Multimodal study of cognitive impairment following radiation therapy for locally advanced head and neck cancer

项目摘要 局部晚期头颈癌（LAHNC）的治疗通常需要使用放射治疗 治疗，这往往暴露部分大脑，特别是小脑和下颞叶， 中等剂量的辐射颅脑照射对认知功能的负面影响是好的 在其他类型的恶性肿瘤中已经建立，但在LAHNC患者中尚未研究。基础疾病 治疗LAHNC的患者的过程、化疗药物和辐射剂量分布是 从根本上不同于以前研究的患者人群，这表明认知模式 损伤也可能不同。这一科学建议将阐明LAHNC中辐射的认知效应 患者有三个具体目标。科学目标1将描述LAHNC幸存者的认知特征 通过管理神经心理学电池和病人问卷调查。个人辐射剂量测定 小脑和颞叶的区域将根据原始治疗计划计算。的影响 术后患者和治疗特征（包括化疗暴露和辐射剂量测定） 将评估治疗认知。科学目标2将确定认知与 缺陷和生殖系变异。生殖系单核苷酸多态性将使用 生物学上合理的，精心策划的候选基因方法，并评估与 神经认知成套测验结果科学目标3将探讨如何现代辐射规划技术可以 用于减少LAHNC治疗的脑辐射暴露。将生成比较辐射计划 使用多标准优化强度调制和质子治疗。这项研究将促进我的长期 提高接受放射治疗的患者的生活质量的职业目标，并将提供机会 进行额外的培训和职业发展。职业发展计划包括生物统计学培训 和研究方法，正常组织并发症的概率建模，以及分子生物学的基本原理。 流行病学和认知评估。科学和培训计划得到了一个团队的支持， 经验丰富的导师和顾问，他们致力于这个项目的成功和我作为一个 临床科学家主要导师是癌症幸存者神经认知结果方面的专家， 年轻研究者的经验丰富的导师，以及UAB癌症结果研究所的主任， 为了生存。该提案的结果将用于形成未来临床试验的基础， 通过确定LAHNC患者中认知功能障碍风险最高的患者， 最大限度地减少脑辐射暴露，并实施量身定制的认知补救措施 干预这个项目将加强我作为临床研究人员的技能，建立一个独立的研究 平台，并为改善癌症幸存者的临床结果做出真正的贡献。

PROJECT SUMMARY Treatment of locally advanced head and neck cancer (LAHNC) commonly entails the use of radiation therapy, which often exposes portions of the brain, particularly the cerebellum and inferior temporal lobes, to moderately high doses of radiation. The negative effects of cranial radiation exposure on cognition are well established in other types of malignancies, but remain unstudied in LAHNC patients. The underlying disease process, chemotherapeutic agents, and radiation dose distribution in patients treated for LAHNC are fundamentally different from the patient populations previously studied, suggesting that patterns of cognitive impairment may also differ. This scientific proposal will elucidate the cognitive effects of radiation in LAHNC patients through three specific aims. Scientific Aim 1 will characterize the cognitive profiles of LAHNC survivors by administering a neuropsychological battery and patient questionnaires. Radiation dosimetry to individual regions of the cerebellum and temporal lobes will be calculated from the original treatment plans. The effects of patient and treatment characteristics (including chemotherapy exposure and radiation dosimetry) on post- treatment cognition will be assessed. Scientific Aim 2 will determine the association between cognitive impairment and germline variants. Germline single nucleotide polymorphisms will be determined using a biologically-plausible, carefully curated candidate gene approach and assessed for association with the neurocognitive battery results. Scientific Aim 3 will explore how modern radiation planning techniques can be utilized to reduce brain radiation exposure for LAHNC treatment. Comparison radiation plans will be generated using Multi-Criteria Optimized intensity modulation and proton therapy. This study will promote my long-term career goal of improving quality of life for patients who received radiation therapy and will provide opportunities for additional training and career development. The career development plan includes training in biostatistical and research methodology, normal tissue complication probability modeling, and fundamentals of molecular epidemiology and cognitive assessment. The scientific and training plans are supported by a team of experienced mentors and advisors who are committed to the success of this project and my development as a clinician scientist. The primary mentor is an expert in neurocognitive outcomes among cancer survivors, an experienced mentor of young investigators, and the director of the UAB Institute for Cancer Outcomes and Survivorship. The results of this proposal will be utilized to form the foundation of a future clinical trial designed to reduce cognitive morbidity in LAHNC patients by identifying those patients at highest risk for cognitive impairment, maximally reducing brain radiation exposure, and implementing a tailored cognitive remediation intervention. This project will strengthen my skills as a clinical researcher, establish an independent research platform, and make a true contribution towards improving clinical outcomes in cancer survivors.