Editorial Comment to Systemic therapy in the management of localized and locally advanced renal cell carcinoma: Current state and future perspectives.

Abstract

Although adjuvant therapy for renal cell carcinoma (RCC) has been much anticipated, previous studies were unable to show prolonged survival of patients. The ASSURE (sunitinib or sorafenib vs placebo),1 PROTECT (pazopanib vs placebo)2 and ATLAS (axitinb vs placebo)3 studies failed to show prolongation of disease-free survival (DFS) in high-risk patients after nephrectomy. In the S-TRAC study (sunitinib vs placebo) in patients with locally advanced RCC (pT3 and pT4), although prolongation of DFS was reported, the efficacy for prolonging overall survival was not proved.4 The benefit appeared to be restricted to patients with short DFS or short overall survival after surgery. DFS typically represents the primary end-point in clinical studies of adjuvant therapy using tyrosine kinase inhibitors (TKIs). When an adjuvant therapy prolongs only DFS, but not overall survival, it is debatable whether there is any benefit in the treatment. Some patients not requiring the treatment are frequently enrolled in adjuvant therapy. Even if adjuvant therapy results prolong DFS after nephrectomy, the patient must continue taking the medication during this period. Furthermore, multiple patients experience adverse events with TKI therapy, leading to decreased quality of life. Because a subset of patients with metastatic RCC do show a complete response with TKI treatment, given that TKIs can cause tumor shrinkage through the inhibition of angiogenesis, adjuvant therapy using TKI seems to be limited in the adjuvant setting. When administered as neoadjuvant therapy, TKI treatment is not indicated for all patients with advanced RCC scheduled to undergo nephrectomy, because evidence for an objective response rate is insufficient and no predictive marker of treatment effectiveness has been reported to date. Neoadjuvant treatment should be used in patients likely to benefit from systemic therapy, such as surgical patients at high risk for inferior vena cava thrombus or imperative cases of partial nephrectomy. In patients with advanced RCC, the therapeutic effect might be of value in determining the surgical indication. Berquist et al. also describe clinical trials that include ongoing or unreported studies on neoadjuvant and adjuvant therapy in high-risk patients with RCC, and discuss the adaptation of these studies.5 However, the issue is not yet settled, because the results from clinical trials remain inconclusive. Several clinical trials investigating novel therapies, such as immune checkpoint inhibitors, are also ongoing, and future novel strategies for adjuvant and neoadjuvant therapy might provide real benefits for patients with RCC. None declared.