Estlin E J, Lashford L, Ablett S, Price L, Gowing R, Gholkar A, Kohler J, Lewis I J, Morland B, Pinkerton C R, Stevens M C, Mott M, Stevens R, Newell D R, Walker D, Dicks-Mireaux C, McDowell H, Reidenberg P, Statkevich P, Marco A, Batra V, Dugan M, Pearson A D
UKCCSG Data Centre, Department of Epidemiology and Public Health, University of Leicester, UK.
Br J Cancer. 1998 Sep;78(5):652-61. doi: 10.1038/bjc.1998.555.
A phase I study of temozolomide administered orally once a day, on 5 consecutive days, between 500 and 1200 mg m(-2) per 28-day cycle was performed. Children were stratified according to prior craniospinal irradiation or nitrosourea therapy. Sixteen of 20 patients who had not received prior craniospinal irradiation or nitrosourea therapy were evaluable. Myelosuppression was dose limiting, with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia occurring in one of six patients receiving 1000 mg m(-2) per cycle, and two of four patients treated at 1200 mg m(-2) per cycle. Therefore, the maximum-tolerated dose (MTD) was 1000 mg m(-2) per cycle. The MTD was not defined for children with prior craniospinal irradiation because of poor recruitment. Plasma pharmacokinetic analyses showed temozolomide to be rapidly absorbed and eliminated, with linear increases in peak plasma concentrations and systemic exposure with increasing dose. Responses (CR and PR) were seen in two out of five patients with high-grade astrocytomas, and one patient had stable disease. One of ten patients with diffuse intrinsic brain stem glioma achieved a long-term partial response, and a further two patients had stable disease. Therefore, the dose recommended for phase II studies in patients who have not received prior craniospinal irradiation or nitrosoureas is 1000 mg m(-2) per cycle. Further evaluation in diffuse intrinsic brain stem gliomas and other high-grade astrocytomas is warranted.
进行了一项I期研究，研究对象为每28天周期连续5天每天口服替莫唑胺，剂量范围为500至1200 mg/m²。根据既往是否接受过颅脊髓照射或亚硝基脲治疗对儿童进行分层。20例未接受过颅脊髓照射或亚硝基脲治疗的患者中有16例可进行评估。骨髓抑制是剂量限制性毒性，接受每周期1000 mg/m²的6例患者中有1例出现4级血小板减少，接受每周期1200 mg/m²治疗的4例患者中有2例出现4级血小板减少。因此，最大耐受剂量（MTD）为每周期1000 mg/m²。由于入组情况不佳，未确定既往接受过颅脊髓照射的儿童的MTD。血浆药代动力学分析显示替莫唑胺吸收和消除迅速，血浆峰浓度和全身暴露量随剂量增加呈线性增加。5例高级别星形细胞瘤患者中有2例出现缓解（完全缓解和部分缓解），1例病情稳定。10例弥漫性脑桥内生型胶质瘤患者中有1例获得长期部分缓解，另有2例病情稳定。因此，对于未接受过颅脊髓照射或亚硝基脲治疗的患者，II期研究推荐的剂量为每周期1000 mg/m²。有必要对弥漫性脑桥内生型胶质瘤和其他高级别星形细胞瘤进行进一步评估。
