HIPEC in Platinum-Sensitive Ovarian Cancer: A Promising Yet Controversial Option

Abstract

Recurrent epithelial ovarian cancer (EOC) often manifests as abdominal disease, leading to significant interest in heated intraperitoneal chemotherapy (HIPEC) as a therapeutic strategy. HIPEC, administered following surgical cytoreduction, has shown potential survival benefits in women with platinum-sensitive relapsed ovarian cancer (PSROC). An open-label randomized trial involving 415 patients demonstrated improved median overall survival (54 vs. 46 months) with HIPEC, although it also led to increased high-grade toxicities. Despite these promising findings, the routine use of HIPEC remains under evaluation, and confirmatory trials are needed. This article explores the current evidence, benefits, risks, and future perspectives of HIPEC in PSROC, guiding clinicians in shared decision-making.

Introduction

Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic malignancies, largely due to its high recurrence rate despite initial responsiveness to platinum-based chemotherapy. In platinum-sensitive relapsed ovarian cancer (PSROC), treatment strategies focus on extending survival while maintaining quality of life. Given the predominant abdominal spread of recurrent disease, heated intraperitoneal chemotherapy (HIPEC) has emerged as a potential intervention to enhance the efficacy of cytoreductive surgery and chemotherapy.

This review examines the role of HIPEC in PSROC, summarizing clinical evidence, therapeutic benefits, associated risks, and the future direction of research in this domain.

Understanding HIPEC in Ovarian Cancer Treatment

HIPEC involves the administration of heated chemotherapy directly into the peritoneal cavity immediately following cytoreductive surgery. The combination of hyperthermia and high drug concentrations within the peritoneal space aims to eradicate residual microscopic disease, improve drug penetration, and enhance cytotoxic effects. Unlike traditional systemic chemotherapy, HIPEC allows for a higher localized drug dose with potentially reduced systemic toxicity.

Rationale for HIPEC in PSROC

• Direct Targeting of Residual Disease: HIPEC enables direct exposure of chemotherapeutic agents to peritoneal metastases, reducing systemic dilution and resistance.

• Hyperthermia-Enhanced Cytotoxicity: Heat (41-43°C) potentiates the effect of chemotherapy, increasing cancer cell apoptosis and altering tumor microenvironment responses.

• Prolonged Drug Exposure: Intraperitoneal chemotherapy has a longer residence time compared to systemic delivery, enhancing drug efficacy at the site of recurrence.

Clinical Evidence Supporting HIPEC in PSROC

Key Clinical Trials

1. The OVHIPEC-1 Trial (Open-Label Randomized Study)

   • Design: 415 patients with PSROC underwent cytoreductive surgery with or without HIPEC after six cycles of platinum-based chemotherapy (with optional bevacizumab).

   • Findings: Median overall survival (OS) was 54 months in the HIPEC group vs. 46 months in the non-HIPEC group.

   • Toxicities: Grade ≥3 adverse events were higher in HIPEC recipients (49% vs. 27%), primarily affecting gastrointestinal and hematologic systems.

   • Conclusion: HIPEC conferred a significant survival benefit at the cost of increased toxicity.

2. Retrospective and Observational Studies

   • Several smaller studies have corroborated improved progression-free survival (PFS) and OS with HIPEC, particularly when complete cytoreduction (CC-0 resection) is achieved.

   • HIPEC has been associated with enhanced platinum sensitivity and reduced peritoneal recurrence rates.

Balancing Benefits and Risks

Benefits of HIPEC in PSROC

• Enhanced survival outcomes in selected patients with optimal cytoreduction.

• Reduced peritoneal recurrences, potentially delaying the need for further systemic chemotherapy.

• Localized drug delivery, decreasing systemic toxicity compared to intravenous chemotherapy.

Risks and Challenges of HIPEC

• Increased perioperative morbidity: Patients undergoing HIPEC experience higher rates of post-surgical complications, including anastomotic leaks, infections, and prolonged ileus.

• Higher incidence of grade ≥3 toxicities: Gastrointestinal and hematologic side effects are more frequent in the HIPEC group.

• Limited long-term data: While initial results are promising, confirmatory trials are needed to validate survival benefits and optimal patient selection criteria.

Current Clinical Recommendations

While HIPEC is not yet standard therapy for PSROC, some institutions offer it selectively, particularly in patients who have responded to neoadjuvant chemotherapy and are candidates for complete cytoreduction.

• Ideal Candidates for HIPEC:

  • Patients with platinum-sensitive relapse and good performance status.

  • Patients achieving CC-0 or CC-1 cytoreduction.

  • Those without significant comorbidities that may increase perioperative risks.

• Patient Counseling Considerations:

  • Discuss survival benefits vs. toxicity risks.

  • Consider institutional experience with HIPEC (centers with specialized expertise may yield better outcomes).

  • Evaluate alternative options such as systemic chemotherapy with or without bevacizumab.

Future Directions and Ongoing Research

• OVHIPEC-2 Trial: A follow-up study evaluating HIPEC in primary ovarian cancer to assess its role in first-line treatment.

• Personalized Approaches: Exploring biomarkers to identify patients who would derive the greatest benefit from HIPEC.

• Refinement of Chemotherapeutic Agents: Investigating novel intraperitoneal agents with reduced toxicity profiles.

• Minimizing Toxicity Strategies: Research on perioperative optimization, enhanced recovery protocols, and patient selection refinement.

Conclusion

Heated intraperitoneal chemotherapy (HIPEC) represents a promising therapeutic modality for platinum-sensitive relapsed ovarian cancer, offering potential survival benefits in select patients. While randomized trials indicate improved overall survival with HIPEC, concerns regarding increased toxicity warrant careful patient selection and further validation through ongoing research. Clinicians should engage in shared decision-making, weighing HIPEC's risks and benefits tailored to individual patient profiles. As more data emerge, HIPEC may become a standard component in the multimodal treatment of recurrent ovarian cancer, refining its role in optimizing patient outcomes.

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