in 46 patients. Multiple complications were found in 21 patients.

| Factors associated with major complications
In the logistic regression model, male, rectal tumor, and open surgery were significantly associated with major complications (Table 3).

| Survival analysis
The OS curves of patients stratified by major or no major postoperative complications are shown in Figure 1.   (Table 4).

| D ISCUSS I ON
In this study, we showed that patients with stage IV colorectal cancer with major postoperative complications after PTR had a poor prognosis. In addition, we identified that male sex, rectal tumor, and open surgery were significantly associated with major complications.
Several mechanisms have been proposed to explain the negative impact of postoperative complications on oncologic outcomes.
Postoperative complications lead to the omission or delay in administering postoperative chemotherapy. 15,18,19 In this study, patients in the major complications group had an increased delay for the start of postoperative chemotherapy compared to patients with no major complications. In addition, postoperative complications cause inhibition of the adaptive immune response secondary to tissue damage, anesthesia, blood transfusion, and, in particular, infectious complications. 13,20 The negative effect of complications was reportedly greater in more advanced stages. 21 The strength of this study is that it is the first study to clarify the association between postoperative complications and sur- Nobuaki Hoshino https://orcid.org/0000-0002-7171-8971