Dr. Kapoor then proceeded to discuss results of the controversial CARMENA trial.1 In this Phase III trial, 450 patients who were suitable candidates for nephrectomy were randomly assigned, in a 1:1 ratio, to undergo nephrectomy and then receive sunitinib or to receive sunitinib alone. Randomization was stratified according to prognostic risk (intermediate or poor) in the Memorial Sloan Kettering Cancer Center prognostic model, and the primary end point 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 noninferior 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; 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 standard of care for patients with metastatic renal cell carcinoma (mRCC) requiring medical treatment.
At ASCO 2019, there was an updated presentation of CARMENA, and there was still no difference in overall survival (OS): HR 0.97 (95% CI 0.79-1.19); cytoreductive nephrectomy + sunitinib had a median OS of 15.6 months versus sunitinib along median OS of 19.8 months. Additionally, there were 40 patients in the sunitinib arm that underwent a delayed nephrectomy, and median OS in the delayed nephrectomy group was significantly higher than those receiving sunitinib only: 48.5 vs 15.7 months, HR 0.34 (95% CI 0.22-0.54). Dr. Kapoor notes that there is obvious selection bias among these patients, but hypothesis provoking that delayed nephrectomy may provide some benefit.
The SURTIME trial assessed immediate surgery or surgery after sunitinib in treating patients with metastatic RCC.2 This study examined whether a period of sunitinib therapy before cytoreductive nephrectomy (CN) improves outcome compared with immediate CN followed by sunitinib. With an estimated sample size need of 458 patients to determine a difference in progression-free survival (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 CN arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate CN 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 out patients with inherent resistance to systemic therapy.
The Kidney Cancer Research Network of Canada (KCRNC) released a consensus statement suggesting that CARMENA should not lead to the abandonment of nephrectomy in mRCC, but instead emphasized the importance of careful selection of patients.3 Furthermore, they noted that contraindications to cytoreductive nephrectomy included patients with poor performance status (ECOG ≥ 2, Karnoffsky performance status <80) and/or limited life expectancy (<1 year). Patients with the following characteristics should receive systemic therapy before consideration of cytoreductive nephrectomy:
- Intermediate and poor-risk patients
- Significant systemic symptoms from metastatic disease
- Active central nervous system (CNS) metastasis
- Limited burden of disease within the kidney relative to the volume of metastasis
- Rapidly progressive disease
Additionally, the following patients should be considered for upfront cytoreductive nephrectomy:
- Good performance status
- Young age
- No systemic symptoms
- Relatively limited burden of metastatic disease
- Patient’s metastases should be managed with metastasectomy (surgical or radiotherapy) or surveillance
Recognizing the complex nature of advanced kidney cancer management, decisions regarding cytoreductive nephrectomy should ideally be made in a multidisciplinary setting.
Presented by: Anil Kapoor, MD, FRCSC, Professor of Urology, Director of Research, Division of Urology, Surgical Director, Renal Transplantation, St. Joseph’s Hospital Chair, Genito-Urinary Oncology Program, Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, Canada
Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California
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.
3. Mason, Ross J., Lori Wood, Anil Kapoor, Naveen Basappa, George Bjarnason, Stephen A. Boorjian, Rodney H. Breau et al. "Kidney Cancer Research Network of Canada (KCRNC) consensus statement on the role of cytoreductive nephrectomy for patients with metastatic renal cell carcinoma." Canadian Urological Association Journal 13, no. 6 (2019): 166.