Oncology · Medical Literature
[Articles] Systemic therapy, gastrectomy, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy versus systemic therapy alone for gastric cancer with limited peritoneal metastases (PERISCOPE II): final results of a multicentre, randomised, controlled, phase 3 trial after an unplanned commissioned interim analysis
Abstract
Gastrectomy with cytoreductive surgery and HIPEC provided no survival benefit in patients with gastric cancer and limited peritoneal metastases compared with systemic therapy alone.
Clinical relevance
In adults with resectable gastric adenocarcinoma and limited peritoneal metastases (Peritoneal Cancer Index <7) or tumor-positive peritoneal cytology who have not progressed on systemic therapy, does the addition of gastrectomy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) to systemic therapy improve overall survival compared with continuation of systemic therapy alone? __SNAPSHOT__ {"studyDesign":"Multicentre, open-label, randomised, controlled, phase 3 trial (PERISCOPE II); final analysis triggered by an unplanned commissioned interim analysis","setting":"Eight European tertiary referral hospitals (Netherlands, Finland, Sweden, Denmark); conducted under European clinical trial frameworks","sampleSize":"n=102 randomised (experimental arm [gastrectomy + CRS/HIPEC]: n=51; standard arm [systemic therapy alone]: n=51)","population":"Adults aged ≥18 years with resectable cT3 or cT4a gastric adenocarcinoma and limited peritoneal metastases (Peritoneal Cancer Index [PCI] <7) and/or tumor-positive peritoneal cytology, with no disease progression after ≥3 cycles of systemic therapy (chemotherapy ± immunotherapy or targeted therapy per tumour characteristics)","intervention":"Gastrectomy combined with cytoreductive surgery and HIPEC (oxaliplatin 460 mg/m² at 41°C plus docetaxel 50 mg/m² at 37°C, as established in PERISCOPE I), following systemic therapy","comparator":"Continuation of systemic therapy alone (fluoropyrimidine-based chemotherapy ± immunotherapy or targeted therapy according to tumour biomarker status [CPS ≥5, HER2 positivity, or claudin-18.2 expression])","primaryOutcome":"Overall survival (OS)","followUp":"Minimum follow-up of 6 months at time of analysis; exact median follow-up not reported in the available abstract","fundingSource":"Government/non-profit: Dutch Cancer Society, Netherlands Organisation for Health Research and Development, Dutch Ministry of Health, Bengt Ihre Research Foundation, Swedish Cancer Society, and a named individual donor (Henk Boot). No industry funding reported."}
Key findings
The trial enrolled 102 patients and found no statistically significant difference in overall survival between treatment arms. Median OS was 16.6 months in the systemic therapy (standard) arm versus 15.7 months in the experimental (gastrectomy + CRS/HIPEC) arm (HR 1.10, p=0.70; 95% CI not reported in the abstract). Progression-free survival (PFS) also did not differ significantly: 7.6 months (standard) vs. 9.3 months (experimental) (HR 0.93, p=0.73; 95% CI not reported in the abstract). NNT is not calculable given the absence of survival benefit. Toxicity was substantially and clinically meaningfully worse in the experimental arm: grade ≥3 adverse events occurred in 42% of experimental patients vs. 20% of standard arm patients. Serious adverse events occurred in 44% vs. 8% (21/51 vs. 4/51 [approximately], per conference data). Among the 37 patients who underwent the protocol-defined surgical procedure, post-operative ileus occurred in 35% and anastomotic leakage in 27%. Three treatment-related deaths occurred within 100 days of randomisation, all in the experimental arm, attributed to acute respiratory distress syndrome, anastomotic leakage, and bleeding. Notably, 13 patients in the experimental arm did not undergo CRS/HIPEC due to disease progression or patient refusal, and 7 patients in the standard arm underwent CRS/HIPEC outside the protocol. A per-protocol analysis yielded a median OS of 17.3 months (experimental) vs. 15.6 months (standard) (HR 0.66, 95% CI 0.38–1.12, p=0.12), which remained non-significant but directionally favourable—this result should be interpreted cautiously given substantial non-adherence and potential selection bias.
Practice implications
PERISCOPE II is, to date, the first and only adequately designed prospective multicentre RCT to directly compare gastrectomy + CRS/HIPEC against standard-of-care systemic therapy in gastric cancer with limited peritoneal metastases. The trial clearly established that the experimental strategy confers no overall survival advantage and is associated with substantially greater toxicity, including a 3-fold increase in serious adverse events and three treatment-related deaths. The findings apply to patients with resectable cT3/T4a gastric adenocarcinoma with a PCI <7 and/or positive peritoneal cytology who have not progressed on modern systemic therapy; they may not apply to patients with more extensive peritoneal disease, those ineligible for systemic therapy, or those with HER2-positive or claudin-18.2-positive tumours treated with current targeted/immunotherapy regimens, who were underrepresented or incompletely characterised in this trial. The per-protocol signal (HR 0.66) hypothetically favouring surgery in those who actually completed the procedure should not be used to justify routine practice change, as it is subject to survivor and completion bias. The trial was stopped early by an unplanned commissioned interim analysis, which may have limited power to detect a modest true benefit and introduces interpretive caution. Importantly, although only the abstract is available for full review, the direction, magnitude of harm, and absence of any OS or PFS signal are internally consistent and clinically unambiguous. Systemic therapy—including modern chemotherapy with immunotherapy and/or targeted agents—remains the appropriate standard of care. The authors and trial conclusions explicitly state that gastrectomy, CRS, and HIPEC should not be offered outside clinical trials until a benefiting patient subgroup can be identified. __LIMITATIONS__ 1. Small sample size (n=102): the trial was stopped early after an unplanned commissioned interim analysis, limiting statistical power to detect a modest but potentially meaningful survival benefit and precluding robust subgroup analyses. 2. Non-adherence: 13 patients randomised to the experimental arm did not undergo CRS/HIPEC, and 7 controls underwent the procedure outside the protocol, introducing substantial ITT dilution and contamination. 3. Open-label design: blinding was not feasible given the surgical intervention, introducing potential performance and detection bias in AE reporting and supportive care decisions. 4. Generalisability: conducted exclusively in highly specialised European tertiary centres, limiting applicability to lower-volume settings. 5. Evolving systemic therapy landscape: the control arm regimen evolved during the trial period to include immunotherapy and targeted agents; heterogeneity in the systemic therapy administered across the trial period may confound comparisons. 6. Surrogate endpoints: PFS was a secondary endpoint; no quality-of-life data are reported in the abstract, a critical gap given the substantially higher surgical morbidity in the experimental arm. 7. Early stopping: unplanned interim analysis triggering trial closure raises concerns about alpha inflation and introduces uncertainty about whether the null result reflects a true absence of benefit or insufficient power. 8. Abstract-only review: full data, including stratification variables, exact follow-up duration, OS confidence intervals, and QoL analyses, are not available for independent verification. __BOTTOM_LINE_CATEGORY__ practice_changing __BOTTOM_LINE__ PERISCOPE II, the first RCT to directly compare gastrectomy + CRS/HIPEC with systemic therapy alone in gastric cancer patients with limited peritoneal metastases, demonstrated no improvement in overall survival (mOS 15.7 vs. 16.6 months, HR 1.10, p=0.70) with significantly greater toxicity, including a doubling of grade ≥3 adverse events and three treatment-related deaths in the surgical arm. These results do not support the routine use of gastrectomy, CRS, and HIPEC for this population outside of a clinical trial setting. Systemic therapy, incorporating modern immunotherapy and targeted agents as appropriate, remains the standard of care.