Krug Lee M, Heelan Robert T, Kris Mark G, Venkatraman Ennapadam, Sirotnak F M
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, New York 10021, USA.
J Thorac Oncol. 2007 Apr;2(4):317-20. doi: 10.1097/01.JTO.0000263715.84567.5f.
Several previous clinical trials have shown that malignant pleural mesothelioma is responsive to antifolates. The dihydrofolate reductase inhibitor, pralatrexate, has a favorable toxicity profile, primarily limited to stomatitis, and has demonstrated activity in patients with non-small cell lung cancer. In mesothelioma cell lines and xenografts, pralatrexate demonstrated significant antitumor activity.
We conducted this phase II study to determine the response rate of malignant pleural mesothelioma to pralatrexate at a dose of 135 mg/m2 i.v. every 2 weeks. After a protocol amendment, patients were supplemented with vitamin B12 and folic acid at the time of starting therapy.
A total of 16 assessable patients were enrolled. No complete or partial responses were observed. Two patients with epithelioid histology had minor responses. Three other patients remained on study with stable disease for 9, 9, and 48 months. The median time to progression was 3 months. The overall median survival time was 7 months (95% confidence interval: 3.2-16.2 months) and the one-year survival was 31% (95% confidence interval: 15%-65%). Three patients (19%) had grade 2 stomatitis, eight (50%) had grade 3, and one (6%) had grade 4.
With this particular dose and schedule, pralatrexate as a single agent had no activity in malignant pleural mesothelioma.
此前多项临床试验表明，恶性胸膜间皮瘤对抗叶酸药物有反应。二氢叶酸还原酶抑制剂普拉曲沙具有良好的毒性特征，主要局限于口腔炎，并且已在非小细胞肺癌患者中显示出活性。在间皮瘤细胞系和异种移植模型中，普拉曲沙表现出显著的抗肿瘤活性。
我们开展了这项II期研究，以确定普拉曲沙以135mg/m²静脉注射、每2周一次的剂量治疗恶性胸膜间皮瘤的缓解率。在方案修订后，患者在开始治疗时补充维生素B12和叶酸。
共纳入16例可评估患者。未观察到完全缓解或部分缓解。两名上皮样组织学类型的患者有轻微反应。另外三名患者在研究中病情稳定，分别为9个月、9个月和48个月。中位疾病进展时间为3个月。总体中位生存时间为7个月（95%置信区间：3.2 - 16.2个月），一年生存率为31%（95%置信区间：15% - 65%）。三名患者（19%）发生2级口腔炎，八名（50%）发生3级，一名（6%）发生4级。
采用这种特定的剂量和给药方案，普拉曲沙作为单一药物在恶性胸膜间皮瘤中无活性。
