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INTRODUCTION
Peritoneal carcinomatosis (PC) occurs when tumors of gastrointestinal or gynecological origin metastasize to the peritoneum or arise from primary tumors. Approximately 7% of patients with advanced colorectal cancer present with peritoneal metastasis [1]. The median survival for patients with peritoneal metastasis from colorectal cancer is 6.9 months [2], which is worse than the median survival of 8–14 months for patients with liver or lung metastases [3]. For patients with PC, curative surgery is not feasible using conventional treatments, and systemic chemotherapy and palliative surgery are typically required to alleviate symptoms. However, in select patients where an R0 resection is achievable and who are treated at experienced centers, cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) may be considered [4]. The prognosis for patients with colorectal cancer and peritoneal metastasis is expected to improve with advancements in CRS and HIPEC [5]. Following the introduction of CRS with HIPEC, the 5-year survival rate for patients with pseudomyxoma peritonei (PMP) increased to 65%–75% [6], and for patients with colorectal cancer with peritoneal metastasis, it reached 35%–45% [7]. Additionally, some large international retrospective studies have suggested applying CRS with HIPEC in patients with colorectal cancer with peritoneal metastasis [8]. However, some studies have indicated that combining HIPEC with CRS does not affect survival rates [19].
The goal of CRS is to achieve complete macroscopic tumor resection, which often requires extensive resection of intra-abdominal organs [10], leading to high morbidity and mortality rates [1112]. Consequently, due to the associated risks, the use of CRS with HIPEC as a standard treatment remains under debate globally. Reducing postoperative complications is crucial to improving long-term survival. Several large, single-institution studies have demonstrated that a lower rate of postoperative complications correlates with better oncologic outcomes after CRS with HIPEC [13]. The effects of institutional expertise on complication rates and outcomes following CRS with HIPEC have also been studied using various methods.
Our institution analyzed the morbidity and mortality rates of patients with peritoneal metastases from colorectal cancer who underwent CRS with HIPEC over the past year, and we examined the factors influencing these outcomes.
METHODS
Ethics statements
This study was reviewed and approved by the Institutional Review Board at Dankook University Hospital (No. 2024-08-030). It was performed in accordance with the Declaration of Helsinki and written informed consent was obtained from all subjects at the time of enrollment.
Patient selection
Data were collected from patients who underwent CRS with HIPEC at Dankook University Hospital between January 2022 and December 2022. Patients with extraperitoneal metastases or unresectable lesions, as determined by preoperative contrast-enhanced CT or positron emission tomography, were excluded. Patients who underwent surgery for peritoneal metastasis originating from other organs (such as the stomach or ovary) or those who only received HIPEC were also excluded.
Data collection
Perioperative outcomes and postoperative complications were prospectively evaluated. Complications were categorized based on the time of occurrence: within 30 days, 30–60 days, and 60–90 days post-surgery. Patients were classified according to the occurrence of grade II or higher complications based on the Clavien-Dindo (CD) classification. The peritoneal cancer index (PCI) was defined as follows: scores of 1–10 as grade I, scores of 11–20 as grade II, and scores above 20 as grade III. Residual disease after CRS was classified using the completeness of cytoreduction (CCR) score: CCR-0 for no visible tumor, CCR-1 for tumors less than 2.5 mm, CCR-2 for tumors between 2.5 mm and 2.5 cm, and CCR-3 for tumors larger than 2.5 cm. Major complications were defined as grades 3–5. Failure to rescue was defined as death within 30 days due to a major complication.
Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy
Preoperative examinations included tumor markers (CEA, CA 19-9, and CA 125 [14]) and contrast-enhanced chest and abdominopelvic CT scans to determine the presence of distant metastases and the extent of CRS. Preoperative bowel preparation was performed using low-volume polyethylene glycol (CoolPrep Powder, Taejoon Pharm) starting the morning of the day before surgery.
The surgery involved a long midline skin incision (from the xiphoid process to the pubic tubercle), followed by careful exploration of the abdominal cavity and PCI assessment. CRS is aimed at complete tumor resection, involving the resection of the organs and peritoneum affected by the tumor [15]. When complete resection was considered feasible, multivisceral resection was performed. In cases where high-risk areas for postoperative complications, such as the common bile duct, duodenum, or pancreas were involved, debulking surgery was considered to maximize the effectiveness of HIPEC rather than attempting complete resection. Conversely, in regions where the risk of complications was lower, such as the small bowel or colon, multivisceral resection was performed with the goal of achieving complete resection. Addressing lesions in the rectum, measures are taken to maintain a tension-free state and reinforce the suture line, including the use of a rectal tube. Ileostomy is generally not performed; however, it is considered in cases where the lesion is located close to the anal verge or when the patient's overall preoperative condition is poor.
HIPEC was performed after the completion of CRS, using the Belmont Hyperthermic Pump (Belmont Medical Technologies) in a closed method. The HIPEC regimen involved mitomycin at 42–43 ℃, with 30 mg administered over 60 minutes and an additional 10 mg over 30 minutes, for a total duration of 90 minutes.
Following CRS, 3 drains were typically inserted into the right and left subphrenic areas and the pelvic cavity. Routine laboratory tests were conducted on postoperative days (PODs) 1, 2, 3, 5, and 7. Follow-up posteroanterior (PA) chest X-ray was performed on PODs 1, 3, 5, and 7, and tumor markers and follow-up abdominal CT were conducted on POD 7. The CT results were used to determine when the Jackson-Pratt (JP) drains could be removed if additional interventions were needed. In cases of no significant complications, routine laboratory follow-up and PA chest X-ray were performed every 3 days starting from POD 7. Around POD 14, total stitch removal was typically carried out, with discharge planned on approximately POD 16 to 18, provided that there were no additional concerns.
Statistical analysis
We statistically described and compared the clinical and pathological characteristics of patients with and without complications. Numerical variables were analyzed using the t-test and Wilcoxon rank-sum test, while categorical variables were assessed using the chi-square test and Fisher exact test. To evaluate the individual risk factors for complications, simple logistic regression was initially performed, followed by multiple logistic regression to adjust for variables. The significance level was set at 0.05, and all statistical analyses were conducted using R software ver. 4.3.1 (The R Foundation).
RESULTS
Clinical and pathologic characteristics
A total number of 42 patients were included in the study, with 25 in the postoperative complication group (POC group) and 17 in the no-POC group. The mean patient age was 55.2 years. In the POC group, 44.0% of patients were aged 60 years or older, compared to 41.2% in the no-POC group, showing no significant difference (P = 0.856). Although the frequency of occurrence was higher in women (n = 13 vs. n = 29), with 60.0% in the POC group and 82.4% in the no-POC group; however, this was not statistically significant (P = 0.124). No statistically significant difference was observed in the occurrence of complications based on tumor location: appendix (29.4% vs. 40.0%), right colon (23.5% vs. 32.0%), or left colon (47.1% vs. 28.0%) (P = 0.568). The disease manifestation was synchronous in 58.8% of patients and metachronous in 41.2%, with no significant difference (P = 0.663). Preoperative chemotherapy was administered to 44.0% of the POC group and 47.1% of the no-POC group, showing no significant difference (P = 0.845). The levels of albumin and protein, which were used to indirectly assess preoperative nutritional status, showed no significant differences (P = 0.124 and P = 0.132, respectively).
The POC and no-POC groups were further classified by PCI grade as follows: grade I (24.0% vs. 64.7%), grade II (28.0% vs. 11.8%), and grade III (48.0% vs. 23.5%). A higher PCI grade was significantly associated with a higher complication rate (P = 0.038). Mean PCI values were also significantly different between the POC and no-POC groups (19.0 vs 11.5, P = 0.019). No statistically significant differences were found in the CCR score or the number of resected organs. The length of hospital stay was significantly shorter in the no-POC group (15 vs. 21 days, P = 0.008) (Table 1).
Postoperative morbidity and mortality
In terms of complications, 4 cases were classified as CD classification grade II, with urinary disturbances being the most common, occurring in 2 cases. There were 19 cases of grade III/IV complications, with pleural effusion being the most frequent, observed in 5 patients (Table 2). Complications occurred within 30 days in 23 cases and between 30 and 60 days in 2 cases. A total of 7 patients required reoperation due to postoperative complications. Of these, 5 reoperations occurred within 30 days, including 2 for wound complications and 3 cases of anastomosis site leakage. Within 30–60 days, there were 2 reoperations: 1 for mechanical ileus and the other for wound complications. Two patients died of septic shock, with 1 expiring on POD 28 and the other on POD 55 (Table 3).
Univariate analysis identified the PCI score (mean) and PCI level as significant risk factors for postoperative complications. Other factors such as sex, age (divided into 60 years), preoperative CEA, albumin, protein levels, and operation time were not associated with postoperative complications. Multivariate analysis using a logistic regression model indicated that a higher PCI score (mean) increased the risk of complications by 1.14 times. For PCI levels, a PCI score of 11–20 increased the risk of complications by 8.95 times, and a score above 21 increased the risk by 10.65 times. CCR and albumin levels were not associated with complications (Table 4).
DISCUSSION
The significance of our study lies in its comprehensive analysis of the morbidity and mortality associated with CRS and HIPEC in patients with peritoneal metastasis from colorectal cancer. Despite advancements in surgical techniques and postoperative care, optimal management of PC remains a topic of ongoing debate. This study fills this gap by providing contemporary data from a single institution, highlighting perioperative outcomes, and identifying key risk factors for complications.
Our center has performed approximately 600–700 CRS procedures using HIPEC since 2012, averaging 40–50 surgeries annually. However, comprehensive reports on the status and postoperative management of CRS and HIPEC in South Korea are lacking. This study focuses on patients with colorectal cancer and PMP with peritoneal metastasis, analyzing morbidity and mortality following CRS and HIPEC in a single institution. These findings are crucial for refining patient selection criteria, optimizing perioperative management, and enhancing the survival and quality of life for patients undergoing CRS with HIPEC. This research provides valuable insights into the practical utility and limitations of CRS and HIPEC and provides foundational data to optimize future therapeutic strategies.
The postoperative morbidity rate in our study was 54.8%, which is consistent with complication rates reported in other studies, ranging from 10% to 55% [12]. Over the past few years, the concept of “failure to rescue” has been recognized as a new metric for managing postoperative patient outcomes [161718]. The number of patients with PCI scores of grade III increased from 16 out of 54 (29.6%) in 2012–2013 to 16 out of 42 (38.1%) in 2022, indicating a higher proportion of patients with elevated PCI scores. Meanwhile, the number of patients with CCR scores of 2–3 decreased from 19 (35.2%) in 2012–2013 to 11 (26.2%) in 2022. Although the number of patients with high PCI scores increased, the number of patients with CCR scores of 2–3 declined. Our data show that the rate of major complications increased from 22.2% in 2012–2013 to 45.2% in 2022; however, the number of patients who died within 30 days post-surgery decreased from 4 in 2012–2013 to 1 in 2022. A previous paper published by our center reported a failure-to-rescue rate of 33.3% in 2012–2013, compared to 5.3% in 2022 (Table 5). Although the morbidity rate has increased, the mortality rate has decreased. Studies have shown that years of specialized training at expert centers can improve postoperative mortality and overall rates [9]. This suggests that although CRS and HIPEC for peritoneal cancer remain extensive and invasive procedures associated with high morbidity due to multiorgan resections, the accumulation of experience and skills at our center has contributed to a reduction in mortality. Furthermore, the decrease in CCR scores despite the increase in patients with higher PCI scores demonstrates the positive effect of this accumulated experience and expertise. CRS with HIPEC is associated with high morbidity and mortality, necessitating extensive experience and substantial support from the medical team. Particularly, surgeries involving major organ resections, multiple bowel resections, and anastomoses are challenging for less experienced surgeons. It is crucial to establish an integrated system with the cooperation of various specialists. Low-volume centers often encounter difficulties building such systems and training skilled surgeons. Centralization has proven beneficial in reducing postoperative morbidity and increasing survival rates across various cancer types [192021]. Concentrating peritoneal cancer treatments in specialized centers, such as ours, can significantly address the issues experienced by low-volume centers.
Previous studies have identified PCI and CCR scores, preoperative nutritional status (albumin and protein levels), and the number of resected organs as influencing factors [22]. In this study, only the PCI scores showed a significant difference. While the PCI score is a factor influencing the occurrence of postoperative complications, the lack of significant impact from CCR scores suggests that, although aggressive resection aiming for CCR-0 is important, selecting an appropriate extent of resection to minimize postoperative complications is also crucial. This study highlights the importance of accurately determining the PCI score through preoperative examinations and using this information to guide patient selection for CRS and HIPEC. Although preoperative assessments indicated PCI scores below 20, intraoperative findings revealed PCI scores over 20 in several cases, wherein resection was still considered feasible; thus, HIPEC was performed. Furthermore, HIPEC was also administered in patients with CCR-2 or CCR-3 (26.1%). Despite the inability to achieve complete tumor resection, HIPEC was deemed beneficial to these cases for its potential to suppress residual tumor cells in certain patient populations. Additionally, although albumin levels have been suggested to have an impact, the small sample size in this study may have precluded a significant difference. Albumin levels reflect a patient’s overall condition and have been reported as a morbidity-related factor in other studies [23]. Poor preoperative nutritional status, indicated by low albumin levels, can be associated with higher morbidity. Therefore, in the context of CRS with HIPEC, where patient selection is crucial, preoperative albumin levels should be considered when determining the appropriate extent of resection.
The most common complication was pleural effusion, which occurred in 5 cases, followed by anastomosis site leakage, wound complications, and pneumonia. The high frequency of pleural effusion is likely due to the common practice of performing subphrenic peritonectomy followed by HIPEC. At other centers, a chest percutaneous catheter drainage (PCD) is often inserted intraoperatively when a subphrenic peritonectomy is performed. However, at our center, we opted for regular chest X-ray follow-ups, and if the amount of effusion was significant on the CT scan performed on the 7th day, thoracentesis or PCD insertion was performed. If the effusion is minimal, it often resolves naturally. Postoperatively, we typically place 3 intraabdominal JP drains, and additional chest drains are avoided to facilitate early ambulation, reduce pain, and improve postoperative lung care. Anastomosis site leakage occurred in approximately 7.1% of cases, which is comparable to the 7%–10% incidence reported in other studies [24]. Causes of leakage include inflammation at the anastomosis site due to adhesions and wound infection near the peritonectomy area. In cases of anastomosis site leakage following HIPEC, conservative treatment (nothing per oral, PCD insertion, antibiotics) often failed to achieve recovery, unlike typical postoperative cases. When leakage occurred, reoperation was performed to conduct reanastomosis and stoma formation. Many patients undergo resection of multiple organs, resulting in 2 or more anastomosis sites. Efforts are made to maintain a tension-free state and reinforce the anastomosis sutures. Three patients with wound complications experienced severe infections that led to dehiscence. In most cases of wound complications, wound infection was accompanied by surrounding bowel injury. Reoperation was performed to manage wound repair and treat bowel injury. The highest frequency of complications corresponded to CD grade III, largely due to numerous interventions classified as grade IIIa (such as thoracentesis, PCD, and wound repair).
Our study had some limitations. First, the patient cohort was retrospectively recruited over a short period, which could lead to variability and inconsistency in data quality compared with that in studies with patients recruited according to a predefined protocol. Second, the number of patients included in this study was limited. The small sample size makes it difficult to generalize the findings and limits the ability to conduct a comprehensive analysis of significant influencing factors. Although the accumulation of experience and improved postoperative care likely contributed to the reduced mortality, we cannot exclude the potential impact of patient selection bias. The smaller cohort might not have fully represented the broader patient population undergoing CRS and HIPEC, which could have influenced the outcomes. To address these issues, a multicenter study with a larger patient cohort should be conducted. Third, this study did not clearly define an Enhanced Recovery After Surgery (ERAS) protocol. Several studies have demonstrated the efficacy of ERAS in reducing morbidity and mortality rates. Therefore, it is necessary to develop a clinical pathway based on the extensive experience gained from numerous cases at our center.
In conclusion, CRS with HIPEC has higher morbidity and mortality rates compared to other abdominal surgeries. Overcoming these challenges requires extensive experience and standardized clinical pathways, which necessitates ongoing research.
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