Oncology · Medical Literature
[Comment] Gastric cancer with peritoneal metastases: hype or hope for HIPEC?
Abstract
Gastric cancer remains a major cause of cancer mortality, and prognosis is particularly poor in individuals with peritoneal metastases.1,2 Although the integration of immunotherapy and targeted agents—such as trastuzumab or zolbetuximab—into systemic chemotherapy has improved survival in selected populations,3,4 treatment for these patients remains a clinical challenge, prompting the exploration of aggressive locoregional strategies.
Clinical relevance
In adults with resectable gastric adenocarcinoma and limited peritoneal metastases (Peritoneal Cancer Index <7) or tumor-positive peritoneal cytology, does the addition of gastrectomy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) to systemic therapy improve overall survival compared with systemic therapy alone? __SNAPSHOT__ {"studyDesign":"Editorial commentary (Comment) in The Lancet Oncology, written in response to and contextualizing the PERISCOPE II multicentre, randomised, controlled, phase 3 trial (Quik et al., Lancet Oncol, July 8, 2026). Only the abstract of the Comment is available; full text requires journal access.","setting":"European tertiary referral oncology centres (8 hospitals); PERISCOPE II enrolled patients across multiple European countries. Commentary authors are affiliated with French academic oncology institutions.","sampleSize":"PERISCOPE II (the indexed trial): n=101 (experimental arm [gastrectomy + CRS/HIPEC]: n=50–51; standard arm [systemic therapy]: n=50–51). Commentary itself does not enroll patients.","population":"Adults aged ≥18 years with resectable cT3 or cT4a gastric adenocarcinoma who had limited peritoneal metastases (Peritoneal Cancer Index [PCI] <7) or tumour-positive peritoneal cytology, or both, in the absence of disease progression after 3 or more cycles of systemic therapy. Patients with more extensive peritoneal disease (PCI ≥7) or non-adenocarcinoma histology were excluded.","intervention":"Gastrectomy plus cytoreductive surgery (CRS) and HIPEC (oxaliplatin 460 mg/m² at 41°C for 30 minutes plus docetaxel 50 mg/m² at 37°C for 90 minutes), administered following induction systemic chemotherapy (with or without immunotherapy or targeted agents, per tumour biomarker profile).","comparator":"Continuation of systemic chemotherapy alone (standard of care), which could include immunotherapy (checkpoint inhibitors) or targeted agents (trastuzumab, zolbetuximab) based on tumour biomarker status (HER2, claudin-18.2, combined positive score).","primaryOutcome":"Overall survival (OS), as defined in PERISCOPE II.","followUp":"Minimum follow-up of 6 months at the time of the commissioned interim analysis that triggered early reporting of final results; longer-term follow-up data not separately reported in the abstract.","fundingSource":"Non-profit/government: Dutch Cancer Society (KWF), Netherlands Organisation for Health Research and Development (ZonMW), Dutch Ministry of Health, Bengt Ihre Research Foundation, and Swedish Cancer Society. No industry funding declared for the trial. Some individual PERISCOPE II co-authors report consulting fees and/or research grants from Bristol Myers Squibb, AstraZeneca, Merck, Servier, and Amgen, unrelated to this intervention."}
Key findings
This article is an expert editorial Commentary, not a primary study; it does not report its own original data. Its core findings derive from contextualizing the PERISCOPE II phase 3 RCT, which it accompanies. In PERISCOPE II, gastrectomy with CRS and HIPEC provided no overall survival benefit compared with systemic therapy alone (median OS: 15.7 months [95% CI: 11.2–25.5] in the experimental arm vs. 16.3–16.6 months in the systemic therapy arm; HR 1.11 [95% CI: 0.70–1.77]; p=0.67). The per-protocol analysis showed a non-significant numerical trend favouring surgery (median OS 17.3 vs. 15.6 months; HR 0.66 [95% CI: 0.38–1.12]; p=0.12). Progression-free survival did not significantly differ between groups. The experimental strategy was associated with substantially higher serious adverse event rates: grade ≥3 AEs occurred in 42% of surgical patients versus 20% of systemic-therapy-only patients. Serious adverse events totalled 49 in the experimental arm (22 patients) versus 5 in the standard arm (3 patients; p<0.001), with ileus (35%) and anastomotic leakage (27%) among patients who underwent the protocol-defined surgery, and 3 treatment-related deaths (6%) in the experimental arm, attributed to ARDS, anastomotic leakage, and haemorrhage, versus 0 deaths in the standard arm. NNH for treatment-related death: approximately 17 (calculated, based on 3/50 experimental vs. 0/51 control). The commentary contextualises these negative results against the broader landscape of HIPEC in gastric cancer, including the GASTRIPEC-I phase 3 trial, which similarly showed no OS benefit (median OS 14.9 vs. 14.9 months; p=0.16) when CRS+HIPEC was compared with CRS alone, though PFS (7.1 vs. 3.5 months; p=0.047) and metastasis-free survival (10.2 vs. 9.2 months; p=0.0286) were significantly prolonged in the HIPEC arm of that trial.
Practice implications
This Commentary by Malka and Goéré, two experienced peritoneal oncology specialists, critically appraises a field that has long been characterised by enthusiasm driven largely by retrospective and non-randomised data. The PERISCOPE II trial—the first adequately powered, prospective RCT to directly compare gastrectomy plus CRS/HIPEC with systemic therapy alone in gastric cancer with limited peritoneal metastases—found no survival benefit and significantly greater harm in the surgical arm, including a 6% treatment-related mortality. These data directly challenge the premise that locoregional surgical intensification improves outcomes in this population. The findings apply specifically to Western patients with limited peritoneal disease (PCI <7) or positive cytology only; they cannot be extrapolated to Asian populations (where intraperitoneal chemotherapy approaches differ substantially), to patients with higher PCI scores, or to those receiving prophylactic HIPEC at the time of primary resection. The question of whether any molecular or clinicopathological subgroup might still benefit from HIPEC remains unanswered. Importantly, the trial was halted after an unplanned commissioned interim analysis, which introduces uncertainty about whether the final sample size achieved adequate power to detect smaller but potentially meaningful treatment effects. The Commentary also notes that systemic therapy has evolved—with immunotherapy and targeted agents now incorporated in eligible patients—further raising the bar for any locoregional strategy to demonstrate additive value. Only the abstract of the Commentary is available; specific arguments, subgroup analyses, or recommendations made within the full text cannot be independently verified or summarised here. __LIMITATIONS__ 1. Article type: This is a commentary/editorial, not a primary study; it generates no independent evidence. 2. PERISCOPE II sample size: 101 patients is modest for a phase 3 survival trial; the trial was stopped early based on an unplanned commissioned interim analysis, which may have reduced statistical power to detect small but real differences, and introduced potential bias in the stopping decision. 3. Minimum follow-up: 6 months minimum follow-up is short for a survival endpoint in a disease with median OS of 15–17 months; long-term outcomes (e.g., 2-year, 3-year OS) are not yet reported. 4. Protocol deviations: 13 of 50 patients in the experimental arm did not undergo CRS/HIPEC (disease progression or refusal), and 7 in the standard arm underwent CRS/HIPEC outside the protocol; this crossover complicates ITT interpretation and reduces internal validity. 5. Generalisability: Trial limited to Western European tertiary centres with high HIPEC expertise; results may not apply to Asian populations, higher-volume centres, or settings using different HIPEC regimens or systemic backbones. 6. Evolving systemic therapy: Systemic regimens varied across enrolment periods as immunotherapy and targeted agents were incorporated; this heterogeneity limits conclusions about the specific comparative value of HIPEC against modern optimised systemic therapy. 7. PCI threshold: Restriction to PCI <7 means findings do not address patients with moderate or extensive peritoneal disease. 8. Biomarker stratification: Whether HER2, claudin-18.2, or PD-L1 status modified the treatment effect was not reported in the abstract. 9. No industry sponsorship bias, but the unplanned commissioned interim analysis process (commissioned by the Dutch Health Ministry) introduces an unconventional stopping mechanism whose operating characteristics are not fully characterised. __BOTTOM_LINE_CATEGORY__ practice_changing __BOTTOM_LINE__ The PERISCOPE II phase 3 RCT, contextualised in this Lancet Oncology Commentary by Malka and Goéré, found that gastrectomy plus CRS/HIPEC added no overall survival benefit compared with systemic therapy alone in patients with limited gastric cancer peritoneal metastases (PCI <7), while more than doubling the rate of grade ≥3 adverse events and causing 3 treatment-related deaths in the surgical arm versus none in the systemic therapy arm. Systemic therapy—including immunotherapy and targeted agents when indicated—should remain the standard of care for this population. Gastrectomy, CRS, and HIPEC should not be offered outside the context of clinical trials until a patient subgroup that derives clear benefit can be prospectively identified.