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HIPEC in Ovarian Cancer: A Detailed Evidence-Based Overview

1. Background and Rationale

1. Maximal cytoreductive surgery (CRS) to debulk visible tumor
2. Immediate instillation of heated chemotherapy (41-43°C) directly into the peritoneal cavity

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2. Technical Aspects

2.1 Technique

2.2 Chemotherapy Agents Used in Trials

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3. Clinical Settings - A Framework

OVARIAN CANCER
│
├── PRIMARY ADVANCED (Stage III-IV)
│     ├── Primary CRS + HIPEC (upfront surgery)
│     │     └── Evidence: Limited (CHOICEM); not yet standard
│     └── Interval CRS + HIPEC (after NACT)  ← STRONGEST EVIDENCE
│           └── OVHIPEC-1 (Phase III) → POSITIVE
│           └── Lim et al./Korean RCT → Positive (iCRS subgroup)
│
└── RECURRENT OVARIAN CANCER
      ├── Platinum-sensitive (≥6 months PFI)
      │     ├── After NACT: CHIPOR → POSITIVE (OS benefit)
      │     └── Without NACT: HORSE/MITO-18 → NEGATIVE (no PFS benefit)
      └── Platinum-resistant (<6 months PFI)
            └── Evidence: Minimal; investigational only

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4. Key Landmark Trials

4.1 The OVHIPEC-1 Trial (The Pivotal Trial)

Key conclusion: HIPEC at interval CRS confers durable long-term survival benefit. The absolute OS gain of ~11.6 months was maintained at 10-year follow-up, confirming that this is not a transient effect.

• Grade 3-4 adverse events were not significantly different between groups (HIPEC benefit achieved without excess morbidity in this trial).

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4.2 Korean RCT - Lim et al. (JAMA Surgery, 2022, PMID 35262624)

Key conclusion: Overall analysis was negative, but the interval CRS subgroup showed significant benefit - corroborating the OVHIPEC-1 findings. Primary CRS subgroup showed no benefit.

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4.3 CHIPOR Trial (Lancet Oncology, 2024, PMID 39549720)

Grade 3+ adverse events: 49% (HIPEC) vs 27% (no HIPEC) - significantly more toxicity with HIPEC

• Anaemia: 23% vs 14%
• Electrolyte disturbance: 14% vs 1%
• Renal failure: 10% vs 1%
• Hepatotoxicity: 11% vs 9%

Key conclusion: In patients with first platinum-sensitive recurrence undergoing secondary CRS after NACT, HIPEC improves OS by ~8.5 months. However, it comes with a significantly higher toxicity burden - critically, renal toxicity is 10-fold higher, warranting careful patient selection.

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4.4 HORSE Trial / MITO-18 (JCO, 2025, PMID 39571127)

Key conclusion: HIPEC did NOT improve PFS when added to secondary CRS performed without prior NACT, in platinum-sensitive recurrent EOC. The contrast with CHIPOR (which WAS positive) highlights a critical finding: prior platinum exposure (NACT) appears to be a prerequisite for HIPEC benefit - possibly by sensitizing residual cells to subsequent cisplatin-based HIPEC.

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4.5 CHOICEM Trial - Primary CRS Setting

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5. Meta-Analyses and Systematic Reviews

5.1 Filis et al., ESMO Open 2022 (PMID 36116421) - Randomized Trials Only

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5.2 Kim et al., Gynecol Oncol 2022 (PMID 36273925) - 15 Studies (RCTs + Case-Control)

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5.3 Bogani et al., Gynecol Oncol 2025 (PMID 40763418) - 7 Phase III RCTs, 1252 Patients

• Confirmed benefit in interval CRS and in platinum-sensitive recurrence after NACT
• Emphasized the importance of patient selection, technical expertise, and integration with PARP inhibitors
• Highlighted emerging data on HIPEC + targeted therapy combinations

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5.4 Taliento et al., Ann Surg Oncol 2025 - Recent Meta-analysis

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6. Guideline Positions (2025)

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7. Toxicity Profile

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8. Patient Selection Criteria

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9. Integration with Modern Therapies (PARP Inhibitors, Bevacizumab)

• OVHIPEC-2 trial (NCT03772028, ongoing): Directly evaluates whether HIPEC benefit persists in the modern era of PARP inhibitor maintenance
• Theoretical concern: If PARP inhibitors already extend PFS/OS markedly, the additive value of HIPEC may be reduced - or it may remain additive in BRCA-wildtype/HRD-negative patients
• NCT05659381: HIPEC followed by niraparib maintenance - specifically recruiting HRD-positive patients

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10. Ongoing Clinical Trials

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11. Evidence Summary and Clinical Decision Framework

PATIENT WITH ADVANCED OVARIAN CANCER
                │
                ▼
     Is primary debulking feasible?
         /                \
        YES               NO (or R0 not achievable)
        │                 │
   Primary CRS            ↓
  (HIPEC here is      NEOADJUVANT CHEMOTHERAPY
   NOT standard;      (3-4 cycles carboplatin/paclitaxel)
   investigational)         │
                            ▼
                   Reassess for interval CRS
                       /         \
                Responding        Not responding
                    │                 │
            INTERVAL CRS          Continue chemo
          ± HIPEC (cisplatin)     (surgery less likely)
           CONSIDER HIPEC
       (ASCO: Conditional rec.)
       (ESGO/ESMO: Recommended
        at specialist centers)

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12. Summary Evidence Table - All Major RCTs

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13. Key Controversies and Unresolved Questions

1. NACT requirement: Should HIPEC only be used after prior NACT? Evidence consistently favors HIPEC in the post-NACT setting. The HORSE trial (no NACT) was negative.
2. Primary CRS setting: No phase III evidence yet supports HIPEC at primary CRS - CHOICEM results are eagerly awaited.
3. Platinum-resistant recurrence: Almost no prospective data; NCT05316181 is addressing this.
4. Agent choice: Cisplatin dominates but nephrotoxicity is a real concern. Carboplatin may be less toxic; trials with carboplatin HIPEC are ongoing.
5. PARP inhibitor interaction: Does HIPEC benefit persist with modern maintenance therapy? OVHIPEC-2/FOCUS will answer this.
6. Optimal temperature and duration: 41-43°C for 60-90 min is standard but not rigorously compared head-to-head.
7. Histological subtype specificity: Most evidence is from high-grade serous EOC. Clear cell, mucinous, low-grade serous histotypes are underrepresented.
8. Cost-effectiveness: Adding HIPEC increases procedure time, hospitalization, and resource use. At high-volume centers, this is generally considered acceptable given OS gain, but varies by healthcare system.

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14. Bottom Line

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• OVHIPEC-1 10-year analysis - Aronson et al., Lancet Oncol 2023 (PMID 37708912)
• CHIPOR trial - Classe et al., Lancet Oncol 2024 (PMID 39549720)
• HORSE/MITO-18 trial - Fagotti et al., JCO 2025 (PMID 39571127)
• Filis meta-analysis - ESMO Open 2022 (PMID 36116421)
• Kim meta-analysis - Gynecol Oncol 2022 (PMID 36273925)
• Bogani 2025 systematic review - Gynecol Oncol 2025 (PMID 40763418)
• ASCO 2025 guideline update on NACT for ovarian cancer - Gaillard et al., JCO 2025 (PMID 39841949)