Good Doctor. Hyperthermic Intraperitoneal Chemotherapy (HIPEC)丨Reprint 5: Focus on active treatment options for peritoneal surface malignancies. Research progress on cytoreductive surgery and HIPEC in Northern Europe.

Research Progress on Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Tumor Cells in Northern Europe

By Peter Cashin

Preface

Colorectal cancer with peritoneal metastasis remains a significant therapeutic challenge. While cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been a primary treatment modality, questions regarding the optimal HIPEC regimen persist. The PRODIGE7 trial challenged the efficacy of oxaliplatin-based HIPEC, prompting a focus on novel combination therapies. The ongoing EFFIPEC trial aims to refine HIPEC by evaluating intensified chemotherapy regimens. This article provides an update on the interim analysis of this trial and highlights international collaborations, particularly with the Indian Peritoneal Surface Malignancies Society (INDEPSO) HIPEC network. Furthermore, potential new research initiatives in the Nordic countries regarding pseudomyxoma peritonei are introduced.

Efficacy of Hyperthermic Intraperitoneal Chemotherapy in the Treatment of Colorectal Cancer—The EFFIPEC Trial

The EFFIPEC trial is a phase I/III combined study designed to investigate the efficacy of 5-fluorouracil (5-FU) and irinotecan-based hyperthermic intraperitoneal chemotherapy in patients with colorectal cancer peritoneal metastasis. As of September 2024, an unplanned interim complication analysis has been conducted due to concerns about neutropenia and two deaths after 52 patients were enrolled. This analysis assessed postoperative complications in patients receiving different dosing regimens. The dose of HIPEC was allowed to be reduced to 75% of the total dose for any reason, at the discretion of the surgeon.

Key findings include:

• Comparison of the standard oxaliplatin monotherapy HIPEC group (n=26) with the experimental group (oxaliplatin combined with irinotecan HIPEC, with early postoperative intraperitoneal chemotherapy with 5-fluorouracil on postoperative day one, n=26)—the experimental group was further divided into a 75% dose group (n=9) and a 100% dose group (n=17).

• The incidence of Clavien-Dindo grade 3 or higher complications was 23% (no deaths) in the control group, 22% (no deaths) in the 75% dose group of the experimental group, and 30% (including 2 deaths) in the 100% dose group.

• The incidence of neutropenia was 4% in the control group, 11% in the 75% dose group of the experimental group, and 53% in the 100% dose group.

• The reoperation rate was 12% in the control group, 11% in the 75% dose group of the experimental group, and 24% in the 100% dose group.

Based on these findings, the trial's Data Monitoring Committee recommended discontinuation of the full-dose regimen due to the unexpectedly high rate of neutropenia, despite prophylactic granulocyte colony-stimulating factor. Neutropenia may have been at least partly responsible for one of the postoperative deaths. Going forward, only the 75% dose level will be used to maintain efficacy while ensuring patient safety.

Expansion of International Collaboration: INDEPSO Joins the Effort

The participation of INDEPSO is a significant milestone for the EFFIPEC trial. Its inclusion broadens the scope and diversity of the trial, allowing for a wider assessment of treatment response across different patient populations. With INDEPSO's involvement, patient recruitment is expected to accelerate, increasing the likelihood of obtaining robust and generalizable results.

Progress in Hyperthermic Intraperitoneal Chemotherapy Research for Appendiceal Malignancies—The APPIPEC Trial

In addition to the ongoing EFFIPEC study, several research centers in the Nordic countries are exploring the feasibility of a randomized trial for pseudomyxoma peritonei. Previous studies have questioned the efficacy of HIPEC in treating pseudomyxoma peritonei, particularly with mitomycin C monotherapy. The APPIPEC trial aims to assess whether the combination of mitomycin C and cisplatin provides superior outcomes compared to mitomycin C monotherapy HIPEC or simple hyperthermia alone (without chemotherapy). This initiative aligns with current international efforts to optimize intraperitoneal chemotherapy regimens for various peritoneal surface malignancies. The success of this trial will require the participation of research centers outside the Nordic countries. Discussions have already taken place at a dedicated workshop last year in Lausanne. A consensus on the trial protocol is expected soon.

Exploring Conversion Therapy for Unresectable Peritoneal Metastases—The COLOVERT Trial

Another promising trial in Nordic research is the COLOVERT trial, currently seeking funding. COLOVERT is a phase II randomized controlled study designed to evaluate conversion therapy for patients with colorectal cancer peritoneal metastases who are initially ineligible for cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS+HIPEC). This trial uses a ‘pick-the-winner’ design, comparing two arms: Arm A receives oral capecitabine, intravenous bevacizumab, and intraperitoneal oxaliplatin; while Arm B uses the same backbone therapy, but the intraperitoneal chemotherapy agent is selected based on chemotherapy resistance testing. The primary objective is to assess the response rate and determine whether personalized intraperitoneal chemotherapy can improve the conversion rate to CRS+HIPEC. Secondary endpoints include overall survival, quality of life, and progression-free survival. This trial will be conducted at major HIPEC centers in Sweden, and its results may significantly impact treatment strategies for patients with extensive peritoneal disease.

Conclusion

The EFFIPEC trial continues to progress, soon to complete enrollment of 60 patients out of the planned 196 randomized patients. The interim complication rate analysis highlights the importance of dose adjustment to balance efficacy and safety. The addition of the Indian Peritoneal Surface Malignancies Society marks a significant step in global collaboration in peritoneal surface oncology research. Furthermore, the potential trial for pseudomyxoma peritonei and the planned COLOVERT study in the Nordic region highlight the region’s commitment to advancing

research on HIPEC for different disease subtypes. Completing these studies is crucial for establishing evidence-based standards that will improve patient outcomes globally. Continued collaboration and dedication within the international HIPEC community are key to guiding the future direction of peritoneal malignancy treatment.