"Peritoneal failure": A new concept to explain negative results of randomized trials evaluating intraperitoneal therapies.

Prof. Jimmy So recently presented the results of the Extensive Peritoneal Lavage after curative gastrectomy for gastric cancer (EXPEL) study at the Gastrointestinal Cancers Symposium 2020 (ASCO GI) in San Francisco [1]. The EXPEL trial is a prospective randomized, high-quality surgical study evaluating the potential benefit of peritoneal lavage after surgical resection of the stomach. The trial involved 800 patients from 22 hospitals from Korea, China, Japan, Malaysia, and Singapore. Patients with cT3, T4 stomach cancer undergoing curative resection were randomized to surgery alone (control group, n = 402 patients) or surgery followed by lavage of the peritoneal cavity with 10 L of saline solution (test group, n = 398 patients). There was no difference in the 3-year cumulative incidence of recurrence between the two groups. The rate of adverse events was higher in the test group (RR= 1.58, P = 0.019). The EXPEL study is not the first study failing to show a benefit of intraperitoneal therapies. Since 2018, the community of peritoneal surgeons is collecting negative results with hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer, both in the prophylactic and in the therapeutic setting [2, 3]. Positive results talk louder than negative studies. They are more appealing to physicians and get broader coverage. But does that mean that peritoneal surgeons should be discouraged from pursuing a fruitless path? Or might these negative studies give them valuable insights into where to look next? Many comments have been made regarding the failure of the French PRODIGE 7 randomized controlled trial examining an additional benefit of HIPEC over cytoreductive surgery alone in patients with peritoneal metastasis of colon cancer [4–6]. The PRODIGE 7 trial showed a remarkable overall survival of around 41months in both groups, and the control group (surgery alone) performed much better than expected. Thus, the additional effect of HIPEC, if any, was too small to be detected with the sample size available. Moreover, the HIPEC effect, if any, was erased by the increased postoperative morbidity in the test group. The reasons for these repeated, unexpected failures of intraperitoneal therapies in clinical trials might differ between trials, but some lessons can be learned for all of them. The first lesson is methodological and might appear self-evident. Medical research does not start with Phase-3 trials. Peritoneal surgeons should first go back to the laboratory to explore new approaches such as advanced drug delivery systems, nanoparticles, carrier solutions, and others. Only a few of these approaches will go successfully through the preclinical development steps and will reach clinical testing in human patients. These new approaches should then be validated step by step in welldesigned Phase-I and (controlled) Phase-II trials. Out of the strategies tested in early-phase clinical trials, only the most promising will make it to Phase-3 trials, with increased chances of success. The second reason is biological, and we would like to introduce, for the first time, the concept of “peritoneal failure”. Peritoneal failure is defined as the loss of function(s) of the organ peritoneum. When treating patients, peritoneal surgeons should protect the protector, the peritoneum, which is the first and highly effective line of defense against aggression. Intraperitoneal therapies should decrease tumor cell viability or combat effectively bacterial pathogens. They should indeed also preserve the function of the peritoneal membrane and the associated immunological structures. Like the abdominal skin, the peritoneum derives embryologically from the lateral plate of the mesoderm [7]. Like the skin, the peritoneum has extraordinary developed immunological properties [8]. The most effective way to impair the immune response of the peritoneum is to damage and destroy it. Pleura and Peritoneum 2020; 20200117