Adjuvant treatment for renal cell carcinoma: in the long run will we get the same answers?

KEYWORDS:

• Renal cell carcinoma
• targeted agents
• adjuvant therapy
• immunecheckpoint inhibitors
• immunotherapy

While adjuvant medical treatment is a standard of care in many solid tumors including colon, breast cancer, and gastrointestinal stromal tumors [1–3], no adjuvant therapy has demonstrated to increase disease-free survival (DFS) in patients receiving nephrectomy for localized renal cell carcinoma (RCC). Interleukin-2 and interferon-a studies as adjuvant treatment have been negative [4,5] while more encouraging results with vaccine therapy were observed. Since targeted agents have been approved for metastatic disease, a series of either completed and ongoing studies testing tyrosine-kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors as adjuvant strategies in RCC are yet to produce positive data. The PROTECT [6] and the S-TRAC trials [7] are phase III, randomized, double-blind, and placebo-controlled studies evaluating the efficacy of adjuvant pazopanib and sunitinib for 1 year, respectively, in patients with resected clear-cell RCC with the primary end point of DFS. Adjuvant trials raise the question about the proper duration of TKIs’ therapy in this setting. This issue is being explored in the ongoing SORCE study [8], which is comparing placebo versus sorafenib for 1 year or 3 years in resected clear cell and non-clear cell RCC patients. The ATLAS study [9] is also investigating prolonged adjuvant therapy for another TKI, axitinib, by comparing placebo versus axitinib for 3 years in very high-risk (as scored by UISS criteria), clear cell RCC patients. These studies may provide answers to whether prolonged duration of treatment is necessary to observe a clinical benefit in these patients. However, even if these trials show a benefit with prolonged administration, the tolerability of these agents is still in question. EVEREST [10] is the only phase III trial evaluating the role of mTOR inhibitor in an adjuvant setting. In this study, high-risk patients (high-grade pT1bN0M0 or pT2-4NþM0) were randomized to either everolimus or placebo for a period of 1 year. Outside of TKIs and mTOR inhibitors, girentuximab, an antibody toward carbonic anhydrase and an heat-shock protein complex, HSPPC-96, were tested as adjuvant approach versus placebo (ARISER study) and observation, respectively, with no differences in DFS observed [11,12].

The recently published phase III ASSURE trial aimed to test the role of sorafenib and sunitinib in prolonging DFS in resected high-risk renal-cell carcinoma [13]. Patients were randomized to 1-year treatment with sorafenib, sunitinib, or placebo. The researchers conclude that there was no benefit in DFS of both agents compared to placebo. One point of interest of this study was the effect of dose, dose-reduction, and drop-out rate on clinical efficacy. Among patients starting at full dose, the overall rates of treatment discontinuation due to adverse events or patients withdrawal was 44% in the sunitinib group, 45% and 11% in the sorafenib and placebo groups, respectively. However, authors did not find any significant correlation between drug discontintuation and DFS. One issue to consider is the heterogeneity of risk score assessment used in adjuvant trials. Using a wide spectrum of stage and grade, the risk of recurrence varies widely and the heterogeneity amongst the nomograms for localized RCC represents a challenge to uniform guidelines for risk assessment. Eventually, the discordance between these nomograms should be taken into consideration when interpreting study results in adjuvant setting. Moreover, the use of recurrence-free survival (defined as time to any event related to the same cancer) as primary end point for adjuvant trials instead of DFS (defined as the time to any event, irrespective of cause) may be more appropriate. These studies highlighted major challenges in the way in which targeted treatments are tested for cancer. However, the precise role and effect on outcome of TKIs in this patient group is still under debate and it raises the question of whether the observed negative results are due to ineffective agents, mechanisms of action, or disease biology. Due to these reasons, results from ASSURE trial should be interpreted with caution and the awaited results of ongoing adjuvant trials may be different since characteristics of either agents tested and patients populations are not directly comparable and this may affect results. Trial enrichment for molecular subgroups of patients at very high risk that may benefit from specific treatments are needed to provide further insights into the assessment of targeted agents as adjuvant strategy. Additional studies with novel emerging immunotherapy approaches such as anti-programmed death-1 therapy warrant further evaluation in this setting.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.