我们评估了联合使用贝伐单抗和曲唑酮治疗晚期非胰腺外分泌神经内分泌肿瘤的疗效和安全性。这项由美国国家癌症研究所赞助的多中心、开放标签、二期临床试验（NCT01010126）入组了晚期、复发或转移的非胰腺外分泌神经内分泌肿瘤患者。所有患者均接受曲唑酮和贝伐单抗治疗，直到疾病进展或不可接受的毒性发生。曲唑酮以25毫克的剂量静脉注射，每个4周周期的第1、8、15和22天；贝伐单抗剂量为每千克体重10毫克，每个4周周期的第1和15天静脉注射。停用曲唑酮或贝伐单抗不需要停用其他药物。主要终点是客观缓解率和6个月无进展生存率。共有59名患者入组，其中54名患者用于评估疗效和不良事件。虽然中位无进展生存期为7.1个月，但曲唑酮治疗的中位治疗持续时间为3.9个月，贝伐单抗治疗的中位治疗持续时间为3.5个月。联合疗法的客观缓解率为2%，6个月无进展生存率为48%。最常见的3-4级不良事件包括疲劳（13%）、高血压（13%）和出血（13%）。近54%的患者因不良事件、拒绝接受进一步治疗或治疗延误而停止治疗。研究中发生了3例死亡病例，其中2例是治疗相关的致命性肠穿孔。基于贝伐单抗和曲唑酮联合治疗的微小疗效和增加的毒性，我们不建议在晚期非胰腺外分泌神经内分泌肿瘤患者中使用该方案。

We assessed the efficacy and safety of combining bevacizumab with temsirolimus in patients with advanced extra-pancreatic neuroendocrine tumors. This NCI-sponsored multicenter, open-label, phase II study (NCT01010126) enrolled patients with advanced, recurrent, or metastatic extra-pancreatic neuroendocrine tumors. All patients were treated with temsirolimus and bevacizumab until disease progression or unacceptable toxicity. Temsirolimus 25 mg was administered intravenously on days 1, 8, 15, and 22, and bevacizumab 10 mg/kg intravenously on days 1 and 15 of a 4-week cycle. Discontinuation of temsirolimus or bevacizumab did not require discontinuation of the other agent. The primary endpoints were objective response rate and 6-month progression-free survival rate. Fifty-nine patients were enrolled in this study, and 54 were evaluable for efficacy and adverse events. While median progression-free survival was 7.1 months, median duration of treatment with temsirolimus was 3.9 months, and with bevacizumab was 3.5 months. The objective response rate of combination therapy was 2%, and 6-month progression-free survival was 48%. The most frequently reported grade 3-4 adverse events included fatigue (13%), hypertension (13%), and bleeding (13%). Close to 54% of patients discontinued treatment due to adverse events, refusal of further treatment, or treatment delays. Three deaths occurred on study, with 2 treatment-related fatal bowel perforations. Given the minimal efficacy and increased toxicity seen with the combination of bevacizumab and temsirolimus, we do not recommend the use of this regimen in patients with advanced extra-pancreatic neuroendocrine tumors.