Omics-guided surgical paradigms may identify specific patients for selective retroperitoneal clearance in advanced ovarian cancerNew Surgical Approach May Reduce Risks for Ovarian Cancer Patients

The LION and CARACO trials demonstrated that routine systematic pelvic and para-aortic lymphadenectomy (LAD) confers no survival benefit in clinically node-negative advanced epithelial ovarian cancer (EOC), while significantly increasing perioperative morbidity. However, these trials evaluated unselected populations without molecular stratification. This review proposes an omics-guided, anatomically precise surgical paradigm to identify patients who may benefit from selective retroperitoneal clearance. A synthesis of recent landmark clinical trials, international surgical guidelines, and emerging multi-omics datasets was conducted to evaluate retroperitoneal lymph nodes as complex architectural niches characterized by passive drug diffusion limits and chemotherapy-induced structural remodelling. Approximately 30–50% of advanced high-grade serous EOC cases exhibit primary or acquired resistance to standard platinum/taxane chemotherapy. Biological and spatial transcriptomic data indicate that retroperitoneal nodes can act as sanctuaries where resistant clones persist despite systemic therapy, driving later recurrence. Validated preoperative biomarkers; including homologous recombination proficiency (HRD-negative status), investigational markers such as enhancer-associated MSH6 downregulation and specific proteomic panels under investigation (e.g., PRKAR2B/SKP2) show strong predictive potential for primary chemoresistance within exploratory validation cohorts. A one-size-fits-all approach to surgical de-escalation tends to overlook a critical, molecularly defined minority. Shifting the surgical paradigm toward biomarker-guided anatomical precision offers a conceptual, hypothesis-generating blueprint for future clinical trials, testing whether restricting systematic para-aortic lymphadenectomy to preoperatively identified chemoresistant subsets provides true therapeutic utility.