Long-term outcomes with hyperthermic intraperitoneal chemotherapy in patients with ovarian cancer: Meta-analysis of 10 randomized trials

Technical Summary: Long-term Outcomes with Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer

Problem Statement
Ovarian cancer (OC) remains a leading cause of cancer-related mortality among women, primarily due to late-stage diagnosis and the high prevalence of peritoneal metastases. Standard treatment involves cytoreductive surgery (CRS) followed by platinum-based systemic chemotherapy. While Hyperthermic Intraperitoneal Chemotherapy (HIPEC) has emerged as a targeted strategy to address microscopic residual disease in the peritoneal cavity, previous meta-analyses indicated survival benefits only within the first three years. The long-term efficacy of HIPEC when added to CRS, particularly beyond five to ten years, and its differential impact based on surgical timing (primary vs. interval) and tumor status (primary vs. recurrent), remains unclear. This study aims to investigate long-term survival and progression rates in OC patients undergoing HIPEC compared to CRS alone.

Methodology
This systematic review and meta-analysis adhered to PRISMA guidelines and the Cochrane Handbook. The authors conducted a comprehensive search of electronic databases (PubMed, Embase, CENTRAL, Scopus, Web of Science) up to December 20, 2024, with an update on August 8, 2025.

• Inclusion Criteria: Randomized Controlled Trials (RCTs) comparing HIPEC plus CRS versus CRS alone in patients with primary or recurrent ovarian cancer, reporting Overall Survival (OS) or Progression-Free/Disease-Free Survival (PFS/DFS).
• Data Synthesis: A total of 10 RCTs involving 1,508 patients were included. Due to the reliance on published Kaplan-Meier (KM) curves, the authors employed a two-stage reconstruction method using the IPDfromKM R package to derive Individual Patient Data (IPD). This allowed for the reconstruction of survival curves and the calculation of Hazard Ratios (HRs) and Restricted Mean Survival Time (RMST).
• Statistical Analysis: Random-effects models were used for pairwise meta-analysis. Subgroup analyses were performed based on surgical approach (primary surgery vs. interval surgery after neoadjuvant chemotherapy) and tumor type (primary vs. recurrent). Heterogeneity was assessed using $I^2$ statistics, and sensitivity analyses (leave-one-out) were conducted to test robustness.
• Quality Assessment: The Cochrane Risk of Bias Tool (ROB-2) and GRADE criteria were applied. Five studies were rated as "low risk" of bias, while five had "some concerns." The overall quality of evidence for OS and PFS/DFS was graded as high.

Key Contributions and Results
The analysis of 10 RCTs (1,508 patients) yielded the following long-term outcomes:

1. Overall Survival (OS):

   • Global Analysis: The addition of HIPEC to CRS showed a trend toward lower mortality (HR: 0.82, 95% CI [0.65 to 1.01], $p=0.09$) over 10 years, though this was not statistically significant. The median survival was slightly higher in the HIPEC group (3.72 years) compared to CRS alone (3.68 years).
   • RMST: The Restricted Mean Survival Time was significantly higher in the HIPEC group (5.16 years vs. 4.56 years; difference 0.59 years, $p=0.04$).
   • Subgroup Analysis (Surgical Timing): A significant survival benefit was observed specifically in patients undergoing interval surgery (surgery after neoadjuvant chemotherapy). In this subgroup, HIPEC reduced mortality by 43% (HR: 0.57, 95% CI [0.43 to 0.82], $p<0.001$). Conversely, no significant difference in OS was found for primary surgery or recurrent tumors.

2. Progression-Free/Disease-Free Survival (PFS/DFS):

   • Global Analysis: HIPEC plus CRS was associated with a similar incidence of progression compared to CRS alone (HR: 0.80, 95% CI [0.66 to 1.02], $p=0.06$).
   • RMST: The RMST difference was statistically significant (1.902 years vs. 1.835 years; difference 0.42 years, $p=0.025$).
   • Subgroup Analysis: Similar to OS, a significant reduction in progression rates (36% reduction, HR: 0.64, $p=0.001$) was found exclusively in the interval surgery subgroup. No significant benefit was observed in primary surgery or recurrent tumor subgroups.

3. Safety and Heterogeneity:

   • The study noted high heterogeneity in the global analysis ($I^2 > 50\%$), which was reduced in subgroup analyses, particularly for interval surgery.
   • Adverse events were noted in included studies, with one study reporting a higher incidence of Grade $\ge$3 adverse events in the HIPEC group (49% vs. 27%).

Significance and Claims
The paper claims that the long-term survival benefit of HIPEC in ovarian cancer is not uniform across all patient populations but is highly dependent on the surgical context.

• Specific Benefit: The authors conclude that adding HIPEC to CRS significantly improves long-term OS and PFS/DFS specifically for patients with primary ovarian cancer who undergo interval surgery following neoadjuvant chemotherapy.
• Lack of Benefit in Other Contexts: The study finds no statistically significant long-term survival or progression advantage for patients undergoing primary surgery or those with recurrent ovarian cancer.
• Clinical Alignment: These findings support current guidelines (e.g., ASCO 2025 update) that suggest HIPEC may be considered for medically fit patients at the time of interval surgery, while noting a lack of consensus or recommendation for its use in primary debulking or relapsed disease.

The authors emphasize that while the overall quality of evidence is high, future research should focus on larger, strictly designed RCTs to further validate these subgroup-specific benefits and address protocol heterogeneity.