Post nephrectomy management of localized renal cell carcinoma. From risk stratification to therapeutic evidence in an evolving clinical scenario

•About 35% of localized RCC patients recur after nephrectomy.•A unique and universally accepted risk factor model is still missing.•VEGFR-TKIs failed in demonstrating a significant activity as adjuvant treatment.•Adjuvant pembrolizumab significantly prolongs the disease-free survival.•The efficacy of others ICIs is controversial in the adjuvant/peri-operative setting.•The management of resected oligo-metastatic RCC patients (M1NED) is evolving. Standard treatment for localized non-metastatic renal cell carcinoma (RCC) is radical or partial nephrectomy. However, after radical surgery, patients with stage II-III have a substantial risk of relapse (around 35%). To date a unique standardized classification for the risk of disease recurrence still lack. Moreover, in the last years great attention has been focused in developing systemic therapies with the aim of improving the disease-free survival (DFS) of high-risk patients, with negative results from adjuvant VEGFR-TKIs. Therefore, there is still a need for developing effective treatments for radically resected RCC patients who are at intermediate/high risk of relapse. Recently, interesting results came from immune-checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway, with a significant benefit in terms of disease-free survival from adjuvant pembrolizumab. However, the conflicting results of diverse clinical trials investigating different ICI-based regimens in the adjuvant setting, together with the still immature data on the overall survival advantage of immunotherapy, requires careful considerations. Furthermore, several questions remain unanswered, primarily regarding the selection of patients who could benefit the most from immunotherapy. In this review, we have summarized the main clinical trials investigating adjuvant therapy in RCC, with a particular focus on immunotherapy. Moreover, we have analyzed the crucial issue of patients’ stratification according to the risk of disease recurrence, and we have described the possible future prospective and novel agents under evaluation for perioperative and adjuvant therapies.