Although surgical treatment cures >90% of differentiated thyroid cancer (DTC) patients, the remaining patients, including advanced DTC cases, have poor clinical outcomes. These patients with inoperable disease have only two choices of radioactive iodine therapy and tyrosine kinase inhibitors such as lenvatinib, which have a high incidence of treatment-related adverse events and can only prolong progression free survival by approximately 5–15 months.

In this study, we investigated the antitumor effects of combination therapy with lenvatinib and radiation (CTLR) for DTC. CTLR synergistically inhibited cell replication and colony formation in vitro and tumor growth in nude mice without apparent toxicities and suppressed the expression of proliferation marker (Ki-67). CTLR also induced apoptosis and G2/M phase cell cycle arrest. Moreover, quantitative analysis of the intracellular uptake of lenvatinib using liquid chromatography and mass spectrometry demonstrated that intracellular uptake of lenvatinib was significantly increased 48 h following irradiation. These data suggest that increased membrane permeability caused by irradiation increases the intracellular concentration of levatinib, contributing to the synergistic effect.

This mechanism-based potential of combination therapy suggests a powerful new therapeutic strategy for advanced thyroid cancer with fewer side effects and might be a milestone for developing a regimen in clinical practice.

尽管外科手术治疗治愈了90％以上的分化型甲状腺癌（DTC）患者，但其余患者（包括晚期DTC病例）的临床预后较差。这些无法手术的患者只有两种选择：放射性碘疗法和酪氨酸激酶抑制剂，例如lenvatinib，它们与治疗相关的不良事件发生率很高，并且只能将无进展生存期延长约5-15个月。

在这项研究中，我们调查了联合使用lenvatinib和放疗（CTLR）对DTC的抗肿瘤作用。在没有明显毒性的裸鼠中，CTLR协同抑制体外细胞复制和集落形成以及肿瘤生长，并抑制增殖标志物（Ki-67）的表达。CTLR还诱导凋亡和G2 / M期细胞周期停滞。此外，使用液相色谱法和质谱法对lenvatinib的细胞内摄取进行定量分析表明，照射后48 h lenvatinib的细胞内摄取显着增加。这些数据表明，由辐射引起的膜通透性增加会增加左旋替尼的细胞内浓度，从而起到协同作用。

这种基于机制的联合疗法潜力，为晚期甲状腺癌带来了副作用少的强有力的新治疗策略，并且可能是临床实践中发展新疗法的里程碑。