Highlights
– A 2025 Cochrane review including nine randomized trials (829 participants) evaluated intraperitoneal chemotherapy (IPC) for both prophylaxis and treatment of peritoneal disease in gastric cancer.
– IPC (mostly hyperthermic intraperitoneal chemotherapy, HIPEC) showed an apparent survival benefit (prophylactic HR 0.66; therapeutic HR 0.52), but certainty is very low because of risk of bias, indirectness, and imprecision.
– Safety, quality of life, and comprehensive adverse event reporting were sparse; current evidence is insufficient to support routine clinical use outside trials, and further high‑quality RCTs are needed, especially outside Asia.
Background: clinical problem and rationale
Gastric cancer remains a leading cause of cancer mortality worldwide. Peritoneal metastasis is a common pattern of spread associated with poor prognosis and limited responsiveness to systemic therapy. Free tumor cells and microscopic peritoneal seeding may occur at presentation or after curative gastrectomy. Intraperitoneal chemotherapy (IPC) — delivered either as heated perfusion during surgery (HIPEC) or as normothermic intraperitoneal chemotherapy (NIPEC) — attempts to expose the peritoneal surface to high local drug concentrations while minimizing systemic toxicity. IPC has been investigated both as a prophylactic adjunct to radical resection in patients at high risk for peritoneal recurrence and as a therapeutic modality combined with cytoreductive surgery (CRS) for established peritoneal metastases.
Study design and methods (what this review evaluated)
The authors performed a systematic review and meta‑analysis of parallel randomized controlled trials (RCTs) comparing IPC versus no IPC in two clinical contexts: (1) prophylactic IPC added to radical surgery in patients considered at high risk for peritoneal metastasis; and (2) therapeutic IPC added to CRS in patients with confirmed peritoneal metastasis. Trials were included only if postoperative systemic chemotherapy was provided. A comprehensive search of major databases and trial registries was conducted up to 12 June 2025, and trial trustworthiness was appraised using the TRACT checklist. Outcomes of interest included overall survival (OS), surrogate survival endpoints (disease‑free survival [DFS] or progression‑free survival [PFS]), serious adverse events (SAEs), total adverse events (AEs), quality of life (QOL), anastomotic leakage, and intra‑abdominal abscess. Risk of bias was assessed using RoB 2, and certainty of evidence was graded with GRADE.
Included trials and patient populations
Nine RCTs (829 participants) met inclusion criteria. Seven trials (656 patients) examined prophylactic IPC; two trials (173 patients) evaluated therapeutic IPC combined with CRS. Most trials were conducted in China (seven trials). IPC modality was predominantly HIPEC (seven trials), with one trial of NIPEC among prophylactic studies. Follow‑up periods ranged widely (0.2 to 83.5 months). The authors judged most outcomes to carry some concerns or a high risk of bias.
Key findings
Overall survival
– Prophylactic IPC (versus surgery alone): Pooled data from six trials (522 participants) suggested a possible OS benefit with IPC (hazard ratio [HR] 0.66; 95% CI 0.48–0.91). Evidence certainty: very low. Interpretation: while the point estimate favors IPC, confidence intervals and trial limitations make this finding uncertain.
– Therapeutic IPC with CRS (versus CRS alone): Two trials (173 participants) reported OS benefit (HR 0.52; 95% CI 0.28–0.96). Evidence certainty: very low. Interpretation: a stronger point estimate favoring IPC is observed for established peritoneal disease, but small sample size and methodological limitations persist.
Disease‑free / progression‑free survival and tumor control
– Prophylactic DFS: One trial (134 participants) found little clear effect on DFS (HR 0.85; 95% CI 0.40–1.82). Very low‑certainty evidence.
– Therapeutic PFS: One trial (105 participants) reported an increase in median PFS from 3.5 to 7.1 months (P = 0.047) with IPC; however, this single small study yields very low‑certainty evidence.
Safety and adverse events
– Serious adverse events: Limited reporting precluded robust conclusions. One trial (68 patients) suggested little clear difference in SAEs (RR 1.25; 95% CI 0.37–4.26). Very low‑certainty evidence.
– Total adverse events and intra‑abdominal abscess: Most trials did not report comprehensive AE profiles. For intra‑abdominal abscess, data were sparse and imprecise (one trial; RR 2.04; 95% CI 0.19–21.80).
– Anastomotic leakage: Pooled data across trials showed no clear increase in leakage with IPC (prophylactic RR 1.68; 95% CI 0.43–6.58; therapeutic RR 0.90; 95% CI 0.15–5.49), but confidence intervals are wide and evidence is very uncertain.
Quality of life
Few data were available. One trial reported no statistically significant difference in QOL measures (EORTC QLQ‑C30 and QLQ‑STO22), but numbers and reporting were insufficient to draw firm conclusions.
Authors’ overall conclusions
The Cochrane review concludes that current RCT evidence for IPC in gastric cancer is limited and of very low certainty. There are signals suggesting possible survival benefits for both prophylactic and therapeutic IPC (primarily HIPEC), but these findings are highly uncertain. Important safety and QOL data are lacking. Therefore, routine clinical adoption cannot be recommended on the basis of current evidence; high‑quality, adequately powered RCTs with thorough safety and QOL reporting are required, particularly in non‑Asian populations.
Expert commentary and clinical context
Biologic plausibility underlies IPC: intraperitoneal delivery generates high locoregional drug exposure and, with heat (HIPEC), may enhance cytotoxicity and drug penetration. However, clinical application is heterogeneous — choice of cytotoxic agent, carrier solution, temperature, duration, timing relative to surgery, patient selection (microscopic risk vs macroscopic disease), and completeness of cytoreduction are all variable and influence outcomes.
Several caveats temper enthusiasm. First, the trials are small and largely conducted in a single geographic region, limiting generalizability. Second, selection criteria and concurrent systemic therapy regimens varied; the review excluded trials without postoperative systemic therapy, but regimens differed. Third, safety reporting was inconsistent — a critical limitation because perioperative morbidity from CRS + HIPEC can be substantial in some series. Finally, many ongoing trials could materially alter pooled estimates when reported.
From a guideline perspective, recommendations have been inconsistent internationally; some centers and guidelines suggest selective use of CRS + HIPEC within clinical trials or for carefully selected patients with limited peritoneal disease and complete cytoreduction, whereas routine prophylactic HIPEC after gastrectomy is not universally endorsed. The Cochrane findings reinforce the need for consensus protocols and robust randomized data before broader implementation.
Practical implications for clinicians
– Do not adopt prophylactic or therapeutic IPC as standard of care for all patients with gastric cancer based on current evidence; consider IPC primarily within clinical trials or multidisciplinary programs experienced in CRS/HIPEC.
– When evaluating a patient for IPC, ensure rigorous selection (PCI assessment, potential for complete cytoreduction), perioperative support capabilities, and informed discussion on the uncertain balance of benefits and harms.
– Advocate for comprehensive trial designs that include standardized IPC protocols, prespecified systemic therapy regimens, robust AE and QOL reporting, and enrollment across diverse populations.
Research gaps and future directions
– Larger, high‑quality RCTs with centralized randomization, blinded outcome assessment where possible, and adherence to reporting standards (CONSORT) are needed.
– Trials should predefine IPC technical parameters (drug, temperature, duration), stratify by disease burden (e.g., peritoneal cancer index), and integrate modern systemic regimens, including perioperative chemotherapy and targeted therapies where appropriate.
– Safety monitoring must be comprehensive; QOL endpoints should be prioritized to capture tradeoffs between survival and treatment burden.
– Inclusion of multiethnic cohorts is essential to assess generalizability beyond East Asia.
Conclusion
Intraperitoneal chemotherapy — especially HIPEC — for gastric cancer shows encouraging survival point estimates in randomized trials but the available evidence is very low in certainty due to small, heterogeneous trials with methodological limitations and sparse safety and QOL data. Current data do not support routine adoption outside well‑conducted clinical trials. Multidisciplinary care teams should discuss IPC only in specialized centers and within research frameworks while awaiting results from larger, definitive studies.
Funding and trial registration
This Cochrane review was funded in part by the foundation of the National Natural Science Foundation of China (No. 82472926), the Foundation of Science & Technology Department of Sichuan Province (2023YFS0060; 23ZDYF2812), the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYJC21006; 2023HXFH005), and the Postdoctor Research Fund of West China Hospital, Sichuan University (2025HXBH063). Protocols are registered and available via doi: 10.1002/14651858.CD008157 (2009) and 10.1002/14651858.CD015698 (updated 2023).
References
Mu M, Cai Z, Hu Y, Liu X, Zhang B, Chen Z, Hu J, Yang K. Intraperitoneal chemotherapy for gastric cancer. Cochrane Database Syst Rev. 2025 Oct 9;10(10):CD015698. doi: 10.1002/14651858.CD015698.pub2. PMID: 41065080; PMCID: PMC12509266.
