PERISCOPE II: Gastrectomy, Cytoreductive Surgery, and HIPEC Do Not Improve Survival in Gastric Cancer With Limited Peritoneal Metastases
Key Insights
The phase III PERISCOPE II trial found that adding gastrectomy, cytoreductive surgery, and HIPEC to systemic therapy did not improve overall survival vs systemic therapy alone in gastric cancer (search) with limited peritoneal metastases (HR 1.10, p=0.70).
Median overall survival was 15.7 months in the experimental group vs 16.6 months in the systemic therapy group after a median follow-up of 67 months.
The intensive surgical approach was associated with substantially higher morbidity, with grade ≥3 adverse events in 42% of experimental patients vs 20% in the systemic therapy group, and three treatment-related deaths.
The final results of the phase III PERISCOPE II trial, published in The Lancet Oncology on July 8, 2026, demonstrate that adding gastrectomy, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy (HIPEC) to systemic therapy does not improve overall survival in patients with gastric cancer (search) and limited peritoneal metastases. The intensive surgical strategy was also associated with substantially higher morbidity and three treatment-related deaths, leading investigators to conclude that this approach should not be considered standard treatment.
Study Design and Patient Population
PERISCOPE II was a European, multicenter, randomized, controlled phase III trial conducted across eight tertiary referral hospitals with experience in gastric cancer (search) surgery and HIPEC. The study enrolled adults with histologically confirmed, resectable cT3 or cT4a gastric adenocarcinoma and limited peritoneal disease, defined as a Peritoneal Cancer Index below 7, tumor-positive peritoneal cytology, or both. Patients were required to have no clinical or radiological disease progression after receiving at least three cycles of systemic therapy, with absence of extraperitoneal metastases confirmed by CT imaging.
Eligible patients were randomly assigned in a 1:1 ratio to continued systemic therapy (standard group) or gastrectomy with cytoreductive surgery and HIPEC (experimental group). The HIPEC regimen consisted of intraperitoneal oxaliplatin at 460 mg/m² administered at 41°C for 30 minutes, followed by docetaxel at 50 mg/m² administered at 37°C for 90 minutes. The primary endpoint was overall survival, with secondary endpoints including progression-free survival, treatment-related toxicity, and health-related quality of life.
Enrollment and Early Closure
Between November 6, 2017, and August 21, 2024, 102 patients were enrolled, with 51 assigned to each treatment group. One patient in the experimental group was excluded after an unexpected postoperative diagnosis of a neuroendocrine tumor, leaving 101 patients in the final intention-to-treat analysis. The median age was 60 years, 57% of participants were men, and 85% were White.
The study was initially designed to enroll 106 patients, but the target sample size was increased to 226 patients in March 2020. However, an unplanned interim analysis for futility was commissioned by the Dutch National Health Care Institute (search). Following a recommendation from the data and safety monitoring board, enrollment was stopped prematurely on September 17, 2024. Simulations estimated a 21% conditional probability that either treatment group would demonstrate a statistically significant survival advantage if enrollment continued to the planned sample size.
Among the 50 patients assigned to the experimental group, 37 (74%) underwent the protocol-defined procedure. Ten patients were found intraoperatively to have extensive peritoneal disease precluding the procedure, one died before surgery, and two declined surgery. Seven patients in the systemic therapy group crossed over to receive cytoreductive surgery and HIPEC outside the trial protocol in nonparticipating countries.
Overall Survival: No Significant Difference
After a median follow-up of 67 months, median overall survival was 16.6 months in the continued systemic therapy group and 15.7 months in the gastrectomy, cytoreductive surgery, and HIPEC group. The hazard ratio for death was 1.10 (95% CI, 0.69–1.74; p = 0.70). There were 39 deaths in each treatment group.
Prespecified subgroup analyses did not identify any group with a statistically significant survival advantage from the experimental treatment. Among the 15 patients with tumor-positive cytology alone, the hazard ratio for death was 0.40; among the 86 patients with macroscopic peritoneal metastases, the hazard ratio was 1.19. However, the interaction between treatment and the extent of peritoneal disease was not statistically significant, and histological subtype did not significantly modify the effect of treatment on overall survival.
Progression-Free Survival
Median progression-free survival was 7.6 months in the systemic therapy group and 9.3 months in the experimental group, with a hazard ratio for progression or death of 0.93 (95% CI, 0.60–1.43; p = 0.73). Disease progression occurred in 42 of 51 patients in the systemic therapy group and 37 of 50 patients in the experimental group.
In a post hoc per-protocol analysis, median progression-free survival was 7.2 months with systemic therapy and 13.2 months with the experimental treatment (HR 0.51; p = 0.0092). However, the investigators emphasized that these findings require careful interpretation, as patients found to have more extensive peritoneal disease during surgery were excluded from the experimental group in the per-protocol analysis, whereas comparable patients could have remained in the systemic therapy group. This loss of balance limits causal interpretation and does not alter the negative findings from the randomized intention-to-treat analysis.
Safety and Toxicity
The experimental strategy was associated with substantially greater toxicity. Grade 3 or worse adverse events occurred in 10 of 51 patients (20%) in the systemic therapy group compared with 21 of 50 patients (42%) in the experimental group. The most common grade 3 or worse adverse events in the experimental group were anemia and elevated liver enzymes, each occurring in four patients.
Serious adverse events were reported in 3 of 51 patients (6%) in the systemic therapy group and 22 of 50 patients (44%) in the experimental group. Among the 37 patients who underwent the protocol-defined surgical procedure, ileus occurred in 13 patients (35%) and anastomotic leakage in 10 patients (27%).
Three treatment-related deaths occurred within 100 days after randomization, all in the experimental group, attributed to acute respiratory distress syndrome, anastomotic leakage, and bleeding. Among patients who underwent surgery according to the study protocol, 90-day postoperative mortality was 8%.
Quality of Life and Study Limitations
At three months, patients in the experimental group experienced a decline in global health status, which the investigators considered likely to reflect the immediate effects of extensive surgery. Scores subsequently improved among patients who remained available for assessment, though later quality-of-life findings may have been affected by decreasing questionnaire completion and selection bias.
The investigators identified several limitations, including restaging after initial systemic therapy using CT imaging without repeat staging laparoscopy, which could have underestimated the extent of peritoneal disease. The study was also closed before reaching its planned enrollment, though simulations suggested continuation was unlikely to change the conclusion. Additionally, most participants were White, limiting generalizability to more diverse populations.
Clinical Implications
According to the investigators, PERISCOPE II was the first prospective, multicenter, randomized controlled trial to directly compare gastrectomy, cytoreductive surgery, and HIPEC with systemic therapy alone in patients with gastric cancer (search) and limited peritoneal metastases who had not progressed during initial systemic treatment. Despite selecting patients with limited peritoneal disease, adequate performance status, and no disease progression after initial systemic therapy, the addition of extensive surgery and HIPEC did not improve overall survival or progression-free survival in the intention-to-treat population.
The investigators concluded that gastrectomy with cytoreductive surgery and HIPEC should not be considered standard treatment for gastric cancer (search) with limited peritoneal metastases or tumor-positive peritoneal cytology. Systemic therapy—including chemotherapy with immunotherapy, targeted therapy, or both when indicated—remains the standard treatment approach. Until a clearly defined population that benefits from this strategy can be identified, gastrectomy, cytoreductive surgery, and HIPEC should not be offered outside clinical trials.