The Efficacy of Pressurised Intraperitoneal aerosol chemotherapy (PIPAC) combined with CURativE intent minimally invasive radical resection in high-risk gastric cancer patients. A multicentre, randomised, open-label phase-II study (EPICURE, PIPAC-OPC6)

Despite declining incidence, gastric adenocarcinoma (GAC) is considered the fifth most common cancer worldwide and the third leading cause of cancer death globally. Its incidence varies across different parts of the globe, with a low incidence in the West. In East Asia, especially Japan and Korea, the incidence of distal GAC remains high, whereas proximal GAC tends to dominate in the West. Gastroesophageal junction (GEJ) adenocarcinomas that have the epicentre in the proximal 2 to 5 cm of the stomach (Siewert type III) should be staged and treated as GAC.

The consensus in most Western countries is that medically fit GAC patients should undergo D2 gastrectomy, carried out in specialised, high-volume centres with perioperative outcomes in terms of morbidity and mortality rates comparable to those presented in Japan and South Korea. A minimally invasive D2 gastrectomy has emerged as a valid and preferable alternative to open surgery.

Despite significant progress in implementing preventive strategies and curative treatment of premalignant and early neoplastic gastric lesions, most GAC patients still present with advanced stages of the disease, leading to a dismal prognosis even after treatments with curative intent. Given that many patients relapse following surgery, various multimodal treatment strategies have been studied to improve survival rates, mainly by combining surgery with systemic treatment in the form of perioperative chemotherapy. Clinical research has explored and documented the concept of perioperative chemotherapy in GAC and cancers originating in the distal esophagus and GEJ. Noteworthy is that some of these have suggested that the tumours with the most obvious responses to corresponding regimens originate in the esophagus and GEJ. Moreover, GACs of poorly differentiated tubular type or poorly cohesive cancer, regardless the presence of signet-ring cells type has been reported to be more resistant to chemotherapy regimens. Another observation with clinical implications is that GAC patients with malignant cells retrieved from peritoneal lavage before surgery have an extremely poor prognosis. Hence, laparoscopy with peritoneal lavage for malignant cells is recommended in all stage IB-III gastric cancers, otherwise considered potentially resectable, to exclude radiologically occult metastatic disease. The true value of this information may be even greater for patients with T3/T4 disease. Considering the above-mentioned challenges, it is critically important to explore novel multimodal therapeutic concepts in GAC since current therapeutic strategies offer these patients a limited option for cure.

The occurrence of peritoneal metastases (PM) has a significant negative impact on the overall prognosis, with a median survival of three to four months without treatment. None of the available chemotherapy regimens has reduced or prevented the risk of PM. It is commonly believed that PM occur through the deposition of tumour cells either by the direct extension and subsequent cellular exfoliation or through the traumatic dissemination of cancer cells during surgery. Clinical validation of the concept of direct spread is also provided by observing the higher rate of PM seen with increasing tumour stages (T-stages) and serosal involvement. This is also supported by the association of between positive peritoneal cytology and a higher tumour stage.

Sixty percent of lavage cytology-negative patients will convert to a cytology-positive state immediately after gastrectomy. Accordingly, it can be argued that during gastrectomy, cancer cells within the dissected lymphatic channels and blood vessels are released to and disseminated throughout the abdominal cavity. Free cancer cells can then attach to the peritoneal surface, a process facilitated by the action of cytokines and the deposition of fibrin layers, allowing for the entrapment of those cells. This new restrictive-peritoneal environment is thought to hinder the penetrance of cytotoxic drugs delivered systemically and provides grounds for the launch of intraperitoneal treatments.