1 Department of Medical Oncology and Hematology, Kobe University Hospital and Kobe University Hospital Cancer Center , Kobe, Japan .
2 Kolling Institute of Medical Research, University of Sydney , New South Wales, Australia .
Thyroid. 2017 Sep;27(9):1135-1141. doi: 10.1089/thy.2016.0549. Epub 2017 Aug 14.
While there is a clear consensus for defining radioiodine-refractory differentiated thyroid cancer (RR-DTC), it is unknown whether these criteria are equally valid for determining when radioiodine (RAI) therapy is no longer beneficial and systemic treatment should be considered. Lenvatinib, a multikinase inhibitor, significantly prolonged progression-free survival (PFS) compared to placebo in a Phase 3 trial in RR-DTC (SELECT; hazard ratio [HR]: 0.21 [99% confidence interval (CI) 0.14-0.31]; p < 0.001). This sub-analysis compared clinical outcomes of lenvatinib-treated patients in SELECT stratified by RR-DTC inclusion criteria.
In SELECT, patients with measurable RR-DTC and radiologic evidence of disease progression ≤13 months prior to study entry were randomized 2:1 to lenvatinib (24 mg/day; 28-day cycle) or placebo. In this analysis, patients were stratified based on the following RR-DTC inclusion criteria: no RAI uptake, disease progression within 12 months of RAI therapy despite RAI avidity at the time of treatment, and extensive (>600 mCi) cumulative RAI exposure. All had disease progression as an inclusion criterion for SELECT.
Of 392 patients (261 lenvatinib; 131 placebo) enrolled, 275, 235, and 73 patients met the inclusion criteria for no RAI uptake, disease progression despite RAI avidity, and extensive RAI exposure, respectively. There was significant overlap between the patient groups, with 167 (42.6%) patients meeting more than one inclusion criterion. Lenvatinib improved median PFS compared to placebo in all groups ("no RAI uptake": lenvatinib not quantifiable [NQ; CI 14.8-NQ] vs. placebo, 3.7 months [CI 2.5-5.3]; "disease progression despite RAI avidity": lenvatinib 16.5 months [CI 12.8-NQ] vs. placebo, 3.7 months [CI 1.9-5.4]; "extensive RAI exposure": lenvatinib 18.7 months [CI 10.7-NQ] vs. placebo, 3.6 months [CI 1.9-5.5]). Objective response rates were 71.8%, 60.0%, and 56.0% for patients with no RAI uptake, disease progression despite RAI avidity, and extensive RAI exposure, respectively. Lenvatinib-related adverse events were similar across groups.
Comparable efficacy and safety profiles were observed in lenvatinib-treated patients regardless of RR-DTC criteria, possibly because of a large overlap among patients fulfilling each criterion. However, differing definitions for RR-DTC may be equally valid because both lenvatinib and placebo arms exhibited similar PFS outcomes across groups.
虽然明确了放射性碘难治性分化型甲状腺癌（RR-DTC）的定义标准，但尚不清楚这些标准是否同样适用于确定放射性碘（RAI）治疗不再有益且应考虑全身治疗的时机。在 RR-DTC 的 3 期试验（SELECT）中，多激酶抑制剂仑伐替尼与安慰剂相比，显著延长了无进展生存期（PFS）（风险比[HR]：0.21[99%置信区间（CI）0.14-0.31]；p<0.001）。这项亚分析比较了 SELECT 中根据 RR-DTC 纳入标准分层的仑伐替尼治疗患者的临床结局。
在 SELECT 中，测量的 RR-DTC 和影像学疾病进展的患者，在研究入组前 13 个月内有疾病进展，随机分为 2:1 接受仑伐替尼（24mg/天；28 天周期）或安慰剂治疗。在此分析中，根据以下 RR-DTC 纳入标准对患者进行分层：无 RAI 摄取，尽管治疗时 RAI 摄取率高，但在 RAI 治疗后 12 个月内疾病进展，以及广泛（>600mCi）累积 RAI 暴露。所有患者的疾病进展均为 SELECT 的纳入标准。
在 392 名患者（261 名接受仑伐替尼治疗；131 名接受安慰剂治疗）中，分别有 275、235 和 73 名患者符合无 RAI 摄取、尽管 RAI 摄取率高但疾病进展以及广泛 RAI 暴露的纳入标准。患者组之间存在显著重叠，167 名（42.6%）患者符合多个纳入标准。与安慰剂相比，仑伐替尼在所有组中均改善了中位 PFS（“无 RAI 摄取”：仑伐替尼不可量化[NQ；CI 14.8-NQ]vs.安慰剂，3.7 个月[CI 2.5-5.3]；“尽管 RAI 摄取率高但疾病进展”：仑伐替尼 16.5 个月[CI 12.8-NQ]vs.安慰剂，3.7 个月[CI 1.9-5.4]；“广泛 RAI 暴露”：仑伐替尼 18.7 个月[CI 10.7-NQ]vs.安慰剂，3.6 个月[CI 1.9-5.5]）。无 RAI 摄取、尽管 RAI 摄取率高但疾病进展以及广泛 RAI 暴露的患者的客观缓解率分别为 71.8%、60.0%和 56.0%。仑伐替尼相关不良事件在各组中相似。
无论 RR-DTC 标准如何，仑伐替尼治疗的患者均观察到相似的疗效和安全性特征，这可能是因为符合每个标准的患者存在很大重叠。然而，RR-DTC 的不同定义可能同样有效，因为仑伐替尼和安慰剂组在所有组中均显示出相似的 PFS 结局。
