Supplementary Material for: Benefits and Limitations of TKIs in Patients with Medullary Thyroid Cancer: A Systematic Review and Meta-Analysis

<b><i>Introduction:</i></b> Tyrosine kinase inhibitors (TKIs) have been used in patients with advanced medullary thyroid carcinoma (MTC); however, data on their effectiveness and safety are limited. The aim of this systematic review and meta-analysis was to document clinical response and toxicities of TKIs in advanced MTC. <b><i>Methods:</i></b> We systematically searched major databases for articles or abstracts on TKI use in MTC patients until May 2018. Objective response (OR), defined as the sum of complete + partial response, expressed as percentage, was our primary endpoint, while disease stability, disease progression (DP), median progression-free survival (PFS), and drug discontinuation rate due to adverse events (AEs) were secondary endpoints. Pooled percentages, PFS time, and 95% CIs were reported. <b><i>Results:</i></b> Thirty-three publications were finally included in the analysis: 1 phase IV, 2 phase III trials evaluating vandetanib and cabozantinib, respectively, 20 phase I or II studies, and the remaining 10 studies of retrospective-observational nature. OR was documented in 28.6% (95% CI 25.9–31.9) of patients. Stable disease was recorded in 46.2% (95% CI 43.3–49.1). Overall, DP was observed in 22.9% (95% CI 20.4–27.6). Grade 3 or more AEs occurred in 48.5% (95% CI 45.5–51.5) of patients, and drug discontinuation was reported in 44.7% (95% CI 41.7–47.6). In general, use of TKIs conferred a PFS of 23.3 months (95% CI 21.07–25.5). In particular, vandetanib induced an OR in 33.8% (95% CI 29.6–38.0) of patients and cabozantinib in 27.7% (95% CI 22.05–33.4). DP occurred in 23.7% (95% CI 19.9–27.6) with vandetanib use and in 22.6% (95% CI 17.4–27.9) in cabozantinib-treated patients. Sorafenib, the third most frequently studied drug, showed intermediate efficacy, but higher discontinuation rates. <b><i>Conclusion:</i></b> Treatment with TKIs in MTC patients with progressive disease is associated with a moderate therapeutic benefit, with achievement of either disease stability or partial response in 73%. The toxicity of these drugs is not negligible, but it is, nonetheless, manageable.

<b><i>引言：</i></b> 酪氨酸激酶抑制剂（Tyrosine kinase inhibitors, TKIs）已应用于晚期甲状腺髓样癌（medullary thyroid carcinoma, MTC）患者，但相关有效性与安全性数据仍较为匮乏。本系统评价与荟萃分析旨在明确TKIs用于晚期MTC的临床应答与毒性反应。<b><i>方法：</i></b> 我们系统检索了截至2018年5月的各大数据库中关于MTC患者使用TKIs的研究文章或摘要。以完全缓解与部分缓解之和定义的客观缓解率（objective response, OR）为主要研究终点，疾病稳定、疾病进展（disease progression, DP）、中位无进展生存期（progression-free survival, PFS）以及因不良事件（adverse events, AEs）导致的停药率为次要研究终点。本研究报告了合并百分比、PFS时长及95%置信区间（confidence interval, CI）。<b><i>结果：</i></b> 最终共纳入33项研究进行分析，其中分别有1项Ⅳ期、2项Ⅲ期试验分别评估凡德他尼（vandetanib）与卡博替尼（cabozantinib）的疗效，20项为Ⅰ/Ⅱ期研究，剩余10项为回顾性观察性研究。所有患者的客观缓解率为28.6%（95%CI 25.9~31.9），疾病稳定率为46.2%（95%CI 43.3~49.1），总体疾病进展率为22.9%（95%CI 20.4~27.6）。48.5%（95%CI 45.5~51.5）的患者出现3级及以上不良事件，因不良事件停药率为44.7%（95%CI 41.7~47.6）。整体而言，TKIs治疗的中位无进展生存期为23.3个月（95%CI 21.07~25.5）。其中，凡德他尼组客观缓解率为33.8%（95%CI 29.6~38.0），卡博替尼组为27.7%（95%CI 22.05~33.4）；凡德他尼组疾病进展率为23.7%（95%CI 19.9~27.6），卡博替尼组为22.6%（95%CI 17.4~27.9）。索拉非尼（sorafenib）是第三大研究药物，其疗效处于中等水平，但停药率更高。<b><i>结论：</i></b> 对于伴疾病进展的MTC患者，TKIs治疗可带来中等程度的治疗获益，73%的患者可实现疾病稳定或部分缓解。此类药物的毒性反应不容忽视，但仍处于可管控范围内。