Clinical-Kidney cancer
Survival outcomes and practice trends for off-label use of adjuvant targeted therapy in high-risk locoregional renal cell carcinoma

https://doi.org/10.1016/j.urolonc.2020.02.028Get rights and content

Highlights

  • From 2006 to 2015, 5% of patients received off-label adjuvant targeted therapy for high risk RCC.

  • Younger age, white race, positive margins, pT4, and pN+ were associated with adjuvant therapy.

  • Propensity matched analysis revealed worse survival for patients who received adjuvant therapy.

  • Subgroup analysis of pN+ patients also revealed worse survival for adjuvant therapy.

Abstract

Importance

The appropriate use of adjuvant targeted therapy (TT) for high-risk locoregional renal cell carcinoma (RCC) after nephrectomy is currently unclear due to mixed results from the relevant randomized controlled trials. National-level survival outcomes and practice trends for the use of adjuvant TT in the United States have not been reported.

Objective

To compare overall survival for patients who did and did not receive adjuvant TT after nephrectomy for high-risk locoregional RCC.

Design, setting, and participants

This cohort study reviewed the National Cancer Database from 2006 to 2015. Patients with nonmetastatic clear cell RCC who underwent nephrectomy with either stage pT3a or greater or pN+ were included.

Main outcomes and measures

Adjuvant TT was defined as receipt of TT within 3 months of nephrectomy. The primary end point was overall survival from initial diagnosis to date of death or censored at last follow-up. Baseline characteristics were described, and a multivariable analysis identified associations for receipt of adjuvant TT. Nearest-neighbor propensity matching was performed to create similar groups for comparison. A survival analysis was performed using Kaplan-Meier analysis and log-rank test.

Results

The final study population included 41,127 patients. Two thousand seventy-one patients (5.04%) received off-label adjuvant TT. Younger age, white race, private insurance, positive margins, pT4, and pN+ were associated with receipt of adjuvant TT. After nearest-neighbor propensity matching for clinically and statistically relevant covariates, 1,604 patients remained in the matched cohort, with statistically nonsignificant differences between the groups for all baseline characteristics. Median overall survival was 52 months for patients in the Adjuvant TT group versus 79 months for those who did not receive adjuvant TT (P < 0.001). Decreased overall survival for patients receiving adjuvant therapy was also seen in pathologic subgroups with and without lymph node involvement.

Conclusions

The propensity matched survival analysis revealed significantly decreased overall survival in patients who received off-label adjuvant TT for high-risk locoregional RCC.

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.

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