The DISSRM prospective multi-institutional registry assessed growth kinetics of small renal masses on active surveillance among 271 patients with at least three follow-up images1. The overall mean growth rate was 0.09 cm per year, whereas in the first six months the growth rate was 0.54 cm. After >1 year the growth rate slowed to 0.07 cm/year; importantly, no patients had metastases or died of kidney cancer over a median 1.83 years of follow-up. According to Dr. Akdogan, this tells us that growth kinetics are highly variable, however variability decreases after six months. Furthermore, growth kinetics do not predict death or adverse pathology.
Among patients undergoing partial nephrectomy at MSKCC, 199 patients were randomized to receive mannitol or placebo 30 minutes prior to renal vascular clamping 2. The primary outcome was the difference in eGFR between the two groups at 6 months following surgery. Comparing placebo with mannitol infusion, the adjusted difference of 0.2 eGFR units at 6 months was not significant (p=0.9), with the upper bound of the 95%CI (-3.1 to 3.5) excluding a clinically relevant effect of mannitol. Based on these results, Dr. Akdogan advocates for discontinuing the routine use of mannitol in clinical practice.
A multi-institutional group of collaborators retrospectively analyzed 3,457 patients undergoing radical (39%) or partial nephrectomy (61%) for cT1-T2 RCC to assess whether eGFR is related to cancer-specific mortality (CSM)3. For eGFR treated as a time-dependent covariate, at landmark analysis with eGFR at the baseline, 12 months, and last functional follow-up, the eGFR was 85, 60, and 65ml/min, respectively. In multivariable competing-risk analysis, CSM was associated with eGFR only for values of eGFR below these cutoffs, with HRs for every 10ml/min of reduction in eGFR of 1.25 (p=0.003), 1.16 (p=0.028), 1.44 (p=0.02), and 1.16 (p=0.042), corresponding to time-dependent eGFR, and eGFR at baseline, 12 months, and last functional follow-up, respectively. As such, Dr. Akdogan suggests that whenever feasible, nephron-sparing surgery should be preferred.
2018 also saw an update of the S-TRAC data, where 615 patients with locoregional RCC at high risk of recurrence after radical nephrectomy were randomized to adjuvant sunitinib vs placebo4. Although there was no difference between the arms for OS, a benefit of adjuvant sunitinib over placebo for DFS was observed across subgroups, including: higher risk (defined as T3, no or undetermined nodal involvement, Fuhrman grade ≥2, ECOG PS ≥1, T4 and/or nodal involvement; HR 0.74, 95%CI 0.55-0.99), NLR ≤3 (HR 0.72, 95%CI 0.54-0.95), and Fuhrman grade 3/4 (HR 0.73, 95%CI 0.55-0.98).
Also in the adjuvant setting, the ATLAS study was a phase 3, randomized, double-blind study among 724 patients with ≥pT2 and/or N+ disease after radical nephrectomy5. Patients were randomized to either twice daily axitinib vs placebo with a primary endpoint of DFS. This study was stopped due to futility in the interim analysis, as there was no difference in DFS (HR 0.870, 95%CI 0.660-1.147). However, In the highest-risk subpopulation, a 36% and 27% reduction in risk of a DFS event was observed per investigator (HR 0.641, 95%CI 0.468-0.879), and by IRC (HR 0.735, 95%CI 0.525-1.028).
The publication of the much anticipated CARMENA study generated significant buzz at ASCO 2018, as well as on social media. Among 450 patients with MSKCC intermediate or poor risk disease, patients were randomized to sunitinib vs cytoreductive nephrectomy followed by sunitinib, with a primary endpoint of OS (non-inferiority trial) 6. The sunitinib alone arm had a longer OS (18.4 vs 13.9 months ITT, stratified HR 0.89, 95%CI 0.71-1.10; upper boundary of the 95%CI for noninferiority, ≤1.20). According to Dr. Akdogan, sunitinib alone is not inferior to nephrectomy + sunitinib for OS in intermediate/poor risk patients with mRCC. Furthermore, cytoreductive nephrectomy should no longer be considered the standard of care in mRCC when medical treatment is required.
Recently, the SURTIME clinical trial reported results for assessing whether a period of sunitinib therapy before cytoreductive nephrectomy (3 cycles of sunitinib) improves outcome compared with immediate cytoreductive nephrectomy followed by sunitinib 7. The planned primary endpoint was PFS with a planned accrual of 458 patients, however, the trial was closed after recruiting only 99 patients and the primary outcome was changed to progression-free rate (PFR). The 28-week PFR was 42% in the immediate cytoreductive nephrectomy arm (n = 50) and 43% in the deferred cytoreductive nephrectomy arm (n = 49) (p = 0.61). With the deferred approach, median OS was better at 32.4 vs 15 months (HR 0.57, 95%CI 0.34-0.95) and no nephrectomy was performed in 29% of patients secondary to systemic progression. Dr. Akdogan notes that pretreatment with sunitinib and deferred cytoreductive nephrectomy may identify patients with inherent resistance to systemic therapy before surgery.
The highly touted CheckMate 214 trial initially presented at ESMO 2017 was also published in 20188. This phase III trial of 1,096 IMDC intermediate/poor risk mRCC patients randomized patients to nivolumab + ipilimumab (n=550) vs sunitinib (n=546) with a primary endpoint of OS. The combination of nivolumab + ipilimumab decreased the risk of death by 37% compared to patients receiving sunitinib.
CAIX antigen is highly expressed in 95% of ccRCC and as such an anti-CAIX monoclonal antibody girentuximab can be used to detect primary renal masses of unknown origin and can clarify the nature of suspected lesions for metastases9. In this study, PET/CT imaging was performed 4 or 5 days after injection of 89Zr-girentuximab in patients with a primary renal mass (n=16) or a history of ccRCC (n=14). All resected PET-positive primary lesions proved to be ccRCC, while no lesion progression was seen in PET-negative masses. According to Dr. Akdogan, 89Zr-girentuximab PET/CT is a valuable tool in guiding clinical decision making in cases of diagnostic dilemmas concerning for ccRCC
Dr. Akdogan concluded this great wrap-up of 2018 RCC literature with the following take-home points:
- AS: growth kinetics of small renal masses varies and does not predict death
- NSS: mannitol has no benefit; as eGFR drops below safety limits, CSM increases
- High-risk locoregional: adjuvant sunitinib and axitinib causes better DFS than placebo after radical nephrectomy but has no effect at this time on OS
- mRCC: immediate cytoreductive nephrectomy does not result in additional benefit; OS is higher with nivolumab + ipilimumab in the first line setting
- 89Zr-girentuximab PET/CT is a valuable diagnostic tool for indistinct primary, recurrent or metastatic ccRCC
Presented by: Bulent Akdogan, MD, Professor, Hacettepe University, Ankara, Turkey
Written By: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 16th Meeting of the European Section of Oncological Urology, #ESOU19, January 18-20, 2019, Prague, Czech Republic
- Uzosike AC, Patel HD, Alam R, et al. Growth kinetics of small renal masses on active surveillance: Variability and results from the DISSRM Registry. J Urol 2018 Mar;199(3):641-648.
- Spaliviero M, Power NE, Murray KS, et al. Intravenous mannitol versus placebo during partial nephrectomy in patients with normal kidney function: A double-blind, clinically-integrated, randomized trial. Eur Urol 2018 Jan;73(1):53-59.
- Antonelli A, Minervini A, Sandri M, et al. Below safety limits, every unit of glomerular filtration rate counts: Assessing the relationship between renal function and cancer-specific mortality in renal cell carcinoma. Eur Urol 2018 Nov;74(5):661-667.
- Motzer RJ, Ravaud A, Patard JJ, et al. Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: Subgroup Analyses and Updated Overall Survival Results. Eur Urol 2018 Jan;73(1):62-68.
- Gross-Goupil M, Kwon TG, Eto M, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Ann Oncol 2018 Dec 1;29(12):2371-2378.
- 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 2018 Dec 13 [Epub ahead of print].
- Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carinoma. N Engl J Med 2018;378(14):1277-1290.
- Hekman MCH, Rijpkema M, Aarntzen EH, et al. Positron emission tomography/computed tomography with 89Zr-girentuximab can aid in diagnostic dilemmas of clear cell renal cell carcinoma suspicion. Eur Urol 2018 Sep;74(3):257-260.
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