Imaging Thymidine Uptake During Treatment for Head and Neck Cancer

描述（由申请人提供）：头颈部鳞状细胞癌每年影响超过40，000名美国人。目前，这些癌症的治疗选择包括手术、放疗和化疗，单独或联合使用。这些癌症及其治疗可能对进食、说话、呼吸和其他重要功能的能力产生深远影响。目前的治疗方法并不都是成功的，但所有的治疗都会产生显著的发病率。改善此类癌症患者护理的一个关键挑战是使用最有可能治愈且最不可能对任何个体患者产生毒性的治疗。没有测试可用于确定哪种治疗方法可能有助于个体患者。目前，治疗疗效是在治疗完成后数月确定的。临床前和临床数据表明，细胞周期动力学的变化后，短暂暴露于放疗，无论是单独或与化疗，可用于确定最终的治疗疗效的局部控制，无病生存期和总生存期。确定细胞周期动力学的变化涉及注入DNA前体的潜在毒性类似物和多次活检，排除了常规评估。临床前数据还表明，可以从放射性标记的DNA前体的亲合力或摄取程度推断细胞周期动力学。用一种这样的前体，3 '-脱氧，3'[18F]氟标记胸苷（FLT）进行的研究表明，快速分裂的组织对FLT具有更高的亲合力。18F标记允许使用正电子发射断层扫描（PET）对该试剂进行成像。该建议的假设是，治疗前肿瘤对FLT的摄取，以及短暂放化疗后肿瘤对FLT摄取的变化将作为最终反应的预测因子。这一假设将在临床试验中通过旨在严格开发FLT PET成像并优化成像数据收集和分析方式的特定目标进行检查。动态FLT PET成像将与连续静脉和动脉血液采样同时获得，以确保准确的FLT动力学数据。将确定最佳时机、血液分析与图像强度之间的相关性以及最有用的成像特征，例如平均或最大强度。使用优化的FLT PET条件，将在接受放化疗治疗头颈部癌症的受试者中获得治疗前和治疗早期中期FLT研究。将检验基线FLT摄取值和FLT摄取变化程度对这些受试者总生存期和局部控制的预测价值。该项目的总体目标是开发一种非侵入性的、基于图像的工具，以更好地个性化癌症治疗。FLT成像可以为头颈癌患者提供个体化癌症治疗的方法，从而为患有这种疾病的患者提供更有效和毒性更小的治疗。该项目与公共卫生的相关性非常重要。该项目的目的是开发一种方法来确定癌症治疗在治疗的早期阶段是否有效，此时仍然可以尝试替代方法。本文提出的研究将完善和表征一种非侵入性成像测试，可以在治疗开始后不久确定治疗反应。

DESCRIPTION (provided by applicant): Squamous cell cancer of the head and neck affects over 40,000 Americans each year. Treatment options for these cancers currently include surgery, radiation and chemotherapy either alone or in combination. These cancers and their treatment can have a profound impact on the ability to eat, speak, breathe and other important functions. Current treatment approaches are not uniformly successful, but all treatments produce significant morbidity. One key challenge to improving care for patients with this type of cancer is to use a treatment most likely to produce cure and least likely to produce toxicity for any individual patient. No test is available to determine which treatment approach is likely to help an individual patient. Treatment efficacy is currently determined months after completion of therapy. Preclinical and clinical data suggest changes in cell cycle kinetics following a brief exposure to radiotherapy, either alone or with chemotherapy, can be used to determine ultimate treatment efficacy in terms of locoregional control, disease free survival and overall survival. Determining changes in cell cycle kinetics involves infusion of potentially toxic analogs of DNA precursors and multiple biopsies, precluding routine assessment. Preclinical data also suggests that cell cycle kinetics can be inferred from the degree of avidity or uptake of radiolabeled DNA precursors. Work with one such precursor, 3'-deoxy, 3'[18F]Fluorolabeled Thymidine (FLT), suggests that rapidly dividing tissues have a higher avidity for FLT. The 18F label allows this agent to be imaged using Positron Emission Tomography (PET). The hypothesis of this proposal is that FLT uptake by the tumor before treatment, and changes in tumor uptake of FLT following a brief course of chemoradiotherapy will serve as predictors of ultimate response. This hypothesis will be examined in a clinical trial by specific aims designed to rigorously develop FLT PET imaging and optimize how imaging data is collected and analyzed. Dynamic FLT PET imaging will be obtained concurrently with serial venous and arterial blood sampling to ensure accurate FLT kinetic data. The optimal timing, correlations between blood analyses and image intensity and which imaging characteristics, such as mean or maximum intensity are most useful, will be determined. Using optimized FLT PET conditions, pretreatment and early mid treatment FLT studies will be obtained in subjects undergoing chemoradiation treatment for their head and neck cancer. Baseline FLT uptake values and the degree of change in FLT uptake will be tested for predictive value for overall survival and locoregional control in these subjects. The overall goal of this project is to develop a non-invasive, image-based tool to better individualize cancer therapy. FLT imaging may provide a means to individualize cancer treatment for patients with head and neck cancer allowing for more effective and less toxic therapy for patients with this disease. The relevance of this project to public health is significant. The purpose of this project is to develop a means of determining if cancer therapy is effective during the early stages of treatment, when alternative approaches can still be tried. The studies proposed here will refine and characterize a non-invasive imaging test that may allow treatment responses to be determined shortly after treatment has begun.