Kumthekar Priya, Grimm Sean, Chandler James, Mehta Minesh, Marymont Maryanne, Levy Robert, Muro Kenji, Helenowski Irene, McCarthy Katie, Fountas Leanne, Raizer Jeffrey
Department of Neurology, Northwestern Medicine, 710 North Lake Shore Dr., Abbott Hall Room 1122, Chicago, IL, 60611, USA.
Department of Neurosurgery, Northwestern Medicine, Chicago, IL, USA.
J Neurooncol. 2017 Jul;133(3):589-594. doi: 10.1007/s11060-017-2469-x. Epub 2017 May 16.
Standard treatment for GBM is radiation (RT) and temozolomide (TMZ). Arsenic trioxide (ATO) is synergistic with RT based on several mechanisms of action previously identified, however not tested herein. The MTD of ATO, RT and TMZ was determined in a Phase I trial. We now present the combined Phase I/II data. Patients with newly diagnosed malignant gliomas were eligible for treatment. Patients were treated with RT (60 GY), TMZ (75 mg/m daily × 42 days) and ATO 0.20 mg/kg daily in week 1 then twice a week ×5 weeks, after completing RT they were treated with TMZ 5/28 for up to 12 months. MRIs were performed every 8 weeks. A total of 42 patients were enrolled in both the Phase I and II trials for this study treatment. Of the 42 enrolled patients (24 M and 18 W) the median age was 54 (24-80) and median KPS 90 (60-100). 28 patients had a GBM and 14 had anaplastic glioma (AG). All patients completed RT/TMZ/ATO and went on to maintenance TMZ. Median number of post RT cycles of TMZ was 4 (0-12). Median PFS was 7 m for GBM and 75 m for AG and median OS was 17 m for GBM and NR for AG. Best response was CR in 2, SD in 28, PR in 5 and PD in 7. There were no unexpected adverse events. Grade 3 toxicities likely attributable to ATO included prolonged Qtc (n = 1), elevated liver enzymes (n = 2 for ALT/n = 1 for AST) and elevated bilirubin (n = 1). Adding ATO to RT and TMZ is feasible with no increased side effects. The addition of arsenic did not improve overall survival in the GBM patients as compared to historic data. MGMT status was analyzed in 20 of the 42 patients where tissue was available for retrieval and MGMT testing.
胶质母细胞瘤（GBM）的标准治疗方法是放疗（RT）和替莫唑胺（TMZ）。基于先前确定的几种作用机制，三氧化二砷（ATO）与放疗具有协同作用，但本文未进行测试。在一项I期试验中确定了ATO、RT和TMZ的最大耐受剂量（MTD）。我们现在展示I/II期联合数据。新诊断为恶性胶质瘤的患者有资格接受治疗。患者接受放疗（60GY）、替莫唑胺（75mg/m²每日×42天）以及ATO，第1周每日0.20mg/kg，然后每周两次共5周，完成放疗后接受替莫唑胺5/28方案治疗长达12个月。每8周进行一次磁共振成像（MRI）检查。本研究治疗的I期和II期试验共纳入42例患者。在这42例入组患者中（24例男性和18例女性），中位年龄为54岁（24 - 80岁），中位 Karnofsky 功能状态评分（KPS）为90分（60 - 100分）。28例患者患有GBM，14例患有间变性胶质瘤（AG）。所有患者均完成了放疗/替莫唑胺/ATO治疗并继续接受替莫唑胺维持治疗。放疗后替莫唑胺的中位周期数为4个（0 - 12个）。GBM的中位无进展生存期（PFS）为7个月，AG为75个月，GBM的中位总生存期（OS）为17个月，AG未达到。最佳反应为2例完全缓解（CR）、28例疾病稳定（SD）、5例部分缓解（PR）和7例疾病进展（PD）。未出现意外不良事件。可能归因于ATO的3级毒性包括Qtc延长（n = 1）、肝酶升高（谷丙转氨酶n = 2/谷草转氨酶n = 1）和胆红素升高（n = 1）。在放疗和替莫唑胺基础上加用ATO是可行的，且未增加副作用。与历史数据相比，在GBM患者中添加砷并未改善总生存期。在42例患者中有20例可获取组织并进行了O6 -甲基鸟嘌呤 - DNA甲基转移酶（MGMT）状态分析及检测。
