Adjuvant treatment of high-risk renal cell carcinoma: the jury is still out
Authors: G. Procopio, P. Sepe, E. Verzoni, S. Pignata, A. Bamias
Journal: Annals of Oncology (2018)

Renal cell carcinoma (RCC) is a heterogeneous disease [1.Lam J.S. Shvarts O. Leppert J.T. et al.Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system.J Urol. 2005; 174: 466-472Crossref PubMed Scopus (238) Google Scholar] with considerable variation in its natural history. Surgery remains the most important curative option for localized disease [2.Capitanio U. Montorsi F. Renal cancer.Lancet. 2016; 387: 894-906Abstract Full Text Full Text PDF PubMed Scopus (590) Google Scholar], however, up to 30% of patients will develop metastases after a potentially curative nephrectomy [3.Li P. Wong Y.N. Armstrong K. et al.Survival among patients with advanced renal cell carcinoma in the pretargeted versus targeted therapy eras.Cancer Med. 2016; 5: 169-181Crossref PubMed Scopus (71) Google Scholar]. Several prognostic factors, such as histologic subtype, pathological Fuhrman grade, tumor dimension or extension and lymph node involvement permit to stratify patients according to prognostic models able to predict the risk of recurrence [4.Escudier B. Porta C. Schmidinger M. et al.Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2016; 27: v58-v68Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar]. Adjuvant systemic therapy following nephrectomy has been used to reduce relapse rates and improve survival in high-risk patients. Interferon-α and interleukin-2 were the first agents to be investigated but failed to improve these end points [5.Pizzocaro G. Piva L. Colavita M. et al.Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: a multicentric randomized study.JCO. 2001; 19: 425-431Crossref PubMed Scopus (235) Google Scholar, 6.Clark J.I. Atkins M.B. Urba W.J. et al.Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial.J Clin Oncol. 2003; 21: 3133-3140Crossref PubMed Scopus (267) Google Scholar]. Recently, the impressive efficacy of VEGFR tyrosine kinase inhibitors (TKIs) in advanced stages led to the investigation of these agents in the adjuvant setting [7.Choueiri T.K. Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma.N Engl J Med. 2017; 376: 354-366Crossref PubMed Scopus (714) Google Scholar]. Up to now, four studies have been reported. Three of them, ASSURE, PROTECT and ATLAS showed no improvement in disease-free survival (DFS) and overall survival (OS) after 1 year of sunitinib, sorafenib, pazopanib or axitinib over placebo as adjuvant treatment in patients with localized RCC in high risk of relapse after nephrectomy [8.Haas N.B. Manola J. Dutcher J.P. et al.Adjuvant treatment for high-risk clear cell renal cancer: updated results of a high-risk subset of ASSURE randomized trial.JAMA Oncol. 2017; 3: 1249-1252Crossref PubMed Scopus (102) Google Scholar, 9.Motzer R.J. Haas N.B. Donskov F. et al.Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma.J Clin Oncol. 2017; 35: 3916-3923Crossref PubMed Scopus (264) Google Scholar, 10.NCT01599754. Adjuvant axitinib therapy of renal cell cancer in high risk patients (ATLAS). https://clinicaltrials.gov/ct2/show/NCT01599754 (5 August 2018, date last accessed).Google Scholar]. In contrast, S-TRAC met its primary end point to improve DFS (HR 0.76; 95% CI 0.59–0.98; P = 0.03) in patients receiving 1 year of sunitinib over placebo after a radical nephrectomy [11.Ravaud A. Motzer R.J. Pandha H.S. et al.Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy.N Engl J Med. 2016; 375: 2246-2254Crossref PubMed Scopus (515) Google Scholar]. Several reasons have been offered to explain these contradictive results [12.Figlin R.A. Leibovich B.C. Stewart G.D. Negrier S. Adjuvant therapy in renal cell carcinoma: does higher risk for recurrence improve the chance for success?.Ann Oncol. 2018; 29: 324-331Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. Among them, the lower exposure to the studied agents for dose and duration in the ASSURE and PROTECT trials has been suggested as being important in this respect. It is exactly, because of this speculation why the paper by Staehler et al. [13.Staehler M. Motzer R.J. George D.J. et al.Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial.Ann Oncol. 2018; 29: 2098-2104Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar], published in this issue of Ann Oncol offers valuable information. Staehler et al. report original data of the S-TRAC trial on treatment interruption, modification and discontinuation, therapy management and patient-reported outcomes (PROs) on global health status and quality of life (GHS/QoL). They conclude that proactive management of side-effects helped to maintain a higher than that reported in the other trials percentage of patients on treatment, while the deterioration on PROs was not clinically meaningful. We believe that some of the results and the conclusions are worth discussing further. We fully concur with the first conclusion. Efforts for prevention and aggressive management of side-effects cannot be overemphasized in the context of treatment with VEGFR TKIs. This is particularly important in the adjuvant setting. This study offers convincing evidence that patients receiving adjuvant TKIs are less tolerant to low or moderate toxicities, which, nevertheless, affect their QoL, compared with patients with active disease. High-grade hypertension, which is normally asymptomatic and treatable, did not affect QoL. On the contrary, low grade but symptomatic and not effectively treatable toxicities, were the cause of permanent discontinuation of therapy in 40% of cases. Similarly, palmar-plantar dysesthesia, which is mainly associated with patients’ perception of severity, was reported as more severe than expected from metastatic setting. In spite of clearly being more successful that other adjuvant studies to maintain exposure to sunitinib, S-TRAC still reported premature discontinuation of sunitinib in 44% of patients, mainly due to side-effects (40% of which grade 1–2, as already mentioned). PROs have emerged as an important tool for the assessment of patients’ perception of toxicity and they have been appropriately used in this study. They showed deterioration during therapy, indicating a detrimental effect of adjuvant sunitinib on GHS/QoL. The authors argue that this effect was not significant by using the clinically important difference (CID) scale [14.Osoba D. Rodrigues G. Myles J. et al.Interpreting the significance of changes in health related quality-of-life scores.J Clin Oncol. 1998; 16: 139-144Crossref PubMed Scopus (2152) Google Scholar, 15.King MT. The interpretation of scores from the EORTC quality of life questionnaire QLQ-C30.Qual Life Res. 1996; 5: 555-567Crossref PubMed Scopus (480) Google Scholar]. Not disregarding the importance of trying to quantify PROs, this scale was developed in different settings 20 years ago. The impact of CID score on patients’ compliance could have been further supported if a correlation between this score and the probability of treatment modification or discontinuation had been sought. Such finding was not reported. Therefore, to our opinion, findings related to CID scale should not override the main QoL analysis results. On the contrary, we believe that these results relate quite convincingly the fairly poor compliance with the side-effects of therapy, which was perceived by patients as significant and led many of them to discontinue it. This last point generates the important question: ‘What is the benefit for which patients in the adjuvant setting should be encouraged to tolerate the undoubted and so accurately described in this paper side-effects of sunitinib?’ At a median follow up time of 5 years, no evidence of OS improvement or reduction of risk of death was observed in the S-TRAC trial for the sunitinib arm [16.Motzer R.J. Ravaud A. Patard J. et al.Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results.Eur Urol. 2017; 73: 62-68Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar]. Currently, the role of angiogenetic inhibitors in adjuvant setting in RCC remains under debate. As a consequence, FDA and EMA have given different opinions on the approval of sunitinib as adjuvant treatment: FDA is in favor, while EMA is not. In addition, guidelines on adjuvant treatment divided: NCCN in favor [17.Jonasch E. Updates to the Management of Kidney Cancer.J Natl Compr Cancer Netw. 2018; 16: 639-641Crossref PubMed Scopus (21) Google Scholar], EAU against [18.EAU Guidelines 2018. http://uroweb.org/guideline/renal-cell-carcinoma/ (20 July 2018, date last accessed).Google Scholar]. Data on the subject will continue to emerge. Other clinical trials assessing the role of targeted therapies have completed the accrual but no data are yet available. The SORCE study investigated the duration of adjuvant treatment comparing sorafenib for 1 year versus sorafenib for 3 years over placebo, while the EVEREST trial tested the role of everolimus compared with placebo [19.Ritchie A.W. Meade A.M. Choo L. et al.MRC SORCE trial: analysis of patients' presenting characteristics, tumor staging, and surgical approach.JCO. 2014; 32 (496-496)Google Scholar, 20.NCT01120249. S0931, Everolimus in treating patients with kidney cancer who have undergone surgery (S0931). https://clinicaltrials.gov/ct2/show/NCT0112024 (5 August 2018, date last accessed).Google Scholar]. In addition, several trials testing new immunotherapy agents, inhibiting the interaction between the programmed cell death-1 (PD-1) receptor with its ligand (PD-L1) are in progress. Studies in advanced disease have suggested a more favorable toxicity profile compared with that of TKIs, suggesting that compliance of patients receiving adjuvant therapy might be improved. In conclusion, the field of systemic adjuvant therapy in high-risk resected RCC is still evolving. Currently, inclusion in a clinical trial represents the best management option. If no clinical trials are available, motivated high-risk patients can be informed about available evidence and make shared decisions with their physicians. In this context, the data presented in the paper in discussion represent a valuable tool for decision-making and patients’ counseling. None declared.