We evaluated outcomes of treatment with 5-fluorouracil (5-FU), doxorubicin, and streptozocin (FAS) in well-differentiated pancreatic neuroendocrine tumors (PanNETs) and its impact on subsequent therapy (everolimus or temozolomide). Advanced PanNET patients treated at our center from 1992 to 2013 were retrospectively reviewed. Patients received bolus 5-FU (400 mg/m2), streptozocin (400 mg/m2) (both IV, days 1-5) and doxorubicin (40 mg/m2 IV, day 1) every 28 days. Overall response rate (ORR) was assessed using RECIST version 1.1. Of 243 eligible patients, 220 were evaluable for ORR, progression-free survival (PFS), and toxicity. Most (90%) had metastatic, nonfunctional PanNETs; 14% had prior therapy. ORR to FAS was 41% (95% confidence interval [CI]: 36-48%). Median follow-up was 61 months. Median PFS was 20 (95% CI: 15-23) months; median overall survival (OS) was 63 (95% CI: 60-71) months. Cox regression analyses suggested improvement with first-line vs subsequent lines of FAS therapy. Main adverse events ≥ grade 3 were neutropenia (10%) and nausea/vomiting (5.5%). Dose reductions were required in 32% of patients. Post-FAS everolimus (n=108; 68% second line) had a median PFS of 10 (95% CI: 8-14) months. Post-FAS temozolomide (n=60; 53% > fourth line) had an ORR of 13% and median PFS of 5.2 (95% CI: 4-12) months. In this largest reported cohort of PanNETs treated with chemotherapy, FAS demonstrated activity without significant safety concerns. FAS did not appear to affect subsequent PFS with everolimus; this sequence is being evaluated prospectively. Responses were noted with subsequent temozolomide-based regimens although PFS was possibly limited by line of therapy.


中文翻译：

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胰腺神经内分泌肿瘤的 FAS 和后续治疗


我们评估了 5-氟尿嘧啶 (5-FU)、阿霉素和链佐星 (FAS) 对分化良好的胰腺神经内分泌肿瘤 (PanNET) 的治疗结果及其对后续治疗（依维莫司或替莫唑胺）的影响。对1992年至2013年在我中心治疗的晚期PanNET患者进行回顾性分析。患者每 28 天接受推注 5-FU (400 mg/m2)、链脲佐菌素 (400 mg/m2)（均为静脉注射，第 1-5 天）和多柔比星（40 mg/m2 IV，第 1 天）。使用 RECIST 1.1 版评估总体缓解率 (ORR)。在 243 名符合条件的患者中，有 220 名可进行 ORR、无进展生存期 (PFS) 和毒性评估。大多数（约 90%）具有转移性、无功能的 PanNET； 14% 之前接受过治疗。 FAS 的 ORR 为 41%（95% 置信区间 [CI]：36-48%）。中位随访时间为 61 个月。中位 PFS 为 20 (95% CI: 15-23) 个月；中位总生存期 (OS) 为 63 (95% CI: 60-71) 个月。 Cox 回归分析表明一线 FAS 治疗与后续线路相比有所改善。 ≥ 3 级的主要不良事件是中性粒细胞减少症 (10%) 和恶心/呕吐 (5.5%)。 32% 的患者需要减少剂量。 FAS 后依维莫司（n=108；68% 二线）的中位 PFS 为 10 个月（95% CI：8-14）个月。 FAS 后替莫唑胺（n=60；53% > 第四线）的 ORR 为 13%，中位 PFS 为 5.2（95% CI：4-12）个月。在这一最大的报道的接受化疗的 PanNET 队列中，FAS 表现出了活性，且没有明显的安全问题。 FAS 似乎并不影响后续使用依维莫司的 PFS；正在对该序列进行前瞻性评估。尽管 PFS 可能受到治疗方案的限制，但随后基于替莫唑胺的治疗方案取得了缓解。