Perioperative Systemic Therapy in Localized Renal Cell Carcinoma: Current Evidence and Future Directions

Area of Science:

• Oncology
• Nephrology
• Immunotherapy
• Clinical Trials

Background:

• Localized renal cell carcinoma (RCC) recurrence post-nephrectomy is a significant concern, especially with adverse pathological features.
• Perioperative systemic therapies are explored to eliminate micrometastatic disease in localized RCC.
• Current evidence for neoadjuvant, adjuvant, and perioperative strategies in localized RCC requires comprehensive review.

Purpose of the Study:

• To review current evidence on neoadjuvant, adjuvant, and perioperative systemic therapies for localized RCC.
• To outline how emerging biological insights can inform future trial designs and clinical practice for localized RCC.
• To assess the efficacy and feasibility of various perioperative strategies in localized RCC.

Main Methods:

• Conducted a narrative, non-systematic review of phase II-III studies and conference presentations up to August 2025.
• Examined trials reporting disease-free survival, recurrence-free survival, overall survival, perioperative feasibility, and translational endpoints.
• Cross-checked data against full texts and meeting abstracts for accuracy.

Main Results:

• Adjuvant pembrolizumab demonstrated improved disease-free and overall survival in high-risk clear-cell RCC, establishing it as standard care.
• Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and mTOR inhibitors showed inconsistent results, lacking a clear survival benefit.
• Neoadjuvant immune checkpoint inhibitor (ICI), TKI, and immuno-oncology-tyrosine kinase inhibitor (IO-TKI) regimens were feasible and safe, with modest radiographic shrinkage but notable surgical facilitation, especially in cases with inferior vena cava tumor thrombus. No randomized neoadjuvant trial improved survival, and the PROSPER RCC trial did not improve recurrence-free survival.

Conclusions:

• Adjuvant pembrolizumab is a practice-changing treatment for high-risk clear-cell RCC.
• Neoadjuvant and perioperative approaches for localized RCC remain investigational, requiring further research into optimal timing, duration, and patient selection.
• Biomarker-driven patient selection and adaptive/platform trial designs are crucial for advancing perioperative immunotherapy strategies in RCC.