Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy and Liver Resection is a Treatment Option for Patients With Peritoneal and Liver Metastases From Colorectal Cancer

Abstract

Objective:

To study outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) in patients also treated for colorectal liver metastases (CLM).

Background:

Colorectal cancer (CRC) frequently metastasizes to the liver and peritoneum and is associated with a poor prognosis. In selected patients, a benefit in overall survival (OS) was shown for both peritoneal metastases (PM-CRC) offered CRS-HIPEC, and CLM treated with surgical resection. However, the presence of CLM was considered a relative contraindication to CRS-HIPEC, causing a paucity of outcome data in this patient group.

Methods:

Patients with PM-CRC having CRS-HIPEC at a single national center between 2007 and 2023, with additional intervention for CLM, were included (previous curative treatment for extraperitoneal and extrahepatic metastases was allowed). Three groups were defined: CLM before CRS-HIPEC (pre-CRS-HIPEC), CLM resected simultaneously with CRS-HIPEC (sim-CRS-HIPEC), and CLM after CRS-HIPEC (post-CRS-HIPEC), aiming to retrospectively analyze outcomes.

Results:

Fifty-seven patients were included and classified as: pre-CRS-HIPEC (n = 11), sim-CRS-HIPEC (n = 29), and post-CRS-HIPEC (n = 17). Median Peritoneal Cancer Index (PCI) was 8; 13 patients had severe complications (Clavien-Dindo ≥3), and no 90-day mortality. Median OS was 48 months after CRS-HIPEC. PCI was a predictor of OS (hazard ratio: 1.11, P < 0.001). We observed no difference in short or long-term outcomes between intervention groups.

Discussion:

This study demonstrated that patients with CLM having CRS-HIPEC had comparable OS to reports on CRS-HIPEC only, likely explained by a low PCI. Simultaneous CLM resection did not increase the risk of severe complications.

Conclusions:

In this national cohort, CRS-HIPEC and CLM intervention offers long-term survival, suggesting that this treatment may be offered to selected patients with PM-CRC and CLM.

Colorectal cancer (CRC), the third most prevalent malignancy globally, contributing significantly to cancer-related mortality due to metastases.¹ Approximately 30% of patients develop metastatic colorectal cancer (mCRC), presenting a formidable challenge in managing CRC with variable treatment options and prognosis.^2–5 The liver is the most commonly affected organ by metastases, followed by the lungs and the peritoneum,⁴ where peritoneal metastases (PM-CRC) have the worst long-term outcomes.^5–7 Only 20% to 30% of patients with colorectal liver metastases (CLM) are eligible for surgical intervention,⁸ where studies report a median overall survival (OS) of up to 80 months for parenchyma-sparing liver resections.⁹ For PM-CRC, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is a treatment option for patients with limited PM-CRC, reporting a median OS of 32 to 50 months.^10–13

Approximately 8% of patients with CRC present with synchronous CLM and PM-CRC, presenting limited treatment options and an abysmal 5-month OS if curative treatment is not possible.¹⁴ Synchronous liver, lung, or other distant metastases were considered a relative contraindication for CRS-HIPEC,¹⁵ but in later years, limited CLM have been accepted.^16–18 Patients not meeting these selection criteria face limited treatment options, relying on palliative systemic chemotherapy.¹⁹ Encouraging results, however, advocate for simultaneous resection of CLM and PM-CRC,^20–22 but controversies persist due to the risk of increased morbidity, mortality, and delayed adjuvant chemotherapy.^23–26

This retrospective study aims to assess the impact of CRS-HIPEC and liver resections on perioperative and survival outcomes in patients with CRC. We seek insights that may guide clinical decision-making and enhance the understanding of the optimal management for this challenging patient population.

METHODS

Study Design

The study period was defined from January 1, 2007 until November 30, 2023. Inclusion criteria were: patients treated with CRS-HIPEC for PM-CRC, achieving complete cytoreduction, and liver resection/ablation for CLM. Patients treated with curative intent for extraperitoneal and extrahepatic metastases were included. Patients were identified from the prospectively registered department databases at the National Treatment Service for Peritoneal Surface Malignancies (PSM) and Hepatobiliary and Pancreatic Surgery, Oslo University Hospital (OUH). Where PMS-OUH is the only provider of CRS-HIPEC in Norway. The use of patient data was approved by the Norwegian Ethics Committee (REC#: s-07160b), and written informed consent was obtained from patients.

Patient Selection for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

Patients with PM-CRC were referred to PMS-OUS based on Norwegian guidelines (completely listed in Supplemental Digital Content Table 1, http://links.lww.com/SLA/F284)¹⁷ and evaluated at multidisciplinary tumor (MDT) board meetings. Patients with limited PM-CRC are offered CRS-HIPEC, including patients with resectable extraperitoneal metastases. PSM-OUH considers the following criteria as relative contraindications for CRS-HIPEC: age above 75 years, significant comorbidity, poor performance status, progression on chemotherapy, Peritoneal Cancer Index (PCI) >25, and retroperitoneal lymph node metastases. Patients were classified into 3 groups (intervention groups) based on the time between CLM intervention and CRS-HIPEC (index operation): (1) CLM intervention before CRS-HIPEC (pre-CRS-HIPEC), (2) CLM intervention simultaneous with CRS-HIPEC (sim-CRS-HIPEC), and (3) CLM intervention after CRS-HIPEC (post-CRS-HIPEC).

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy and Liver Surgery

At index operation, the extent of PM was classified by PCI score and CC score to evaluate residual tumor after CRS, where CC-0 defined complete cytoreduction²⁷ All patients treated at PMS-OUH had standard HIPEC regimen of mitomycin, 35 mg/m² (maximum 70 mg), administered over 90 minutes in 3 fractions aiming for an intra-abdominal temperature of 41 to 42 °C. 5-flurouracil intravenous bolus was not used perioperatively. CRS was performed through a midline incision, and all macroscopic tumor tissue was resected. If not previously done, omentectomy and oophorectomy were routinely performed, even if macroscopically no evidence of tumor. The HIPEC technique was performed as an open Coliseum technique until 2008 and as a closed technique thereafter. At index operation, the following variables were registered: preoperative performance status by Eastern Cooperative Oncology Group, and physical status by American Society of Anesthesiologists (ASA) classification system; perioperative variables: number of organs resected, estimated blood loss in milliliters (mL), and operating time in minutes (min). At index operation, simultaneous liver resections were performed with open access and registered with a number of resected CLM and a number of liver resections. Liver resections were classified as either local wedge resections, segmentectomy, or bisegmentectomy. In staged CLM intervention (pre-CRS-HIPEC and post-CRS-HIPEC groups), open/laparoscopic access to the abdomen or radio-frequency ablation (RFA) was decided at the discretion of the MDT and operating surgeon. Perioperative variables were: sequential metastasectomies, defined as consecutive interventions for mCRC at different time points during follow-up. The administration of chemotherapy and regimens in pre or post-index operation was documented.

Follow-up After Surgery

Complications were recorded at 30 days postoperatively and classified according to Clavien-Dindo.²⁸ Length of hospital stay was classified as postoperative days in hospital, including readmissions and stay at referring hospital when transferred from PSM-OUH. Postoperative mortality was defined as death within 90 days after index operation. Patients were followed up for 5 years according to national guidelines with computed tomography of chest, abdomen, and pelvis and carcinoembryonic antigen (CEA) at postoperative month 3 at OUH, then at referring hospitals at postoperative months 6, 12, and annually thereafter.¹⁷ Progression-free survival (PFS) was defined as months from index operation to first event, death, or last follow-up (maximum 72 months). OS was defined as the time from index operation until death (data from The National Registry in Norway) or censor date (December 1, 2023).

Statistical Analyses

Variables were described using percentages and medians (interquartile range). Percentages were compared using χ², medians were compared using Mann-Whitney U for pairs, and Kruskal-Wallis for multiple testing, with Bonferroni correction. The Kaplan-Meier method was used to estimate OS and PFS in months (95% CI), and percentage alive at 1, 3, and 5 years after index operation. The reverse Kaplan-Meier method was used to estimate median follow-up. Univariable analyses were performed by hazard ratio (HR), calculated by Cox proportional hazard analysis and reported with 95% CI. P <0.05 was considered statistically significant. Univariable with P <0.10 were included in a multivariable analysis with age and sex. Data were collated and analyzed using IBM SPSS statistics software (version 29, IBM Corp).

Histopathology and Molecular Analysis

In total, 56 of 57 patients had tumors analyzed for mutational status. Surgical specimens were collected from 30 cases and subjected to routine histologic examination, analyzing mutations in KRAS (exon 2, 3, and 4), BRAF (V600E/K/D mutations), and NRAS (codon 12, 13, and 61) as previously described.²⁹ KRAS exon 2, 3, and 4 assessments were performed in all available cases, with additional BRAF testing where KRAS was wild type. In 26 cases, specimens were snap-frozen in liquid nitrogen postresection and stored at −80 °C in a tissue bank. DNA was isolated as previously described,³⁰ and targeted next-generation sequencing was performed by PGM/Ion GeneStudio S5 system (Ion AmpliSeqTM Cancer Hotspot panel v2 or Oncomine Comprehensive panel v3). Microsatellite instability (MSI) status was determined in 54 patients by using the MSI Assay from Biocartis (Mechelen) or polymerase chain reaction analysis as previously described.²⁹

RESULTS

Patient Selection

During the study period, 534 patients were screened (Fig. 1). Among these, 79 patients underwent liver resection at any time point during follow-up. Eighteen patients were subsequently excluded from the analysis: 10 benign liver lesions and 8 patients with PM-CRC infiltrating the liver. This resulted in 61 out of 534 patients (11%) having intervention for PM-CRC and CLM. Further, 4 patients were excluded due to incomplete medical records, leaving a total of 57 eligible patients for this study.

FIGURE 1.

Flowchart of patients treated with CRS-HIPEC for PM originating from CRC, as well as treatment for CLM.

Patient Characteristics

Out of 57 patients, 35 (61%) were females, 34 (59%) had primary CRC (pCRC) located in the left colon or rectum, 55 (98%) were pT3 or pT4, and 48 (84%) had lymph node metastases (Table 1). Mutations in tumors were detected in: KRAS 26 (46%) and BRAF 10 (18%); (Supplemental Digital Content Table 2, http://links.lww.com/SLA/F284). At the index operation, the median age was 59 years (51–66), Eastern Cooperative Oncology Group status was 0 in 50 patients (89%), and the median CEA level was 6 μg/L (3–23; Table 1). Preoperatively, the majority of patients, 45 (79%), were classified as ASA class 2. The median PCI was 8 (5–13)

TABLE 1.

Clinicopathological Parameters

Variable (n = 57)	n (%)	Median (IQR)
Sex
Male	22 (39)	—
Female	35 (61)	—
Data pertaining pCRC
Sidedness
Right colon	23 (40)	—
Left colon	27 (47)	—
Rectum	7 (12)	—
TNM (n = 56)
pT-stage
T2	1 (2)	—
T3	27 (48)	—
T4	28 (50)	—
pN-stage
N0	9 (16)	—
N1	28 (50)	—
N2	19 (34)	—
M-stage (n = 55)
M0	13 (24)	—
M1	42 (76)	—
Data pertaining CRS-HIPEC
Age		59 (51–66)
ECOG (n = 56)
0	50 (89)	—
1	5 (9)	—
3	1 (2)	—
ASA
2	45 (79)	—
3	11 (19)	—
4	1 (2)	—
CEA (μg/L)	—	6 (3–23)
CA125 μg/L (n = 42)	—	15 (10–44)
CA19-9 μg/L (n = 46)	—	20 (8–36)
PCI	—	8 (5–13)

CA indicates cancer antigen; ECOG, Eastern Cooperative Oncology Group; IQR, interquartile range.

Sequential Metastasectomies and Simultaneous Colorectal Liver Metastases and Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

The treatment trajectory for most patients was complex (Fig. 2). Forty-two patients (76%) had synchronous mCRC (M1) at pCRC resection. Forty-three patients (75%) underwent resection of pCRC before the index operation, with a median interval of 14 months (4–53) between pCRC resection and index operation. The remaining 14 patients (33%) had pCRC resected at index operation, with 6 of them also undergoing simultaneous CLM intervention. Fifteen patients (26%) had an intervention for other mCRC than CLM (Fig. 2 and Supplemental Digital Content Table 3, http://links.lww.com/SLA/F284). All except 1 patient (98%) received chemotherapy, where as 48 (84%) had chemotherapy before index operation. Regimens included 5-fluorouracil in 53 (95%) and oxaliplatin in 36 (64%) patients (Supplemental Digital Content Table 4, http://links.lww.com/SLA/F284).

FIGURE 2.

Swimmer plot depicts the different treatment trajectories for the included patients. The x-axis shows time (years). The reference point of 0 denotes the time of pCRC resection, and the vertical dotted lines indicate each year following pCRC resection. On the y-axis, each bar representing a case. The gray bar illustrates the duration from pCRC resection to CRS-HIPEC, whereas the blue bar represents OS from CRS-HIPEC, extending to either death (vertical black line marked “d”) or status as alive (vertical black line marked “a”) on the y-axis. The patients who died or had the last follow-up more than 6 years after pCRC resection are depicted by a blue bar continuing beyond 6 years. A, Twenty-nine patients, who underwent sim-CRC-HIPEC and CLM intervention. B, Eleven patients with CLM intervention before CRS-HIPEC (pre-CRS-HIPEC) only. C, Seventeen patients with CLM intervention following previous CRS-HIPEC (post–CRC-HIPEC). The colored symbols represent different interventions: a blue-colored square (filled) denotes CRS-HIPEC and intervention for CLM, whereas a blue square (open) denotes CRS-HIPEC only. A blue circle (filled) represents CLM resection only, a blue circle (open) denotes simultaneous pCRC and CLM resection, a blue circle with a dot signifies RFA, and a blue circle with a cross CLM resection and resection of PM without HIPEC. Orange denotes resection of metastatic CRC, with a right-pointing arrow (filled) indicating PM resected with pCRC (CRC+PM) without HIPEC, and a right arrow (open) representing PM resection alone without HIPEC. A left pointing arrow (open) signifies treatment for lung metastases (lung intervention) by resection or radiation. Events are denoted by black stars, whereas follow-up without events is represented by black diamonds.

Forty-nine patients (86%) underwent multiple sequential interventions for mCRC, among whom 25 (44%) had multiple CLM interventions (Fig. 2). Twenty-nine patients (51%) underwent simultaneous CLM resection with CRS-HIPEC (sim-CRS-HIPEC group), including 3 patients having CLM intervention within 10 days before CRS-HIPEC (Fig. 2A). The median number of CLM was 1 (range: 1–6). The number of liver resections performed during index operation was as follows: 1 resection in 22 patients (75%), 2 resections in 5 patients (17%), 3 resections in 1 patient, and 5 resections in 1 patient. Twenty-eight patients underwent local wedge resections. Among these, 1 patient had a combined segmentectomy of segment 4b, and another patient had a combined bisegmentectomy of segments 2 and 3. One patient had a bisegmentectomy of segments 2 and 3 only. Eleven patients (19%) underwent CLM intervention before the index operation (pre–CRS-HIPEC group; Fig. 2B), with no patients having mCRC intervention afterward. Seventeen patients (30%) underwent mCRC intervention also after the index operation (post-CRS-HIPEC group; Fig. 2C), with 8 patients (47%) having laparotomy and 4 patients (24%) undergoing minimally invasive procedures. Thirteen patients (23%) had RFA for CLM, whereas 5 of 13 had RFA only.

Short-term Outcomes After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

During index operation, the median number of resected organs was 4 (range: 1–7), with an operating time of 462 minutes (402–516), and estimated blood loss of 560 mL (300–975); (Supplemental Digital Content Table 5, http://links.lww.com/SLA/F284). Postoperatively, 17 patients (30%) experienced no complications, whereas 11 patients (19%) had grade I complications, and 16 patients (28%) had grade II complications (Supplemental Digital Content Table 6, http://links.lww.com/SLA/F284). Thirteen patients (23%) experienced severe complications graded III or higher. Among the 57 patients, 6 (10%) developed intraabdominal abscesses requiring percutaneous drainage, and3 patients (5%) required relaparotomy, with the reasons being: 2 cases of anastomotic leakage and 1 case of gastric perforation (Supplemental Digital Content Table 6, http://links.lww.com/SLA/F284). There were no fatalities within the first 90 days following the index operation. The median hospital stay was 11 days (9–16), with 4 patients requiring readmission to PMS-OUH due to complications. No significant differences were observed in the incidence of grade III to IV complications between the sim-CRS-HIPEC (6 cases, 21%), the pre-CRS-HIPEC (3 cases, 27%), and the post-CRS-HIPEC groups (4 cases, 24%). Furthermore, no disparities were noted in PCI, blood loss, or operating time among the 3 groups (Supplemental Digital Content Table 7, http://links.lww.com/SLA/F284).

Long-term Outcomes Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

The median follow-up after the index operation was 81 months (72–90), during which 40 patients (70%) succumbed. Median OS was 48 months (37–60; Fig. 3), with estimated 1, 3, and 5-year OS of 98%, 64%, and 30%, respectively. The following variables were associated with increased risk of mortality: ASA grade 3 versus ASA grade 2, HR: 3.26 (95% CI: 1.45–7.31), P = 0.004; increasing CEA, HR: 1.00, (95% CI: 1.00–1.01), P = 0.022, and increasing PCI, HR: 1.11 (95% CI: 1.05–1.18), P < 0.001 (Supplemental Digital Content Table 7, http://links.lww.com/SLA/F284). Multivariable analysis revealed that increasing PCI was the most significant predictor of mortality, with HR of 1.11 (95% CI: 1.05–1.17), P < 0.001 (Table 2). The median PFS was 6 months (5–8), with 51 patients (89%) experiencing an event after index operation. Recurrence of CLM occurred in 32 patients (56%), with 3 of these also involving recurrence of PM-CRC. Including these 3 cases, a total of 16 patients (28%) experienced PM-CRC recurrence. ASA grades 3 and 4 were associated with an increased risk of an event, with HRs of 2.24 (95% CI: 1.12–4.44), P = 0.022 and 34.46 (95% CI: 3.09–384.81), and P = 0.004 compared with ASA grade 2. Estimated blood loss and MSI status were also linked to an increased risk of an event (Supplemental Digital Content Table 8, http://links.lww.com/SLA/F284). Having mCRC (M1) at the time of pCRC resection was associated with a reduced risk of an event, HR: 0.21 (95% CI: 0.1–0.44) compared with M0, P = 0.001. Regarding OS in the 3 defined intervention groups, patients in the sim-CRS-HIPEC had an OS of 43 months (22–65), pre-CRS-HIPEC group 36 months (16–57), and post-CRS-HIPEC 58 months (41–75). While we observed no significant difference in OS overall between intervention groups (P = 0.085), a significant difference in OS emerged when comparing the only 2 subgroups pre-CRS-HIPEC and post-CRS-HIPEC, P = 0.002 (Supplemental Digital Content Table 7, http://links.lww.com/SLA/F284). Examinations of recurrence patterns among the intervention groups revealed peritoneal recurrences in 8 patients (28%) in the sim-CRS-HIPEC group, 7 patients (64%) in the pre-CRS-HIPEC group, and only 1 patient (6%) in the post-CRS-HIPEC group. Complications were not significantly associated with differences in OS or PFS.

FIGURE 3.

Kaplan-Meier plot showing OS (blue line) and PFS (orange line) after CRS-HIPEC. Numbers at risk show the patients entering each time interval.

Table 2.

Multivariable Analyses of OS After CRS-HIPEC

Variable	HR (95% CI )	P
Sex
Male	Reference	—
Female	0.39 (0.19–0.81)	0.011
Age
Increasing	0.98 (0.94–1.02)	0.288
PCI
Increasing	1.11 (1.05–1.17)	<0.001
ASA
2	Reference	—
3	3.96 (1.41–11.11)	0.009
4	19.07 (1.73–210.56)	0.016
CEA
Increasing	1.01 (1.00–1.01)	0.005
Intervention groups
post-CRS-HIPEC	Reference	—
sim-CRS-HIPEC	1.62 (0.70–3.41)	0.377
pre-CRS-HIPEC	3.76 (1.40–10.10)	0.009

post-CRS-HIPEC indicates CLM intervention also after CRS-HIPEC (n = 17); pre-CRS-HIPEC, patients having CLM intervention only before CRS-HIPEC (n = 11); sim-CRS-HIPEC, patients having CLM intervention simultaneously with CRS-HIPEC (n = 29).

DISCUSSION

This study presents outcomes from a national cohort of patients who underwent CRS-HIPEC in addition to intervention for CLM. The results revealed important findings regarding treatment trajectories, short-term outcomes, and long-term survival. Of the 534 patients treated with CRS-HIPEC during the study period, only 61 patients (11%) also underwent surgical intervention for CLM, suggesting a highly selected patient group.

Following CRS-HIPEC, half of the patients experienced grade II complications, and about 1 in 4 had grade III to IV. The morbidity rate and notably the absence of 90-day mortality in our study, aligns with previous reports from our and other high-volume centers.^10–13,23 Particularly, the sim-CRS-HIPEC group did not have a significantly higher rate of severe complications compared with the pre or post–CRS-HIPEC groups. Although a few studies found resection of CLM and CRS-HIPEC to be associated with a higher risk of complications,^19,31 others demonstrate, in line with our results, that parenchyma-sparing CLM resection with simultaneous CRS-HIPEC did not significantly increase complication rates compared with CRS-HIPEC alone.^23,32–36 Our results suggest that CLM resection adds minimally to the overall surgical trauma of CRS-HIPEC.

Although our study shows PFS of 6 months, the long-term survival outcomes were encouraging, with a median OS rate of 48 months and 3-year and 5-year survival after CRC-HIPEC of 64% and 30%, respectively. Our results are comparable to previous reports on CRS-HIPEC only from PMS-OUS,¹⁰ and other authors,¹² and better than 2 randomized control trials on PM-CRC, including the recent PRODIGE 7 trial.^13,37 The median OS in our study was similar to the largest study to date by Lo Dico et al²² reporting on 534 patients from 33 centers treated with CRS-HIPEC and liver resection. The encouraging OS in our study is likely explained by a median PCI of 8, all patients having CRS to CC-0, and overall treatment burden, as the majority of patients received systemic chemotherapy and had multiple interventions for mCRC with curative intent. Interestingly, PCI was the most significant predictor of death, also in this patient group with PM-CRC and CLM. For patients having PM-CRC without other metastases, the association between PCI and long-term outcomes is well documented,^10,13,38 thus PCI may also guide the selection of patients with CLM to treatment with CRS-HIPEC. A median OS of 43 months in sim-CRS-HIPEC was not significantly different from the other intervention groups in our study and within the range found in similar studies reporting on simultaneous CRS-HIPEC and CLM intervention.^{20,22–24,33,35,36,39} However, reports on OS in this patient group has been variable, included few patients, variable HIPEC regimens, variation in PCI, and some studies including appendiceal primaries.^{22,31,33,40,41} In addition, we found the sequence of interventions not to be a major determinant of OS, whereas Lo Dico et al²² found a better OS in patients having a 2-step approach with liver resection before CRS-HIPEC. This discrepancy may be due to a difference in measuring OS, where we report OS from CRS-HIPEC, Lo Dico and colleagues measure from the diagnosis of peritoneal or liver metastases, making comparisons challenging.

All patients in this study had CRS-HIPEC, thus the current question of HIPEC in addition to CRS in this patient groups cannot be addressed in our study, nor in PRODIGE 7 as CLM was a contraindication to inclusion.¹³ However, PRODIGE 7 did find a lower frequency of complications in the CRS-only group versus CRS-HIPEC, and further studies are needed to address the role of HIPEC in this patient group. The ORCHESTRA trial (NCT01792934) may bring more knowledge to the field regarding the benefits of tumor debulking as a treatment option for mCRC patients.

Our study demonstrates the complex treatment trajectory in this highly selected patient group, who repeatedly was found eligible for further surgical resections and chemotherapy for mCRC. Our findings contribute to the understanding of the multifaceted management of patients with PM-CRC and CLM. The results underscore the importance of comprehensive patient selection, multimodal treatment strategies, and careful perioperative management to achieve favorable outcomes.

In the current study, the following limitations must be considered: potential selection bias, sample size opening for type II errors when interpreting the data, and lack of data on quality of life. In addition, the study’s generalizability may be limited by its single-center design and heterogeneity of data. However, it is noteworthy that our center is the sole nationwide provider of CRC-HIPEC for PM-CRC.

CONCLUSIONS

This study provides valuable insights into the management and outcomes of patients undergoing CRS-HIPEC for PM-CRC along with hepatic resection for CLM. In well-selected patients, the combination of CRS-HIPEC and liver resection for metastases provides long-term survival. Further research, including larger prospective studies and validation of prognostic factors, is warranted to enhance our understanding of selection and optimize the care of these patients.

Supplementary Material

sla-280-745-s001.docx ^{(38.9KB, docx)}

DISCUSSANT

Kuno Lehmann (Zurich, Switzerland)

I would like to thank the ESA for the privilege of serving as the first discussant and congratulate Dr Dagenborg and coauthors for the effort in analyzing combined CRS/HIPEC and liver resection in patients with peritoneal and concomitant hepatic metastasis. The analysis of patients (n = 57) with hepatic and peritoneal metastasis after CRS/HIPEC resulted in an impressive mOS of 48 months in the context of a median PCI of 8, which confirms available and published data from other national or multi-institutional series. The study, therefore, confirms surgery as a part of the multimodal concept in these patients. I fully agree with the conclusion of the authors that well-selected patients with colorectal hepatic and peritoneal metastasis are potential candidates for CRS/HIPEC.

The real challenge, however, remains patient selection, identifying which patient will likely end up with a favorable outcome, or will suffer from early and sometimes diffuse recurrence—representing poor candidates for CRS/HIPEC. Many groups worked on selection criteria or predictive scores in the past. Among these parameters are the PCI, nodal positivity of the primary tumor, the molecular tumor profile, or the response to preoperative chemotherapy. The presence of hematogenous metastasis was earlier identified as an independent negative prognostic factor in the context of peritoneal metastasis, but it would be interesting to learn about the impact of additional hepatic metastasis in patients with a minimal PCI. Such a study would require an adequate control group which is currently not available (or was not analyzed) in the present study.

I have some questions: First, did you consider stratifying your analysis according to (at least) the most important prognostic risk factors [eg, PCI, nodal status (pN2), BRAF mutations]? The analyzed national cohort would bear a great potential for this.

Second, in your analysis of patients (n = 57), liver surgery before CRS was identified as a predictive factor. I wonder whether the sample of this study size is sufficient for this analysis and statement, given the high number of relevant prognostic factors mentioned previously. Did you, exclude the possibility that your groups do not differ regarding known prognostic factors?

Finally, I would appreciate some information about the systemic treatment of the included patients, which is probably as important as the surgery part. In addition, I would like to learn how you selected patients for surgery. For example, were patients with BRAFVE600 mutations excluded, or did you set an upper PCI limit for patients with hepatic and peritoneal metastasis?

Response From Vegar Johansen Dagenborg (Oslo, Norway)

Thank you. I will start with your last question. All, but one patient received systemic chemotherapy. The one patient who did not receive chemotherapy had severe postoperative complications and was hospitalized for about 50 days. Meaning that the patients are highly selected as most have chemotherapy, as well as multiple surgical procedures.

Our study cohort comprises patients who had CRS-HIPEC and liver surgery for CRC metastases in Norway from 2007 to 2023. Obviously, there could be some patients missing, but as the only center in Norway performing CRS-HIPEC, we record all patients and types of surgical procedures performed, and we also record all follow-ups after CRS-HIPEC. Thus, all patients having CRS-HIPEC and liver surgery are likely included in our study, except for the 4 patients with missing data, meaning that there was n/we tend not to offer CRS ando selection to participate in this study.

Time is an important factor in our study. We did not record the number of MDT discussions, but for most patients, there is a delay of more than a year from the primary tumor resection to CRS-HIPEC. During this time, patients were heavily pretreated with chemotherapy and underwent resection for extraperitoneal metastases. We often reevaluate the response to treatment at our MDT before offering CRS-HIPEC. In Norway, our national guidelines allow CRS-HIPEC for patients with liver metastases. We consider the PCI and the number of liver metastases, as these factors are associated with prognosis, as demonstrated by Elias and colleagues in 2014 in Annals of Surgical Oncology. We are cautious about offering CRS-HIPEC to patients with many liver metastases. However, with stable disease over time and with resectable liver metastases, as determined by our HPB surgical colleagues, we may offer CRS-HIPEC. For PCI, we tend not to offer CRS and HIPEC for patients with a PCI >25, and we are even more cautious with liver metastases, despite our national guidelines not specifying an upper limit for hepatic metastases or PCI.

Regarding BRAF mutations, our data from the study by Lund-Andersen et al, Journal of Translational Medicine, 2024, (DOI: 10.1186/s12967-024-05467-2), show that BRAF is strongly associated with a poorer prognosis. However, it remains challenging not to offer CRS-HIPEC for BRAF-mutated patients, as systemic treatment seems to offer a poorer prognosis. Therefore, BRAF-mutated tumors are not a deciding factor at our institution. For this study, there were very few BRAF-mutated patients, so we did not perform any stratification based on this mutation due to the low number.

Inne Borel-Rinkes (Utrecht, The Netherlands)

Thank you very much. I enjoyed this paper very much. I just have a brief question; do you have any restrictions on the extent of liver surgery when performing simultaneous resection? Specifically, would you consider a hemi-hepatectomy or an extended hemi-hepatectomy at the same time? We always have this discussion in our center.

Response From Vegar Johansen Dagenborg (Oslo, Norway)

In our study, we did not perform extended hemi-hepatectomies, so our data cannot provide insights into the feasibility of such extensive liver resections. In general, we are cautious about offering extended liver surgery to patients undergoing CRS-HIPEC.

Mickaël Lesurtel (Clichy, France)

As a liver surgeon, I feel somewhat frustrated because I am eager to understand whether a liver resection can be performed simultaneously with HIPEC, and to which extent. Unfortunately, it seems this question is not addressed in your study. Was it not possible to compare two groups –one with HIPEC alone and the other with HIPEC plus liver resection with an equivalent PCI?

Response From Vegar Johansen Dagenborg (Oslo, Norway)

Unfortunately, we have too few patients in our cohort to answer your question with confidence. To explore this further, we would need a much larger study, likely involving multiple countries. I agree that it is frustrating not to have clear guidelines on when to perform liver resection in conjunction with CRS-HIPEC.

Wojciech Polkowski (Lublin, Poland)

The first discussant (Kuno Lehmann) already mentioned BRAF mutations. My question concerns KRAS mutations. Have you evaluated the prognostic influence of KRAS mutations?

Response From Vegar Johansen Dagenborg (Oslo, Norway)

In our study, 46% of patients had KRAS mutations, and these mutations did not influence the prognosis.