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Additional holmium-166 radioembolisation after lutetium-177-dotatate in patients with neuroendocrine tumour liver metastases (HEPAR PLuS): a single-centre, single-arm, open-label, phase 2 study.
The Lancet Oncology ( IF 41.6 ) Pub Date : 2020-02-26 , DOI: 10.1016/s1470-2045(20)30027-9
Arthur J A T Braat 1 , Rutger C G Bruijnen 1 , Rob van Rooij 1 , Manon N G J A Braat 1 , Frank J Wessels 1 , Rachel S van Leeuwaarde 2 , Mark J C van Treijen 2 , Wouter W de Herder 3 , Johannes Hofland 3 , Margot E T Tesselaar 4 , Hugo W A M de Jong 1 , Marnix G E H Lam 1
Affiliation  

BACKGROUND In patients with metastatic neuroendocrine neoplasms, the liver is the most commonly affected organ and a crucial factor for prognosis and survival. Peptide receptor radionuclide therapy can prolong progression-free survival in these patients. Additional treatment of liver disease might further improve outcomes. We aimed to investigate the safety and efficacy of additional holmium-166 (166Ho) radioembolisation after peptide receptor radionuclide therapy in patients with metastatic liver neuroendocrine neoplasms. METHODS The Holmium Embolization Particles for Arterial Radiotherapy Plus 177Lu-Dotatate in Salvage Neuroendocrine Tumour Patients (HEPAR PLuS) study was a single-centre, phase 2 study done at the University Medical Center Utrecht (Utrecht, Netherlands). Patients, aged at least 18 years, with histologically proven grade 1 or 2 neuroendocrine neoplasms of all origins, an Eastern Cooperative Oncology Group performance status of 0-2, and three or more measurable liver metastases according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria received 166Ho-radioembolisation within 20 weeks after four cycles of peptide receptor radionuclide therapy (lutetium-177-dotatate [177Lu-dotatate]). The primary endpoint was objective liver tumour response in the treated liver volume, defined as complete response (disappearance of all lesions) or partial response (≥30% decrease in the sum of the longest diameters of the target lesions, compared with baseline measurements), according to RECIST 1.1, analysed per protocol at 3 months. Safety was assessed in all patients who received treatment. This study is registered with ClinicalTrials.gov, NCT02067988. Recruitment is completed and long-term follow-up is ongoing. FINDINGS From Oct 15, 2014, to Sept 12, 2018, 34 patients were assessed for eligibility. 31 patients received treatment and 30 (97%) patients were available for primary endpoint assessment and completed 6 months of follow-up. Three (9%) patients were excluded at screening and one (3%) patient was treated and died before the primary endpoint and was replaced. According to the per-protocol analysis 13 (43%; 95% CI 26-63) of 30 patients achieved an objective response in the treated volume. The most frequently reported Common Terminology Criteria for Adverse Events (CTCAE) grade 3-4 clinical and laboratory toxicities within 6 months included abdominal pain (three [10%] of 31 patients), increased γ-glutamyl transpeptidase (16 [54%]), and lymphocytopenia (seven [23%]). One (3%) fatal treatment-related serious adverse event occurred (radioembolisation-induced liver disease). Two (6%) patients had serious adverse events deemed to be unrelated to treatment (gastric ulcer and perforated cholecystitis). INTERPRETATION 166Ho-radioembolisation, as an adjunct to peptide receptor radionuclide therapy in patients with neuroendocrine neoplasm liver metastases, is safe and efficacious. Radioembolisation can be considered in patients with bulky liver disease, including after peptide receptor radionuclide therapy. A future randomised, controlled study should investigate the added benefit of this treatment on progression-free survival. FUNDING None.

中文翻译:

神经内分泌肿瘤肝转移(HEPAR PLuS)患者中使用dot-dot-177后再进行166放射栓塞:一项单中心,单臂,开放标签的2期研究。

背景技术在患有转移性神经内分泌肿瘤的患者中,肝脏是最常见的器官,也是预后和生存的关键因素。肽受体放射性核素疗法可以延长这些患者的无进展生存期。肝病的其他治疗可能会进一步改善预后。我们的目的是研究转移性肝神经内分泌肿瘤患者接受肽受体放射性核素治疗后附加additional166(166Ho)放射栓塞的安全性和有效性。方法挽救神经内分泌肿瘤患者的动脉放疗加上177Lu-Dotatate Emb栓塞颗粒研究(HEPAR PLuS)是一项单中心的2期研究,在乌得勒支大学医学中心(荷兰乌特勒支)进行。年龄至少18岁的患者,根据实体肿瘤反应评估标准(RECIST)1.1版标准,具有经组织学证实为所有来源的1或2级神经内分泌肿瘤,东部合作肿瘤小组的工作状态为0-2和三个或更多可测量的肝转移,接受了166Ho放射栓塞在肽受体放射性核素治疗(lut 177-dotatate [177Lu-dotatate])的四个周期后的20周内。主要终点是治疗肝脏体积中的客观肝肿瘤反应,定义为完全反应(所有病变消失)或部分反应(与基线测量值相比,目标病变最长直径的总和减少≥30%),根据RECIST 1.1,每个方案在3个月时进行了分析。评估所有接受治疗的患者的安全性。该研究已在ClinicalTrials.gov注册,NCT02067988。招聘已完成,正在进行长期跟进。结果从2014年10月15日至2018年9月12日,对34例患者进行了资格评估。31名患者接受了治疗,其中30名(97%)患者可用于主要终点评估并完成6个月的随访。筛选时排除了三名(9%)患者,一名患者(3%)在主要终点之前接受了治疗并死亡,并被更换。根据方案分析,30例患者中有13例(43%; 95%CI 26-63)在治疗量方面达到了客观缓解。在6个月内,最常报告的3-4级不良事件通用术语标准(CTCAE)临床和实验室毒性包括腹痛(31例患者中有3例[10%]),增加了γ-谷氨酰转肽酶(16 [54%])和淋巴细胞减少(七[23%])。发生了一次(3%)与致命治疗相关的严重不良事件(放射性栓塞诱发的肝病)。2名(6%)患者有严重不良事件,认为与治疗无关(胃溃疡和穿孔性胆囊炎)。166放疗是神经内分泌肿瘤肝转移患者的肽受体放射性核素治疗的辅助手段,是安全有效的。患有大块肝病的患者可以考虑进行放射栓塞,包括在接受肽受体放射性核素治疗后。未来的一项随机对照研究应该研究这种治疗对无进展生存的附加益处。资金无。发生了一次(3%)与致命治疗相关的严重不良事件(放射性栓塞诱发的肝病)。2名(6%)患者有严重不良事件,认为与治疗无关(胃溃疡和穿孔性胆囊炎)。166放疗是神经内分泌肿瘤肝转移患者的肽受体放射性核素治疗的辅助手段,是安全有效的。患有大块肝病的患者可以考虑进行放射栓塞,包括在接受肽受体放射性核素治疗后。未来的一项随机对照研究应该研究这种治疗对无进展生存的附加益处。资金无。发生了一次(3%)与致命治疗相关的严重不良事件(放射性栓塞诱发的肝病)。2名(6%)患者有严重不良事件,认为与治疗无关(胃溃疡和穿孔性胆囊炎)。166放疗是神经内分泌肿瘤肝转移患者的肽受体放射性核素治疗的辅助手段,是安全有效的。患有大块肝病的患者可以考虑进行放射栓塞,包括在接受肽受体放射性核素治疗后。未来的一项随机对照研究应该研究这种治疗对无进展生存的附加益处。资金无。166放疗是神经内分泌肿瘤肝转移患者的肽受体放射性核素治疗的辅助手段,是安全有效的。患有大块肝病的患者可以考虑进行放射栓塞,包括在接受肽受体放射性核素治疗后。未来的一项随机对照研究应该研究这种治疗对无进展生存的附加益处。资金无。166放疗是神经内分泌肿瘤肝转移患者的肽受体放射性核素治疗的辅助手段,是安全有效的。患有大块肝病的患者可以考虑进行放射栓塞,包括在接受肽受体放射性核素治疗后。未来的一项随机对照研究应该研究这种治疗对无进展生存的附加益处。资金无。对照研究应研究这种治疗对无进展生存的附加益处。资金无。对照研究应研究这种治疗对无进展生存的附加益处。资金无。
更新日期:2020-02-26
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