Extensive intraoperative peritoneal lavage (EIPL) had no 3-year survival benefit versus surgery alone, the multicenter Asian EXPEL study found. Saline EIPL was also associated with more adverse events and deaths and was therefore not recommended for patients undergoing curative gastrectomy for locally advanced gastric cancer, concluded Jimmy Bok Yan So, MD, of Yong Loo Lin School of Medicine at the National University of Singapore, and colleagues.
As the investigators explained in their study online in The Lancet Gastroenterology & Hepatology, earlier research had suggested that EIPL might reduce the risk of peritoneal recurrence and improve survival. For example, the recent Chinese SEIPLUS trial reported that peritoneal lavage resulted in a lower overall complication rate than surgery alone (11% vs 17%), leading the authors to propose that dilution might decrease regional and systemic inflammation and improve overall outcomes.
With no effective treatment for peritoneal recurrence, EIPL therefore seemed an attractive strategy because of its simplicity, low cost, and apparent safety. Peritoneal washing is a common surgical practice in peritonitis and perforated viscus.
To evaluate EIPL in gastrectomy for locally advanced gastric cancer, the EXPEL researchers conducted an open-label, phase III, randomized trial in patients ages 21 to 80 with cT3 or cT4 gastric cancer undergoing curative resection. Participants were enrolled from September 2012 to August 2018 at 22 centers in South Korea, China, Japan, Malaysia, Hong Kong, and Singapore, and the 800 patients were randomly assigned to either EIPL (398 patients) or standard surgery (402).
The median ages in the EIPL and standard arms were 61 and 62, respectively, and 73% and 71% of patients were male. In the EIPL group, peritoneal lavage was performed with 1 L of warm (42oC) normal 0.9% saline. The peritoneal cavity was stirred and washed, and the fluid aspirated completely. This procedure was repeated 10 times for a total of 10 L of saline.
At the third interim analysis in August 2019, the predictive probability of a significant overall survival (OS) in the EIPL group was found to be less than 0.5%, and so the trial was terminated early.
Among the key findings at a median follow-up of 2.4 years (interquartile range 1.5-3.0):
- OS rates were similar in both arms: hazard ratio 1.09 (95% CI 0.78-1.52, P=0.62)
- 3-year OS was 77.0% (95% CI 71.4-81.6) for the EIPL group and 76.7% (71.0-81.5) for the standard surgery group
- Re-admission rates were comparable (10% and 8%, respectively)
- 60 adverse events were reported for EIPL vs 41 for standard surgery
The most common adverse events were:
- Anastomotic leak (3% of 346 patients in the final EIPL group vs 2% of 362 patients in the standard surgery group)
- Bleeding (2% in both groups)
- Abnormal liver function (2% vs less than 1%)
- Intra-abdominal abscess (1% in both groups)
- Superficial wound infections (2% vs 1%)
- Adverse events that resulted in death (eight in the EIPL group vs two in the standard surgery group)
“The reason for the higher number of adverse events in the EIPL group is unknown, but it might be associated with bowel manipulation during lavage, and infective complications in the abdomen might be the cause of the higher number of superficial wound infections in the EIPL group,” the authors speculated.
Writing in an accompanying commentary, Mautin T. Hundeyin, MD, and Vivian E. Strong, MD, both of Memorial Sloan Kettering Cancer Center in New York City, said the “thorough and well-designed” trial conclusively showed little benefit from EIPL in the general population of patients with locally advanced gastric cancer.
However, Hundeyin and Strong noted, patients were not selected on the basis of peritoneal cytology, and only about 5% had positive cytology. Although an earlier study suggested that EIPL might benefit patients with positive cytology, the new study was not powered to detect this. “However, it is plausible that EIPL might benefit only patients with positive cytology,” the commentators wrote.
They cautioned that EIPL studies so far have been done in Asian populations only and so might not be replicated in European and American patients, who might receive neoadjuvant therapy. “Future studies investigating EIPL as a method of sterilizing the peritoneum in conjunction with neoadjuvant chemotherapy to reduce peritoneal recurrence might be warranted,” the commentators wrote.
The researchers agreed that other strategies need to be explored, noting that the phase III, multicenter, randomized GASTRICHIP trial is currently investigating the use of prophylactic hyperthermic intraperitoneal chemotherapy, with results expected in 2024.
EXPEL study limitations, the team noted, included the prior over-staging of some patients — i.e., about 17% were found to have pT1 or pT2 disease after histological examination, and these patients might have had only limited benefit from EIPL. In addition, 12% of patients did not return for follow-up in the 12 months before the termination of the trial, and the sample size was based on an assumption of a 10% benefit from EIPL, while a smaller, still clinically relevant, benefit would render the trial inadequately powered. Finally, because patients received surgery upfront rather than after neoadjuvant chemotherapy, the results might not apply to patients in countries outside of Asia, the researchers said.
The study was funded by the National Medical Research Council, Singapore.
Jimmy Bok Yan So reported having no competing interests; several co-authors disclosed financial relationship outside of the study with Bristol Myers Squibb, Takeda, Novartis, Eli Lilly Japan, Abbott, Daiichi Sankyo, Johnson & Johnson, Abbott, AbbVie, and Celgene.
Hundeyin and Strong reported no competing interests.