Long-term outcomes of laparoscopic cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: comparable with the open approach for limited colorectal peritoneal metastases (KNUCRC-25CR1).

Materials and methods

Patients
This was a retrospective study including patients who underwent CRS and HIPEC at a single tertiary university hospital between January 2014 and December 2021. There were 190 patients who underwent CRS during the study period. The maximum PCI of patients who underwent L-CRS and HIPEC was 13, which was the cutoff of the PCI for the inclusion criteria (Fig. 1), resulting in a total of 68 patients (Fig. 2). Exclusion criteria included patients who underwent palliative surgery or CRS for appendiceal origin tumors or received HIPEC and EPIC sequentially. Unresectable extraperitoneal metastases were contraindications to CRS/HIPEC. This study was approved by the Ethics Committee of the institution (approval number KNUCH 2024–01-023).
While the decision to perform laparoscopic approach was mainly based on our institutional strategy, including tumor location and extent, intra-abdomen status related to adhesion, and technical feasibility as previously reported [8], the definitive determination was made following laparoscopic exploration. Consistent with our earlier report, involvement of the porta hepatis, and subhepatic area (including the posterior subphrenic region and caudate lobe) has remained an absolute contraindication to L-CRS. In contrast, partial peritonectomy of the anterior subphrenic area, and a PCI higher than 10 are not considered absolute contraindications to L-CRS when the procedure is technically feasible. CRS was performed to remove all grossly identified metastatic nodules using the Sugarbaker technique [1]. The extent of peritoneal carcinomatosis was evaluated using the PCI, and surgical completeness was assessed using the completeness of cytoreduction (CC) score [9]. HIPEC was performed using mitomycin C at a dose of 35 mg/m2 diluted in 2.5–3 L of crystalloid fluid at a temperature of 41 °C–43 °C for 90 min.

L-CRS and HIPEC
Mechanical bowel preparation was performed on the day before surgery. On the day of surgery, prophylactic antibiotics were administered, and a urinary catheter was inserted. A nasogastric tube was not routinely inserted. L-CRS was performed following the institutional standardized approach by four experienced colorectal surgeons [8, 10]. Ports were placed where no metastatic nodules were visible: an 11 mm optical port in the umbilical quadrant and three or four 5 mm working ports in the abdominal quadrant. The greater omentum was removed in all patients, regardless of visible metastatic nodules. Organ resection, such as colectomy, oophorectomy, splenectomy, and hysterectomy, was performed when it was necessary to achieve complete removal of visceral peritoneal metastases. Parietal peritonectomy was performed in areas where the metastatic nodules were visible, as in the previous report [8]. Mini-laparotomy was used to retrieve specimens, and explore the small intestine. Port and mini-laparotomy incisions were used to introduce HIPEC catheters (Supplementary Fig. 1).

Systemic chemotherapy and follow-up
Adjuvant chemotherapy was recommended for patients with Eastern Cooperative Oncology Group performance status 2 or less, according to the institutional strategy. Patients were referred to a medical oncologist, who had the final discretion to perform systemic chemotherapy. The chemotherapy regimens included 5-fluorouracil/leucovorin, capecitabine, oxaliplatin, irinotecan, and/or monoclonal antibodies. Patients were followed up for at least 5 years with regular physical examination and imaging studies, such as CT and PET/CT scans.

Outcome variables
The primary outcomes were OS, progression-free survival (PFS), and peritoneal PFS (P-PFS). The secondary outcomes were operative outcomes, including operation time, length of hospital stay, 60-day postoperative complications, and 60-day postoperative mortality, and the pattern of initial progression locations after CRS and HIPEC. The severity of surgical complications was assessed based on the Clavien–Dindo classification. Factors associated with survival outcomes were identified using univariate and multivariable Cox proportional hazards models.

Statistical analysis
The outcomes of patients who underwent L-CRS/HIPEC (L-CRS group) were compared with those of patients who underwent O-CRS/HIPEC (O-CRS group) before and after propensity-score (PS) matching. PS matching analysis was performed to eliminate any potential bias due to the lack of an equal distribution between the two groups. The variables used for PS matching were sex and tumor burden-related factors that could be identified preoperatively and intraoperatively, including PCI, and the presence of extraperitoneal metastasis (e.g., liver, lung, distant lymph node). The specific locations of peritoneal metastasis and extraperitoneal metastases were not included in PS matching because the limited number of patients, while they were included in comparison variables between the two groups. PS was estimated using logistic regression, and patients were matched at a ratio of 1:1 using nearest-neighbor matching. Since the propensity scores did not satisfy normality, a logit transformation was performed. A love plot was created and set a threshold to less than 0.5 to evaluate the balance of covariates (Supplementary Fig. 2). The results of the paired data tests are presented in Tables 1 and 2. Categorical variables were presented as frequency and percentage and compared using the chi-square test. Parametric continuous variables were presented as mean ± standard deviation and compared using Student’s t-test. Nonparametric continuous variables were presented as median and range and compared using the Mann–Whitney U test.

Survival curves were generated using the Kaplan–Meier method and compared using the log-rank test. A multivariate logistic regression model adjusted for all clinically relevant variables, including PCI, surgery type (L-CRS or O-CRS), CC score, distant metastasis status (R0, R1, or R2), and perioperative systemic chemotherapy was used to determine independent factors associated with survival outcomes. The hazard ratios (HRs) and 95% confidence intervals (CIs) for OS were estimated using multivariate Cox regression analysis. All statistical analyzes were performed using IBM SPSS Statistics for Windows, version 27.0 (SPSS Inc., Chicago, IL, USA). All tests were two-sided. A p value < 0.05 indicated statistical significance.

Results
Of the 68 patients in this study, 42 underwent L-CRS/HIPEC, and 26 underwent O-CRS/HIPEC (Fig. 2). The reasons for open surgery are detailed in Supplementary Table 1. The most common reasons were those related to the primary tumor (large, fixed primary tumor, or adhesion from the primary tumor surgery) (46.2%), followed by those related to peritoneal metastasis (location, fixed, or large ovarian metastasis) (34.6%), and those related to extraperitoneal metastasis (11.5%). No conversion from laparoscopic to open surgery occurred. Tables 1 and 2 show the patients’ baseline characteristics, operative outcomes, and postoperative outcomes. Before PS matching, the mean age was 57.8 ± 12.3 years in the L-CRS and 54.7 ± 12.8 years in the O-CRS, without statistical difference (p = 0.06). The median PCI was significantly lower in the L-CRS group than in the O-CRS group (6 [2–13] vs. 4 [2–13], p = 0.0009). The incidence of extraperitoneal metastasis was lower in the L-CRS group than in the O-CRS group, with marginal statistical significance (p = 0.056). Other baseline characteristics were comparable between the two groups. After PS matching, 26 patients were included in each group (Fig. 2), and their preoperative characteristics were well-balanced.
The intraoperative findings and postoperative complications were not different between the two groups before and after PS matching (Table 2). The proportions of procedures were similar between the two groups, except that a significantly number of patients underwent small bowel resection in the O-CRS group before PS matching. There were no differences in the procedures after PS matching. The incidence of postoperative grade 3 or more complications was similar between the two groups. The median length of hospital stay was significantly shorter (6 days) in the L-CRS group than in the O-CRS group before and after PS matching. Postoperatively, nine patients did not receive adjuvant chemotherapy, with similar proportions in the two groups (Table 1). The reasons for not receiving adjuvant chemotherapy were: completion of preoperative chemotherapy period (2 patients in each group), patient refusal (2 patients in each group), a major postoperative complication (1 patient in the O-CRS group), and poor performance status (1 patient in the L-CRS group). In patients who received adjuvant chemotherapy, the median time to adjuvant chemotherapy was significantly shorter (3 weeks) in the L-CRS group than in the O-CRS group before and after PS matching analysis.
The median follow-up periods were 33.9 (95% CI 5.5–91.6) and 29.6 (95% CI 1.1–79.1) months (p = 0.796) in the L-CRS and O-CRS groups, respectively. Before PS matching, no differences in OS, PFS, and P-PFS were observed between the two groups (Supplementary Fig. 3). In patients with only peritoneal metastasis (no history of extraperitoneal metastasis or synchronous extraperitoneal metastasis at the time of CRS/HIPEC), no differences in OS, PFS, and P-PFS were observed between the two groups (Supplementary Fig. 4).
After PS matching, no significant differences in median OS, PFS, and P-PFS were observed between the L-CRS and O-CRS groups (OS: 37.3 [95% CI 15.6–59.0] and 34.1 [95% CI 1.9–66.4] months, p = 0.535; PFS: 11.6 [95% CI 4.0–19.4] months and 10.7 [95% CI 7.1–14.4], p = 0.690; P-PFS: 19.7 [95% CI 4.9–34.5] months and not reached, p = 0.584) (Fig. 3). In patients with only peritoneal metastasis, the median PCI scores were comparable between the L-CRS and O-CRS groups (6 [3–13] and 6 [2–13], p = 0.655). Additionally, no differences in median OS, PFS, and P-PFS were observed between the L-CRS and O-CRS groups (OS: 90.6 [95% CI NA] and not reached, p = 0.698; PFS: 14.7 [95% CI 0.0–29.7] and 11.1 [5.6–16.5], p = 0.718; P-PFS: 19.7 [95% CI 13.8–25.6], and 21.3 [95% CI NA], p = 0.783) (Supplementary Fig. 5).
Before PS matching, multivariate analysis revealed that the PCI and extraperitoneal metastasis status were independently associated with OS (Supplementary Table 2). The extraperitoneal metastasis status was the only significant factor associated with PFS and P-PFS (Supplementary Table 2). Surgery type (L-CRS or O-CRS) was not associated with OS, PFS, or P-PFS. After PS matching, multivariate analysis revealed that only extraperitoneal metastasis status was significantly associated with OS (Table 3). Univariate analysis revealed that extraperitoneal metastasis status was the only significant factor of PFS and P-PFS. Surgery type was not associated with all survival outcomes.

The initial progression patterns of all matched patients and patients who initially had only peritoneal metastasis are presented in Supplementary Fig. 6 (before PS matching) and Fig. 4 (after PS matching). No differences were observed between the two groups in this regard.

Discussion
Several studies have shown the feasibility and safety of laparoscopic surgery in patients with limited peritoneal metastasis, as evidenced by single-arm studies or comparative studies across various tumor types [2, 6, 7, 11–13]. Esquival et al. first evaluated the feasibility of laparoscopic surgery in patients with low-volume peritoneal metastasis from appendiceal, peritoneal, or colon cancer [2]. They defined low-volume peritoneal metastasis as a PCI of ≤ 10. In their study, 10 out of 13 patients successfully underwent L-CRS/HIPEC, whereas open conversion was necessitated for the remaining 3 patients (23%) due to a PCI of 13, high BMI, and peritoneal metastasis involving the previous anastomosis, respectively. Esquival et al. also reported the feasibility of L-CRS/HIPEC in 19 patients with limited peritoneal metastasis (PCI ≤ 10) from low-grade appendiceal mucinous neoplasm, with one case requiring conversion due to the location of the peritoneal metastasis (this case was one of the cases of open conversion in their initial study) [11]. Two studies from the PSOGI registry, which included the largest number of patients, reported on L-CRS/HIPEC outcomes [6, 7]. First study involved 143 patients, 18 of whom had colorectal peritoneal metastasis with a median PCI of 5 (range 3–9), showing acceptable major complication rates (22.2%), 5-year OS of 54%, and 5-year DFS of 43% [6]. Second study reviewed 50 patients with colorectal peritoneal metastasis and a median PCI of 3 (3–5) and reporting 5-year OS and DFS rates of 61% and 37.4%, respectively [7]. In the PRODIGE 7 trial, 5-year OS and DFS rates for patients with PCI < 11 were 51% and 24%, respectively [14]. In the present study, the entire cohort’s 5-year OS and PFS rates were 43.6% and 29.0%, respectively. Patients exclusively presenting with peritoneal metastasis exhibited 5-year OS and PFS rates of 57.3% and 36%, respectively, similar to those in previous studies.
Previous comparative studies have shown similar survival outcomes between L-CRS/HIPEC and O-CRS/HIPEC groups [12, 13]. However, one of the two studies evaluated mixed tumors, including colorectal cancer, and other tumor types such as mesothelioma, hepatocellular carcinoma, and sarcoma [12]. Chang et al. reported that the 3-year OS rates of the laparoscopic and open surgery groups were 79% and 64%, respectively, and no statistical difference was observed between the two groups. However, they included patients with appendiceal cancer, accounting for 8% of the study population [13]. The present study exclusively evaluated outcomes of laparoscopic and open CRS in a well-matched cohort of patients diagnosed with colorectal cancer peritoneal metastasis with a PCI ≤ 13. Consistent with the general advantages of laparoscopic surgery in other malignancies, L-CRS facilitated postoperative recovery. Importantly, this approach maintained oncologic outcomes, as evidenced by similar OS, PFS, P-PFS, and progression patterns between L-CRS/HIPEC and O-CRS/HIPEC.
Our previous study confirmed earlier postoperative recovery of L-CRS/EPIC and similar survival outcomes between L-CRS/EPIC and open surgery [3]. Our other previous study showed similar survival outcomes between L-CRS and O-CRS [8]. However, patients who underwent either HIPEC or EPIC following CRS were evaluated in that study. Among the 42 patients who underwent L-CRS, only 11 received HIPEC, whereas the remaining received EPIC following CRS. Since the introduction of HIPEC in December 2014, the use of EPIC has been reduced at our institution. Currently, we mostly replaced EPIC with HIPEC for intraperitoneal chemotherapy. In this study, data from patients who received HIPEC were collected, excluding those who received EPIC. The L-CRS group showed a 6-day shorter hospital stay and initiated adjuvant chemotherapy 3 weeks earlier than those in the O-CRS group.
In peritonectomy procedures using the laparoscopic approach, the higher the PCI is associated with the greater risk of prolonged operation time because the laparoscopic manipulation of solid organs for traction or countertraction is more ineffective particularly in complex and deeper areas. Moreover, although laparoscopic exploration for peritoneal metastasis has provided more accurate diagnostic performance than radiologic diagnosis, limitations in estimating accurate PCI or the risk of missing nodules have been advocated [15]. Given these potential risks, studies on L-CRS/HIPEC usually set the indication for a laparoscopic approach for peritoneal metastasis as a PCI ≤ 10 following the initial study by Esquival et al. [2]. In our previous study, we suggested selection criteria, including the PCI ≤ 10, tumor size, and location of peritoneal metastasis (subphrenic, subhepatic, and porta hepatis) [8]. However, as our experience with laparoscopic surgery has accumulated, laparoscopic surgery seemed feasible in a few patients with a PCI > 10 or with partial involvement of the anterior subphrenic peritoneum. In this study, 4 patients with a PCI > 10 underwent L-CRS/HIPEC; the maximum PCI was 13. Chang et al. performed L-CRS/HIPEC regardless of the PCI or location of the peritoneal metastasis [13]. Their maximum PCI was 13, and 32% of the L-CRS/HIPEC group underwent peritonectomy involving the subphrenic area, achieving a CC-0 rate of 88.9%, but the median operation time exceeded 10 h. Major diaphragm involvement is usually associated with higher PCI, longer operation time, and more frequent postoperative complications [16, 17]. Metastatic nodules of colorectal cancer can easily infiltrate into the visceral structures, increasing the risk of diaphragm injury during peritonectomy in this area. If the diaphragm opening develops during laparoscopy, abdominal positive pressure can increase the difficulty of closing the defect, and cancer cells may be immediately disseminated to the pleura. Therefore, at our institution, disease involving the subhepatic/porta hepatis location, and major involvement of subphrenic peritoneum and/or posterior subphrenic peritoneum remain absolute contraindication to L-CRS. Moreover, no studies have reported laparoscopic approach to the caudate lobe, lesser sac, or gastro-esophageal junction due to structural complexity and limited visualization. Further studies are needed to optimize the selection criteria and standardize surgical techniques for minimally invasive CRS/HIPEC.
Peritoneal recurrence after CRS/HIPEC has been reported to be the major progression after CRS/HIPEC for colorectal cancer [8, 18, 19]. The risk of peritoneal recurrence mainly depends on the extent of peritoneal metastasis and CC score [20]. In this study, the progression patterns after CRS/HIPEC were similar between the two groups in all patients and those with exclusively peritoneal metastasis. Although this included patients with low PCI, and the CC score after CRS/HIPEC was mostly CC-0, peritoneal metastasis was the major type of initial progression in both groups. Notably, extraperitoneal metastasis was another major progression type in both groups, and extraperitoneal metastasis status was the only factor associated with OS, PFS, and P-PFS. Peritoneal metastasis of colorectal cancer is frequently associated with extraperitoneal metastasis, as systemic spread is a major route of distant metastasis in colorectal cancer [21]. Our institution routinely recommends systemic chemotherapy, either adjuvant or perioperative treatment. L-CRS/HIPEC could provide earlier postoperative recovery, which might contribute to the earlier commencement of adjuvant chemotherapy in the L-CRS group than in the O-CRS group. These are additional benefits of the laparoscopic approach for CRS/HIPEC, considering the significance of extraperitoneal metastasis after CRS/HIPEC and the well-known importance of earlier commencement of adjuvant chemotherapy [22, 23].
This study has several limitations that should be considered when interpreting the results. This was a retrospective study analyzing data from a prospectively registered database. Therefore, there may be a selection bias when choosing between the two types of approaches. PS matching and multivariate analyses were performed, including all relative variables to control for potential confounding factors related to postoperative and survival outcomes. Nonetheless, patient selection for L-CRS in the present study was not based on a prospective design with strict selection criteria, implicating that the indications for L-CRS remain unclear and laparoscopic cases likely represent favorable biology. Careful consideration is required when selecting patients for L-CRS until stronger evidence is available from prospective studies. Although the same four colorectal surgeons and three oncologists followed an institutional standardized treatment protocol over the eight-years study period, surgical techniques and patient selection evolved in ways that could not be accounted for in the analysis. The number of eligible patients was small due to the low incidence of limited peritoneal metastasis and the single-center nature of study. To the best of our knowledge, no other institutions in our country have performed a laparoscopic approach for CRS and HIPEC; therefore, national multicenter studies could not be conducted.

Conclusions
Our results demonstrated that L-CRS/HIPEC achieved similar long-term oncologic outcomes to open surgery in highly selected patients with limited peritoneal metastases of colorectal cancer. Additional prospective studies are needed to validate these findings and optimize the criteria.

Supplementary Information
Below is the link to the electronic supplementary material.