PURPOSE

Tyrosine kinase inhibitors (TKIs) have been widely used in the management of patients with metastatic renal cell carcinoma (RCC). However, the use of systemic therapies in the adjuvant setting of localized and locally advanced RCC has shown conflicting results across the literature. Therefore, we aimed to conduct an updated systematic review and meta-analysis comparing the efficacy and safety of TKIs in the adjuvant setting for patients with localized and locally advanced RCC.

MATERIALS AND METHODS

The MEDLINE and EMBASE databases were searched in December 2020 to identify phase III randomized controlled trials of patients receiving adjuvant therapies with TKI for RCC. Disease-free survival (DFS) and overall survival (OS) were the primary endpoints. The secondary endpoints included treatment-related adverse events (TRAEs) of high and any grade.

RESULTS

Five trials (S-TRAC, ASSURE, PROTECT, ATLAS, and SORCE) were included in our meta-analysis comprising 6,531 patients. The forest plot revealed that TKI therapy was associated with a significantly longer DFS compared to placebo (pooled HR: 0.88, 95% CI: 0.81–0.96, P= 0.004). The Cochrane's Q test (P = 0.51) and I2 test (I2 = 0%) revealed no significant heterogeneity. Adjuvant TKI was not associated with improved OS compared to placebo (pooled HR: 0.93, 95% CI: 0.83–1.04, P= 0.23). The Cochrane's Q test (P = 0.74) and I2 test (I2 = 0%) revealed no significant heterogeneity. The forest plot revealed that TKI therapy, compared to placebo, was associated with higher rates of high grade TRAEs (OR: 5.20, 95% CI: 4.10–6.59, P< 0.00001) as well as any grade TRAEs (OR: 3.85, 95% CI: 1.22–12.17, P= 0.02). The Cochrane's Q tests (P < 0.0001 and P < 0.00001, respectively) and I2 tests (I2 = 79% and I2 = 90%, respectively) revealed significant heterogeneity.

CONCLUSIONS

The findings of our analyses suggest an improved DFS in patients with localized and locally advanced RCC receiving adjuvant TKI as compared to placebo; however, this did not translate into any significant OS benefit. Additionally, TKI therapy led to significant toxicity. Adjuvant TKI does not seem to offer a satisfactory risk and/orbenefit balance for all patients. Select patients with very poor prognosis may be considered in a shared decision-making process with the patient. With the successful arrival of immune-based therapies in RCC, these may allow a more favorable risk/benefit profile.

中文翻译：

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酪氨酸激酶抑制剂辅助治疗局部和局部晚期肾细胞癌：更新的系统评价和荟萃分析

目的

酪氨酸激酶抑制剂 (TKI) 已广泛用于治疗转移性肾细胞癌 (RCC) 患者。然而，在局部和局部晚期 RCC 的辅助环境中使用全身治疗在文献中显示出相互矛盾的结果。因此，我们旨在进行更新的系统评价和荟萃分析，比较 TKI 在局部和局部晚期 RCC 患者辅助治疗中的疗效和安全性。

材料和方法

2020 年 12 月检索了 MEDLINE 和 EMBASE 数据库，以确定接受 TKI 辅助治疗 RCC 的患者的 III 期随机对照试验。无病生存期（DFS）和总生存期（OS）是主要终点。次要终点包括高级别和任何级别的治疗相关不良事件（TRAE）。

结果

五项试验（S-TRAC、ASSURE、PROTECT、ATLAS 和 SORCE）被纳入我们的荟萃分析，包括 6,531 名患者。森林图显示，与安慰剂相比，TKI 治疗与显着更长的 DFS 相关（合并 HR：0.88，95% CI：0.81-0.96，P = 0.004）。Cochrane 的 Q 检验 ( P  = 0.51) 和 I2 检验 (I2 = 0%) 显示没有显着的异质性。与安慰剂相比，辅助 TKI 与改善 OS 无关（合并 HR：0.93，95% CI：0.83–1.04，P = 0.23）。Cochrane 的 Q 检验 ( P  = 0.74) 和 I2 检验 (I2 = 0%) 显示没有显着的异质性。森林图显示，与安慰剂相比，TKI 治疗与较高的高级别 TRAE 发生率相关（OR：5.20，95% CI：4.10-6.59，P< 0.00001) 以及任何等级的 TRAE (OR: 3.85, 95% CI: 1.22–12.17, P = 0.02)。Cochrane 的 Q 检验（分别为P < 0.0001 和P < 0.00001）和 I2 检验（分别为 I2 = 79% 和 I2 = 90%）显示出显着的异质性。

结论

我们的分析结果表明，与安慰剂相比，接受辅助 TKI 的局部和局部晚期 RCC 患者的 DFS 有所改善；然而，这并没有转化为任何显着的操作系统优势。此外，TKI 治疗导致显着毒性。辅助 TKI 似乎不能为所有患者提供令人满意的风险和/或收益平衡。在与患者共同决策过程中可以考虑选择预后非常差的患者。随着基于免疫的疗法在 RCC 中的成功到来，这些可能会带来更有利的风险/收益状况。