Dose Escalation Study of No-Carrier-Added 131I-Metaiodobenzylguanidine for Relapsed or Refractory Neuroblastoma: New Approaches to Neuroblastoma Therapy Consortium Trial
Dose Escalation Study of No-Carrier-Added 131I-Metaiodobenzylguanidine for Relapsed or Refractory Neuroblastoma: New Approaches to Neuroblastoma Therapy Consortium Trial
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DOI：
10.2967/jnumed.111.098624
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发表时间：
2012-07-01
影响因子：
9.3
通讯作者：
Babich, John
中科院分区：
文献类型：
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作者：
Matthay, Katherine K.;Weiss, Brian;Babich, John
~(131)I-间碘苯甲基胍(MIBG)专用于神经母细胞瘤，复发有效率为20%~37%。非放射性载体MIBG分子抑制I-131-MIBG的摄取，理论上导致肿瘤辐射减少和心血管毒性风险增加。我们的目的是建立无载体(NCA)I-131-MIBG的最大耐受剂量，其次是评估肿瘤和器官剂量学以及总体反应。方法：符合条件的患者年龄1-30岁，患有耐药神经母细胞瘤，摄取I-131-MIBG，并将造血干细胞冷冻保存。在诊断剂量NCA I-131-MIBG之后，进行3次剂量扫描，以评估关键器官和软组织肿瘤的辐射剂量。NCAI-131-MIBG的治疗剂量(比活度，165MBq/mUg)根据器官临界耐受限度进行必要的调整。治疗14d后输注自体造血干细胞以消除长期的骨髓抑制。在第60天评价其疗效和毒性。NCA I-131-MIBG采用3+3设计，从444 MBq/kg(12-21 MCI/kg)升级到777 MBq/kg。剂量限制毒性包括中性粒细胞在28天内未能重建至大于500个/亩L或血小板未能在56天内重建至大于20,000个/亩L，或除预先定义的排除外，按不良事件通用术语标准(版本3.0)评定为3级或4级非血液毒性。结果：在没有DLT的情况下，3名患者的体重分别为444、555和666MBq/kg。由于器官剂量学的限制，777MBq/kg的剂量是不可行的；然而，3名指定的患者可以接受666MBq/kg的接受剂量进行评估，在没有DLT的情况下，总共有6名患者可以在666MBq/kg的剂量下评估毒性。肝脏、肺和肾脏的平均全身照射剂量为0.23mGyMBq，器官平均剂量分别为0.92、0.82和1.2mGyMBq。8例患者有13个软组织病变，肿瘤吸收剂量26~378Gy.15例患者中，4例完全反应(n=1)或部分反应(n=3)，1例混合反应，4例病情稳定，6例病情进展。结论：Nca I-131-MIBG联合自体外周血干细胞移植在666MBq/kg剂量下是可行的，无明显的血液毒性，具有良好的应用前景。
I-131-metaiodobenzylguanidine (MIBG) is specifically taken up in neuroblastoma, with a response rate of 20%-37% in relapsed disease. Nonradioactive carrier MIBG molecules inhibit uptake of I-131-MIBG, theoretically resulting in less tumor radiation and increased risk of cardiovascular toxicity. Our aim was to establish the maximum tolerated dose of no-carrier-added (NCA) I-131-MIBG, with secondary aims of assessing tumor and organ dosimetry and overall response. Methods: Eligible patients were 1-30 y old with resistant neuroblastoma, I-131-MIBG uptake, and cryopreserved hematopoietic stem cells. A diagnostic dose of NCA I-131-MIBG was followed by 3 dosimetry scans to assess radiation dose to critical organs and soft-tissue tumors. The treatment dose of NCA I-131-MIBG (specific activity, 165 MBq/mu g) was adjusted as necessary on the basis of critical organ tolerance limits. Autologous hematopoietic stem cells were infused 14 d after therapy to abrogate prolonged myelosuppression. Response and toxicity were evaluated on day 60. The NCA I-131-MIBG was escalated from 444 to 777 MBq/kg (12-21 mCi/kg) using a 3 + 3 design. Dose-limiting toxicity (DLT) was failure to reconstitute neutrophils to greater than 500/mu L within 28 d or platelets to greater than 20,000/mu L within 56 d, or grade 3 or 4 nonhematologic toxicity by Common Terminology Criteria for Adverse Events (version 3.0) except for predefined exclusions. Results: Three patients each were evaluable at 444, 555, and 666 MBq/kg without DLT. The dose of 777 MBq/kg dose was not feasible because of organ dosimetry limits; however, 3 assigned patients were evaluable for a received dose of 666 MBq/kg, providing a total of 6 patients evaluable for toxicity at 666 MBq/kg without DLT. Mean whole-body radiation was 0.23 mGy/MBq, and mean organ doses were 0.92, 0.82, and 1.2 mGy/MBq of MIBG for the liver, lung, and kidney, respectively. Eight patients had 13 soft-tissue lesions with tumor-absorbed doses of 26-378 Gy. Four of 15 patients had a complete (n = 1) or partial (n = 3) response, 1 had a mixed response, 4 had stable disease, and 6 had progressive disease. Conclusion: NCA I-131-MIBG with autologous peripheral blood stem cell transplantation is feasible at 666 MBq/kg without significant nonhematologic toxicity and with promising activity.