The rationale for cytoreductive nephrectomy is that (i) there is an inability of targeted therapies or immunotherapy to induce meaningful, durable responses, (ii) there are anecdotal reports of spontaneous regression of metastases after nephrectomy, and (iii) surgery meaningfully diminishes the burden of disease in select patients.
Based on two recent trials, one would think there is no longer a role for cytoreductive nephrectomy. The CARMENA trial was a phase 3 trial of 450 patients who were suitable candidates for nephrectomy and were randomly assigned, in a 1:1 ratio, to undergo nephrectomy and then receive sunitinib or to receive sunitinib alone.1 Randomization was stratified according to prognostic risk (intermediate or poor) in the Memorial Sloan Kettering Cancer Center prognostic model, and the primary endpoint was overall survival. 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 (HR for death 0.89, 95% CI 0.71-1.10; the upper boundary of the 95% confidence interval for noninferiority, ≤1.20). The median overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy-sunitinib group. The investigators concluded that cytoreductive nephrectomy should no longer be part of the standard of care for patients with mRCC requiring medical treatment.
The second trial was the SURTIME trial,2 which assessed immediate surgery or surgery after sunitinib in treating patients with metastatic RCC. This study examined whether a period of sunitinib therapy before cytoreductive nephrectomy improves outcome compared with immediate cytoreductive nephrectomy followed by sunitinib. With an estimated sample size need of 458 patients to determine a difference PFS, unfortunately, the study closed after 5.7 years with 99 patients accrued. The 28-week progression-free rate was 42% in the immediate cytoreductive nephrectomy arm (n = 50) and 43% in the deferred cytoreductive nephrectomy arm (n = 49) (p = 0.61). The intention-to-treat 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. The consensus among experts is that because the trial accrued poorly, the results are mainly exploratory. Interestingly, the sequence of cytoreductive nephrectomy did not affect PFS, however, deferred cytoreductive nephrectomy appears to select outpatients with inherent resistance to systemic therapy.
However, Dr. Finelli notes that there is historic data demonstrating an overall survival benefit to cytoreductive nephrectomy, including many retrospective studies and two randomized trials showing the benefit of cytoreductive nephrectomy in the interferon era. Furthermore, in a study from Bhindi et al.3 looking at comparative survival following initial cytoreductive nephrectomy versus initial targeted therapy for metastatic renal cell carcinoma, patients treated with initial cytoreductive nephrectomy or those treated with targeted therapy then cytoreductive nephrectomy had significantly improved probability of overall survival at 3 and 6-month landmark analyses:
Dr. Finelli argues that given the greater likelihood of receiving multimodal therapy and the associated overall survival benefit, upfront cytoreductive nephrectomy should be considered in select surgical candidates. Additionally, data from the IMDC group also suggests that those undergoing upfront cytoreductive nephrectomy had a median OS of 20.6 months vs 9.6 months among those not undergoing cytoreductive nephrectomy (HR 0.60, 95% CI 0.52-0.69).4
A subsequent systematic review assessing the role of cytoreductive nephrectomy in the targeted therapy was also published by Bhindi et al. last year.5 Cytoreductive nephrectomy was associated with improved overall survival among patients with mRCC in 10 nonrandomized studies, while only CARMENA was found to have comparable survival with sunitinib alone and was non-inferior to that with cytoreductive nephrectomy followed by sunitinib.
The risk of perioperative mortality and Clavien ≥3 complications ranged from 0% to 10.4% and from 3% to 29.4%, respectively, with no meaningful differences between upfront cytoreductive nephrectomy or cytoreductive nephrectomy after presurgical systemic therapy. Importantly, 12.9-30.4% of patients did not receive systemic after cytoreductive nephrectomy.
Dr. Finelli notes that recent clinical trials have flaws, including that good-risk patients, were not addressed, the trials did not meet their recruitment goals, and there are unmatched groups (ie. CARMENA, node-positive versus locally invasive). Additional limitations of the literature are that (i) we still do not have data from a randomized controlled trial in the present era regarding cytoreductive nephrectomy for patients with limited disease, (ii) much of the literature focuses on clear cell mRCC, (iii) we do not know how cytoreductive nephrectomy affects OS with ipilimumab plus nivolumab in the first-line setting, and (iv) improved risk stratification and/or biomarkers are needed.
In conclusion, Dr. Finelli summarized with the following remarks:
- Cytoreductive nephrectomy remains a valuable intervention in mRCC
- Overall survival is the most important, but not the only measure in treating patients with mRCC
- Patient selection remains paramount – do no harm, ie. engage in multidisciplinary care and minimize the morbidity from surgery where benefit is unlikely
- Improved risk stratification and/or biomarkers are needed, as IMDC criteria alone are inadequate
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the Virtual 2020 EAU Annual Meeting #EAU20, July 17-19, 2020.
- Mejean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal cell carcinoma. N Engl J Med 2018 Aug 2;379(5):417-427.
- Bex A, Mulders P, Jewett M, 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 Oncol 2019 Feb 1;5(2):164-170.
- Bhindi B, Habermann EB, Mason RJ, et al. Comparative survival following initial cytoreductive nephrectomy versus initial targeted therapy for metastatic renal cell carcinoma. J Urol 2018;200:528-534.
- Heng DYC, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients with synchronous metastases from Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol 2014;66:704-710.
- Bhindi B, Abel EJ, Albiges L, et al. Systematic review of the role of cytoreductive nephrectomy in the targeted therapy era and beyond: An Individualized Approach to Metastatic renal cell carcinoma. Eur Urol 2019 Jan;75(1):111-128.