2012年8月14日 讯 /生物谷BIOON/ --对晚期分化型甲状腺癌(advanced differentiated thyroid cancer, DTC)病人的II期随机性临床试验结果表明接受口服靶向药物凡德他尼(vandetanib)治疗的病人无疾病恶化存活期要比接受安慰剂治疗的那些病人长将近1倍(11.2个月对5.9个月)。这项发现在线发表在Lancet Oncology期刊上，也是第一次提供清晰的证据表明利用靶向药物凡德他尼治疗晚期分化型甲状腺癌能够延长病人的无疾病恶化存活期(progression free survival, PFS)。就目前而言，还不存在有效的治疗方法来自医治这种癌症。
在过去10年时间里，甲状腺癌发病率在全世界增加了1倍多。最近，多靶点激酶抑制剂(multi-targeted kinase inhibitor)正成为大有希望的治疗晚期分化型甲状腺癌的候选药物，但是在此之前，科学家们从没有开展过安慰剂对照临床试验研究。
在这项研究中，来自法国古斯塔夫-鲁西研究所(Institut Gustave Roussy)的Martin Schlumberger和同事们旨在确定凡德他尼---该药物靶向3种已知在甲状腺癌生长和扩散中发挥作用的蛋白：内皮生长因子受体(endothelial growth factor receptor, EGFR)、血管内皮生长因子(vascular endothelial growth factor, VEGF)和感染期间发生重排的原癌基因RET(rearranged during transfection protooncogene)---是否影响无疾病恶化存活期和总存活期(overall survival, OS)。
在这项研究中，研究人员随机性地将145名来自7个欧洲国家的晚期分化型甲状腺癌病人分配为两组：72名病人接受每天300 mg凡德他尼治疗；73名病人安慰剂治疗。
与接受安慰剂治疗的那组病人相比，服用凡德他尼与病人无疾病恶化存活期显著性提高(从5.9个月提高至11.1个月)相关联。治疗6个月后，相比于接受安慰剂治疗的那组病人，接受凡德他尼治疗的病人也拥有更加好的疾病控制率(disease control rate, DCR)。然而，这两组病人在总存活期上并不存在显著性差别。
有意思的是，在接受凡德他尼治疗后，患有更为常见的甲状腺乳头状癌(papillary thyroid cancer, PTC)的病人拥有比甲状腺滤泡状癌(follicular thyroid cancer, FTC)病人和分化型甲状腺癌病人(前两者的中位无疾病恶化存活期为7.7个月)更加长的无疾病恶化存活期(中位无疾病恶化存活期为16.2个月)。
接受凡德他尼治疗的病人也经历着更加大的毒副作用，特别是QT间期(QTc)延长时间增加、痢疾、无力和疲劳。接受凡德他尼治疗的那组病人当中，还有两名与治疗相关的病人死亡。
这些结果表明凡德他尼可能一种潜在有效的治疗选择来保持晚期分化型甲状腺癌病人的病情稳定，特别是甲状腺乳头状癌病人而言。不过，还需要更多的研究来更好地阐述激酶抑制剂可能对哪些晚期分化型甲状腺癌最为有效，以便开发出个人化疗法来治疗晚期分化型甲状腺癌病人。(生物谷Bioon.com)
本文编译自Vandetanib almost doubles progression free survival in patients with thyroid cancer
doi: 10.1016/S1470-2045(12)70335-2
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Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial
Sophie Leboulleux MD a, Lars Bastholt MD b, Prof Thomas Krause MD c, Christelle de la Fouchardiere MD d, Prof Jan Tennvall MD e f, Prof Ahmad Awada MD g, José Manuel Gómez MD h, Françoise Bonichon MD i, Prof Laurence Leenhardt MD j, Christine Soufflet MD k, Muriel Licour MSc k, Prof Martin J Schlumberger
Background No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting. Methods In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095. Findings Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54—0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7—14·0) for patients in the vandetanib group and 5·9 months (4·0—8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group). Interpretation Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted. Funding AstraZeneca.
