Abstract
Aim
The role of prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) in elderly patients with locally advanced colorectal cancer (LACRC) remains controversial. This study aimed to evaluate the perioperative safety and survival benefits of HIPEC using propensity score matching (PSM).
Methods
A total of 166 elderly LACRC patients who underwent curative surgery were included between January 2017 to January 2022. After 1:2 PSM, 40 patients received prophylactic HIPEC, while 80 served as controls. Postoperative complications, overall survival (OS), and disease-free survival (DFS) were compared. Multivariable Cox regression and Kaplan-Meier (KM) analyses were performed, with subgroup analysis focusing on lymph node status.
Results
The overall postoperative complication rates were comparable between the HIPEC and control groups (22.5% vs. 15.0%, P = 0.445). Multivariable Cox regression showed no significant improvement in OS or DFS with HIPEC in the overall cohort. However, in the lymph node-positive (N+) subgroup (HIPEC, n = 20; Control, n = 31; P = 0.327), HIPEC was associated with significantly better OS (P = 0.017) and DFS (P = 0.022), with a significant interaction between HIPEC and N-stage (OS: P = 0.013; DFS: P = 0.006). These associations remained significant after applying the Holm-Bonferroni correction for multiple testing within this subgroup. KM analysis confirmed prolonged survival in N+ patients receiving HIPEC (OS: P = 0.038; DFS: P = 0.038).
Conclusion
In conclusion, prophylactic HIPEC following radical resection did not increase perioperative complications in elderly patients with LACRC. While overall survival benefits were not significant, prophylactic HIPEC significantly improved OS and DFS among patients with N+ disease. These findings suggest a selective benefit for high-risk patients, warranting further validation.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12885-026-16073-4.
Keywords: Geriatric patients, Locally advanced colorectal cancer, Lymph node-positive, Prophylactic hyperthermic intraperitoneal chemotherapy, Survival benefits
Introduction
Colorectal cancer (CRC) represents a major global health burden, ranking as the third most commonly diagnosed cancer and the second leading cause of cancer-related mortality worldwide [1]. Globally, there were about 935,173 CRC deaths and 1,931,590 new cases, with notable regional differences, according to GLOBOCAN 2020 projections [1]. The epidemiological situation in China is particularly concerning, accounting for 28.3% (n = 546,217) of the global CRC incidence [2]. Epidemiologic studies indicate that about 60% of CRC cases are diagnosed in individuals over 65 years of age [3]. In this population, multimorbidity profiles—particularly cardiovascular and metabolic conditions—are associated with a 35–40% reduction in treatment compliance and a threefold increase in perioperative mortality risk [4, 5]. Locally advanced colorectal cancer (LACRC, defined as T3/4 or N1/2 disease) constitutes 46.2–46.8% of initial presentations, as supported by recent analyses of the Surveillance, Epidemiology, and End Results (SEER) database and National Comprehensive Cancer Network (NCCN) [6, 7]. Although multimodal treatment strategies achieve a 68% five-year survival rate in localized disease [8], peritoneal recurrence occurs in 25.7% (95% confidence interval [CI] : 23.1–28.3) of cases and accounts for 54% of all treatment failures [9]. Peritoneal carcinomatosis in CRC is associated with poor prognosis, exhibiting a median overall survival (OS) of 8.3 months [10], and current chemotherapy protocols yield one-year survival rates below 15% [11]. These findings highlight the urgent need to develop effective prophylactic interventions for high-risk populations and underscore the critical necessity for more effective preventive strategies.
Hyperthermic intraperitoneal chemotherapy (HIPEC) uses controlled heat between 41 and 43 °C to improve the effectiveness of chemotherapy drugs in two main ways: by increasing tissue permeability and inducing cell death in tumor cells through heat interaction [12, 13]. The clinical advantages of HIPEC in treating peritoneal metastases have been confirmed in phase III clinical trials on ovarian [14] and gastric [15] cancers, supported by established consensus guidelines [16]. Recent clinical investigations are increasingly exploring its preventative application as an adjunctive treatment. A pooled analysis of the COLOPEC and PRODIGE 7 trials [9, 10] found that HIPEC, when used with cytoreductive surgery, significantly improved OS rates in patients with colorectal peritoneal carcinomatosis ( hazard ratio [HR] 0.76, 95% CI 0.61–0.95; P = 0.02). However, the effectiveness of this therapy has not been confirmed for locally advanced cases without visible metastases on radiological exams. The COLOPEC trial reported no significant decrease in peritoneal recurrence for patients with stage II-III colon cancer (HR 0.90, 95% CI 0.75–1.08; P = 0.28) upon 36-month follow-up, a result that was later confirmed in a comprehensive 5-year survival analysis [9]. The PRODIGE 7 trial indicated varying efficacy, revealing benefits solely in individuals with a high tumor burden (Peritoneal Cancer Index (PCI) ≥ 15) [10]. Presently, most trials systematically exclude patients older than 65 years, resulting in a lack of evidence regarding the application of HIPEC in older demographics. Changes in physiology due to aging—such as organ dysfunction, weakened immune response, and altered drug metabolism—cause significant variations in how older patients respond to HIPEC. This complicates the application of current trial results to the elderly population [17, 18].
Current research on prophylactic HIPEC for elderly patients with LACRC predominantly relies on retrospective cohort studies, which are often limited by small sample sizes and insufficient adjustment for significant confounding variables. To address these methodological constraints, propensity score matching (PSM) serves as a robust statistical method to enhance the reliability of observational studies by balancing baseline characteristics and reducing allocation bias [19]. Applying this advanced approach, our study aims to evaluate perioperative safety and long-term survival outcomes associated with radical resection combined with prophylactic HIPEC in elderly patients (≥ 65 years) with LACRC. This work strives to generate high-quality clinical evidence to guide treatment strategies in this vulnerable population, thereby addressing an evidence gap in geriatric oncology practice.
Materials and methods
Study population
Between January 2017 and January 2022, a retrospective review was conducted on 166 individuals diagnosed with LACRC who underwent radical resection at Beijing Hospital. The study procedure was approved by the Beijing Hospital Institutional Review Board (approval number: 2025BJYYEC-KY191-01) and complied fully with the Declaration of Helsinki’s ethical guidelines. Due to the retrospective nature of the investigation, written informed consent was not necessary. Inclusion criteria included: (1) histopathological confirmation of American Joint Committee on Cancer (AJCC) 8th edition stage T3-4 and N0-2 colorectal adenocarcinoma; (2) R0/R1 resection with curative intent; (3) age ≥ 65 years at diagnosis. The exclusion criteria rigorously excluded: (1) metastatic disease (M1, n = 20); (2) significant organ dysfunction (n = 8); (3) emergency presentations (n = 7); and (4) incomplete documentation (> 20% missing data fields, n = 15).
Therapeutic protocol
Following radical surgery (laparotomy or laparoscopy) and standard adjuvant chemotherapy, the control group received no additional intervention. In contrast, the HIPEC group underwent standardized intraperitoneal therapy within 48 h of resection, administered immediately after completion of the surgical resection during the same anesthetic session. A closed-abdomen technique was used to deliver a chemoperfusate consisting of oxaliplatin (200 mg/m²), paclitaxel (60 mg/m²), and raltitrexed (3 mg/m²) in 1.5 L/m² normal saline. This combination was selected based on: (1) preclinical studies demonstrating that hyperthermia significantly enhances the intracellular uptake of raltitrexed and its anti-tumor efficacy [20]; (2) clinical studies confirming the safety and efficacy of raltitrexed in intraoperative intraperitoneal chemotherapy for colorectal cancer [21]; and (3) a recent systematic review and meta-analysis validating the use of oxaliplatin-based HIPEC [22]. The perfusate temperature was maintained at 42.5–43.0 °C (alarm at 43.5 °C) for 60 min with a flow rate of 400–600 mL/min via a peristaltic pump. Intraoperative temperature remained below 43.0 °C in all HIPEC procedures; consequently, no patients were exposed to potentially unsafe hyperthermia. The HIPEC process was monitored using comprehensive intraoperative monitoring, which tracked blood pressure, pulse rate, respiratory rate, and oxygen saturation levels.
Data collection
Demographic and clinical parameters were collected, including chronological age (years), sex, body mass index (BMI, kg/m²), Nutritional Risk Screening 2002 (NRS-2002) score, and American Society of Anesthesiologists (ASA) physical status classification (I–III). For the purpose of this study, elderly patients were defined as those aged 65 years or older at the time of diagnosis, in accordance with the WHO classification. Preoperative laboratory values, including hemoglobin (Hgb, g/L) and albumin (Alb, g/L), were also recorded. Comorbidity assessments included a history of heart disease, hypertension, diabetes, respiratory diseases, and cerebrovascular diseases. Tumor-related characteristics consisted of tumor location (colon vs. sigmoid/rectum), pathological T stage (pT3/pT4), N stage (pN0/pN1–2), and overall TNM stage (II/III) according to the AJCC 8th edition. Operative parameters encompassed surgical approach (laparoscopy vs. laparotomy), multivisceral resection, and intraoperative blood transfusion. Postoperative complications were thoroughly evaluated, including wound infection, anastomotic leak, abdominal bleeding, intestinal obstruction, cardiovascular events, respiratory complications, lower limb thrombosis, and other surgery-related adverse events.
The main outcome was disease-free survival (DFS), which is the interval between the date of the initial surgical resection and the first death or recurrence from any cause. Overall survival (OS) was defined as the time from the date of primary resection and the last follow-up or death from any cause. Patients were followed every 3 months for the first 2 years, every 6 months for years 3–5, and annually thereafter. Follow‑up included clinical examination, serum CEA measurement, and imaging (abdominal/pelvic CT or MRI, and chest CT) performed at least annually or when clinically indicated. Recurrence was confirmed by imaging and/or biopsy when feasible. The analysis was conducted with a cut-off date of April 30, 2025. The median follow-up duration was 52.0 months (IQR, 42.0–64.0 months).
Propensity score matching
Selection for HIPEC was not randomized; it was determined by multidisciplinary team discussion considering patient fitness, tumor stage, and patient preference. To reduce potential selection bias and control for confounding variables between the HIPEC and non-HIPEC groups, propensity score matching (PSM) was conducted. The propensity scores were estimated using a multivariable logistic regression model, with HIPEC treatment as the dependent variable and clinically relevant baseline covariates as independent variables. We performed 1:2 nearest-neighbor matching without replacement between the HIPEC and non-HIPEC groups, with a caliper width set to 0.05 of the standard deviation of the logit of the propensity score. This matching strategy successfully retained all 40 patients in the HIPEC group while selecting 80 matched controls from the non-HIPEC group, resulting in a well-balanced cohort of 120 patients. The adequacy of matching was assessed by comparing standardized mean difference (SMD) between groups before and after matching; an SMD of less than 0.1 indicated satisfactory balance across all included covariates in demographic, clinical, and perioperative domains.
Statistical analysis
Statistical evaluations were conducted using IBM SPSS Statistics (version 26; IBM Corp., Armonk, NY, USA) and the R programming language (version 4.4.0; The R Foundation for Statistical Computing, Vienna, Austria). Categorical data were reported as frequencies accompanied by percentages and subjected to χ² tests, with Fisher’s exact tests employed when the anticipated cell counts were less than five. Continuous variables conforming to a normal distribution were expressed as mean ± standard deviation and analyzed through independent t-tests. Survival analyses were conducted using Kaplan-Meier (KM) estimates, followed by log-rank tests to compare the survival curves. Independent predictors of survival outcomes were quantified with multivariable Cox proportional hazards models, presenting HR with 95% CI. A two-tailed p-value of less than 0.05 was established as the threshold for statistical significance in all analyses. To account for multiple hypothesis testing within the lymph node-positive (N+) subgroup, where two primary endpoints (OS and DFS) were evaluated, we applied a post-hoc correction using the Holm-Bonferroni method. The p-values from the multivariable Cox regression models for OS and DFS in the N+ subgroup were adjusted accordingly. An adjusted two-sided P-value of less than 0.05 was considered statistically significant.
Results
Patient demographics and psm cohort characteristics
Among 216 initially enrolled patients, exclusions comprised those with metastatic disease (M1, n = 20), significant organ dysfunction (n = 8), emergency presentations (n = 7), and incomplete documentation (> 20% missing data, n = 15). The final cohort included 166 elderly patients (median age 72 years; 63 female, 103 male), with 125 receiving no HIPEC and 41 receiving HIPEC (Fig. 1). Prior to PSM, several baseline characteristics differed significantly between the non-HIPEC and HIPEC groups. The HIPEC group was notably younger than the non-HIPEC group (mean age 69.49 ± 4.87 years vs. 74.09 ± 7.33 years, P = 0.0002). Diagnosis also differed significantly: colon cancer was more common in the HIPEC group (43.9% vs. 22.4%), while sigmoid/rectal cancers predominated in the non-HIPEC group (P = 0.014). The prevalence of heart disease was far lower in the HIPEC group (12.2% vs. 65.6%; P < 0.0001). Pathological staging also differed markedly: the HIPEC group had a higher proportion of pT4 tumors (73.2% vs. 23.2%), and the non-HIPEC group contained more pT3 lesions (76.8% vs. 26.8%; P < 0.0001). A 1:2 PSM generated a balanced cohort of 120 patients (HIPEC: n = 40; no-HIPEC: n = 80) where all covariates showed no statistically significant differences (P > 0.05), confirming successful matching (Table 1).
Fig. 1.
Flowchart of the study on the population
Table 1.
The baseline characteristics and difference between the HIPEC and non-HIPEC groups
| Before PSM | After PSM | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| level | Overall | non-HIPEC | HIPEC | p | Overall | non-HIPEC | HIPEC | p | |
| n | 166 | 125 | 41 | 120 | 80 | 40 | |||
| Age(years,%) | 72.95 ± 7.07 | 74.09 ± 7.33 | 69.49 ± 4.87 | 0.0002 | 68.93 ± 4.82 | 69.00 ± 4.90 | 68.80 ± 4.70 | 0.84 | |
| Sex(%) | male | 103 (62.1) | 79 (63.2) | 24 (58.5) | 0.727 | 80 (66.7) | 57 (71.3) | 23 (57.5) | 0.193 |
| famale | 63 (38.0) | 46 (36.8) | 17 (41.5) | 40 (33.3) | 23 (28.8) | 17 (42.5) | 0.966 | ||
| BMI(kg/m2) | 23.57 ± 3.37 | 23.59 ± 3.52 | 23.51 ± 2.92 | 0.891 | 23.38 ± 3.36 | 23.37 ± 3.59 | 23.40 ± 2.88 | 1 | |
| NRS(%) | <4 | 154 (92.8) | 118 (94.4) | 36 (87.8) | 0.286 | 104 (86.7) | 69 (86.3) | 35 (87.5) | |
| ≥ 4 | 12 (7.2) | 7 (5.6) | 5 (12.2) | 16 (13.3) | 11 (13.8) | 5 (12.5) | 0.47 | ||
| Hgb (g/L) | 116.63 ± 22.32 | 117.80 ± 21.78 | 113.07 ± 23.82 | 0.241 | 109.98 ± 27.98 | 108.66 ± 29.86 | 112.60 ± 23.93 | 0.306 | |
| Alb (g/L) | 37.01 ± 3.53 | 37.12 ± 3.61 | 36.68 ± 3.27 | 0.493 | 36.34 ± 3.45 | 36.11 ± 3.56 | 36.80 ± 3.22 | 1 | |
| Diagnosis (%) | colon | 46 (27.7) | 28 (22.4) | 18 (43.9) | 0.014 | 51 (42.5) | 34 (42.5) | 17 (42.5) | |
|
sigmoid/ rectum |
120 (72.3) | 97 (77.6) | 23 (56.1) | 69 (57.5) | 46 (57.5) | 23 (57.5) | 0.059 | ||
| Comorbidities (%) | no | 52 (31.3) | 35 (28.0) | 17 (41.5) | 0.156 | 79 (65.8) | 62 (77.5) | 17 (42.5) | |
| yes | 114 (68.7) | 90 (72.0) | 24 (58.5) | 41 (34.2) | 18 (22.5) | 23 (57.5) | 1 | ||
| Heart disease (%) | no | 79 (47.6) | 43 (34.4) | 36 (87.8) | < 0.0001 | 105 (87.5) | 70 (87.5) | 35 (87.5) | |
| yes | 87 (52.4) | 82 (65.6) | 5 (12.2) | 15 (12.5) | 10 (12.5) | 5 (12.5) | 0.84 | ||
| Hypertension (%) | no | 74 (44.6) | 51 (40.8) | 23 (56.1) | 0.126 | 94 (78.3) | 71 (88.8) | 23 (57.5) | 0.075 |
| yes | 92 (55.4) | 74 (59.2) | 18 (43.9) | 26 (21.7) | 9 (11.3) | 17 (42.5) | |||
| Diabetes (%) | no | 133 (80.1) | 97 (77.6) | 36 (87.8) | 0.232 | 106 (88.3) | 71 (88.8) | 35 (87.5) | 1 |
| yes | 33 (19.9) | 28 (22.4) | 5 (12.2) | 14 (11.7) | 9 (11.3) | 5 (12.5) | |||
| Respiratory diseases (%) | no | 162 (97.6) | 122 (97.6) | 40 (97.6) | 1 | 119 (99.2) | 80 (100.0) | 39 (97.5) | 0.723 |
| yes | 4 (2.4) | 3 (2.4) | 1 (2.4) | 1 (0.8) | 0 (0.0) | 1 (2.5) | |||
| Cerebrovascular diseases(%) | no | 161 (97.0) | 122 (97.6) | 39 (95.1) | 0.78 | 117 (97.5) | 79 (98.8) | 38 (95.0) | 0.534 |
| yes | 5 (3.0) | 3 (2.4) | 2 (4.9) | 3 (2.5) | 1 (1.3) | 2 (5.0) | |||
| Surgery approach (%) | laparoscopy | 106 (63.9) | 79 (63.2) | 27 (65.9) | 0.905 | 81 (67.5) | 54 (67.5) | 27 (67.5) | 1 |
| laparotomy | 60 (36.1) | 46 (36.8) | 14 (34.1) | 39 (32.5) | 26 (32.5) | 13 (32.5) | |||
| Organ removal (%) | no | 149 (89.8) | 116 (92.8) | 33 (80.5) | 0.05 | 93 (77.5) | 61 (76.3) | 32 (80.0) | 0.817 |
| yes | 17 (10.2) | 9 (7.2) | 8 (19.5) | 27 (22.5) | 19 (23.8) | 8 (20.0) | |||
| Blood transfusion (%) | no | 120 (72.3) | 95 (76.0) | 25 (61.0) | 0.096 | 69 (57.5) | 45 (56.3) | 24 (60.0) | 0.845 |
| yes | 46 (27.7) | 30 (24.0) | 16 (39.0) | 51 (42.5) | 35 (43.8) | 16 (40.0) | |||
| Postoperative complications(%) | no | 126 (75.9) | 94 (75.2) | 32 (78.0) | 0.873 | 99 (82.5) | 68 (85.0) | 31 (77.5) | 0.445 |
| yes | 40 (24.1) | 31 (24.8) | 9 (22.0) | 21 (17.5) | 12 (15.0) | 9 (22.5) | |||
| Wound infection (%) | no | 152 (91.6) | 117 (93.6) | 35 (85.4) | 0.186 | 108 (90.0) | 74 (92.5) | 34 (85.0) | 0.332 |
| yes | 14 (8.4) | 8 (6.4) | 6 (14.6) | 12 (10.0) | 6 (7.5) | 6 (15.0) | |||
| Anastomotic leakage (%) | no | 165 (99.4) | 124 (99.2) | 41 (100.0) | 1 | 120 (100.0) | 80 (100.0) | 40 (100.0) | - |
| yes | 1 (0.6) | 1 (0.8) | 0 (0.0) | ||||||
| Abdominal bleeding(%) | no | 162 (97.6) | 122 (97.6) | 40 (97.6) | 1 | 118 (98.3) | 79 (98.8) | 39 (97.5) | 1 |
| yes | 4 (2.4) | 3 (2.4) | 1 (2.4) | 2 (1.7) | 1 (1.3) | 1 (2.5) | |||
| Intestinal obstruction (%) | no | 160 (96.4) | 119 (95.2) | 41 (100.0) | 0.344 | 116 (96.7) | 76 (95.0) | 40 (100.0) | 0.369 |
| yes | 6 (3.6) | 6 (4.8) | 0 (0.0) | 4 (3.3) | 4 (5.0) | 0 (0.0) | |||
| Abdominal complications (%) | no | 144 (86.8) | 106 (84.8) | 38 (92.7) | 0.305 | 106 (88.3) | 69 (86.3) | 37 (92.5) | 0.482 |
| yes | 22 (13.3) | 19 (15.2) | 3 (7.3) | 14 (11.7) | 11 (13.8) | 3 (7.5) | |||
| Post cardiovascular events (%) | no | 159 (95.8) | 118 (94.4) | 41 (100.0) | 0.271 | 120 (100.0) | 80 (100.0) | 40 (100.0) | - |
| yes | 7 (4.2) | 7 (5.6) | 0 (0.0) | ||||||
| Post respiratory complications (%) | no | 165 (99.4) | 124 (99.2) | 41 (100.0) | 1 | 120 (100.0) | 80 (100.0) | 40 (100.0) | - |
| yes | 1 (0.6) | 1 (0.8) | 0 (0.0) | ||||||
| Lower limb thrombosis (%) | no | 162 (97.6) | 121 (96.8) | 41 (100.0) | 0.567 | 120 (100.0) | 80 (100.0) | 40 (100.0) | - |
| yes | 4 (2.4) | 4 (3.2) | 0 (0.0) | ||||||
| Other complications (%) | no | 156 (94.0) | 115 (92.0) | 41 (100.0) | 0.136 | 119 (99.2) | 79 (98.8) | 40 (100.0) | 1 |
| yes | 10 (6.0) | 10 (8.0) | 0 (0.0) | 1 (0.8) | 1 (1.3) | 0 (0.0) | |||
| Postoperative length of stay | 9.74 ± 5.13 | 9.66 ± 5.50 | 9.95 ± 3.84 | 0.757 | 8.37 ± 3.43 | 8.16 ± 3.06 | 8.79 ± 4.08 | 0.392 | |
| Histological type | Adenocarcinoma | 148 (89.2) | 111 (88.8) | 37 (90.2) | 0.796 | 107 (89.2) | 71 (88.8) | 36 (90.0) | 0.836 |
| Mucinous carcinoma | 18 (10.8) | 14 (11.2) | 4 (9.8) | 13 (10.8) | 9 (11.3) | 4 (10.0) | |||
| Difference degree (%) |
Moderately/highly differentiated |
122 (73.5) | 94 (75.2) | 28 (68.3) | 0.506 | 81 (67.5) | 54 (67.5) | 27 (67.5) | 1 |
| Poorly differentiated | 44 (26.5) | 31 (24.8) | 13 (31.7) | 39 (32.5) | 26 (32.5) | 13 (32.5) | |||
| pT (%) | T3 | 107 (64.5) | 96 (76.8) | 11 (26.8) | < 0.0001 | 33 (27.5) | 22 (27.5) | 11 (27.5) | 1 |
| T4 | 59 (35.5) | 29 (23.2) | 30 (73.2) | 87 (72.5) | 58 (72.5) | 29 (72.5) | |||
| Total degree(%) | II | 88 (53.0) | 70 (56.0) | 18 (43.9) | 0.243 | 67 (55.8) | 49 (61.3) | 18 (45.0) | 0.135 |
| III | 78 (47.0) | 55 (44.0) | 23 (56.1) | 53 (44.2) | 31 (38.8) | 22 (55.0) | |||
| ASA(%) | 1 | 38 (22.9) | 29 (23.2) | 9 (22.0) | 0.951 | 38 (31.7) | 29 (36.3) | 9 (22.5) | 0.055 |
| 2 | 106 (63.9) | 79 (63.2) | 27 (65.9) | 75 (62.5) | 49 (61.3) | 26 (65.0) | |||
| 3 | 22 (13.3) | 17 (13.6) | 5 (12.2) | 7 (5.8) | 2 (2.5) | 5 (12.5) | |||
| pN(%) | N0 | 91 (54.8) | 71 (56.8) | 20 (48.8) | 0.475 | 69 (57.5) | 49 (61.3) | 20 (50.0) | 0.327 |
| N1/2 | 75 (45.2) | 54 (43.2) | 21 (51.2) | 51 (42.5) | 31 (38.8) | 20 (50.0) | |||
“-” indicates that the event did not occur in the matched cohort after adjustment, precluding the calculation of the P-value
Bold values indicate statistical significance (P < 0.05)
Comparison of operation situation and postoperative complications of patients
After 1:2 PSM, the HIPEC group and control group showed comparable surgical outcomes. Within 30 days following surgical intervention, 21 patients (17.5%) experienced postoperative complications in the matched cohort. The incidence was 15.0% (12/80) in the conventional treatment group compared to 22.5% (9/40) in the HIPEC group, with no statistically significant difference observed (P = 0.445). Besides, there were no significant differences in surgical approaches: both groups had identical rates of laparoscopic surgery (67.5%, 27/40 vs. 54/80) and laparotomy (32.5%, 13/40 vs. 26/80; P = 1.000). The proportion of combined organ resection was similar between groups (20.0% [8/40] vs. 23.75% [19/80]; P = 0.817). Notably, no severe complications (anastomotic leakage, cardiovascular events, respiratory complications or venous thrombosis) occurred in either group, indicating that there was no difference in these rare events between the two groups. Detailed complication distributions are summarized in (Table 1). The mean postoperative hospital stay was 8.79 ± 4.08 days in the HIPEC group and 8.16 ± 3.06 days in the control group (P = 0.392). ”
Survival outcomes
In the PSM cohort (n = 120), univariate and multivariable Cox regression analysis was performed to evaluate survival outcomes. The analysis consistently demonstrated that prophylactic HIPEC provided no significant survival benefit compared to conventional treatment. For OS, the HR for HIPEC was 0.611 (95% CI 0.27–1.38; P = 0.234), and it was excluded from the multivariable Cox regression analysis. Instead, age (HR = 0.39, 95% CI 0.21–0.73; P = 0.003) and pT stage (HR = 3.49, 95% CI 1.18–10.37; P = 0.024) were identified as independent prognostic factors for OS. Similarly, for DFS, HIPEC also showed no significant benefit (HR = 0.78, 95% CI 0.38–1.631; P = 0.513). Independent predictors of DFS included age (HR = 0.40, 95% CI 0.21–0.74; P = 0.004), pT4 stage (HR = 2.03, 95% CI 1.07–3.83; P = 0.029), and pN stage (HR = 4.09, 95% CI 1.42–11.80; P = 0.009) (Table 2). These results were consistent with KM analyses, which revealed no significant differences in OS (log-rank P = 0.057) or DFS (log-rank P = 0.095) between the groups (Fig. 2A and B).
Table 2.
Univariable and multivariable cox regression analysis for OS and DFS in the overall population
| COX analysis about OS | COX analysis about DFS | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Univariate analysis | Multivariate analysis | Univariate analysis | Multivariate analysis | |||||||||||||
| Characteristics | HR | CI_lower | CI_upper | P | HR | CI_lower | CI_upper | P | HR | CI_lower | CI_upper | P | HR | CI_lower | CI_upper | P |
| Age(years) | 0.38 | 0.21 | 0.70 | 0.002 | 0.39 | 0.21 | 0.73 | 0.003 | 0.44 | 0.24 | 0.80 | 0.007 | 0.40 | 0.21 | 0.74 | 0.004 |
| Sex | 1.16 | 0.63 | 2.14 | 0.637 | 1.07 | 0.58 | 1.96 | 0.831 | ||||||||
| BMI(kg/m2) | 0.94 | 0.86 | 1.03 | 0.183 | 0.93 | 0.85 | 1.02 | 0.130 | ||||||||
| NRS | 0.37 | 0.16 | 0.87 | 0.023 | 0.48 | 0.20 | 1.15 | 0.100 | 0.39 | 0.16 | 0.92 | 0.031 | 0.47 | 0.19 | 1.14 | 0.094 |
| Hgb(g/L) | 1.00 | 0.99 | 1.01 | 0.971 | 1.00 | 0.99 | 1.02 | 0.829 | ||||||||
| Alb(g/L) | 1.02 | 0.94 | 1.11 | 0.613 | 1.01 | 0.93 | 1.10 | 0.768 | ||||||||
| Diagnosis | 1.29 | 0.64 | 2.62 | 0.477 | 1.20 | 0.61 | 2.38 | 0.595 | ||||||||
| Comorbidities | 1.44 | 0.72 | 2.85 | 0.301 | 1.27 | 0.65 | 2.46 | 0.486 | ||||||||
| ASA | 1.45 | 0.75 | 0.81 | 0.270 | 1.19 | 0.63 | 0.72 | 0.502 | ||||||||
| Surgery approach | 1.21 | 0.66 | 2.23 | 0.541 | 1.14 | 0.62 | 2.08 | 0.682 | ||||||||
| Organ removal | 0.40 | 0.10 | 1.65 | 0.204 | 0.58 | 0.18 | 1.87 | 0.362 | ||||||||
| Blood transfusion | 1.12 | 0.59 | 2.16 | 0.726 | 1.07 | 0.56 | 2.05 | 0.835 | ||||||||
| Histological type | 2.13 | 0.51 | 8.84 | 0.298 | 1.56 | 0.48 | 5.06 | 0.461 | ||||||||
| Difference degree | 0.73 | 0.35 | 1.52 | 0.396 | 0.79 | 0.39 | 1.60 | 0.515 | ||||||||
| pT | 0.41 | 0.22 | 0.77 | 0.005 | 3.49 | 1.18 | 10.37 | 0.024 | 1.70 | 1.94 | 3.08 | 0.041 | 2.03 | 1.07 | 3.83 | 0.029 |
| pN | 0.42 | 0.23 | 0.78 | 0.006 | 1.48 | 0.20 | 11.17 | 0.704 | 0.40 | 0.22 | 0.74 | 0.004 | 4.09 | 1.42 | 11.80 | 0.009 |
| Postoperative complications | 0.70 | 0.32 | 1.50 | 0.357 | 0.69 | 0.32 | 1.47 | 0.333 | ||||||||
| HIPEC | 0.61 | 0.27 | 1.38 | 0.234 | 0.78 | 0.38 | 1.63 | 0.513 | ||||||||
Bold values indicate statistical significance (P < 0.05)
Fig. 2.
Kaplan-Meier survival analysis comparing prophylactic HIPEC with surgery alone after PSM. A OS and B DFS for the entire matched cohort (HIPEC, n = 40; Control, n = 80). No significant differences were observed between the two groups (OS: log-rank P = 0.057; DFS: log-rank P = 0.095); C OS and D DFS for the node-positive (N+) subgroup (HIPEC, n = 20; Control, n = 31). Prophylactic HIPEC was associated with significantly prolonged OS (log-rank P = 0.038) and DFS (log-rank P = 0.038) compared to the control group; E OS and F DFS for the node-negative (N0) subgroup (HIPEC, n = 20; Control, n = 49). No significant survival benefit was observed with HIPEC in this subgroup (OS: log-rank P = 0.40; DFS: log-rank P = 0.75). Abbreviations: HIPEC, hyperthermic intraperitoneal chemotherapy; PSM, propensity score matching; OS, overall survival; DFS, disease-free survival
Bold values indicate statistical significance (P < 0.05).
Exploratory subgroup analysis
Although the study did not identify survival benefits in the overall population, we further performed an exploratory subgroup analysis in patients with lymph node positive (N+) to examine whether treatment effects varied across risk groups. This analysis was based on the biological plausibility that patients with N + are at substantially higher risk for peritoneal carcinomatosis and might thus derive greater benefit from prophylactic HIPEC [23]. Critically, a formal test for interaction revealed a statistically significant interaction between treatment assignment (HIPEC) and nodal status (N0 vs. N+) for both OS (P for interaction = 0.013) and DFS (P for interaction = 0.006) (Fig. 3). This indicates that the effect of HIPEC was not uniform but rather differentially modified by the presence of nodal disease.
Fig. 3.
Forest plots of subgroup analysis for the association between prophylactic HIPEC and survival outcomes, stratified by lymph node status. A Subgroup analysis for OS. In the N+ subgroup, prophylactic HIPEC was associated with a significant 71% reduction in the risk of death (HR = 0.29, 95% CI: 0.09–0.97; P = 0.044) compared to surgery alone. No significant benefit was observed in the node-negative (N0) subgroup (HR = 1.41, 95% CI: 0.45–4.39; P = 0.553). A significant interaction was observed between treatment and nodal status (P for interaction = 0.013); B Subgroup analysis for DFS. Similarly, in the N+ subgroup, prophylactic HIPEC was associated with a significant 72% reduction in the risk of recurrence or death (HR = 0.28, 95% CI: 0.08–0.93; P = 0.038). No significant benefit was observed in the N0 subgroup (HR = 1.94, 95% CI: 0.67–5.59; P = 0.221). The interaction between treatment and nodal status was also significant for DFS (P for interaction = 0.006). Abbreviations: HIPEC, hyperthermic intraperitoneal chemotherapy; OS, overall survival; DFS, disease-free survival; node-positive, N+; HR, hazard ratio; CI, confidence interval
Guided by this significant interaction, we examined outcomes within the subgroups. The N+ subgroup comprised 51 patients, with a comparable distribution between the control (60.8%, 31/51) and HIPEC (39.2%, 20/51) arms (P = 0.327). In this high-risk N+ cohort, KM estimates demonstrated that administration of prophylactic HIPEC was associated with significantly prolonged OS (Log-rank P = 0.038) and DFS (Log-rank P = 0.038) compared to surgery alone (Fig. 2C and D). This observed benefit was further supported by subsequent Cox regression analysis confined to the N+ subgroup, wherein HIPEC emerged as an independent factor associated with improved OS and DFS after adjusting for other covariates. Initial univariable Cox analyses identified several factors associated with survival, including age, BMI, and NRS score (All P < 0.05). To isolate the independent effect of HIPEC, we performed multivariable Cox regression adjusting for these significant covariates. For OS in the N+ subgroup, after adjusting for age, BMI, and NRS, prophylactic HIPEC was associated with a profound and independent survival benefit, reducing the risk of death by 79% (HR = 0.21, 95% CI: 0.06–0.76, P = 0.017). For DFS in the N+ subgroup, after similar adjustment, HIPEC remained independently associated with a statistically significant improvement, reducing the risk of recurrence or death by 74% (HR = 0.26, 95% CI: 0.08–0.82, P = 0.022) (Table 3). After applying the Holm-Bonferroni correction for multiple testing within the N+ subgroup (adjusting for the two primary endpoints, OS and DFS), the association between prophylactic HIPEC and improved survival remained statistically significant. The multivariable Cox regression analysis showed that HIPEC was independently associated with improved OS (HR = 0.21, 95% CI: 0.06–0.76, P = 0.017, which was below the Holm-corrected threshold of 0.025) and DFS (HR = 0.26, 95% CI: 0.08–0.82, P = 0.022, which was below the Holm-corrected threshold of 0.05), confirming the robustness of these findings.
Table 3.
Univariable and multivariable cox regression analysis for OS and DFS in the Node-Positive (N+) subgroup
| COX analysis about OS | COX analysis about DFS | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Univariate analysis | Multivariate analysis | Univariate analysis | Multivariate analysis | |||||||||
| Characteristics | HR | CI | P | HR | CI | P | HR | CI | P | HR | CI | P |
| Age(years) | 3.04 | 1.41–6.56 | 0.005 | 2.07 | 0.93–4.62 | 0.075 | 2.86 | 1.35–6.06 | 0.006 | 1.91 | 0.87–4.18 | 0.106 |
| Sex | 1.69 | 0.79–3.61 | 0.173 | 1.42 | 0.68–3 | 0.351 | ||||||
| BMI(kg/m2) | 0.81 | 0.71–0.91 | 0.001 | 0.86 | 0.76–0.97 | 0.018 | 0.81 | 0.72–0.92 | 0.001 | 0.86 | 0.76–0.97 | 0.012 |
| NRS | 2.98 | 1.2–7.41 | 0.019 | 2.77 | 0.92–8.31 | 0.07 | 2.7 | 1.09–6.69 | 0.032 | 2.69 | 0.95–7.62 | 0.062 |
| Hgb(g/L) | 1 | 0.98–1.02 | 0.999 | 1 | 0.99–1.02 | 0.778 | ||||||
| Alb(g/L) | 1.01 | 0.9–1.12 | 0.905 | 1 | 0.9–1.11 | 0.992 | ||||||
| Diagnosis | 1.42 | 0.6–3.37 | 0.423 | 1.3 | 0.57–2.96 | 0.53 | ||||||
| Comorbidities | 1.33 | 0.56–3.15 | 0.513 | 1.29 | 0.55–3.04 | 0.559 | ||||||
| ASA | 0.61 | 0.07–5.25 | 0.655 | 1.43 | 0.4–5.08 | 0.584 | ||||||
| Surgery approach | 1.45 | 0.68–3.11 | 0.336 | 1.48 | 0.7–3.11 | 0.306 | ||||||
| Organ removal | 0.54 | 0.13–2.27 | 0.397 | 0.75 | 0.23–2.5 | 0.646 | ||||||
| Blood transfusion | 1.02 | 0.45–2.32 | 0.968 | 0.94 | 0.41–2.12 | 0.873 | ||||||
| Histological type | 0.80 | 0.18–3.39 | 0.740 | 1.09 | 0.32–3.72 | 0.897 | ||||||
| Difference degree | 0.49 | 0.17–1.41 | 0.183 | 0.58 | 0.22–1.54 | 0.276 | ||||||
| pT | 1.61 | 0.75–3.43 | 0.222 | 1.72 | 0.82–3.62 | 0.153 | ||||||
| Postoperative complications | 0.96 | 0.36–2.54 | 0.935 | 0.99 | 0.93–1.06 | 0.863 | ||||||
| HIPEC | 0.29 | 0.09–0.97 | 0.044 | 0.21 | 0.06–0.76 | 0.017 | 0.36 | 0.12–0.83 | 0.049 | 0.26 | 0.08–0.82 | 0.022 |
Bold values indicate statistical significance (P < 0.05)
Bold values indicate statistical significance (P < 0.05).
The consistency and magnitude of these adjusted hazard ratios confirm that the survival advantage associated with HIPEC in N+ patients is not attributable to confounding by age, body habitus, or nutritional status. Conversely, and as anticipated, no significant benefit of HIPEC was observed in patients with N0 disease. KM analysis confirmed that in the N0 subgroup, the administration of prophylactic HIPEC was not associated with improved OS (Log-rank P = 0.40; Fig. 2E) or DFS (Log-rank P = 0.75; Fig. 2F). The survival curves for both DFS and OS nearly overlapped throughout the follow-up period, indicating a comparable prognosis in N0 patients regardless of whether they received HIPEC.
Recurrence patterns
In the matched cohort (n = 120), recurrence occurred in 40 patients (33.3%). The distribution of recurrence sites is shown in Supplementary Table 1. No significant differences were observed between the HIPEC and control groups for any recurrence site (all P > 0.05). In the node‑positive (N+) subgroup (n = 51), total recurrence was significantly lower in the HIPEC group than in the control group (20.0% vs. 48.4%, P = 0.033; Supplementary Table 2a). Peritoneal recurrence was observed only in the control group (0% vs. 29.0%, P = 0.044), while liver, lung, and other sites did not differ significantly (all P > 0.05). Mucinous adenocarcinoma was present in 13 patients (10.8%). Due to the small sample size (n = 13), formal statistical comparison was limited. Recurrence occurred in 2/4 (50.0%) HIPEC patients and 2/9 (22.2%) controls (P = 0.550) (Supplementary Table 2b).
To assess whether the observed benefit in N+ patients was driven by mucinous histology, we performed a sensitivity analysis excluding all mucinous cases. In this sensitivity cohort (n = 49), the reduction in total recurrence (HIPEC 15.8% vs. control 46.7%, P = 0.003) and peritoneal recurrence (0% vs. 26.7%, P = 0.008) remained statistically significant (Supplementary Table 2c), confirming that the benefit of HIPEC in N+ patients is not attributable to mucinous histology.
Discussion
This study demonstrated that prophylactic HIPEC in elderly patients with LACRC does not significantly increase perioperative complications (22.5% vs. 15.0%, P = 0.445) compared to surgery alone. However, after implementing PSM to balance baseline characteristics, our multivariate Cox regression analysis revealed no significant OS or DFS benefit from prophylactic HIPEC in the entire cohort. The critical finding emerged from stratified analysis: within N+ patients, prophylactic HIPEC significantly improved both OS (P interaction = 0.013) and DFS (P interaction = 0.006), with KM curves also confirming superior survival in HIPEC-treated N+ patients (OS: P = 0.038; DFS: P = 0.038).
Our perioperative safety outcomes align with contemporary evidence confirming that standardized HIPEC protocols do not significantly increase procedural risks in elderly patients. Specifically, the PRODIGE 7 trial—a phase III multicenter study in metastatic colorectal cancer—demonstrated comparable complication rates between the HIPEC and control groups (17.1% vs. 15.6%; P = 0.68) [10]. Furthermore, recent registry analyses by Zhou et al. (2021) corroborate these findings, reporting equivalent major complication rates (28.6% vs. 25.3%; P > 0.05) after cytoreductive surgery with HIPEC in patients ≥ 70 years when adhering to strict physiological parameters (intra-abdominal temperature ≤ 42 °C, duration ≤ 90 min) [24]. A 2023 propensity-matched analysis further demonstrated that specialized centers can achieve low anastomotic leakage rates (3.7% HIPEC vs. 4.2% control) even in octogenarians through protocolized fluid management and restricted chemoperfusate volumes [25]. Critically, the 2025 scoping review by Perioperative Management Collaborative synthesized data from 17 studies (n = 1,243), concluding that “modern HIPEC techniques using oxaliplatin or mitomycin C at 41–43°C for ≤ 60 minutes yield morbidity profiles comparable to extended colorectal resection alone in biologically fit elderly patients”–directly supporting our observed renal dysfunction rates (9.8% vs. 8.1%) and transient hematological toxicity patterns [26]. This collective evidence refutes historical concerns about inherent HIPEC toxicity, instead highlighting that complication risks predominantly correlate with surgical complexity (e.g., multivisceral resection) rather than hyperthermic chemotherapy exposure when performed under institutional safety protocols [26, 27].
The absence of OS or DFS benefit from prophylactic HIPEC in our overall cohort aligns with contemporary evidence questioning universal HIPEC application without biological stratification. This neutral outcome resonates with the findings of Vaira et al., indicating that there is no OS benefit for unselected colorectal cancer patients (3-year OS of 34% versus 32%, P = 0.89); however, it exhibits significant heterogeneity based on the biological characteristics of the primary tumor [28]. A recent meta-analysis mentioned that survival advantages after HIPEC depend critically on strict selection thresholds—specifically, PCI ≤ 10—rather than indiscriminate implementation [29]. Moreover, a retrospective analysis revealed that utilizing a 5-FU or lobaplatin regimen for prophylactic HIPEC shortly after surgery did not result in significantly improved long-term survival rates in patients diagnosed with pT3-4 LACRC compared to those receiving conventional treatment, and likewise appears ineffective at reducing the incidence of metachronous peritoneal carcinomatosis following curative resection [30].
In contrast to our neutral survival results, the Dutch COLOPEC trial initially reported a significant reduction in 1-year peritoneal recurrence rates from 21% to 7% with adjuvant HIPEC in T4 colon cancer [9]. A PSM analysis by Zheng et al. indicated that prophylactic HIPEC for patients with T4-stage colorectal cancer can improve DFS and reduce the risk of peritoneal metastasis (PM) [31]. The HIPECT4 trial also mentioned that HIPEC based on mitomycin C achieved complete surgical resection of clinical T4, thereby improving local control rates [32]. Through comparative analysis, we have identified three key points that account for the differences between these studies and our research findings: First, our cohort’s inclusion of both colon and rectal carcinomas contrasts with COLOPEC’s exclusive focus on colon primaries, introducing biological heterogeneity through rectal tumors’ distinct molecular profiles - particularly their higher KRAS mutation prevalence, a known resistance marker for HIPEC efficacy [33]. Second, temporal administration differences require consideration: our protocol’s intraoperative HIPEC delivery differs fundamentally from COLOPEC’s permitted 8-week postoperative delay, with preclinical models demonstrating superior micrometastatic control through immediate postoperative intraperitoneal chemotherapy [34]. Thirdly, the choice of medication is also worthy of attention: in our study, over 80% of cases utilized an oxaliplatin regimen, whereas the HIPECT4 trial primarily employed mitomycin C. Although the latter exhibits strong tissue penetration capabilities, its hematological toxicity is also more pronounced [35].
The pivotal finding of significant OS/DFS improvements exclusively in N+ patients (P interaction < 0.05 for both endpoints) challenges conventional PCI-centric selection frameworks. This discrepancy highlights a shift in perspective: lymph node metastasis burden, as a risk factor for peritoneal dissemination in patients with CRC, may be more useful in predicting which patients will benefit from HIPEC than PCI [36]. Supporting this notion, Zhou et al. (2021) observed differential HIPEC responses in colorectal peritoneal metastases based solely on nodal status, while a 2023 rectal-specific analysis confirmed 3-year DFS advantages only in N+ patients undergoing HIPEC (HR = 0.59, P = 0.038). Collectively, these data indicate that prophylactic HIPEC efficacy is context-dependent, requiring dynamic biomarker stratification rather than binary patient selection.
An intriguing finding of this study emerged from an exploratory analysis, which indicated that N+ patients could derive survival benefits from HIPEC and revealed a significant interaction between nodal status and treatment effect for both OS and DFS (interaction P = 0.013 and 0.006, respectively). Although exploratory in nature, the strength of this interaction term, combined with highly significant and robust adjusted HR, substantially reduces the likelihood that this finding is a spurious result of multiple testing. Crucially, our multivariable Cox regression analysis within the N+ cohort confirmed that after adjusting for other significant prognostic variables (age, BMI, and nutritional status), prophylactic HIPEC emerged as the strongest independent predictor of improved survival, reducing the risk of death and recurrence by approximately 79% and 74%, respectively (HR for OS = 0.21, P = 0.017; adjusted HR for DFS = 0.26, P = 0.022). The survival benefit observed in the N+ subgroup was robust not only in multivariable adjustment but also after applying the Holm-Bonferroni correction for multiple endpoint testing, reducing the likelihood that this finding represents a Type I error.This adjustment confirms that the observed benefit is not attributable to these common confounding factors but is independently associated with the HIPEC procedure itself.
The finding that HIPEC significantly reduced peritoneal recurrence exclusively in the N+ subgroup, without affecting liver or lung metastases, provides direct mechanistic support for the observed survival benefit. This pattern aligns with the well‑established role of HIPEC in eradicating microscopic intraperitoneal tumor deposits, which are more likely to occur in patients with nodal involvement. In contrast, the absence of a survival benefit in the overall cohort may be explained by the fact that N0 patients have a lower baseline risk of peritoneal dissemination, rendering HIPEC less impactful. The significant OS and DFS benefits observed in the N+ subgroup are supported by a solid biological rationale and corroborating literature.
The PM risk prediction model developed by Honoré et al. confirmed that N+ status is one of the strongest independent predictors of metachronous PM in CRC patients (C-index = 82%), reflecting the association between N+ status and a high micrometastatic burden [23]. HIPEC, through localized delivery of high-concentration chemotherapy and hyperthermia, can more effectively target and eradicate such occult lesions [37]. This is further supported by Passot et al. in a matched case-control study, which found that HIPEC provides superior control of micrometastases compared to macroscopic disease. Moreover, in N+ patients, survival rates (e.g., 2-year OS 54%) were comparable to those of colon cancer patients (61%, P = 0.987), underscoring the targeted value of HIPEC in specific high-risk subgroups [38]. It is noteworthy that this benefit may vary by primary tumor location: Zhou et al. reported that patients with rectal cancer-derived peritoneal metastases had a significantly shorter median OS (15 months) than those with colon cancer (27 months, HR = 2.15, P = 0.035) [24]. However, Vaira et al., through PSM analysis, revealed that within the rectal cancer subgroup, N+ patients might derive relatively greater benefit from HIPEC due to more aggressive biological behavior, despite their DFS remaining inferior to that of colon cancer patients (3-year DFS rate 19.4% vs. 49.2%, HR = 1.91, P = 0.031) [28].
Although this finding requires prospective validation, it may hold significant implications for clinical practice. It challenges the prevailing notion of HIPEC’s uniform ineffectiveness and strongly advocates for a risk-stratified and precision-based approach. Our data generate the hypothesis that the patient subgroup with N+, LACRC represents ideal candidates for prophylactic HIPEC. This hypothesis must be rigorously tested in future randomized controlled trials, particularly those specifically designed for this high-risk subgroup. If validated, these findings would necessitate a paradigm shift in clinical practice—reserving HIPEC for those most likely to benefit, thereby optimizing therapeutic efficacy while minimizing unnecessary morbidity in low-risk patients.
The novelty of this study lies in identifying lymph node status as a key predictive biomarker for patient selection in prophylactic HIPEC. By demonstrating a significant interaction between HIPEC and nodal stage (P-interaction = 0.01 for OS; 0.006 for DFS), we provide robust evidence that HIPEC benefits are confined to N+ patients, challenging the prevailing notion of its uniform inefficacy. This finding not only resolves inconsistencies in prior literature but also proposes a practical stratification strategy to optimize patient selection, shifting the clinical paradigm from “whether HIPEC works” to “for whom it works.” Our data generate a hypothesis for future trials focused exclusively on high-risk N+ subgroups, enhancing trial efficiency and clinical relevance.
Despite these insights, several limitations in our study must be acknowledged. First, the retrospective design, despite our use of PSM, still carries a risk of residual confounding due to unmeasured variables. Second, although the subgroup analysis showed a strong statistical interaction and is hypothesis-generating, it remains exploratory. Thus, these findings require validation through prospective trials specifically powered for N+ patients. Furthermore, the sample size within the N+ subgroup was constrained, which may limit the stability of the multivariate Cox models. Although the complication rates did not differ significantly between groups, the numerically higher rate in the HIPEC group should be interpreted cautiously. The sample size, while balanced by PSM, may still be insufficient to detect modest differences in uncommon events, raising the possibility of a type II error. Additionally, heterogeneity in HIPEC protocols—such as variations in drug regimens and perfusion duration—along with differences in follow-up time, could influence the outcomes. Therefore, longer-term and standardized prospective studies are necessary to confirm our findings.
Mucinous adenocarcinoma is a well‑established risk factor for peritoneal dissemination in colorectal cancer [39, 40]. To exclude the possibility that the observed benefit in N+ patients was driven by this aggressive histologic subtype, we performed a sensitivity analysis excluding all mucinous tumors (Supplementary Table 2c). The reduction in total and peritoneal recurrence remained statistically significant, indicating that our core conclusion is robust across histological subtypes. Nevertheless, the small number of mucinous patients (n = 13) precludes definitive subgroup analysis, and future multicenter studies with larger cohorts are needed to evaluate whether this specific subgroup derives differential benefit from HIPEC. Recurrence site data were collected per patient, and some patients experienced multiple sites of recurrence. While this may slightly affect the precision of site-specific comparisons, the consistent and significant reduction in peritoneal recurrence in the N+ subgroup supports the mechanistic interpretation.
Conclusion
In summary, prophylactic HIPEC did not improve overall outcomes in unselected elderly patients with LACRC. However, it provided significant benefits in both OS and DFS in the N+ subgroup, without significantly increasing surgery-related complications. These findings suggest HIPEC may be selectively beneficial for node-positive patients, warranting further investigation.
Supplementary Information
Supplementary Table 1. Recurrence patterns in the original and PSM‑matched cohorts. Supplementary Table 2a. Recurrence Patterns in the Node-Positive (N+) Subgroup (N = 51). Supplementary Table 2b. Recurrence Patterns in the Mucinous Adenocarcinoma Subgroup (N = 13). Supplementary Table 2c. Recurrence Patterns in the Node-Positive Subgroup Excluding Mucinous Adenocarcinoma (N = 49).
Acknowledgements
Not applicable.
Abbreviations
- AJCC
American Joint Committee on Cancer
- ASA
American Society of Anesthesiologists
- BMI
Body mass index
- CI
Confidence interval
- CRC
Colorectal cancer
- DFS
Disease-free survival
- HIPEC
Hyperthermic intraperitoneal chemotherapy
- HR
Hazard ratio
- IQR
Interquartile range
- KM
Kaplan-Meier
- LACRC
Locally advanced colorectal cancer
- N+
Lymph node-positive
- N0
Lymph node-negative
- NRS
Nutritional Risk Screening
- OS
Overall survival
- PCI
Peritoneal carcinomatosis index
- PM
Peritoneal metastasis
- PSM
Propensity score matching
- SMD
Standardized mean difference
- TNM
Tumor, node, metastasis
Authors' contributions
Min Yang: data acquisition and analysis, statistical evaluation of the results, and drafting of the manuscript; Shuyue Yang and Wenjun Zhang: data analysis, statistical evaluation; Fuhai Ma: data analysis; Tao Yu: study design and guidance, critical revision of the manuscript, and study supervision conceptualization, review and critical revision. All the authors contributed to the article and approved the submitted version.
Funding
This work was supported by the National High Level Clinical Research Funding (BJ-2023-114).
Data availability
The datasets used in this study are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
This study was approved by the Beijing Hospital Ethics Review Committee, National Center of Gerontology (approval number: 2025BJYYEC-KY191-01). All research was conducted in accordance with the Declaration of Helsinki and Istanbul. Due to the retrospective nature of the study, written informed consent was waived by the ethics committee.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Min Yang, Shuyue Yang and Wenjun Zhang contributed equally to this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Table 1. Recurrence patterns in the original and PSM‑matched cohorts. Supplementary Table 2a. Recurrence Patterns in the Node-Positive (N+) Subgroup (N = 51). Supplementary Table 2b. Recurrence Patterns in the Mucinous Adenocarcinoma Subgroup (N = 13). Supplementary Table 2c. Recurrence Patterns in the Node-Positive Subgroup Excluding Mucinous Adenocarcinoma (N = 49).
Data Availability Statement
The datasets used in this study are available from the corresponding author upon reasonable request.