**8. Conclusions and future directions**

Targeted therapy has become the current mainstay in the management of metastatic RCC and its success with advanced stage disease has been the driving force behind the increasing number of targeted therapy trials in the adjuvant setting. The emergence of immune checkpoint inhibitors in the last couple of years has further led to important advances in our understanding and management of mRCC. However, many ongoing trials are yet to be completed in both cases and there is ample potential for further investigation—especially with respect to combinational therapy regimes. This includes the combination of TKIs with immune therapies (e.g., NCT01513187: Pazopanib with Interferon Alfa 2-A), combination of TKIs with chemotherapeutics (e.g., NCT00556049: Sunitinib with Gemcitabine), and the combination of anti-VEGF antibodies and mTOR inhibitors (e.g., NCT01399918: bevacizumab and everolimus). All of these treatments may be of interest for future adjuvant trials in RCC if they are found to be effective in stage IV disease. However, they may have more side effects, making them less suitable in particular for adjuvant treatment. Nonetheless, the current information, which has resulted from all the progress in the field, remains incongruent. While the current set of completed adjuvant clinical trials have provided negative or conflicting results (ARISER, PROTECT, S-TRAC vs. ASSURE), there are additional large-scale trials that are still in progress. The existing trial design has several limitations, the key one being the overall lack of standardization seen across various assessment criteria. Future directions include incorporating a genetic recurrence score to evaluate risk of relapse in patients, developing an adequate and an objectively standardized adjuvant trial design, identifying novel biomarkers and evaluating novel drug targets.

That based on results from current trials, the "high risk for recurrence" RCC patient population (T3-T4, grade 3-4) may benefit from adjuvant sunitinib providing DFS advantage but pending OS results. Patients, in this category, interested in adjuvant therapy would benefit from a discussion with an oncologist regarding the potential benefits and risks of adjuvant treatment post kidney cancer surgery. Overall, the landscape of adjuvant treatment in nonmetastatic high-risk RCC is expected to expand and to further develop in the coming years.
