难治性神经母细胞瘤中碘-131-间碘苄胍联合清髓性化疗及自体干细胞移植的I期剂量递增研究：神经母细胞瘤治疗联盟研究的新方法

Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: a new approaches to Neuroblastoma Therapy Consortium Study.

作者信息

Matthay Katherine K, Tan Jessica C, Villablanca Judith G, Yanik Gregory A, Veatch Janet, Franc Benjamin, Twomey Eilish, Horn Biljana, Reynolds C Patrick, Groshen Susan, Seeger Robert C, Maris John M

机构信息

Department of Pediatrics, University of California, San Francisco, School of Medicine, and UCSF Children's Hospital, San Francisco, CA 94143-0106, USA.

出版信息

J Clin Oncol. 2006 Jan 20;24(3):500-6. doi: 10.1200/JCO.2005.03.6400.

DOI:10.1200/JCO.2005.03.6400

PMID:16421427

Abstract

PURPOSE

To determine the maximum-tolerated dose (MTD) and toxicity of iodine-131-metaiodobenzylguanidine ((131)I-MIBG) with carboplatin, etoposide, melphalan (CEM) and autologous stem-cell transplantation (ASCT) in refractory neuroblastoma.

PATIENTS AND METHODS

Twenty-four children with primary refractory neuroblastoma and no prior ASCT were entered; 22 were assessable for toxicity and response. (131)I-MIBG was administered on day -21, CEM was administered on days -7 to -4, and ASCT was performed on day 0, followed by 13-cis-retinoic acid. (131)I-MIBG was escalated in groups of three to six patients, stratified by corrected glomerular filtration rate (GFR).

RESULTS

The MTD for patients with normal GFR (> or = 100 mL/min/1.73 m2) was 131I-MIBG 12 mCi/kg, carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and melphalan 210 mg/m2. In the low-GFR cohort, at the initial dose level using 12 mCi/kg of 131I-MIBG and reduced chemotherapy, one in six patients had dose limiting toxicity (DLT), including veno-occlusive disease (VOD). Three more patients in this group had grade 3 or 4 hepatotoxicity, and two had VOD, without meeting DLT criteria. There was only one death as a result of toxicity among all 24 patients. All assessable patients engrafted, with median time for neutrophils > or = 500/microL of 10 days and median time for platelets > or = 20,000/microL of 26 days. Six of 22 assessable patients had complete or partial response, and 15 patients had mixed response or stable disease. The estimated probability of event-free survival and survival from the day of MIBG infusion for all patients at 3 years was 0.31 +/- 0.10 and 0.58 +/- 0.10, respectively.

CONCLUSION

131I-MIBG with myeloablative chemotherapy is feasible and effective for patients with neuroblastoma exhibiting de novo resistance to chemotherapy.

摘要

目的

确定难治性神经母细胞瘤患者接受碘-131-间碘苄胍（(131)I-MIBG）联合卡铂、依托泊苷、美法仑（CEM）及自体干细胞移植（ASCT）时的最大耐受剂量（MTD）及毒性。

患者与方法

纳入24例初治难治性神经母细胞瘤且未接受过ASCT的儿童患者；22例可评估毒性及反应。(131)I-MIBG于第-21天给药，CEM于第-7天至第-4天给药，ASCT于第0天进行，随后给予13-顺式维甲酸。(131)I-MIBG按每组三至六名患者递增，根据校正肾小球滤过率（GFR）分层。

结果

GFR正常（≥100 mL/min/1.73 m2）患者的MTD为(131)I-MIBG 12 mCi/kg、卡铂1500 mg/m2、依托泊苷1200 mg/m2及美法仑210 mg/m2。在低GFR队列中，在初始剂量水平使用12 mCi/kg的(131)I-MIBG并减少化疗时，六名患者中有一名出现剂量限制性毒性（DLT），包括静脉闭塞性疾病（VOD）。该组另外三名患者出现3级或4级肝毒性，两名患者出现VOD，但未达到DLT标准。24例患者中仅1例因毒性死亡。所有可评估患者均植入成功，中性粒细胞≥500/μL的中位时间为10天，血小板≥20,000/μL的中位时间为26天。22例可评估患者中有6例完全或部分缓解，15例患者为混合反应或病情稳定。所有患者自MIBG输注日起3年的无事件生存率和生存率估计概率分别为0.31±0.10和0.58±0.10。