Memantine for Prevention of Cognitive Late Effects in Pediatric Patients Receiving Cranial Radiation Therapy for Low Grade Glioma

项目总结/摘要 接受脑肿瘤放射治疗的儿童， 疾病和治疗（例如，注意力、记忆力和处理速度方面的问题）， 生活质量，包括学业和社会成就下降。低级别胶质瘤占30 - 50%， 儿童脑肿瘤的生存率很高，无进展生存率约为80%， 长期随访。随着幸存者人数的增加，改善长期认知结果的努力 变得势在必行。这项研究计划的主要目标是开发干预措施， CNS导向治疗对儿童癌症幸存者生活质量的影响。血管假说 放射损伤的机制与小血管病变相似， 血管性痴呆的发病率，引起了人们对血管性痴呆治疗的兴趣。随机化安慰剂- 对照试验显示美金刚（一种阻断神经递质NMDA受体的药物 谷氨酸）改善轻度至中度血管性痴呆患者的认知功能， 方面的影响.此外，在成人脑转移瘤的放射治疗期间，美金刚已被证明是良好的。 与安慰剂相比，耐受性随时间的认知下降更少。注意力缺陷儿童的研究 多动障碍或自闭症谱系障碍已显示美金刚胺是安全的证据， 改善认知。重要的是，没有发表的研究美金刚在儿童接受治疗 治疗脑瘤决定我们是否能保持认知能力， 在晚期效应出现之前，通过干预治疗癌症的儿童的功能。 因此，本研究的具体目的是：1）估计参与率，服药依从性 并完成美金刚作为儿童神经保护剂的认知评估 低级别胶质瘤接受放射治疗; 2）估计神经行为变化的幅度 结果（认知，社会，生活质量，神经）与美金刚;和3）评估 美金刚副作用的频率和性质。为了研究这些目标，我们建议使用 随机、双盲、安慰剂对照设计，6 - 21岁儿童计划 接受低级别胶质瘤的颅放射治疗受试者将随机接受美金刚 (20 mg/d）或匹配的安慰剂。在为期12周的药物治疗阶段，参与者将每周接受一次电话咨询。 评估药物依从性和副作用的电话。基线、6周（放疗结束）和12周时 几周（美金刚用药阶段结束）将使用以下方法进行额外的副作用监测 实验室检查值、体格检查和完成ECG。在相同的三个时间点， 一年后，参与者将完成认知功能的实验室测量， 考试我们将招募参与者，直到30人完成12周的评估时间点。

PROJECT SUMMARY/ABSTRACT Children who receive radiation therapy for brain tumors are at significant risk for cognitive effects of their disease and treatment (e.g., problems with attention, memory and processing speed) that negatively impact quality of life, including reduced academic and social attainment. Low grade gliomas account for 30 to 50% of childhood brain tumors and have high survival rates, with progression-free survival rates approximately 80% on long-term follow-up. With a growing survivor population, efforts to improve long-term cognitive outcomes become imperative. A primary goal of this research program is development of interventions that mitigate the impact of CNS-directed therapies on the quality of life of childhood cancer survivors. The vascular hypothesis of radiation injury suggests that the mechanism of radiation-induced injury is similar to small vessel disease as seen with vascular dementia, prompting interest in treatments for vascular dementia. Randomized placebo- controlled trials have shown memantine (a drug that blocks NMDA receptors for the neurotransmitter glutamate) improves cognition in patients with mild to moderate vascular dementia without concerning side effects. Further, memantine during radiotherapy for brain metastases in adults has been shown to be well tolerated with less cognitive declines over time relative to placebo. Studies with children with Attention Deficit Hyperactivity Disorder or autism spectrum disorders have shown memantine is safe with evidence for improved cognition. Importantly, there are no published studies of memantine in children undergoing treatment for brain tumors. It has become of paramount importance to determine whether we can preserve cognitive function of children treated for cancer by intervening prophylactically, before the emergence of late effects. Accordingly, the specific aims of this study are: 1) To estimate the rate of participation, medication adherence and completion of cognitive assessments in a study of memantine used as a neuroprotective agent in children undergoing radiotherapy for low grade glioma; 2) To estimate the magnitude of change in neurobehavioral outcomes (cognitive, social, quality of life, neurologic) associated with memantine; and 3) To evaluate the frequency and nature of memantine side effects. In order to investigate these aims, we propose to use a randomized, double-blind, placebo-controlled design with children between 6 and 21 years of age scheduled to undergo cranial radiation therapy for a low grade glioma. Participants will be randomized to either memantine (20 mg/d) or a matching placebo. During the 12 week medication phase, participants will receive weekly phone calls to assess medication adherence and side effects. At baseline, 6 weeks (end of radiation therapy) and 12 weeks (end of the memantine medication phase) additional side effect monitoring will take place using laboratory values, physical examination and completion of an ECG. At the same three time points, and one year later, participants will complete laboratory measures of cognitive function and participate in neurologic exams. We will recruit participants until 30 have completed the 12 week assessment time point.