联合使用 177Lu-DOTATATE 和卡培他滨节拍化疗（Lu-X）治疗 FDG 阳性胃肠胰神经内分泌肿瘤。
Combined use of 177Lu-DOTATATE and metronomic capecitabine (Lu-X) in FDG-positive gastro-entero-pancreatic neuroendocrine tumors.
机构信息
Nuclear Medicine and Radiometabolic Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola, Italy.
Department of Nuclear Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
出版信息
Eur J Nucl Med Mol Imaging. 2021 Sep;48(10):3260-3267. doi: 10.1007/s00259-021-05236-z. Epub 2021 Feb 18.
PURPOSE
FDG-positive neuroendocrine tumors (NETs) have a poorer prognosis and exhibit shorter response duration to peptide receptor radionuclide therapy (PRRT). The aim of this prospective phase II study was to evaluate the efficacy and toxicity of PRRT with Lu-DOTATATE associated with metronomic capecitabine as a radiosensitizer agent in patients with advanced progressive FDG-positive gastro-entero-pancreatic (GEP) NETs.
PATIENTS AND METHODS
Patients with advanced somatostatin receptor- and FDG-positive G1-G3 GEP-NETs (Ki67 < 55%) were treated with a cumulative activity of 27.5 GBq of Lu-DOTATATE divided in five cycles of 5.5 GBq each every 8 weeks. Capecitabine (1000-1500 mg daily) was administered orally in the inter-cycle period between Lu-DOTATATE treatments. Prior to commencing capecitabine, all patients were triaged with the dihydropyrimidine dehydrogenase (DPD) test. Only DPD-proficient individuals were enrolled. The primary objectives were disease control rate (DCR) and safety. Secondary aims included progression-free (PFS) and overall survival (OS). Treatment response was assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Toxicity was assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
RESULTS
From August 2015 to December 2016, 37 subjects were consecutively enrolled. A total of 25 (68%) were affected by pancreatic neuroendocrine tumors (P-NETs), and 12 (32%) had gastrointestinal neuroendocrine tumors (GI-NETs). By grading (WHO 2010 classification), 12 patients (32%) had G1 (Ki67 ≤ 2%), 22 (59%) had G2 (3% < Ki67 ≤ 20%), and 3 patients (9%) had G3 (Ki67 > 20%) NETs. Grade 3 (G3) or 4 (G4) hematological toxicity occurred in 16.2% of patients. Other G3-G4 adverse events were diarrhea in 5.4% of cases and asthenia in 5.4%. No renal toxicity was observed for the duration of follow-up. In 37 patients, 33 were evaluable for response. Objective responses included partial response (PR) in 10 patients (30%) and stable disease (SD) in 18 patients (55%), with a DCR of 85%. The median follow-up was 38 months (range 4.6-51.1 months). The median PFS was 31.4 months (17.6-45.4), and mOS was not reached.
CONCLUSIONS
This study demonstrated that the combination of PRRT with Lu-DOTATATE and metronomic capecitabine is active and well tolerated in patients with aggressive FDG-positive G1-G3 GEP-NETs. These data constitute the basis for a randomized study of PPRT alone vs. PRRT plus metronomic capecitabine.
目的
正电子发射断层扫描（FDG）阳性神经内分泌肿瘤（NET）的预后较差，对肽受体放射性核素治疗（PRRT）的反应持续时间更短。本前瞻性 II 期研究的目的是评估 Lu-DOTATATE 联合卡培他滨作为增敏剂在晚期进展性 FDG 阳性胃肠胰（GEP）NET 患者中的疗效和毒性。
方法
对晚期生长抑素受体阳性和 FDG 阳性 G1-G3 GEP-NETs（Ki67<55%）患者进行治疗，累积活性为 27.5GBq 的 Lu-DOTATATE，分为五个周期，每个周期 5.5GBq，每 8 周一次。在 Lu-DOTATATE 治疗之间的周期内，卡培他滨（每天 1000-1500mg）口服给药。在开始卡培他滨之前，所有患者均进行二氢嘧啶脱氢酶（DPD）检测。只有 DPD 功能正常的患者才被纳入研究。主要目的是疾病控制率（DCR）和安全性。次要目的包括无进展生存期（PFS）和总生存期（OS）。根据实体瘤反应评估标准 1.1 版（RECIST 1.1）评估治疗反应。采用不良事件通用术语标准（CTCAE）4.0 版评估毒性。
结果
从 2015 年 8 月至 2016 年 12 月，连续纳入了 37 名患者。共有 25 名（68%）患者患有胰腺神经内分泌肿瘤（P-NETs），12 名（32%）患者患有胃肠道神经内分泌肿瘤（GI-NETs）。根据分级（2010 年 WHO 分类），12 名患者（32%）为 G1（Ki67≤2%），22 名患者（59%）为 G2（3%<Ki67≤20%），3 名患者（9%）为 G3（Ki67>20%）NETs。16.2%的患者出现 3 级（G3）或 4 级（G4）血液学毒性。其他 G3-G4 不良事件包括 5.4%的腹泻和 5.4%的乏力。在随访期间未观察到肾毒性。在 37 名患者中，有 33 名可评估反应。客观缓解包括 10 名患者（30%）的部分缓解（PR）和 18 名患者（55%）的稳定疾病（SD），DCR 为 85%。中位随访时间为 38 个月（范围 4.6-51.1 个月）。中位 PFS 为 31.4 个月（17.6-45.4 个月），mOS 尚未达到。
结论
本研究表明，PRRT 联合 Lu-DOTATATE 和卡培他滨在侵袭性 FDG 阳性 G1-G3 GEP-NETs 患者中具有活性且耐受良好。这些数据为 PRRT 单药与 PRRT 联合卡培他滨的随机研究奠定了基础。
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