A novel minimally invasive approach for treating peritoneal metastases from colorectal and appendiceal cancers has shown promising safety results in a phase 1 clinical trial, potentially addressing what researchers describe as "nihilism" surrounding these historically difficult-to-treat cancers.
The dose-escalation trial (NCT04329494) evaluated pressurized intraperitoneal aerosolized chemotherapy with mitomycin C (PIPAC-MMC) combined with standard systemic chemotherapy in patients with peritoneal carcinomatosis. Results were presented at the Society of Surgical Oncology 2025 Annual Meeting by Mustafa Raoof, MD, MS, from City of Hope Cancer Center.
Addressing Treatment Challenges in Peritoneal Disease
Peritoneal metastases represent one of the most challenging aspects of advanced colorectal and appendiceal cancers, with patients experiencing limited survival and severe symptoms including intestinal blockages, ureter obstructions, and fluid accumulation. According to Raoof, these patients traditionally have limited treatment options and are often not considered candidates for clinical trials.
"There is a lot of nihilism around peritoneal metastases because, within stage IV colon cancer or appendix cancer, peritoneal metastases have the worst prognosis," Raoof explained during his presentation.
The rationale for intraperitoneal therapy stems from observations that intravenous treatments fail to adequately reach peritoneal tumors. The PIPAC approach, originally developed in Europe, delivers chemotherapy directly to the abdominal cavity through a minimally invasive laparoscopic procedure.
Trial Design and Treatment Protocol
The phase 1 trial employed a dose-escalation design across four planned dose levels of PIPAC-MMC, with patients receiving treatment every 6 weeks for three cycles. The procedure involves performing laparoscopy through small incisions and administering aerosolized mitomycin C directly to the peritoneal cavity, combined with standard systemic chemotherapy.
"We perform a laparoscopy every 6 weeks. Through small incision surgery, we can then give this aerosol treatment directly to the abdomen. I look at it as an optimized way to deliver intraperitoneal therapy," Raoof described.
Safety Profile Demonstrates Tolerability
Safety results from the trial showed manageable toxicity profiles across dose levels. Overall, 58% of patients experienced grade 1-2 toxicities as their highest grade, while 31% experienced grade 3 or higher toxicities.
Dose-specific analysis revealed varying toxicity patterns: 67% of patients receiving 7 mg/m² experienced grade 1-2 toxicities with no grade 3+ events, while 87% of those receiving 12.5 mg/m² had grade 1-2 toxicities with 12% experiencing grade 3+ events. At the highest tested dose of 19 mg/m², 25% had grade 1-2 toxicities while 62% experienced grade 3 or higher toxicities.
Advantages Over Traditional Approaches
Benjamin Golas, MD, from Hackensack Meridian Health, highlighted the significant advantages of PIPAC over traditional treatment modalities for peritoneal carcinomatosis. Conventional approaches include systemic chemotherapy with challenging adverse effect profiles or highly invasive cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC).
"CRS and HIPEC represent a major surgical undertaking, often lasting 10 to 14 hours and involving the resection of multiple organs," Golas noted, emphasizing the significant complication rates and prolonged recovery periods associated with these procedures.
In contrast, PIPAC requires only two small abdominal incisions and typically lasts 45 minutes to an hour, allowing patients to return home the same day. The procedure delivers chemotherapy in aerosolized form with pressure enhancement to improve penetration into the peritoneal lining.
Clinical Applications and Future Directions
According to Golas, any patient with peritoneal carcinomatosis could potentially be a candidate for PIPAC, with particular benefits for those not physically robust enough for major surgeries like CRS and HIPEC. The treatment can serve as a bridge to future surgical debulking or as therapy for early recurrence when repeat major surgery is not feasible.
The laparoscopic approach offers unique advantages in treatment monitoring, allowing for real-time visual inspection and biopsies to provide immediate feedback on therapy effectiveness. When combined with intravenous chemotherapy, PIPAC provides what Golas described as a "bimodal approach" that directly addresses peritoneal disease while maintaining systemic control.
There is growing interest in using PIPAC in neoadjuvant settings for cancers with high propensity for peritoneal spread, including gastric and ovarian cancers. Treatment plans typically incorporate serial PIPAC procedures every 2 to 3 months.
Clinical Impact and Accessibility
The development of PIPAC represents what experts consider a significant advancement in peritoneal carcinomatosis treatment, offering a less invasive, more tolerable alternative while providing patients with improved quality of life options. The approach allows patients to continue regular systemic treatment without interruption, addressing a critical gap in current therapeutic strategies.
Golas emphasized the importance of physician awareness and appropriate patient referrals to specialized centers with PIPAC expertise, suggesting this innovative approach could transform treatment paradigms for patients with peritoneal metastases who previously had limited therapeutic options.
