Urologic Oncology: Seminars and Original Investigations
Clinical-Kidney cancerSurvival outcomes and practice trends for off-label use of adjuvant targeted therapy in high-risk locoregional renal cell carcinoma
Introduction
In the United States, renal cell carcinoma (RCC) is the seventh and tenth most commonly diagnosed cancer amongst men and women, respectively, accounting for 3.8% of all cancer cases and 2.5% of all cancer deaths [1]. Approximately 40% of patients with locoregional RCC who undergo surgery will subsequently recur and develop metastases [2]. Systemic targeted therapy (TT), or more specifically, tyrosine kinase inhibitors, have emerged as the most commonly utilized systemic therapies for the treatment of metastatic RCC since their FDA approval for this indication in 2006 [3].
Since that time, significant effort has been made to explore the potential benefit of adjuvant TT after nephrectomy for the treatment of high-risk locoregional RCC. Multiple randomized controlled trials (RCTs) have been completed on this topic [4], [5], [6], [7]. The ASSURE trial utilized either sunitinib or sorafenib in the adjuvant treatment arm, the PROTECT trial utilized pazopanib, and the ATLAS trial utilized axitinib. None of these trials found a significant difference in disease free survival (DFS) between groups [4,5,7]. The S-TRAC trial utilized adjuvant sunitinib in the treatment arm. Patients in the adjuvant sunitinib arm experienced a significantly longer DFS than controls (Hazard ratio 0.76, 95%CI 0.59–0.98) [6]. Based on this data, in 2017 the FDA approved sunitinib for adjuvant treatment of high-risk RCC after nephrectomy [8]. Numerous meta-analyses and systematic reviews of these trials have concluded that there is no apparent DFS benefit for adjuvant TT [9], [10], [11], [12], [13]. Currently, there is no consensus guideline statement or recommendation regarding the use of adjuvant TT [14,15].
The effectiveness of adjuvant TT for high risk locoregional RCC has not been assessed using a large national cohort of real-world patients. Additionally, the practice trends for the utilization of off-label adjuvant TT in RCC have yet to be reported. Our primary objective is to compare the effect of receipt of adjuvant TT on overall survival (OS) in high risk locoregional RCC using a large national cohort, with a planned subgroup analysis of patients with or without pathologically positive lymph nodes. Our secondary objective is to describe the national trends for utilization of off-label adjuvant TT prior to FDA approval in 2017.
Section snippets
Study population
This study was conducted after approval of the local Institutional Review Board. The analysis set included RCC patients from the National Cancer Database (NCDB) diagnosed from 2006 to 2015. The NCDB includes roughly 70% of cancer cases in the United States and are reported by member facilities of the CoC. The year 2006 was chosen as the earliest date for the analysis as this was the year of FDA approval for tyrosine kinase inhibitors for the treatment of metastatic RCC [3]. Patients were
Study population
465,126 patients who had a tumor of the kidney or renal pelvis were identified in the NCDB. Patients were excluded who had tumors of the renal pelvis, non–clear-cell histology, received radiation therapy, had metastatic disease, had incomplete staging or treatment information, or received treatment as part of a double-blind clinical trial protocol. Patients who had either pathologic T stage 3a or greater, or pathologically positive lymph nodes, were included in the final cohort (n = 41,127).
Discussion
The survival analysis showed decreased OS for patients who received off-label adjuvant TT, as compared with those who did not, for high risk locoregional RCC after nephrectomy. Subgroup analysis of patients with and without pN+ also showed decreased OS for patients receiving adjuvant TT in both subgroups. Though the relevant RCTs utilized DFS as their primary endpoint [4], [5], [6], [7], this analysis utilized OS for the survival analysis due to limitations in the available survival variables
Conclusion
This large-population propensity matched study demonstrated that receipt of off-label adjuvant TT resulted in decreased OS for patients with high-risk locoregional RCC after nephrectomy.
Conflicts of interest
None.
References (20)
- et al.
Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease
Urol Clin North Am
(2003) - et al.
Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial
Lancet
(2016) - et al.
Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial
Ann Oncol
(2018) - et al.
Adjuvant vascular endothelial growth factor-targeted therapy in renal cell carcinoma: a systematic review and pooled analysis
Eur Urol
(2018) - et al.
Adjuvant therapies in nonmetastatic renal-cell carcinoma: a review of the literature
Clin Genitourin Cancer
(2018) - et al.
Adjuvant sunitinib for high-risk-resected renal cell carcinoma: a meta-analysis of ASSURE and S-TRAC trials
Ann Oncol
(2017) - et al.
Adjuvant antiangiogenic agents in post-nephrectomy renal cell carcinoma: a systematic review and meta-analysis
Eur Urol Oncol
(2018) - et al.
Adjuvant therapy for locally advanced renal cell carcinoma: a meta-analysis and systematic review
Urol Oncol
(2018) - et al.
Renal mass and localized renal cancer: AUA guideline
J Urol
(2017) - et al.
Comparative survival following initial cytoreductive nephrectomy versus initial targeted therapy for metastatic renal cell carcinoma
J Urol
(2018)
Cited by (0)
Funding: None.