Two trials investigated the role and sequence of cytoreductive nephrectomy: CARMENA1 and SURTIME.2 CARMENA randomized patients 1:1 ratio to undergo nephrectomy and then receive sunitinib or to receive sunitinib alone. At the planned interim analysis, the median follow-up was 50.9 months, and the results in the sunitinib-alone group were non-inferior to those in the nephrectomy-sunitinib group with regard to overall survival (hazard ratio [HR] for death 0.89, 95% confidence interval [CI] 0.71-1.10; the upper boundary of the 95% confidence interval for noninferiority, ≤1.20). The SURTIME trial assessed immediate surgery or surgery after sunitinib in treating patients with metastatic renal cell carcinoma (RCC). The intention-to-treat overall survival (OS) HR of deferred vs immediate cytoreductive nephrectomy was 0.57 (95% CI, 0.34-0.95; p = 0.03), with a median OS of 32.4 months (95% CI, 14.5-65.3 months) in the deferred cytoreductive nephrectomy arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate cytoreductive nephrectomy arm.
Dr. Bex notes that it is important to highlight in SURTIME that a survival difference of 17.4 months was achieved among those having systemic therapy upfront and only undergoing a cytoreductive nephrectomy if they did not progress to metastatic disease during that treatment interval. These results were also achieved in CARMENA in an updated analysis in that 18% of the patients in the sunitinib arm underwent a delayed cytoreductive nephrectomy. Furthermore, an updated presentation of the results of CARMENA at the 2019 ASCO meeting suggested that in a posthoc analysis, those with two c risk factors still benefited from sunitinib alone:
Data from the last several years has lead the European Society for Medical Oncology (ESMO) and EAU guidelines to suggest that patients with intermediate-and poor-risk disease should be given upfront systemic therapy, leaving the window open for a deferred nephrectomy if they have adequate response and do not progress with upfront systemic therapy. Moving into a new immunotherapy treatment landscape, Dr. Bex notes that more and more patients are receiving upfront IO-TKI or IO-IO combination therapy with their kidney in situ and that upfront treatment (and those that respond to treatment) is a way to stratify those that may (or may not benefit) from a cytoreductive nephrectomy.
To summarize, Dr. Bex notes that the concept of systemic therapy first is a legacy of SURTIME and CARMENA and that downsizing of a primary tumor with combination therapy is likely a concept that is here to stay.
Presented by: Axel Bex, MD, PhD, Consultant Clinical Lead Specialist Centre for Kidney Cancer, Associate Professor UCL Division of Surgical and Interventional Science, The Royal Free London NHS Foundation Trust, London, United Kingdom
Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, Twitter: @zklaassen_md at the Virtual 2020 EAU Annual Meeting #EAU20, July 17-19, 2020
References:
1. Méjean, Arnaud, Alain Ravaud, Simon Thezenas, Sandra Colas, Jean-Baptiste Beauval, Karim Bensalah, Lionnel Geoffrois et al. "Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma." New England Journal of Medicine 379, no. 5 (2018): 417-427.
2. Bex, Axel, Peter Mulders, Michael Jewett, John Wagstaff, Johannes V. Van Thienen, Christian U. Blank, Roland Van Velthoven et al. "Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial." JAMA oncology 5, no. 2 (2019): 164-170.