兰瑞肽治疗转移性胃肠胰神经内分泌肿瘤。

Lanreotide in metastatic enteropancreatic neuroendocrine tumors.

机构信息

From Royal Free Hospital, London (M.E.C.); Charité University Medicine Berlin, Berlin (M.P.); University of Warmia and Mazury, Olsztyn, Poland (J.B.Ć.); University of Texas M.D. Anderson Cancer Center, Houston (A.T.P.); University Hospital, Vienna (M.R.); Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic (E.S.); Robert-Debré Hospital, Reims (G.C.), Ipsen, Les Ulis, (A.L., S.M., J.B.), Beaujon Hospital, Clichy (P.R.), and Paris Diderot University, Paris (P.R.) - all in France; Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles (E.M.W.); Vall d'Hebron University Hospital, Barcelona (J.C.); Western General Hospital, Edinburgh (L.W.); and Università Cattolica del Sacro Cuore, Rome (G.R.).

出版信息

N Engl J Med. 2014 Jul 17;371(3):224-33. doi: 10.1056/NEJMoa1316158.

DOI:10.1056/NEJMoa1316158

PMID:25014687

Abstract

BACKGROUND

Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited.

METHODS

We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety.

RESULTS

Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group).

CONCLUSIONS

Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

摘要

背景

生长抑素类似物常用于治疗神经内分泌肿瘤中激素过度分泌相关的症状；然而，关于其抗肿瘤作用的数据有限。

方法

我们开展了一项随机、双盲、安慰剂对照、多国研究，评估生长抑素类似物兰瑞肽（lanreotide）治疗 1 级或 2 级（Ki-67 抗原染色肿瘤增殖指数<10%）、分化良好或中度分化、非功能性、生长抑素受体阳性、起源于胰腺、中肠或后肠的神经内分泌肿瘤患者的疗效。患者随机分配接受每 28 天一次的 120mg 缓释水凝胶制剂（Autogel[在美国称为 Depot]，Ipsen）或安慰剂（103 例）治疗，共 96 周。主要终点为无进展生存期，定义为疾病进展（根据实体瘤反应评价标准 1.0）或死亡时间。次要终点包括总生存期、生活质量（欧洲癌症研究和治疗组织问卷 QLQ-C30 和 QLQ-GI.NET21 评估）和安全性。

结果

大多数患者（96%）在随机分组前 3 至 6 个月内没有肿瘤进展，33%的患者肝脏肿瘤体积大于 25%。与安慰剂相比，兰瑞肽显著延长了无进展生存期（中位无进展生存期未达到 vs. 18.0 个月，分层对数秩检验 P<0.001；进展或死亡风险比，0.47；95%置信区间[CI]，0.30 至 0.73）。兰瑞肽组 24 个月时无进展生存率为 65.1%（95%CI，54.0 至 74.1），安慰剂组为 33.0%（95%CI，23.0 至 43.3）。在预先设定的亚组中，除了置信区间较宽的小亚组外，治疗效果通常与总体人群一致。两组间生活质量或总生存期无显著差异。最常见的治疗相关不良事件是腹泻（兰瑞肽组 26%，安慰剂组 9%）。