Complementary roles of surgery and systemic treatment in clear cell renal cell carcinoma

Standard-of-care management of renal cell carcinoma (RCC) relies on surgery for low-risk localized disease and systemic treatment for poor-prognosis metastatic tumours, but patients with high-risk localized tumours and with metastatic disease that has a good-to-intermediate prognosis are in a grey area for treatment. In this Review, the authors provide a comprehensive overview of the current knowledge on surgery and systemic treatment in the management of metastatic and localized RCC.Standard-of-care management of renal cell carcinoma (RCC) indisputably relies on surgery for low-risk localized tumours and systemic treatment for poor-prognosis metastatic disease, but a grey area remains, encompassing high-risk localized tumours and patients with metastatic disease with a good-to-intermediate prognosis. Over the past few years, results of major practice-changing trials for the management of metastatic RCC have completely transformed the therapeutic options for this disease. Treatments targeting vascular endothelial growth factor (VEGF) have been the mainstay of therapy for metastatic RCC in the past decade, but the advent of immune checkpoint inhibitors has revolutionized the therapeutic landscape in the metastatic setting. Results from several pivotal trials have shown a substantial benefit from the combination of VEGF-directed therapy and immune checkpoint inhibition, raising new hopes for the treatment of high-risk localized RCC. The potential of these therapeutics to facilitate the surgical extirpation of the tumour in the neoadjuvant setting or to improve disease-free survival in the adjuvant setting has been investigated. The role of surgery for metastatic RCC has been redefined, with results of large trials bringing into question the paradigm of upfront cytoreductive nephrectomy, inherited from the era of cytokine therapy, when initial extirpation of the primary tumour did show clinical benefits. The potential benefits and risks of deferred surgery for residual primary tumours or metastases after partial response to checkpoint inhibitor treatment are also gaining interest, considering the long-lasting effects of these new drugs, which encourages the complete removal of residual masses.