Abstract
Aim:
The objective of this study was to identify the factors influencing postoperative morbidity in patients with colorectal cancer (CRC) and synchronous peritoneal metastasis (PM).
Methods:
This multicenter prospective observational study was conducted by the Japanese Society for Cancer of the Colon and Rectum. Patients with CRC and synchronous PM were recruited from 28 institutions in Japan between October 2012 and December 2016. Postoperative morbidity was the primary endpoint of the analysis, and diverse variables were included for evaluation via logistic regression analysis.
Results:
A total of 137 patients, including 78 men and 59 women, were enrolled in this study. The median age was 67 years. Among patients with synchronous PM, 55 had PM alone, classified as M1c1, whereas 82 had PM with metastases to other organs, classified as M1c2. In multivariate analysis, M1c2 status and operation time >170 minutes were significantly associated with postoperative morbidity (odds ratio [OR] = 3.89, 95% confidence interval [CI] 1.31–11.51, p = 0.01; and OR = 4.56, 95% CI 1.32–11.51, p = 0.01, respectively). In the overall cohort, postoperative morbidity was not significantly associated with overall survival.
Conclusion:
This study demonstrated that M1c2 is an independent risk factor for postoperative morbidity. When planning surgery for peritoneal metastasis, particularly in patients with distant organ metastases, the elevated risk of postoperative morbidity should be carefully considered in surgical decision-making.
Keywords: carcinomatosis, colorectal cancer, complication, peritoneal metastasis, morbidity
INTRODUCTION
Colorectal cancer (CRC) is the third most common cancer worldwide. After liver metastasis, synchronous peritoneal metastasis (PM) is the second most frequent form of synchronous metastasis, present in 3.5 to 8.3% of patients with CRC at the time of diagnosis[1]. It is the third most common site of recurrence after curative resection, after the liver and lungs. PM is associated with a poor prognosis compared to other forms of metastasis[2-4]. Therefore, in the Tumor, Node, Metastasis (TNM) classification, PM is classified as M1c separately from other metastatic forms. Further, in the Japanese Classification of Colorectal Carcinoma, PM is subdivided into M1c1 for PM without metastasis to other organs and M1c2 for PM with metastasis to other organs[5]. Based on previous reports of favourable 5-year survival rates, complete surgical resection is considered the most effective therapy for localized PM[6-8]. Additionally, the guidelines of the Japanese Society for Cancer of the Colon and Rectum (JSCCR) and the National Comprehensive Cancer Network recommend complete resection, including the primary lesion for localised PM, if the surgery is not excessively invasive[9]. Although there have been many reports on the relationship between complete surgical resection and improved overall survival in primary CRC with PM, few studies have examined the factors influencing postoperative morbidity after surgery for PM. Therefore, this study aimed to identify factors associated with postoperative morbidity in patients with CRC and synchronous PM.
METHODS
This multicenter, prospective, observational study targeting patients with CRC and synchronous PM was conducted by the JSCCR and named “Grading of peritoneal metastasis from colorectal cancer.” Between October 2012 and December 2016, a total of 150 patients were enrolled at 28 institutions belonging to JSCCR. Eligibility criteria were clinically or histologically confirmed CRC and age ≥ 20 years. PM was diagnosed intraoperatively based on the presence of peritoneal tumors, at least one of which was resected and histologically confirmed as peritoneal metastasis from CRC. Patients with other malignancies, except carcinoma in situ, either synchronously or metachronously within 5 years, were excluded. Written informed consent was obtained from all patients before enrollment. Initial treatment decisions were made at each institution. The study protocol was approved by the ethics committee of the JSCCR and Tochigi Cancer Center (Approval Number: A-227).
Data collection
The following clinical and pathological parameters were assessed: sex, age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), body mass index, clinical T category, clinical N category, clinical M category, clinical P category, histological type, presence of ascites, diabetes mellitus, and surgical procedure. Histological type was classified as well-differentiated adenocarcinoma (tub1), moderately differentiated adenocarcinoma (tub2), or others, including poorly differentiated adenocarcinoma, mucinous adenocarcinoma, and signet ring cell carcinoma. Surgical procedures included resection of the primary lesion with peritoneal metastasis (PL+PM resection), resection of the primary lesion alone (PL resection), resection of peritoneal metastasis alone (PM resection), no resection (palliative procedures such as bypass surgery or stoma creation), and simultaneous resection of other organs. Tumor location was classified as right-sided (cecum, ascending colon, and transverse colon) or left-sided (descending colon, sigmoid colon, rectosigmoid junction, and rectum).
The clinical T, N, M, and P categories were defined according to the Japanese classification of colorectal carcinoma as follows. T1 indicated tumor invasion confined to the submucosa (SM) without involvement of the muscularis propria (MP); T2, tumor invasion into but not beyond the MP; T3, tumor invasion beyond the MP, extending into the subserosa in sites with serosa or into the adventitia in sites without serosa; and T4, tumor invasion of or perforation through the serosa, or direct invasion of adjacent organs or structures. Nodal status was classified as N0, no regional lymph node (LN) metastasis; N1, metastasis in 1–3 pericolic, perirectal, or intermediate LNs; N2, metastasis in four or more pericolic, perirectal, or intermediate LNs; and N3, metastasis in the main LNs, including main and/or lateral LNs in lower rectal cancer. Distant metastasis was categorized as M1c1, peritoneal metastasis only; or M1c2, peritoneal metastasis with additional distant metastases. Peritoneal metastasis was further classified as P0, no peritoneal metastasis; P1, localized peritoneal metastasis adjacent to the primary tumor; P2, limited peritoneal metastasis to distant peritoneal sites; and P3, diffuse peritoneal metastasis to distant peritoneal sites[5]. In this study, patients with P1–P3 disease were included.
Residual tumor status was classified according to the R classification of the TNM staging system[10] as R0 (no residual tumor), R1 (microscopic residual tumor), or R2 (macroscopic residual tumor). The extent of peritoneal metastasis was evaluated using the peritoneal cancer index. The Peritoneal Cancer Index (PCI) is a quantitative scoring system used to assess the extent and distribution of peritoneal metastases within the abdominal cavity. The abdominal cavity is divided into 13 regions, and lesion size scores are assigned to each region. The total PCI score ranges from 0 to 39, with higher scores indicating more extensive peritoneal disease[11]. Postoperative morbidity was defined as complications occurring during postoperative hospitalization and graded according to the Clavien–Dindo classification. Complications of Clavien–Dindo grade ≥2 were defined as events.
Statistical analysis
Categorical variables were compared using the chi-square test or Fisher's exact test, as appropriate. Factors associated with postoperative morbidity were evaluated using logistic regression analysis. Receiver operating characteristic (ROC) curve analysis was used to determine optimal cutoff values for continuous variables in relation to postoperative morbidity. Overall survival was analyzed using the Kaplan–Meier method, and survival curves were compared using the log-rank test. Prognostic factors for overall survival were evaluated using the Cox proportional hazards model. Data were statistically analyzed using Stata 14.1 (Stata Corporation, College Station, TX, USA) and JMP 16.2.0 (SAS Institute Inc., Cary, NC, USA) software packages. Statistical significance was established at p < 0.05 for all results.
RESULTS
Characteristics of the study cohort
Figure 1 shows the study flow diagram for the patients included in this study. Between October 2012 and December 2016, a total of 150 patients were enrolled across 28 institutions in Japan. Of these, two patients with appendiceal carcinoma, two patients who underwent hyperthermic intraperitoneal chemotherapy (HIPEC), and nine patients who received neoadjuvant chemotherapy were excluded. Finally, 137 patients were included in the analysis.
Figure 1.
Flow chart showing the selection of the study population.
After excluding two patients with appendiceal carcinoma, two patients who underwent hyperthermic intraperitoneal chemotherapy, and nine patients who received neoadjuvant chemotherapy, 137 patients were enrolled.
Table 1 summarizes the clinicopathological characteristics of the 137 patients who underwent resection or non-resection of the primary tumor and/or peritoneal metastasis (PM). Among these patients, 55 had PM alone (M1c1), whereas the remaining 82 had PM with metastases to other organs (M1c2). Among the M1c2 patients, 60 had liver metastases, 26 had lung metastases, 21 had extra-regional lymph node metastases, and 3 had metastases to other regions. Surgery for primary tumor resection was performed in 116 patients (84.7%), whereas 21 patients (15.3%) underwent palliative surgery. Operative procedures stratified by metastatic status are shown in Table 2. No significant differences in the distribution of surgical procedures were observed between the M1c1 and M1c2 groups. R0 or R1 resection was achieved in 30 patients (54.5%) in the M1c1 group and in 4 patients (4.9%) in the M1c2 group. Postoperative morbidity of Clavien–Dindo grade ≥2 occurred in 24 patients (5 in the M1c1 group and 19 in the M1c2 group), with detailed morbidity data shown in Table 3. The most common postoperative complication was ileus or bowel obstruction (15 in 137, 10.9%). There were no in-hospital postoperative deaths.
Table 1.
Patient Characteristics.
| Variables | All (n=137) | |
|---|---|---|
| Age (years) | Median (range) | 67 (30-89) |
| Sex | Male/Female (%) | 78 (56.9)/59 (43.1) |
| PS | 0/1/2 (%) | 88 (64.2)/37 (27.0)/12 (8.7) |
| BMI (kg/m2) | Median (range) | 20.9 (9.4-40.5) |
| cT category | cT2-3/cT4/Misssing | 27 (19.7)/109 (79.6)/1 (0.7) |
| cN category | cN0-1/cN2-3/Misssing | 74 (54.0)/61 (44.5)/2 (1.5) |
| cM category | M1c1 | 55 (40.1) |
| M1c2 | 82 (59.9) | |
| cP category | P1/P2/P3 | 29 (21.2)/52 (37.9)/56 (40.9) |
| PCI score | 1-6/7 or over | 83 (60.6)/54 (39.4) |
| Ascites | Absent/Present | 57 (41.6)/80 (58.4) |
| Histrogical type | tub1-2/others/Missing | 116 (84.7)/19 (13.9)/2 (1.4) |
| Tumor location | colon/rectum | 110 (80.3)/27 (19.7) |
| Right-sided/Left-sided | 70 (51.0)/67 (49.0) | |
| Diabetes mellitus | Absent/Present | 117 (85.4)/20 (14.6) |
| Surgery | PL resection/No PL resection | 116 (84.7)/21 (15.3) |
| PM resection/No PM resection | 82 (59.9)/55 (40.1) | |
| PL+PM resection | 80 (58.4) | |
| No resection | 19 (13.9) | |
| Operation time (min) | Median (range) | 194 (30-719) |
| Estimated blood loss (g) | Median (range) | 132 (0-2856) |
| Residual tumor status after surgery | R0/1/2 | 29 (21.1) 5 (3.7)/103 (75.2) |
| Postopeative morbidity | absent/CD Grade 1/2/3/4 | 104 (75.9)/11 (8.0)/17 (12.4)/6 (4.4)/2 (1.5) |
PS, performance status; BMI, body mass index; PL, primary lesion; PM, peritoneal metastasis; PCI, peritoneal cancer index; LN, lymph node; CD, Clavien-Dindo classification; tub1, well differentiated adenocarcinoma; tub2, moderately differentiated adenocarcinoma; others, poorly differentiated adenocarcinoma or mucinous adenocarcinoma or signet ring cell carcinoma
Table 2.
Details of Operative Procedures.
| M1c1 (n=55) | M1c2 (n=82) | P value | |
|---|---|---|---|
| Ileocecal resection | 4 (7.3%) | 11 (13.4%) | 0.26 |
| Right hemicolectomy | 16 (29.1%) | 17 (20.7%) | 0.18 |
| Left hemicolectomy | 2 (3.6%) | 2 (2.4%) | 0.70 |
| Partial colectomy | 6 (10.9%) | 6 (7.3%) | 0.47 |
| Sigmoidectomy | 6 (10.9%) | 12 (14.6%) | 0.53 |
| Total Colectomy | 2 (3.6%) | 0 (0%) | 0.16 |
| High anterior resection | 3 (5.5%) | 2 (2.4%) | 0.40 |
| Low anterior resection | 5 (9.1%) | 2 (2.4%) | 0.11 |
| Hartmann’s procedure | 5 (9.1%) | 14 (17.1%) | 0.20 |
| Stoma creation | 4 (7.3%) | 10 (12.2%) | 0.35 |
| Bypass | 0 (0%) | 4 (4.9%) | 0.13 |
| Other procedures | 2 (3.6%) | 2 (2.4%) | 0.71 |
Table 3.
Types and Clavien–Dindo Grades of Postoperative Morbidity in Patients with M1c1 and M1c2 Disease.
| Grade 1 | Grade 2 | Grade 3 | Grade 4 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| All | M1c1 | M1c2 | All | M1c1 | M1c2 | All | M1c1 | M1c2 | All | M1c1 | M1c2 | |
| SSI | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Wound dehiscence | 8 | 6 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Ileus or bowel obstruction | 0 | 0 | 0 | 14 | 4 | 10 | 1 | 0 | 1 | 0 | 0 | 0 |
| Anastomotic leakage | 2 | 2 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 2 | 0 | 2 |
| Thrombosis | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 |
| Cholesistits | 0 | 0 | 0 | 1 | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 0 |
| Intrapelvic abscess | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 |
| Pneumonia | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 |
| Urinary tract infection | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Chylous ascites | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| All morbidity | 11 | 8 | 2 | 17 | 4 | 13 | 6 | 0 | 6 | 2 | 0 | 2 |
SSI, surgical site infection
Factors associated with postoperative morbidity in M1c patients
Table 4 summarises the results of univariate and multivariate analyses of clinicopathological factors associated with postoperative morbidity (Clavien–Dindo grade 2–4). M1c2 status and operative time >170 minutes were identified as significant risk factors for postoperative morbidity in both univariate and multivariate analyses (odds ratio [OR] = 3.89, 95% confidence interval [CI]: 1.31–11.51, p = 0.01; and OR = 4.56, 95% CI: 1.42–14.63, p = 0.01, respectively). Additionally, no significant difference in postoperative morbidity was observed between patients with colon cancer and those with rectal cancer (colon: 20/110 [18.2%] vs. rectum: 4/27 [14.8%], p = 0.68).
Table 4.
Risk Factors for Postoperative Morbidity (Clavien–Dindo Grade 2–4) in All Patients.
| Variables | Category | n | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|---|---|
| OR | 95% CI | p value | OR | 95% CI | p value | |||
| Age | <65/65 or over | 56/81 | ref/1.85 | 0.72-4.84 | 0.2 | |||
| Sex | Male/Female | 78/59 | 1.07/ref | 0.44-2.62 | 0.88 | |||
| PS | PS0-1/2 | 125/12 | ref/1.65 | 0.41-6.61 | 0.48 | |||
| BMI (kg/m2) | <25/25 or over | 121/16 | 3.52/ref | 0.44-28.02 | 0.23 | |||
| cT category | cT2-3/4 | 27/109 | ref/0.92 | 0.31-2.76 | 0.89 | |||
| cN category | cN0-1/2-3 | 74/61 | ref/1.55 | 0.64-3.76 | 0.33 | |||
| Japanese P classification | P1/2-3 | 29/108 | ref/1.02 | 0.34-3.02 | 0.96 | |||
| PCI score | 1-6/7 or over | 83/54 | ref/1.12 | 0.46-2.74 | 0.8 | |||
| Peritoneal metastasis with other organ metastasis | Absent (M1c1)/Present (M1c2) | 55/82 | ref/3.02 | 1.05-8.64 | 0.04 | 3.89 | 1.31-11.51 | 0.01 |
| Ascites | Absent/Present | 57/80 | ref/0.99 | 0.41-2.43 | 0.99 | |||
| Histological type | tub1 or tub2/others | 105/17 | ref/0.97 | 0.25-3.71 | 0.96 | |||
| Tumor location | colon/rectum | 110/27 | ref/0.78 | 0.24-2.51 | 0.6 | |||
| Right-sided/Left-sided | 70/67 | ref/0.70 | 0.29-1.71 | 0.44 | ||||
| Diabetes mellitus | Absent/Present | 117/20 | ref/1.71 | 0.55-5.29 | 0.35 | |||
| Surgery, Primary lesion resection | Absent/Present | 21/116 | ref/2.22 | 0.48-10.25 | 0.31 | |||
| Surgery, Peritoneal metastasis resection | Absent/Present | 55/82 | ref/2.30 | 0.85-6.22 | 0.1 | |||
| Operation time (min) | <170/170 or over | 51/86 | ref/3.56 | 1.14-11.10 | 0.03 | 4.56 | 1.42-14.63 | 0.01 |
| Estimated blood loss (g) | <280/280 or over | 98/39 | ref/2.06 | 0.83-5.16 | 0.12 | |||
| Residual tumor status after surgery | R0-1/2 | 34/103 | ref/1.31 | 0.44-3.83 | 0.62 | |||
PS, performance status; BMI, body mass index; PL, primary lesion; PM, peritoneal metastasis; PCI, peritoneal cancer index; LN, lymph node; CD, Clavien-Dindo classification; OR, odds ratio; CI, confidence interval; ref, reference; tub1, well differentiated adenocarcinoma; tub2, moderately differentiated adenocarcinoma; others, poorly differentiated adenocarcinoma or mucinous adenocarcinoma or signet ring cell carcinoma
Postoperative morbidity in patients undergoing primary lesion resection
Among the 116 patients who underwent primary lesion resection, M1c2 status was significantly associated with postoperative morbidity in both univariate and multivariate analyses (univariate OR = 3.12, 95% CI 1.06–9.16, p = 0.04; multivariate OR = 3.51, 95% CI 1.14–10.71, p = 0.03; Table 5). Among the 21 patients who underwent palliative procedures only, such as stoma creation or bypass surgery, postoperative morbidity did not differ significantly between the M1c1 and M1c2 groups.
Table 5.
Risk Factors for Postoperative Morbidity (Clavien–Dindo Grade 2–4) in Patients Undergoing Primary Lesion Resection.
| Variables | Category | n | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|---|---|
| OR | 95% CI | p value | OR | 95% CI | p value | |||
| Age | <65/65 or over | 46/70 | ref/2.63 | 0.90-7.72 | 0.08 | 2.59 | 0.84-7.92 | 0.09 |
| Sex | Male/Female | 66/50 | 1.13/ref | 0.44-2.86 | 0.81 | |||
| PS | PS0-1/2 | 105/11 | ref/1.70 | 0.41-7.00 | 0.46 | |||
| BMI (kg/m2) | <25/25 or over | 105/11 | 2.69/ref | 0.30-20.63 | 0.39 | |||
| cT category | cT2-3/4 | 24/91 | ref/1.14 | 0.37-3.50 | 0.81 | |||
| cN category | cN0-1/2-3 | 64/50 | ref/2.15 | 0.83-5.53 | 0.11 | |||
| Japanese P classification | P1/2-3 | 28/88 | ref/1.10 | 0.37-3.32 | 0.86 | |||
| PCI score | 1-6/7 or over | 78/38 | ref/1.55 | 0.60-4.04 | 0.37 | |||
| Peritoneal metastasis with other organ metastasis | Absent (M1c1)/Present (M1c2) | 50/66 | ref/3.12 | 1.06-9.16 | 0.04 | 3.51 | 1.14-10.71 | 0.03 |
| Ascites | Absent/Present | 51/65 | ref/1.16 | 0.45-2.99 | 0.75 | |||
| Histological type | tub1 or tub2/others | 92/13 | ref/1.32 | 0.33-5.33 | 0.69 | |||
| Tumor location | colon/rectum | 93/23 | ref/0.87 | 0.27-2.90 | 0.83 | |||
| Right-sided/Left-sided | 61/55 | ref/0.72 | 0.28-1.82 | 0.49 | ||||
| Diabetes mellitus | Absent/Present | 100/16 | ref/1.52 | 0.44-5.25 | 0.51 | |||
| Surgery, Peritoneal metastasis resection | Absent/Present | 36/80 | ref/1.67 | 0.56-4.96 | 0.35 | |||
| Operation time (min) | <170/170 or over | 34/82 | ref/3.12 | 0.86-11.33 | 0.08 | 4.28 | 1.13-16.22 | 0.03 |
| Estimated blood loss (g) | <280/280 or over | 79/37 | ref/2.07 | 0.79-5.35 | 0.13 | |||
| Residual tumor status after surgery | R0-1/2 | 34/82 | ref/1.52 | 0.51-4.51 | 0.45 | |||
PS, performance status; BMI, body mass index; PL, primary lesion; PM, peritoneal metastasis; PCI, peritoneal cancer index; LN, lymph node; CD, Clavien-Dindo classification; OR, odds ratio; CI, confidence interval; ref, reference; tub1, well differentiated adenocarcinoma; tub2, moderately differentiated adenocarcinoma; others, poorly differentiated adenocarcinoma or mucinous adenocarcinoma or signet ring cell carcinoma
Impact of postoperative morbidity on overall survival
Postoperative morbidity, defined as Clavien–Dindo grade 2–4 complications, was not significantly associated with overall survival in the overall cohort (p = 0.26; Figure 2). Subgroup analyses were then performed in the M1c1 and M1c2 groups to further evaluate the relationship between postoperative morbidity and overall survival. No significant association was observed in the M1c2 group (p = 0.69; Figure 3). In contrast, in the M1c1 group, patients with postoperative morbidity appeared to have longer overall survival in the log-rank test (p = 0.02; Figure 4). However, Cox proportional hazards regression could not be performed for the M1c1 subgroup because all five patients with postoperative morbidity were alive during follow-up, resulting in no death events in this category.
Figure 2.
Kaplan–Meier curves of overall survival according to postoperative morbidity.
Postoperative morbidity was not significantly associated with overall survival.
Figure 3.
Kaplan–Meier curves of overall survival according to postoperative morbidity in the M1c2 group.
Postoperative morbidity was not significantly associated with overall survival in the M1c2 group.
Figure 4.
Kaplan–Meier curves for overall survival according to postoperative morbidity in the M1c1 group.
Postoperative morbidity was significantly associated with overall survival in the M1c1 group by the log-rank test. Cox proportional hazards regression could not be performed because no death events were observed among patients with postoperative morbidity in this subgroup.
DISCUSSION
Previous studies have consistently reported that R0 resection is associated with improved survival outcomes in patients with peritoneal metastasis (PM)[7,8,12-14]. However, postoperative morbidity in patients with PM has been less extensively studied. In this multicenter prospective observational study of patients with colorectal cancer (CRC) and synchronous PM, we demonstrated that PM accompanied by metastases to other organs—classified as M1c2 according to the Japanese Classification of Colorectal Carcinoma—was an independent risk factor for postoperative morbidity. These findings suggest that, although achieving R0 resection remains an important determinant of oncological outcomes in patients with PM, surgical decision-making for patients with M1c2 disease should carefully balance the potential survival benefit against the higher risk of postoperative morbidity and the lower likelihood of achieving complete resection, particularly in comparison with patients with M1c1 disease and when primary tumor resection is performed. Such decision-making may include careful selection of surgical candidates, optimization of operative extent and intent, and consideration of less invasive or symptom-oriented approaches rather than excessively aggressive surgery in patients with extensive systemic disease burden.
In the present study, postoperative morbidity was significantly more frequent in patients with M1c2 disease than in those with M1c1 disease. Previous studies have shown that high-grade tumors and stage IV disease are associated with higher postoperative complication rates than earlier-stage colorectal cancer[15], suggesting that advanced tumor burden adversely affects short-term surgical outcomes. However, to the best of our knowledge, no previous studies have specifically examined differences in postoperative morbidity between M1c1 and M1c2 categories.
Although primary lesion resection itself was not significantly associated with postoperative morbidity, M1c2 status remained a significant risk factor both in the overall cohort and in the subgroup of patients who underwent primary lesion resection. This suggests that the increased morbidity observed in patients with M1c2 disease cannot be explained solely by whether primary tumor resection was performed. However, the small number of patients who underwent palliative procedures limited further subgroup analysis.
Direct comparison of postoperative morbidity rates between the M1c1 and M1c2 groups and previous reports is challenging, as most prior studies have focused on cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC), and data on morbidity following surgery without HIPEC remain limited. In addition, standard indications for CRS generally exclude patients with uncontrolled distant metastases, making it challenging to appropriately contextualize morbidity outcomes in patients with M1c2 disease.
Notably, a limited number of studies have reported aggressive surgical strategies combining CRS and HIPEC with liver resection in carefully selected patients with colorectal cancer and synchronous, resectable liver metastases[16-23]. These studies provide indirect evidence regarding the impact of extra-peritoneal disease on postoperative morbidity. Among patients with PM alone undergoing CRS and HIPEC, reported morbidity rates range from 30% to 45%[24-26]. Moreover, in a large international collaborative study, Lo Dico et al. reported Clavien–Dindo grade III–IV and grade II–IV morbidity rates of 32.3% and 49.2%, respectively, with a 90-day postoperative mortality rate of 4% among patients treated with CRS and HIPEC combined with liver resection for synchronous PM and liver metastases[20]. Although the authors concluded that this aggressive approach was feasible with acceptable morbidity and relatively low mortality even in patients with M1c2 disease, they also acknowledged the potential impact of selection bias.
In the present cohort, R0 or R1 resection was achieved substantially less frequently in the M1c2 group than in the M1c1 group, whereas postoperative morbidity was more frequent in the M1c2 group. This contrast highlights the clinical dilemma in treating patients with M1c2 disease: these patients may be less likely to achieve complete resection but more likely to experience postoperative morbidity. Notably, patients with M1c2 disease exhibited not only a higher frequency of ileus but also a broader spectrum of systemic and severe complications compared with patients with M1c1 disease.
The mechanisms underlying the higher postoperative morbidity observed in patients with M1c2 disease compared with those with M1c1 disease remain unclear. However, M1c2 disease may reflect a greater systemic tumor burden and biologically more aggressive disease, potentially associated with cancer-related inflammation, malnutrition, sarcopenia, and impaired immune function[27-29]. These factors may increase susceptibility to postoperative infectious and systemic complications. This interpretation is consistent with previous reports showing that palliative resection in patients with stage IV colorectal cancer is associated with higher postoperative morbidity and mortality than curative resection in patients with stage I–III disease[30].
In addition, patients with M1c2 disease often present with more extensive intra-abdominal disease, bowel obstruction, or multiorgan involvement. These conditions may require technically more demanding procedures, leading to prolonged operative time and increased surgical stress, even when the operative procedure itself is not identified as an independent risk factor. Consistent with this hypothesis, prolonged operative time (>170 min) was also identified as a significant predictor of postoperative morbidity in the present study. Operative time is generally considered a surrogate marker of surgical complexity and invasiveness, reflecting increased bowel manipulation, blood loss, fluid shifts, tissue trauma, and physiological stress during surgery[31,32]. These factors may contribute to postoperative complications, particularly in patients with advanced metastatic disease.
Therefore, the higher morbidity observed in patients with M1c2 disease is likely multifactorial, reflecting not only patient frailty but also increased systemic disease burden, adverse tumor biology, and greater technical complexity of surgical management. Furthermore, although ileus was the most common postoperative complication in both groups, patients with M1c2 disease experienced a broader spectrum of systemic complications, including pneumonia, thrombosis, and cholecystitis, and tended to have more severe complications such as Clavien–Dindo grade 3 and 4 complications. This observation further supports the hypothesis that patients with M1c2 disease have poorer overall physiological reserve.
In the present study, no significant association was observed between postoperative morbidity and overall survival in either the overall cohort or the M1c2 group. In contrast, the M1c1 subgroup with postoperative morbidity showed a paradoxically better survival outcome. This finding should be interpreted with caution, as it may reflect the influence of multiple factors beyond postoperative morbidity alone, including the dose intensity and duration of postoperative chemotherapy, the presence of comorbidities, and tumor-related molecular characteristics, such as RAS and BRAF mutation status and microsatellite instability status. In this study, postoperative morbidity was defined as Clavien–Dindo grade ≥2 complications, because complications of this severity require pharmacological treatment and may delay the initiation of postoperative chemotherapy, which is an important component of treatment for many patients with peritoneal metastasis. However, detailed data on the timing of postoperative chemotherapy were not available, precluding further analysis of the relationship between postoperative morbidity and delays in chemotherapy initiation. Further investigation is warranted to clarify the impact of postoperative morbidity on survival in this population.
Importantly, our results do not support the notion that patients with colorectal cancer and M1c2 disease should categorically avoid surgical intervention. Instead, when R0 resection is deemed achievable, surgery should be considered and ideally performed at experienced centers[15,16] with careful attention to the increased risk of postoperative morbidity.
This study has several limitations. First, the sample size was relatively small; however, collecting surgical data on patients with peritoneal metastasis is inherently challenging, and broader multicenter collaboration will be necessary to increase cohort size. Second, this was not a randomized controlled study, and selection bias related to surgeon judgment or institutional treatment policies may have influenced the results. Third, data regarding whether surgery was performed in an emergency setting were unavailable. As emergency surgery has been reported to be associated with a higher risk of postoperative complications, this factor should be addressed in future studies. Fourth, macroscopic radical resection (MRR) was the primary curative procedure for peritoneal metastasis in this cohort; although MRR is not an internationally established standard, previous studies have demonstrated its non-inferiority to cytoreductive surgery (CRS)[14,33,34]. Given the lower invasiveness and comparable efficacy of MRR and CRS, the applicability of our findings beyond Japan warrants further investigation. Finally, molecular genetic data, including MSI status, RAS and BRAF mutations, and circulating tumor DNA, were not available. Addressing these limitations will require future studies with larger, more comprehensive datasets.
In conclusion, our findings indicate that M1c2 disease is independently associated with an increased risk of postoperative morbidity. Although R0 resection remains a key determinant of oncological outcomes in patients with PM, the increased morbidity risk associated with M1c2 disease should be incorporated into surgical decision-making. These findings underscore the need for careful patient selection, individualized determination of surgical extent and intent, and consideration of less invasive or symptom-oriented strategies in patients with extensive systemic disease burden.
Disclaimer
Hirotoshi Kobayashi is one of the Associate Editors of Journal of the Anus, Rectum and Colon and on the journal's Editorial Board. He was not involved in the editorial evaluation or decision to accept this article for publication at all.
Competing interests
The authors declare that they have no conflicts of interest.
Author Contributions
NT and HO contributed to the conception and design of the study, data analysis, drafting of the manuscript, and critical revision of the manuscript. HK, KK, MK, YK, YK, HU, KM, TS, KS, and YA contributed to the conception of the study, critically reviewed the manuscript, and approved the final version.
Ethics statement
This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and applicable local laws and regulations. The study protocol was approved by the ethics committees of the Japanese Society for Cancer of the Colon and Rectum and Tochigi Cancer Center (approval number: A-227).
Informed consent
Written informed consent was obtained from all patients before enrollment.
Registry and Registration No. of study/trial: Not applicable.
ORCID
Naoyuki Toyota: https://orcid.org/0009-0004-0621-4883
Acknowledgments
This study was performed as part of a project by the Japanese Society for Cancer of the Colon and Rectum.
Funding Statement
No funding was received for this study.
References
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