Reprinted: [Article] A Multicenter Real-World Study of 940 Cases of Peritoneal Pseudomyxoma Treated with Cytoreductive Surgery Combined with Hyperthermic Intraperitoneal Chemotherapy

Corresponding author: Li Yan

Author: Cui Yurun

Citation: Cui Yurun, Ma Ru, Ren Guangliang, et al. A multicenter real-world study of 940 cases of peritoneal pseudomyxoma treated with cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy [J]. Chinese Journal of Gastrointestinal Surgery, 2026, 29(4): 492–498. DOI: 10.3760/cma.j.cn441530-2026 0105-00011.

Authors: Cui Yurun, Ma Ru, Ren Guangliang, Yang Rui, Yang Xiaojun, An Songlin, Wu Guobin, Li Xinbao, Lai Shichao, Li Yan

Affiliations: Department of Peritoneal Oncology, Beijing Century Tan Hospital, Capital Medical University; Department of Peritoneal Oncology, Tumor Center, Peking Union Medical College Hospital, Tsinghua University; Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University; Department of General Surgery, Shijiazhuang People’s Hospital.

Corresponding author: Li Yan, Email: liyansd2@163.com

Abstract

Objective: Based on multicenter data, to evaluate the long-term survival, perioperative severe adverse events, and prognostic risk factors in patients with peritoneal pseudomyxoma (PMP) treated with cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC).

Methods: This study was a retrospective observational study. Based on a multicenter collaborative database, we included the clinical and pathological data of 940 patients with peritoneal malignant mesothelioma (PMP) who underwent CRS plus HIPEC between January 2004 and November 2025, drawn from four hospitals within the Peritoneal Oncology Specialist Alliance: Beijing Century Tan Hospital affiliated to Capital Medical University (n = 532), Beijing Tsinghua Changgeng Hospital affiliated to Tsinghua University (n = 388), Zhongnan Hospital of Wuhan University (n = 18), and Shijiazhuang People’s Hospital (n = 2). We recorded long-term survival outcomes and the incidence of severe perioperative adverse events in this cohort, and used Cox regression to identify independent prognostic risk factors, assess interaction effects, and perform stratified joint-effect analyses.

Results: The cohort comprised 418 males (44.5%) and 522 females (55.5%), with 348 patients aged ≥60 years (37.0%). Pathological histologic subtypes were as follows: acellular mucinous type, 20 cases (2.1%); low-grade PMP, 511 cases (54.4%); high-grade PMP, 302 cases (32.1%); and high-grade PMP with signet-ring cell features, 107 cases (11.4%). A total of 587 patients (62.4%) underwent CRS plus HIPEC for the first time. Mean operative duration was 592 minutes (range, 120–1,080 min). Peritoneal cancer index (PCI) scores ≥20 were observed in 695 patients (73.9%), and cytoreductive completeness (CC) scores of 2–3 were recorded in 434 patients (46.2%). The incidence of severe perioperative adverse events was 27.0% (254/940). Median follow-up was 39.6 months (range, 0.5–254.6), and median overall survival (OS) was 116.7 months (95% CI, 99.2–134.1). Multivariate Cox regression analysis identified the following independent prognostic factors: body mass index (HR=0.92, P<0.01), history of abdominal surgery (HR=0.40, P<0.01), number of organs resected (HR=0.58, P<0.01), PCI score (HR=1.65, P=0.04), CC score (HR=1.37, P=0.03), intraoperative blood loss (HR=1.00, P=0.03), pathological subtype (HR=1.90, P<0.01), Ki‑67 index (HR=1.67, P=0.01), preoperative carcinoembryonic antigen (CEA) level (HR=1.45, P=0.03), preoperative carbohydrate antigen 125 (CA 125) level (HR=2.31, P<0.01), postoperative CEA level (HR=1.45, P=0.03), and lymph node metastasis (HR=1.88, P<0.01). Interaction analyses further revealed that patients with PCI ≥20 and a CC score of 2–3 exhibited an elevated risk of death (HR=2.32, 95% CI, 1.46–3.67, P<0.01); those with normal preoperative CEA levels and ≥2 organ resections had a reduced risk of death (HR=0.31, 95% CI, 0.15–0.62, P<0.01); and patients with Ki‑67 >15% and normal preoperative CEA levels faced an increased risk of death (HR=6.34, 95% CI, 1.50–26.84, P=0.03). All these interactions were statistically significant.

Conclusion: CRS plus HIPEC can confer prolonged survival benefits to patients with PMP, and tumor burden, the quality of cytoreduction, the proliferation index, tumor markers, and the number of organ resections are independently associated with patient prognosis.

Pseudomyxoma peritonei (PMP) is a malignant neoplastic syndrome characterized by the accumulation and redistribution of mucin within the peritoneal cavity, clinically manifesting as mucinous ascites, peritoneal implantation, omental plaques, and ovarian involvement. PMP is classified as a rare disease, with an incidence of 2–4 per million [1]. According to the Peritoneal Surface Oncology Group International (PSOGI) and domestic expert consensus, a comprehensive treatment strategy centered on cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) constitutes the standard approach for PMP, significantly improving survival outcomes. The median overall survival (OS) exceeds 100 months, with 3-year disease-specific survival (DSS) rates reaching 70.9% and 5-year DSS rates at 59.5% [2–5].

Several domestic cancer centers have initiated prognostic studies on patients with peritoneal malignant mesothelioma (PMP) treated with CRS plus HIPEC; however, most of these studies remain single-center, small-sample in nature and lack long-term follow-up data as well as robust multivariate analyses incorporating key clinicopathological factors. Drawing on a multi-center collaborative database, this study systematically evaluates the long-term survival outcomes and perioperative serious adverse events (SAEs) associated with CRS plus HIPEC for PMP, while identifying independent prognostic factors influencing overall survival and their interactions. The findings aim to provide real-world evidence to inform clinical risk stratification and perioperative management.

Materials and Methods

I. Research Subjects

This study is a retrospective observational study.

Indications for CRS plus HIPEC in patients with PMP: (1) Pathological histology and/or cytology confirms the diagnosis of PMP; (2) Karnofsky Performance Status score (KPS) ≥ 60; (3) Peripheral white blood cell count ≥ 3.5 × 10^9/L and platelet count ≥ 80 × 10^9/L; (4) Hepatic, renal, and major organ functions are sufficient to tolerate surgery.

Contraindications: (1) Preoperative routine examinations reveal distant metastases to the lungs, brain, bones, liver, or other sites; (2) Total bilirubin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) exceed 2 times the upper limit of normal (ULN); (3) Serum creatinine exceeds 1.2 times the ULN; (4) Imaging studies demonstrate marked mesenteric contracture; (5) The patient’s general condition and the function of vital organs are insufficient to tolerate major surgery.

Based on the aforementioned criteria and utilizing a multi-center, jointly developed database, we included the clinical and pathological data of 940 patients with peritoneal malignant tumors who underwent CRS plus HIPEC between January 2004 and November 2025 at four hospitals within this specialized peritoneal oncology alliance: 532 cases from Beijing Century Tan Hospital affiliated with Capital Medical University, 388 cases from Peking Union Medical College Hospital–Tsinghua University, 18 cases from Zhongnan Hospital of Wuhan University, and 2 cases from Shijiazhuang People’s Hospital. The patients’ clinical and pathological characteristics are presented in Table 1. This study protocol was approved by the Ethics Committee of Beijing Century Tan Hospital [Approval No.: Research Ethics Review No. (28) of 2015], and all patients provided informed consent.

II. Treatment Methods

1. CRS + HIPEC: This procedure is performed by a specialized team dedicated to the treatment of peritoneal cancer. Following laparotomy and exploration, the peritoneal cancer index (PCI) is assessed, followed by maximal cytoreductive surgery, which includes resection of the primary tumor and any involved tissues or organs, lymph node dissection, and removal of the invaded peritoneum, with evaluation of the completeness of cytoreduction (CC) [6]. After completing CRS, HIPEC is administered: 120 mg of cisplatin combined with 120 mg of docetaxel or 30 mg of mitomycin C is added to 3 liters of normal saline, maintained at a temperature of (43 ± 0.5)°C, with an infusion rate of 600 mL/min, for a continuous perfusion lasting 60 minutes. Following HIPEC, gastrointestinal reconstruction is performed, hemostasis is achieved, and the abdomen is closed. The patient is then transferred to the intensive care unit for close monitoring; once vital signs are stable, the patient is moved to a regular ward for continued observation and supportive care.

2. Adjunctive therapy: (1) For patients achieving complete CRS (CC 0 or 1): in the absence of mucinous components and with low-grade PMP, regular follow-up is recommended; for high-grade PMP, systemic chemotherapy with either the FOLFOX regimen (5-fluorouracil + leucovorin + oxaliplatin) or the FOLFIRI regimen (5-fluorouracil + leucovorin + irinotecan) for six cycles. (2) For patients who do not achieve complete CRS, regardless of histologic subtype, administer systemic FOLFOX or FOLFIRI chemotherapy combined with bevacizumab targeted therapy for six cycles.

III. Observation Indicators and Evaluation Criteria

The primary outcome measure of this study is overall survival (OS), while other observed data include surgical details related to CRS plus HIPEC, perioperative treatment regimens, and the incidence of adverse events.

The perioperative period was defined as the time from the day of CRS plus HIPEC to 30 days postoperatively. Adverse events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 5.0; grades 3–5 were classified as SAEs [7]. Overall survival (OS) was defined as the interval from the day of CRS plus HIPEC to death (from any cause) or the date of the last follow-up; for survivors, follow-up continued until the date of the last visit and was censored at that time.

IV. Follow-up Methods

Follow-up records primarily include general condition, survival status, and information on repeat examinations (such as imaging studies and tumor markers). Follow-up is conducted mainly through outpatient visits, supplemented by telephone calls. Within the first year after surgery, follow-up occurs every 3 months; during the subsequent 3 years, it is performed every 6 months; and thereafter, annual follow-up is scheduled. The final standardized telephone follow-up date is November 30, 2025.

V. Statistical Methods

Data analysis was performed using SPSS 25.0, R (version 5.2.1), and RStudio (version 2025.05.1). Continuous variables are presented as median (range), and categorical variables are expressed as number (percentage). Univariate and multivariate Cox regression models were used to identify prognostic factors, and interaction effects among independent prognostic factors were examined. Kaplan–Meier curves were constructed to depict survival outcomes. A P-value less than 0.05 was considered statistically significant.

Result

I. Intraoperative and Postoperative Course

The total operative duration for the entire cohort was 592 (120–1,080) minutes; 695 patients (73.9%) had a PCI score ≥20. Intraoperative details for all patients are presented in Table 2. Among the 940 PMP patients, 254 (27.0%) experienced perioperative serious adverse events (SAEs), including 113 (12.0%) involving the respiratory system, 74 (7.9%) related to infection, 63 (6.7%) affecting the gastrointestinal system, 30 (3.1%) involving the cardiovascular system, 22 (2.3%) impacting the urinary system, 18 (1.9%) due to bone marrow suppression, and 5 (0.5%) with neurological complications. Within 30 days postoperatively, 17 patients (1.8%) died; of these, 15 (1.6%) succumbed to gastrointestinal SAEs, and 2 (0.2%) died from cardiovascular SAEs.

II. Analysis of Survival Factors

The median follow-up duration for the entire cohort was 39.6 months (range, 0.5–254.6), with a 100% follow-up rate. Among the 940 patients, the median overall survival (OS) was 116.7 months (95% confidence interval: 99.2–134.1) (Figure 1). Univariate analysis identified 25 factors associated with mortality; these were incorporated into multivariate analysis, which yielded 12 independent prognostic factors (all P < 0.05), including body mass index (BMI), surgical history, percutaneous coronary intervention (PCI), cardiac comorbidities (CC), intraoperative blood loss, number of organs resected, pathological subtype, Ki‑67 index, preoperative carcinoembryonic antigen (CEA), preoperative carbohydrate antigen 125 (CA 125), postoperative CEA levels, and lymph node metastasis (Table 3).

Further analysis of the aforementioned 12 independent prognostic factors revealed significant interactions among the following three pairs: PCI × CC, preoperative CEA × number of organs resected, and preoperative CEA × Ki‑67 (Table 4). In the PCI × CC interaction, the highest mortality risk was observed in patients with PCI ≥ 20 and CC grade 2–3 (HR = 2.32; 95% CI: 1.46–3.67; P = 0.02) (Figure 2A). For the preoperative CEA × number of organs resected interaction, the lowest mortality risk was seen in patients with normal preoperative CEA and ≥ 2 organs resected (HR = 0.31; 95% CI: 0.15–0.62; P = 0.04) (Figure 2B). Lastly, in the preoperative CEA × Ki‑67 interaction, the highest mortality risk was associated with patients who had normal preoperative CEA and a Ki‑67 level > 15% (HR = 6.34; 95% CI: 1.50–26.84; P = 0.03) (Figure 2C).

Discussion

This study, based on data from 940 PMP patients across multiple centers, constructed multivariate Cox regression and stratified survival models to conduct interaction analyses. The median overall survival (OS) for the entire cohort was 116.7 months. Multivariate analysis identified BMI, surgical history, PCI, CC, intraoperative blood loss, pathological subtype, Ki‑67 index, tumor markers, lymph node metastasis, and the number of organs resected as independent prognostic factors. Significant interactions were observed between PCI and CC, preoperative CEA and the number of organs resected, and preoperative CEA and Ki‑67, suggesting that tumor burden, the extent of debulking, biological aggressiveness, and the scope of surgery exert combined effects on prognosis.

PMP, as a rare tumor syndrome, is often diagnosed at a relapsed or advanced stage, resulting in limited long-term survival. CRS plus HIPEC represents the standard treatment for improving outcomes in PMP patients [2,4–5]. In a single-center cohort of 175 cases reported by Narasimhan et al. [5], the median overall survival (OS) after CRS plus HIPEC was approximately 100 months, with a 5-year OS rate of about 71%. A 2023 study involving 1,102 PMP patients demonstrated a median OS of 16.5 years (95% CI: 13.7–19.2) [8]. In the present study, the median OS was 116.7 months, which is broadly consistent with these findings.

PCI is a standardized tool for assessing peritoneal tumor burden [2]; the CC score reflects the quality of cytoreductive surgery [9]. The results of this study demonstrate that a PCI ≥ 20 and a CC score of 2–3 are associated with poor prognosis. Interaction analysis indicates that patients with a high PCI who achieve complete cytoreduction (CC 0–1) can derive long-term survival benefits, whereas those who fail to attain satisfactory cytoreduction have a poorer prognosis. Therefore, preoperative assessment of tumor resectability is essential; patients with a high PCI but expected to achieve only a CC of 0–1 should undergo standardized surgical procedures at specialized peritoneal cancer centers. Previous studies have shown that tumor markers correlate with disease burden, adequacy of cytoreduction, and prognosis, and may also be influenced by peritoneal origin, ascites volume, and peritoneal dissemination burden [10–13]. Although Chandrakumaran et al. [8] confirmed that both surgical resection status and tumor markers are independent prognostic factors for progression-free survival, they did not conduct further interaction analyses. In this study, we observed a significant interaction between preoperative CEA levels and the number of organs resected: patients with normal preoperative CEA were more likely to achieve adequate cytoreduction. The Ki‑67 index reflects proliferative activity, correlates with histopathological subtype and prognosis, and can help refine risk stratification in high‑risk populations [14]. Our findings confirm that an elevated Ki‑67 index is associated with poor prognosis. Interaction analysis revealed a statistically significant association between Ki‑67 and preoperative CEA (P = 0.03); among patients with normal preoperative CEA but a Ki‑67 > 15%, the risk of death was markedly increased (HR = 6.34), suggesting that patients with normal preoperative CEA yet high tumor proliferative activity are prone to unfavorable outcomes.

This study simultaneously documented and analyzed both chemotherapy‑related and surgical complications, using the CTCAE and Clavien–Dindo classification systems [7, 15–16]. The results indicate that patients with PMP may experience venous thromboembolism, respiratory complications, gastrointestinal leaks, and intestinal obstruction, suggesting that perioperative management should prioritize key interventions such as thromboprophylaxis, respiratory rehabilitation, nutritional support, and early restoration of bowel function. Currently, the enhanced recovery after surgery (ERAS) paradigm has been increasingly applied to patients undergoing CRS and HIPEC [17–18]. Therefore, for patients with a substantial tumor burden or those expected to undergo extensive surgical trauma, it is essential to further strengthen ERAS protocols and comprehensive complication management to reduce the incidence of adverse perioperative events.

This study also has several limitations. First, retrospective studies are inherently subject to selection bias and information bias. Second, given the long follow-up period, there may be temporal heterogeneity across centers in perioperative management, systemic therapy strategies, and pathological classification criteria. Third, some variables are missing, highlighting the need to improve data completeness and consistency in prospective studies. Future research could, within a multicenter framework, integrate molecular subtyping, radiomics, and pathomics to develop comprehensive predictive models that simultaneously capture tumor burden, surgical quality, and biological aggressiveness, thereby better guiding the selection of surgical indications, the formulation of perioperative systemic therapy strategies, and the intensity of follow-up.

In summary, this study demonstrates that both tumor biological characteristics and key surgical parameters are closely associated with long-term survival. Achieving satisfactory cytoreduction remains central across varying levels of tumor burden. Clinical risk assessment should employ a multi‑factorial stratification approach to identify high‑risk patients and optimize follow-up and perioperative management.

Conflict of interest 　All authors declare that there are no conflicts of interest in this study.

Author Contributions: Cui Yurun: research conception, methodology, statistical analysis, data organization, data collection, data visualization, and drafting the initial manuscript; Ma Ru: drafting the initial manuscript, reviewing and revising it. Ren Guangliang: data organization and data collection; Yang Rui: data organization and data collection; Yang Xiaojun: data organization and data collection. An Songlin: data organization and data collection; Wu Guobin: data organization and data collection; Li Xinbao: data organization and data collection. Lai Shichao: data organization and data collection; Li Yan: research conception, supervision and guidance, project management, and reviewing and revising the manuscript.

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Contributed by: Cui Yurun

Reviewed by: Zhu Wenjie

Approved and issued by: Wang Ting