Perioperative systemic therapy in high-risk renal cell carcinoma following nephrectomy: a narrative review

Background and Objective: For patients with resectable renal cell carcinoma (RCC), extirpative surgery with curative intent remains the standard of care. Despite surgical resection, most patients with high- risk features experience disease recurrence. The role of perioperative systemic therapy in the management of these patients' disease remains unclear. Several studies have evaluated the efficacy and safety of tyrosine kinase inhibitors (TKIs); however, most trials have yielded negative results. Adjuvant pembrolizumab demonstrated a disease-free survival benefit in the KEYNOTE-564 trial; however, multiple studies of other immune checkpoint inhibitors (ICIs) in a similar patient population did not yield consistent results. This review summarizes the current evidence for perioperative systemic therapy studies in RCC. Methods: The PubMed, American Society of Clinical Oncology (ASCO), and clinicaltrials.gov databases were used to retrieve articles published from January 1, 2001 to December 31, 2023 using the following search terms: "adjuvant", "neoadjuvant", "perioperative", "VEGF inhibitors", "immune checkpoint inhibitors", and "renal cell carcinoma". The search was limited to articles published in English. Key Content and Findings: We summarize the major perioperative systemic therapy studies in RCC patients and provide an analysis of study outcomes, comparing differences in trial design and patient selection. We also discuss ongoing trials and the emergence of novel biomarkers designed to improve patient selection. Conclusions: The optimal use of perioperative systemic therapy in high-risk RCC is an area of active investigation. The use of adjuvant TKIs failed to demonstrate a survival benefit and was limited by high rates of toxicity. Several neoadjuvant and adjuvant ICI-based combination studies are being carried out to further improve clinical outcomes. Further studies will be needed to identify effective biomarkers to improve patient selection while avoiding overtreatment.