A phase-1 trial of intraperitoneal 5-fluorouracil and oxaliplatin in patients with colorectal cancer and unresectable peritoneal metastasis.

SUMMARY Patients with colorectal cancer (CRC) and peritoneal metastases (PM) have significantly worse outcomes than metastases to other sites like the lungs or liver. In patients with a limited volume of disease based on an intraoperatively calculated peritoneal carcinomatosis index (PCI) of less than 20, cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemoperfusion (HIPEC) may provide a survival benefit. Unfortunately, only a minority of patients are candidates for CRS+HIPEC, and even in patients that undergo CRS + HIPEC, there is almost universal cancer recurrence. There is a critical need for novel therapeutic strategies, including regional delivery of anti-tumor agents in patients with CRC PM. Although 5-fluorouracil (5FU) and oxaliplatin forms the foundation of intravenous (IV) systemic therapy for patients with metastatic CRC, poor penetration and efficacy of IV chemotherapy in the peritoneum leads to much poorer outcomes. In animal models, chemotherapies such as 5FU have higher intra-tumoral concentrations and longer half-lives when administered directly to the peritoneal cavity compared to IV administration, making intraperitoneal (IP) chemotherapy an attractive treatment modality. While small pilot studies of IP 5FU from the 1980s and 90s showed promising efficacy, no systematic trials have been conducted to assess the feasibility of IP chemotherapy in patients with CRC and unresectable PM, and none using the modern chemotherapy combination of 5-FU + oxaliplatin. Furthermore, there have been no studies on the effects of IP 5FU+oxaliplatin on stimulating an anti-tumor immune response. To address these knowledge gaps, we have designed a phase-1 dose-escalation trial of 5FU and oxaliplatin administered IP in patients with CRC and PM not eligible for CRS+HIPEC due to PCI > 20. This trial will use the Bayesian optimal interval design (BOIN) to determine the maximally tolerated dose (MTD), with 6 additional patients treated at the MTD for additional safety, response, and correlative analyses. Patients will undergo a diagnostic laparoscopy with tumor biopsy at baseline and again after 4 cycles of IP chemotherapy. PCI is calculated intraoperatively at each diagnostic laparoscopy. Imaging as per SOC will be performed every 2 cycles, and response assessed by RECIST 1.1. Markers for tumor response and immune phenotype will be analyzed by spectral flow cytometry on tumor and blood samples. Our central hypothesis is that IP 5FU+oxaliplatin will be safe, lead to direct cytotoxicity, and stimulate anti-tumor immune responses due to immunogenic cell death. Additionally, local administration of chemotherapy may avoid the systemic immunosuppressive effects of systemic chemotherapy. If successful, this research will form the foundation of larger efficacy trials to optimize IP chemotherapy alone or in combination with immune-modulating agents, and ultimately, offers the potential to improve outcomes for a population of patients with poor survival, limited treatment options, and significant morbidity using affordable and widely available chemotherapy agents.