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伊文思蓝修饰的放射性标记生长抑素类似物镥-多胺大环配体-伊文思蓝-酪胺酸-奥曲肽在转移性神经内分泌肿瘤治疗中的剂量递增研究

Dose escalation of an Evans blue-modified radiolabeled somatostatin analog Lu-DOTA-EB-TATE in the treatment of metastatic neuroendocrine tumors.

作者信息

Liu Qingxing, Cheng Yuejuan, Zang Jie, Sui Huimin, Wang Hao, Jacobson Orit, Zhu Zhaohui, Chen Xiaoyuan

机构信息

Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.

Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, 100730, China.

出版信息

Eur J Nucl Med Mol Imaging. 2020 Apr;47(4):947-957. doi: 10.1007/s00259-019-04530-1. Epub 2019 Dec 12.

DOI:10.1007/s00259-019-04530-1
PMID:31832728
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7080608/
Abstract

PURPOSE: To evaluate the safety and efficacy of Lu-DOTA-EB-TATE, a radiolabeled somatostatin analog modified by Evans blue, at escalating doses, was used to increase tumor retention in patients with progressive metastatic neuroendocrine tumors (NETs). METHODS: Thirty-three patients with metastatic NETs were prospectively enrolled into four groups: group A (n = 6, 43 ± 12 years) administered approximately 3.7 GBq (100 mCi) Lu-DOTATATE as controls; group B (n = 7, 55 ± 7 years) administered approximately 1.11 GBq (30 mCi) Lu-DOTA-EB-TATE; group C (n = 6, 55 ± 10 years) administered approximately 1.85 GBq (50 mCi) Lu-DOTA-EB-TATE; group D (n = 14, 50 ± 10 years) administered approximately 3.7 GBq (100 mCi) Lu-DOTA-EB-TATE. Treatment-related adverse events were graded according to the CTCAE v.5.0. Ga-DOTATATE PET/CT were performed at baseline and 2-3 months after treatment for response evaluation. RESULTS: Administration was well tolerated. No CTC 3/4 hematotoxicity, nephrotoxicity, or hepatotoxicity was observed during or after treatment in groups A-C. In group D, CTC-3 hematotoxicity was recorded in 2 patients with multicourse chemotherapy previously. After one-cycle treatment, the SUVmax decreased in group C (Δ% = - 17.4 ± 29.3%) and group D (Δ% = - 15.1 ± 39.1%), but greatly increased in group B (Δ% = 30.0 ± 68.0%) and mildly increased in group A (Δ% = 5.4 ± 45.9%). Referring to EORTC criteria, 16.7% (1/6), 0% (0/7), 50% (3/6), and 50% (7/14) were evaluated as partial response in groups A, B, C, and D, respectively. When selecting lesions with comparable baseline SUVmax ranging from 15 to 40, SUVmax showed no significant decrease in group B (Δ% = - 7.3 ± 24.5%) (P = 0.214), significant decrease in group C (Δ% = - 34.9 ± 12.4%) (P = 0.001), and in group D (Δ% = - 17.9 ± 19.7%) (P = 0.012) as compared with group A with increased SUVmax (Δ% = 8.4 ± 48.8%). SUVmax significantly decreased in the EBTATE groups (groups B-D combined) (Δ% = - 19.0 ± 21.5%) as compared with the TATE group (P = 0.045). CONCLUSION: Lu-DOTA-EB-TATE is well tolerated and is more effective than Lu-DOTATATE. Both 1.85 GBq (50 mCi) and 3.7 GBq (100 mCi) doses appear to be more effective than 1.11 GBq (30 mCi) dose. Further investigation with more cycles of Lu-DOTA-EB-TATE treatment and longer follow-up is warranted. TRIAL REGISTRATION: Treatment Using 177Lu-DOTA-EB-TATE in Patients with Advanced Neuroendocrine Tumors (NCT03478358). URL: https://register.clinicaltrials.gov/prs/app/action/ViewOrUnrelease?uid=U0001JRW&ts=13&sid=S0007RNX&cx=y3yqv4.

摘要

目的：评估经伊文思蓝修饰的放射性标记生长抑素类似物Lu-DOTA-EB-TATE在递增剂量下的安全性和有效性，该药物用于增加进展期转移性神经内分泌肿瘤（NETs）患者的肿瘤滞留。 方法：33例转移性NETs患者被前瞻性纳入四组：A组（n = 6，43±12岁）给予约3.7 GBq（100 mCi）Lu-DOTATATE作为对照；B组（n = 7，55±7岁）给予约1.11 GBq（30 mCi）Lu-DOTA-EB-TATE；C组（n = 6，55±10岁）给予约1.85 GBq（50 mCi）Lu-DOTA-EB-TATE；D组（n = 14，50±10岁）给予约3.7 GBq（100 mCi）Lu-DOTA-EB-TATE。治疗相关不良事件根据CTCAE v.5.0进行分级。在基线和治疗后2 - 3个月进行Ga-DOTATATE PET/CT以评估反应。 结果：给药耐受性良好。A - C组在治疗期间或之后未观察到CTCAE 3/4级血液毒性、肾毒性或肝毒性。在D组中，2例先前接受多程化疗的患者记录到CTCAE - 3级血液毒性。经过一个周期治疗后，C组（Δ% = - 17.4±29.3%）和D组（Δ% = - 15.1±39.1%）的SUVmax降低，但B组（Δ% = 30.0±68.0%）大幅升高，A组（Δ% = 5.4±45.9%）轻度升高。参照欧洲癌症研究与治疗组织（EORTC）标准，A、B、C、D组分别有16.7%（1/6）、0%（0/7）、50%（3/6）和50%（7/14）被评估为部分缓解。当选择基线SUVmax在15至40之间的可比病变时，与SUVmax升高（Δ% = 8.4±48.8%）的A组相比，B组（Δ% = - 7.3±24.5%）（P = 0.214）的SUVmax无显著降低，C组（Δ% = - 34.9±12.4%）（P = 0.001）和D组（Δ% = - 17.9±19.7%）（P = 0.012）有显著降低。与TATE组相比，EBTATE组（B - D组合）的SUVmax显著降低（Δ% = - 19.0±21.5%）（P = 0.045）。 结论：Lu-DOTA-EB-TATE耐受性良好且比Lu-DOTATATE更有效。1.85 GBq（50 mCi）和3.7 GBq（100 mCi）剂量似乎比1.11 GBq（30 mCi）剂量更有效。有必要对更多周期的Lu-DOTA-EB-TATE治疗和更长时间的随访进行进一步研究。 试验注册：晚期神经内分泌肿瘤患者使用177Lu-DOTA-EB-TATE治疗（NCT03478358）。网址：https://register.clinicaltrials.gov/prs/app/action/ViewOrUnrelease?uid=U0001JRW&ts=13&sid=S0007RNX&cx=y3yqv4

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本文引用的文献

[1]
Bench to Bedside: Albumin Binders for Improved Cancer Radioligand Therapies.

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Response to Single Low-dose Lu-DOTA-EB-TATE Treatment in Patients with Advanced Neuroendocrine Neoplasm: A Prospective Pilot Study.

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Safety, Pharmacokinetics, and Dosimetry of a Long-Acting Radiolabeled Somatostatin Analog Lu-DOTA-EB-TATE in Patients with Advanced Metastatic Neuroendocrine Tumors.

J Nucl Med. 2018-4-13

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Nucl Med Commun. 2017-7

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