Villablanca J G, Khan A A, Avramis V I, Seeger R C, Matthay K K, Ramsay N K, Reynolds C P
Department of Pediatrics, Childrens Hospital, Los Angeles, CA 90027-6016, USA.
J Clin Oncol. 1995 Apr;13(4):894-901. doi: 10.1200/JCO.1995.13.4.894.
Treatment of neuroblastoma cell lines with 13-cis-retinoic acid (cis-RA) can cause sustained inhibition of proliferation. Since cis-RA has demonstrated clinical responses in neuroblastoma patients, it may be effective in preventing relapse after cytotoxic therapy. This phase I trial was designed to determine the maximal-tolerated dosage (MTD), toxicities, and pharmacokinetics of cis-RA administered on an intermittent schedule in children with neuroblastoma following bone marrow transplantation (BMT).
Fifty-one assessable patients, 2 to 12 years of age, were treated with oral cis-RA administered in two equally divided doses daily for 2 weeks, followed by a 2-week rest period, for up to 12 courses. The dose was escalated from 100 to 200 mg/m2/d until dose-limiting toxicity (DLT) was observed. A single intrapatient dose escalation was permitted.
The MTD of cis-RA was 160 mg/m2/d. Dose-limiting toxicities in six of nine patients at 200 mg/m2/d included hypercalcemia (n = 3), rash (n = 2), and anemia/thrombocytopenia/emesis/rash (n = 1). All toxicities resolved after cis-RA was discontinued. Three complete responses were observed in marrow metastases. Serum levels of 7.4 +/- 3.0 mumol/L (peak) and 4.0 +/- 2.8 mumol/L (trough) at the MTD were maintained during 14 days of therapy. The DLT correlated with serum levels > or = 10 mumol/L.
The MTD of cis-RA given on this intermittent schedule was 160 mg/m2/d. Serum levels known to be effective against neuroblastoma in vitro were achieved at this dose. The DLT included hypercalcemia, and may be predicted by serum cis-RA levels. Monitoring of serum calcium and cis-RA levels is indicated in future trials.
用13 - 顺式维甲酸（顺式RA）处理神经母细胞瘤细胞系可导致增殖的持续抑制。由于顺式RA已在神经母细胞瘤患者中显示出临床反应，它可能对预防细胞毒性治疗后的复发有效。本I期试验旨在确定骨髓移植（BMT）后间歇性给药的顺式RA在神经母细胞瘤儿童中的最大耐受剂量（MTD）、毒性和药代动力学。
51例可评估患者，年龄2至12岁，接受口服顺式RA治疗，每日分两次等量给药，共2周，随后休息2周，最多进行12个疗程。剂量从100 mg/m²/d逐步增加至200 mg/m²/d，直至观察到剂量限制性毒性（DLT）。允许在患者个体内单次增加剂量。
顺式RA的MTD为160 mg/m²/d。9例接受200 mg/m²/d治疗的患者中有6例出现剂量限制性毒性，包括高钙血症（n = 3）、皮疹（n = 2）以及贫血/血小板减少/呕吐/皮疹（n = 1）。停用顺式RA后所有毒性均得到缓解。在骨髓转移患者中观察到3例完全缓解。在治疗的14天内，MTD时血清水平维持在7.4±3.0 μmol/L（峰值）和4.0±2.8 μmol/L（谷值）。DLT与血清水平≥10 μmol/L相关。
这种间歇性给药方案的顺式RA的MTD为160 mg/m²/d。在此剂量下达到了已知在体外对神经母细胞瘤有效的血清水平。DLT包括高钙血症，并且可能通过血清顺式RA水平预测。未来试验中建议监测血清钙和顺式RA水平。
