Notwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue.

中文翻译：

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酪氨酸激酶抑制剂治疗放射性碘难治性分化型甲状腺癌的临床应用问题与争议：专家观点

尽管乐伐替尼和索拉非尼已获监管机构批准用于治疗放射性碘难治性分化型甲状腺癌 (RAI-R DTC)，但关于这些酪氨酸激酶抑制剂 (TKI) 的这种用途仍存在重要问题和争议。来自德国三级转诊中心的 RAI-R DTC 专家召集来识别和探讨此类问题；本文总结了他们的讨论。一项挑战是确定何时开始 TKI 治疗。决策应在患者和多学科护理人员之间共享，并应考虑肿瘤大小/负担、生长速度和部位、RAI-R DTC 发病率和死亡率的关键驱动因素，以及当前和预计的肿瘤相关症状、合并症和体能状态。另一个问题涉及一线 TKI 的选择。目前，乐伐替尼通常是首选，由于与安慰剂治疗相比，无进展生存期有更大的增加，并且在其关键试验中与索拉非尼相比有更高的反应率；此外，在这些研究中，乐伐替尼而非索拉非尼在亚组分析中显示出总体生存获益。推荐的最大或更低的 TKI 起始剂量是否能更好地平衡抗肿瘤作用与耐受性也未解决。乐伐替尼关键研究数据的探索性分析表明存在剂量反应效应，可能有利于更高剂量；然而，等待乐伐替尼起始方案的前瞻性比较结果。一些争议围绕着净治疗获益的确定，这是继续 TKI 治疗的关键标准：如果耐受性是可以接受的，尽管进展有限但可以控制，总体疾病控制可能证明进一步治疗是合理的。未来的研究应评估启动 TKI 的潜在指南；微调给药策略并进一步表征抗肿瘤功效；并评估干预措施以预防和/或治疗 TKI 毒性，特别是掌跖红斑感觉异常和疲劳。