Phase III Study of Donepezil in the Irradiated Brain

描述（由申请方提供）：与原发性或转移性脑肿瘤和相关治疗（包括放射治疗）相关的认知障碍发生在相当大比例的患者中，10%的患者发展为进行性痴呆，50%至90%的患者在进行认知功能敏感性测试评估时显示出缺陷。在2004年诊断的> 1，300，000名新癌症患者中，约20-40%发生脑转移（mets）。每年至少有200，000名癌症患者接受全脑照射（WBI）治疗脑转移瘤，而15，000名接受部分（P）或WBI治疗原发性脑肿瘤。临床上，患者经常抱怨神经认知症状群，包括记忆困难，组织思想和语言流畅性。这种神经认知症状群反过来又与生活质量和情绪的显着降低有关。目前，有很少的可用治疗的神经认知症状的患者谁接受了颅脑照射，并没有已知的预防干预措施存在。乙酰胆碱酯酶的选择性抑制剂如多奈哌齐（安理申）的管理已被证明有效地改善阿尔茨海默病患者的神经认知功能和行为症状。该研究小组最近进行的一项关于多奈哌齐在P/WBI长期（>6个月）幸存者中的前瞻性开放标签2期研究表明，神经认知症状显着减少，情绪，疲劳和生活质量显着改善。我们假设乙酰胆碱酯酶抑制剂多奈哌齐将减轻脑辐射长期幸存者的神经认知症状群，改善生活质量和情绪。因此，我们提出了一个为期24周，III期，随机，双盲，安慰剂对照试验多奈哌齐与200例患者后，部分或全脑照射。这项申请的重要性在于，它代表了多奈哌齐（一种耐受性良好的药物，已证明可有效减少阿尔茨海默氏痴呆症的认知和功能障碍）在部分或全脑照射幸存者中的首次前瞻性对照试验。相关性：这项研究将证明一种帮助痴呆症患者的药物是否也有助于减少肿瘤脑放射治疗后的认知障碍。如果成功的话，这项研究将为医生提供一种治疗辐射引起的认知障碍的方法，这也可能改善情绪和生活质量。

DESCRIPTION (provided by applicant): Cognitive impairment associated with primary or metastatic brain tumors and related treatments, including radiation therapy, occurs in a significant proportion of patients with 10% of patients developing progressive dementia, and 50% to 90% showing deficits when assessed with sensitive tests of cognitive function. About 20-40% of the >1,300,000 new cancer patients diagnosed in 2004 developed brain metastases (mets). At least 200,000 cancer patients/year receive whole brain irradiation (WBI) for brain mets, while 15,000 receive partial (P) or WBI for the treatment of a primary brain tumor. Clinically, patients frequently complain of a neurocognitive symptom cluster that includes difficulty remembering, organizing thoughts, and language fluency. This neurocognitive symptom cluster in turn is associated with significantly reduced quality of life and mood. Presently, there are very few available treatments for neurocognitive symptoms in patients who have received cranial irradiation; and no known preventive interventions exist. Administration of selective inhibitors of acetylcholinesterase like donepezil (Aricept) has proven effective in improving neurocognitive functioning and behavioral symptoms in patients with Alzheimer's disease. A recent prospective, open-label Phase 2 study of donepezil in long-term (>6 month) survivors of P/WBI conducted by this research team demonstrated a significant reduction in neurocognitive symptoms, as well as a significant improvement in mood, fatigue and quality of life. We hypothesize that the AChE inhibitor, donepezil, will lessen the neurocognitive symptom cluster and improve quality of life and mood in long-term survivors of brain irradiation. Thus we propose a 24-week, Phase III, randomized, double-blind, placebo-controlled trial of donepezil with 200 patients following partial or whole brain irradiation. The significance of this application is that it represents the first prospective controlled trial of donepezil (a well-tolerated drug with proven efficacy for reducing cognitive and functional impairment in Alzheimer's dementia) in survivors of partial or whole brain irradiation. RELEVANCE: This study will demonstrate whether a drug that helps dementia patients will also help to reduce cognitive impairment following brain radiation treatment for tumors. If successful the study will offer physicians a treatment for radiation-induced cognitive impairment which also may improve mood and quality of life.