Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Department of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
J Thorac Oncol. 2016 May;11(5):758-768. doi: 10.1016/j.jtho.2016.01.014. Epub 2016 Feb 2.
Mesothelioma often presents with a high vessel count and increased vascular growth factors levels. Interference with angiogenesis may therefore improve outcome. This study reports on clinical and translational parameters in patients treated with the small molecule tyrosine kinase inhibitor axitinib and chemotherapy.
Chemonaive patients with mesothelioma were eligible. Patients received pemetrexed (500 mg/m(2) every 3 weeks) and cisplatin (75 mg/m(2) every 3 weeks) and were randomized to receive axitinib daily (two 5-mg tablets on days 2-19) or observation. Before treatment and after three cycles of chemotherapy, a thoracoscopy was performed to evaluate vascular changes.
Twenty-five patients were randomized after a successful lead-in with six patients who received axitinib. Median follow-up was 45 months. In all but one patient, it was feasible to perform a second thoracoscopy. However, there was more grade 3 or 4 neutropenia leading to pneumonia in the axitinib group. The rates of partial response and stable disease in the axitinib arm were 36% and 43% compared with 18% and 73% in the chemotherapy-only arm. Median progression-free survival and overall survival (5.8 and 18.9 months versus 8.3 and 18.5 months) were not different between the two groups. Axitinib reduced vessel number and vessel immaturation. Yet, the mRNA levels of a number of vascular growth factors, their receptors, serum VEGF levels, and activation of tissue vascular endothelial growth factor receptor 2 were increased. Gene expression of platelet-derived growth factor receptor beta, fms-related tyrosine kinase 1, and fms-related tyrosine kinase 4 even correlated with outcome.
Axitinib was well tolerated in combination with cisplatin and pemetrexed. Despite the lack of a clinical benefit, axitinib reduced angiogenesis. Whether changes in differentially expressed growth factors in tissue and serum may serve as a biomarker needs further investigation.
间皮瘤通常表现为高血管计数和血管生长因子水平升高。因此，干扰血管生成可能会改善预后。本研究报告了接受小分子酪氨酸激酶抑制剂阿西替尼联合化疗的患者的临床和转化参数。
初治的间皮瘤患者符合条件。患者接受培美曲塞（每 3 周 500mg/m2）和顺铂（每 3 周 75mg/m2）治疗，并随机接受阿西替尼每日治疗（2-19 日每天两片 5mg 片剂）或观察。在治疗前和化疗 3 周期后，进行胸腔镜检查以评估血管变化。
25 例患者在成功进行先导治疗后接受了随机分组，其中 6 例患者接受了阿西替尼治疗。中位随访时间为 45 个月。除 1 例患者外，其余患者均可行第二次胸腔镜检查。然而，阿西替尼组的中性粒细胞减少症 3 或 4 级和肺炎发生率更高。阿西替尼组的部分缓解率和稳定疾病率分别为 36%和 43%，而化疗组分别为 18%和 73%。两组之间无进展生存期和总生存期（5.8 和 18.9 个月与 8.3 和 18.5 个月）无差异。阿西替尼减少了血管数量和血管不成熟。然而，多种血管生长因子及其受体、血清 VEGF 水平和组织血管内皮生长因子受体 2 的激活的 mRNA 水平升高。血小板衍生生长因子受体β、fms 相关酪氨酸激酶 1 和 fms 相关酪氨酸激酶 4 的基因表达甚至与预后相关。
阿西替尼联合顺铂和培美曲塞耐受性良好。尽管缺乏临床获益，但阿西替尼可减少血管生成。组织和血清中差异表达的生长因子的变化是否可以作为生物标志物需要进一步研究。
