Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
Lancet Oncol. 2010 Oct;11(10):962-72. doi: 10.1016/S1470-2045(10)70203-5. Epub 2010 Sep 17.
Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib.
This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846.
39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35-68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=-0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders.
Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient's response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done.
National Cancer Institute, supported in part by NCI CA15083 and CM62205.
化疗在晚期分化型甲状腺癌中的疗效一直不佳，但各种酪氨酸激酶在该疾病中被激活这一事实表明，酪氨酸激酶抑制剂可能具有潜在的治疗作用。我们研究了帕唑帕尼的安全性和疗效。
这项 2 期临床试验于 2008 年 2 月 22 日至 2009 年 1 月 31 日进行，入组的是转移性、快速进展、放射性碘难治性分化型甲状腺癌患者。每个患者在 4 周的周期内每天接受 800 mg 帕唑帕尼连续治疗，直到疾病进展、药物不耐受或两者同时发生。允许使用最多两种之前的治疗药物，并且在入组前 6 个月内，有可测量的疾病影像学进展是纳入的要求。主要终点是根据实体瘤反应评价标准 1.0 评估的任何肿瘤反应。这项研究在 ClinicalTrials.gov 注册，编号为 NCT00625846。
共入组 39 例患者。1 例患者未接受过放射性碘治疗，另 1 例在治疗前退出了同意。因此，37 例患者（19 例[51%]为男性，中位年龄 63 岁）的临床结局可进行评估。该研究已不再招募新患者，但仍有几名入组患者在接受治疗。患者接受的中位周期数为 12 个（范围 1 至>23 个，总计>383 个）。18 例患者（反应率 49%，95%CI 35-68）确认有部分缓解，计算得出反应持续时间超过 1 年的可能性为 66%。第 1 个周期中帕唑帕尼在血浆中的最大浓度与影像学反应显著相关（r=-0.40，p=0.021）。16 例（43%）患者因不良事件需要减少剂量，最常见的不良事件（任何级别）为疲劳（29 例）、皮肤和毛发色素减退（28 例）、腹泻（27 例）和恶心（27 例）。2 例在治疗期间死亡的患者存在先前存在的促成疾病的因素。
帕唑帕尼似乎是治疗晚期分化型甲状腺癌患者的一种很有前途的治疗选择。在第一个周期中患者的反应和帕唑帕尼浓度之间的相关性可能表明，治疗可以个体化以达到最佳疗效。目前正在对更多分化型甲状腺癌患者、髓样和间变性甲状腺癌患者进行帕唑帕尼的评估。
美国国立癌症研究所，部分由 NCI CA15083 和 CM62205 资助。
