Understanding and integrating cytoreductive nephrectomy with immune checkpoint inhibitors in the management of metastatic RCC

Cytoreductive nephrectomy became accepted as standard of care for selected patients with metastatic renal cell carcinoma (mRCC) because of improved survival observed in patients treated with cytoreductive nephrectomy in combination with interferon-α in two randomized clinical trials published in 2001. Over the past two decades, novel systemic therapies have shown higher treatment response rates and improved survival outcomes compared with interferon-α. During this rapid evolution of mRCC treatments, systemic therapies have been the primary focus of clinical trials. Results from multiple retrospective studies continue to suggest an overall survival benefit for selected patients treated with nephrectomy in combination with systemic mRCC treatments, with the notable exception of one debated clinical trial. The optimal timing for surgery is unknown, and proper patient selection remains crucial to improving surgical outcomes. As systemic therapies continue to evolve, clinicians have an increasing need to understand how to incorporate cytoreductive nephrectomy into the management of mRCC. In this Review, the authors present the history of cytoreductive nephrectomy, discuss controversial results from clinical trials and assess future perspectives about the role of surgery in the management pathway of patients with metastatic renal cell carcinoma. Key points Cytoreductive nephrectomy is an integral part of the management of patients with metastatic renal cell carcinoma (mRCC) with good performance status and limited metastatic burden. Results from the CARMENA trial suggested no survival benefit for cytoreductive nephrectomy in patients with high-risk mRCC and substantial metastatic burden treated with sunitinib. As systemic therapies evolve, optimal timing of cytoreductive surgery and proper patient selection continue to be investigated. Treatment of patients with mRCC should include evaluation by an experienced and multidisciplinary team. Integrating surgery into future mRCC treatment algorithms should involve the development of accurate pre-surgery risk stratification systems and novel clinical trial designs to investigate the continued utility and optimal timing of cytoreductive nephrectomy.