PIPAC and FOLFOX for Gastric Cancer Peritoneal Cancer

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) and Systemic Chemotherapy as a First-line Treatment for Gastric Cancer Peritoneal Metastases: Open-label, Single-arm, Multi-center Feasibility Study

Peritoneum is among the most common sites of metastases in gastric cancer. Systemic chemotherapy is the current standard for peritoneal carcinomatosis (PC), although, the treatment results remain extremely poor. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a modern treatment modality for PC, that 1) optimize the drug distribution by applying an aerosol rather than a liquid solution; and 2) apply increased intraperitoneal hydrostatic pressure to increase drug penetration to the target. Despite some encouraging preliminary results for PIPAC efficacy, it is still an investigational treatment. Furthermore, only very limited data exist for bidirectional treatment, which includes a combination of systemic chemotherapy and PIPAC. Thus, this study will investigate the feasibility of PIPAC and systemic chemotherapy combination for gastric cancer patients with peritoneal metastases.

This open-label, single-arm feasibility study will be conducted at two major gastrointestinal cancer treatment centers in Lithuania and will include 37 participants. Gastric cancer patients diagnosed with a synchronous or metachronous peritoneal carcinomatosis based on a clinical, radiological, cytological, and histological examination will be considered for enrollment. Thirty-seven patients willing to participate and meeting the enrollment criteria will be scheduled for the experimental treatment. Three cycles of 1st line palliative systemic chemotherapy will be administered every 28 days and PIPAC with cisplatin 10,5 mg/m2 and doxorubicin 2,1 mg/m2 will be utilized 14 days after each of the systemic chemotherapy cycles. After the 3rd PIPAC procedure patients will be re-assessed and discussed at multidisciplinary team meetings. In case of downstaging patients will be considered for radical gastrectomy±cytoreductive surgery; others for further systemic therapy. All patients will be followed up for 24 months.

Each patient will be scheduled for 3 courses of combined treatment: in total 3 PIPAC with cisplatin 10.5 mg/m2 and doxorubicin 2.1 mg/m2 and 6 cycles of FOLFOX systemic chemotherapy.

Combined Doxorubicin and Cisplatin Pressurized IntraPeritoneal Aerosol Chemotherapy With Systemic FOLFOX chemotherapy

Each course of combined treatment will start with PIPAC (a pressurized aerosol containing cisplatin 10.5 mg/m2 and doxorubicin 2.1 mg/m2 diluted in NaCl 0.9% applied through the nebulizer inside the abdominal cavity during laparoscopy). Fourteen days afterward 2 cycles of systemic FOLFOX chemotherapy will be applied within 28 days. The interval between combined treatment courses will be 14 days.

Objective tumor response according to RECIST v 1.1 in CT scan performed 1 week after second PIPAC procedure

Objective tumor response according to RECIST v 1.1 in CT scan performed 1 week after third PIPAC procedure

The number of patients with postoperative complications, defined and graded according to Clavien-Dindo classification

Peritoneal carcinomatosis index and histological regression according to peritoneal regression grading score (PRGS).

A pathologist blinded to clinical outcomes will evaluate histological tumor response using the Peritoneal Regression Grading Score (PRGS): 1-Complete regression without cancer cells; 2-higher response with prevalence of regressive phenomena and only a few residual cancer cells - PRGS; 3-minor response with prevalence of residual cancer cells and poor regressive phenomena; 4-no response to therapy without regressive phenomena. A patient will be considered a responder if any reduction in the PRGS during subsequent biopsies will be recorded.

The number of patients with toxicity according to Common Terminology Criteria for Adverse Events (CTCAE) V5.0 during the study period

Inclusion Criteria: Histologically verified gastric adenocarcinoma (HER2 negative) with peritoneal carcinomatosis; Age≥18; ECOG≤1; Patient willing to participate; Patient is the candidate for 1st line FOLFOX palliative systemic chemotherapy. Exclusion Criteria: Extra-abdominal metastases; Siewert I type gastroesophageal junction cancer; Mechanical bowel obstruction; Allergy to study drugs; History of previous intraperitoneal chemotherapy; Pregnancy of refusal for birth-control at least 6 months post-study treatment