There is no standardized treatment for grade 3 neuroendocrine tumors (G3 NETs). We aimed to describe the treatments received in patients with advanced G3 NETs and compare their efficacy. Patients with advanced digestive G3 NETs treated between 2010 and 2018 in seven expert centers were retrospectively studied. Pathological samples were centrally reviewed, and radiological data were locally reviewed. We analyzed RECIST-defined objective response (OR), tumor growth rate (TGR) and progression-free survival (PFS) obtained with first- (L1) or second-line (L2) treatments. We included 74 patients with advanced G3 NETs, mostly from the duodenal or pancreatic origin (71.6%), with median Ki-67 of 30%. The 126 treatments (L1 = 74; L2 = 52) included alkylating-based (n = 32), etoposide-platinum (n = 22) or adenocarcinoma-like (n = 20) chemotherapy, somatostatin analogs (n = 21), targeted therapies (n = 22) and liver-directed therapies (n = 7). Alkylating-based chemotherapy achieved the highest OR rate (37.9%) compared to other treatments (multivariable OR 4.22, 95% CI (1.5-12.2); P = 0.008). Adenocarcinoma-like and alkylating-based chemotherapies showed the highest reductions in 3-month TGR (P < 0.001 and P = 0.008, respectively). The longest median PFS was obtained with adenocarcinoma-like chemotherapy (16.5 months (9.0-24.0)) and targeted therapies (12.0 months (8.2-15.8)), while the shortest PFS was observed with somatostatin analogs (6.2 months (3.8-8.5)) and etoposide-platinum chemotherapy (7.2 months (5.2-9.1)). Etoposide-platinum CT achieved shorter PFS than adenocarcinoma-like (multivariable HR 3.69 (1.61-8.44), P = 0.002) and alkylating-based chemotherapies (multivariable HR 1.95 (1.01-3.78), P = 0.049). Overall, adenocarcinoma-like and alkylating-based chemotherapies may be the most effective treatments for patients with advanced G3 NETs regarding OR and PFS. Etoposide-platinum chemotherapy has poor efficacy in this setting.

中文翻译：

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晚期消化道高分化 3 级 NET 的治疗结果。

3 级神经内分泌肿瘤 (G3 NETs) 没有标准化的治疗方法。我们旨在描述晚期 G3 NETs 患者接受的治疗并比较其疗效。回顾性研究了 2010 年至 2018 年间在七个专家中心接受治疗的晚期消化道 G3 NET 患者。病理样本集中审查，放射学数据在当地审查。我们分析了通过一线 (L1) 或二线 (L2) 治疗获得的 RECIST 定义的客观反应 (OR)、肿瘤生长率 (TGR) 和无进展生存期 (PFS)。我们纳入了 74 名晚期 G3 NET 患者，大部分来自十二指肠或胰腺（71.6%），中位 Ki-67 为 30%。126 种治疗 (L1 = 74; L2 = 52) 包括基于烷基化 (n = 32)、依托泊苷-铂 (n = 22) 或腺癌样 (n = 20) 化疗，生长抑素类似物 (n = 21)、靶向治疗 (n = 22) 和肝脏导向治疗 (n = 7)。与其他治疗相比，基于烷基化的化学疗法的 OR 率最高（37.9%）（多变量 OR 4.22, 95% CI (1.5-12.2)；P = 0.008）。腺癌样和基于烷基化的化疗显示 3 个月 TGR 的降低幅度最大（分别为 P < 0.001 和 P = 0.008）。腺癌样化疗（16.5 个月（9.0-24.0））和靶向治疗（12.0 个月（8.2-15.8））的中位 PFS 最长，而生长抑素类似物的 PFS 最短（6.2 个月（3.8-8.5） ) 和依托泊苷-铂化疗 (7.2 个月 (5.2-9.1))。依托泊苷-铂 CT 的 PFS 比腺癌样（多变量 HR 3.69 (1.61-8.44)，P = 0.002）和基于烷基化的化疗（多变量 HR 1. 95 (1.01-3.78)，P = 0.049)。总体而言，对于晚期 G3 NETs 患者的 OR 和 PFS，腺癌样和烷基化化疗可能是最有效的治疗方法。依托泊苷-铂化疗在这种情况下疗效不佳。