What are the criticisms of the OVijipec trial regarding Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for stage III ovarian cancer?

Major Criticisms of the OVHIPEC Trial for HIPEC in Stage III Ovarian Cancer

The OVHIPEC trial has significant methodological flaws that limit its applicability to the broader ovarian cancer population, making HIPEC not recommended as standard therapy for stage III ovarian cancer patients.

Patient Selection and Generalizability Issues

• The trial excluded all stage IV patients and included only a very small subset of stage III patients with disease too extensive for upfront debulking surgery or with residual disease >1cm after upfront surgery, making extrapolation to all advanced ovarian cancer patients impossible 1
• The slow recruitment rate reflected the highly selective nature of the eligible population 1
• The majority of stage III patients could be primarily debulked to <1cm in clinical practice, meaning most ovarian cancer patients would not meet the trial's inclusion criteria 1

Statistical and Methodological Concerns

• Overall survival (OS) was not designated as a primary/co-primary endpoint, which is problematic given the importance of this outcome 1
• The small study size introduces significant potential for bias, possibly explaining the imbalance in the progression-free survival (PFS) to overall survival (OS) improvement ratio 1
• The trial lacked stratification for critical prognostic factors including:
  • BRCA mutation status 1
  • FIGO subclassification 1
  • Response rates to neoadjuvant chemotherapy 1
  • Histological tumor type 1

Toxicity Reporting Issues

• HIPEC toxicity appeared to be underreported, with toxicity reported equally in both study arms despite:
  • Longer operation times in the HIPEC arm 1
  • Longer hospitalization periods in the HIPEC arm 1
  • More perioperative gastrostomies/stomas in the HIPEC arm 1
  • Vague reporting on known adverse events associated with HIPEC (e.g., acute renal failure) 1

Conflicting Evidence

• At the ASCO 2017 Congress, Lim et al. presented another trial of HIPEC in stage III and IV ovarian cancer that did not show statistical superiority of the HIPEC arm 1
• A meta-analysis of retrospective studies in advanced or recurrent epithelial ovarian cancer did not demonstrate any survival advantage with HIPEC but rather showed an increase in adverse events including anemia and acute kidney injury 1

Consensus Recommendations

• The ESMO-ESGO consensus conference (2019) explicitly states that HIPEC is not a standard of care as first-line treatment for ovarian cancer (Level of evidence: II, Strength of recommendation: A, with 95% consensus) 1
• The consensus recommends that HIPEC should be limited to well-designed prospective randomized controlled trials 1
• The 2023 ESMO guidelines continue to emphasize that HIPEC remains an area of research and should not be considered standard therapy 1

Ongoing Research

• Large prospective studies are still required to:
  • Further quantify the true efficacy of HIPEC 1
  • Compare HIPEC's efficacy and compatibility with targeted therapies (e.g., bevacizumab) 1
  • The OVHIPEC-2 trial is currently investigating HIPEC in the primary cytoreductive surgery setting 2

Despite showing improved PFS and OS in a specific subset of patients 3, the significant methodological limitations of the OVHIPEC trial prevent its findings from changing the standard of care for ovarian cancer treatment at this time.