Adding intraperitoneal (IP) paclitaxel to standard intravenous (IV) paclitaxel plus S-1 (oral fluoropyrimidine derivative) significantly extended overall survival for patients with gastric cancer peritoneal metastases, according to data presented at the 2025 ASCO Gastrointestinal Cancers Symposium.¹

Results of the phase III, multicenter DRAGON-01 trial demonstrated a median overall survival of 19.4 months for patients treated with IP paclitaxel plus IV paclitaxel and S-1, compared with 13.9 months for those who received IV paclitaxel and S-1 without the IP component. This yielded a hazard ratio of 0.66, marking a statistically significant and clinically meaningful improvement in survival (P = .0056).

“These findings offer robust evidence to support changes in current clinical practices,” said principal investigator Chao Yan, MD, PhD, of Ruijin Hospital at Shanghai Jiao Tong University School of Medicine. “This is the first positive phase III multicenter trial to definitively show a survival advantage of intraperitoneal chemotherapy.”

Chao Yan, MD, PhD

As Dr. Yan reported, gastric cancer ranks among the leading causes of cancer mortality worldwide, particularly in East Asia. Peritoneal metastases represent a common and serious complication of advanced gastric cancer, he added, often characterized by malignant ascites, poor quality of life, and limited survival despite aggressive chemotherapy.

Neoadjuvant intraperitoneal and systemic chemotherapy has generated interest because of its ability to deliver higher local drug concentrations directly into the peritoneal cavity, potentially improving tumor response while minimizing systemic toxicity. However, earlier studies such as the PHOENIX-GC trial,² though suggestive of a survival trend favoring IP chemotherapy, did not reach statistical significance. As a result, said Dr. Yan, major guidelines have been slow to adopt IP chemotherapy in standard practice for gastric cancer peritoneal metastases.

Study Methods

DRAGON-01 study investigators sought to determine whether intraperitoneal paclitaxel, coupled with a standard backbone of intravenous paclitaxel and S-1, could confer a definitive survival advantage over the same regimen without the IP drug component.

This trial was conducted across nine clinical centers in China. Investigators enrolled patients with histologically confirmed gastric cancer and laparoscopically diagnosed peritoneal metastases. They were randomly assigned in a 2:1 ratio to one of two study arms: neoadjuvant IP paclitaxel plus IV paclitaxel and S-1 (n = 148); and IV paclitaxel plus S-1 (n = 74).

The study was powered to detect a difference in overall survival, the primary endpoint. Secondary endpoints included conversion surgery rates, R0 resection rates (ie, no visible residual tumor), and toxicity profiles. Investigators also examined how many cycles of therapy were optimal before attempting surgery. Patients with higher peritoneal cancer indices (> 20) often received more than five to six cycles of chemotherapy before conversion surgery, if feasible. (The Peritoneal Cancer Indexis a scoring system used to assess the extent of peritoneal cancer spread by evaluating tumor size and distribution across 13 abdominopelvic regions, with a total score ranging from 0 to 39.)

Key eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, absence of other distant metastases outside the peritoneum, and the potential for surgical resection if peritoneal lesions responded.

Key Results

At a median follow-up of 60.2 months, the neoadjuvant intraperitoneal and systemic chemotherapy arm achieved a median overall survival of 19.4 months vs 13.9 months in the IV paclitaxel plus S-1 arm (hazard ratio = 0.66; P = .0056).

“The 5.5-month difference in median survival was both statistically significant and clinically notable, especially given the aggressive nature of peritoneal involvement in gastric cancer,” said Dr. Yan. He added that subgroup analysis suggested a benefit of intraperitoneal chemotherapy applied broadly across different baseline characteristics, with the exception of patients with an ECOG performance status of 1, for whom results were less pronounced.

Beyond the overall survival benefit, conversion surgery for select patients emerged as an important factor. Among those who responded to chemotherapy sufficiently to undergo resection, median survival reached 33.1 months in those given neoadjuvant intraperitoneal and systemic chemotherapy.

“When patients [with gastric cancer peritoneal metastases] achieve complete regression of peritoneal lesions, surgery can be transformative, leading to remarkable survival outcomes,” declared Dr. Yan.

Similarly, for those given IV paclitaxel plus S-1, the median overall survival for patients who underwent conversion surgery was 18.8 months, vs 10.0 months for those not eligible for resection. Patients achieving R0 resection (no visible residual tumor) had even better survival. In the group given neoadjuvant intraperitoneal and systemic chemotherapy, median overall survival reached 35.5 months for those who underwent R0 resection. By contrast, R2 resections (macroscopic residual disease) were associated with poor outcomes, especially in the IV paclitaxel plus S-1 arm (median overall survival, 10.1 months).

“These results highlight the importance of complete resection and confirm that combining IP and systemic chemotherapy can make more patients eligible for potentially curative surgery,” said Dr. Yan.

Safety Profile

Investigators underscored that “both treatments were well tolerated, with manageable side effects.” Both treatment arms demonstrated comparable rates of grade 3 or 4 adverse events, predominantly hematologic toxicities such as leukopenia and neutropenia. Fatigue was another common adverse event in both arms. The incidence of complications from the IP ports was low; port-related issues such as infection or subcutaneous fluid accumulation were generally manageable with standard measures, Dr. Yan noted, and few patients required surgical port removal. 

DISCLOSURE: Dr. Yan reported no conflicts of interest.

REFERENCES

1. Yan C, Yang Z, Shi Z, et al: Intraperitoneal and intravenous paclitaxel plus S-1 versus intravenous paclitaxel plus S-1 in gastric cancer patients with peritoneal metastasis: Results from the multicenter, randomized, phase 3 DRAGON-01 trial. 2025 ASCO Gastrointestinal Cancers Symposium. Abstract 327. Presented January 23, 2025.

2. Ishigami H, Fujiwara Y, Fukushima R, et al: Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. J Clin Oncol 36:1922-1929, 2018.

EXPERT POINT OF VIEW 

Invited discussant Maheswari Senthil, MD, FACS, FSSO, Professor of Surgery at the University of California, Irvine, School of Medicine, commended the DRAGON-01 trial investigators for “the first randomized controlled trial that has shown improved overall survival with intraperitoneal [IP] chemotherapy.” However, she emphasized several considerations for future research.

Maheswari Senthil, MD, FACS, FSSO

Dr. Senthil noted that the trial design did not employ “the current standard of care we would use in metastatic gastric cancer in the first line,” specifically referencing the lack of platinum agents or immunotherapy in both study arms.

She also questioned the role of prolonged therapy after surgery, observing that in DRAGON-01, “patients who underwent conversion gastrectomy had continuation of the intraperitoneal and systemic chemotherapy regimen for 3 years or even longer,” which may present challenges with compliance. Dr. Senthil noted that postoperative therapy compliance after gastric resection in trials such as MAGIC and FLOT is around 50% or less.

Regarding conversion gastrectomy, Dr. Senthil pointed out that “disappearance of peritoneal metastasis” can be difficult to validate, because “cytology is not a great test to identify treatment response in patients with gastric carcinomatosis.” She further stressed that the Western population might not see comparable conversion rates using an intravenous (IV)-only regimen.

Ultimately, Dr. Senthil viewed these findings as an opportunity to integrate intraperitoneal chemotherapy with modern regimens. “If IP chemotherapy can improve outcomes just with IV paclitaxel and S-1,” she stated, “what improved outcome can be achieved if you use standard-of-care therapy along with immunotherapy or targeted therapies?”

According to Dr. Senthil, this study underscores the need for additional prospective clinical trials that incorporate current systemic standards, refine patient selection criteria, and clarify which components of the multimodal approach truly drive the survival benefit. 

DISCLOSURE: Dr. Senthil reported financial relationships with GE HealthCare and On Target Laboratories. A patent application is pending for an exosome isolation reagent.