MRI-Guided Radiotherapy and Biomarkers for Prostate Cancer

描述（由申请人提供）：对接受放射疗法（RT）治疗的前列腺癌患者的长期随访显示，几乎一半的患者复发。此外，有一些证据支持，在前列腺中的区域与最大的肿瘤负荷是在RT后窝藏持续性疾病的风险最高的区域。我们建议使用一种新的方法，高剂量消融RT输送到肿瘤体积确定的成像研究。多参数MRI，特别是动态对比增强磁共振成像（DCE-MRI）是非常有前途的肿瘤区域的体内3D定位。我们已经开发了一种新的方法，用于分析DCE-MRI的基础上的无监督模式识别技术。我们的初步数据表明，该技术在检测肿瘤的存在/不存在方面是敏感的，其结果可以直接转化为RT计划系统，用于量身定制的辐射剂量递送。RT技术，被称为格型极端消融剂量（LEAD）RT，涉及通过DCE-MRI定义的区域和格型框架中的相邻明显正常前列腺创建圆柱形高剂量。我们提出了一项单臂I期临床试验，在标准分次（每天2. 0戈伊）额外76戈伊之前，以12-14戈伊的单次分次进行LEAD RT输送。该方法的假设益处是诱导肿瘤内皮细胞死亡和可能的旁观者效应，包括由于快速细胞杀伤而降低密集肿瘤中的肿瘤间质液压力。我们还假设，由此产生的肿瘤组织的氧合改善将增强标准外部射束RT组件的效果。通过使用小直径（6-7 mm）的剂量圆柱体，并且不试图覆盖肿瘤的全部范围，正常组织将更容易被保留。随着越来越多的男性在年轻时出现前列腺癌并且寿命更长，需要确保RT后完全根除肿瘤细胞，同时保持正常组织毒性和并发症低对于该疾病的临床管理至关重要。在该提案中，我们还旨在开发一种用于使用DCE-MRI肿瘤图从定向活检获得生物标志物的方法，所述DCE-MRI肿瘤图经由Artemis ™系统（Eigen Inc.，草谷，加州）。将索引病变活检的生物标志物与前列腺其他区域肿瘤的生物标志物进行比较。我们将建立一种新的方法来评估这些侵袭性区域与其他肿瘤区域的生物标志物，这将更好地为确定分子异常如何决定放疗期间患者的预后奠定基础。 公共卫生相关性：我们建议使用一种新的方法，通过成像来确定消融辐射剂量。前列腺的肿瘤区域。通过使用具有小直径的集中剂量圆柱体，正常组织将更容易幸免，同时可能成功地根除肿瘤细胞。我们将在I期临床试验中确定该方法的可行性和毒性。

DESCRIPTION (provided by applicant): Long-term follow up of prostate cancer patients treated with radiation therapy (RT) reveals that almost half suffer a relapse. Moreover, there is some evidence to support that the regions in the prostate with the greatest tumor burden are the regions that are at highest risk of harboring persistent disease after RT. We propose to use a novel method of high-dose ablative RT delivery to the tumor volume identified by imaging studies. Multiparameter MRI, and in particular Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) is very promising for the in vivo 3D localization of the tumor area. We have developed a novel approach for analysis of DCE-MRI based on an unsupervised pattern recognition technique. Our preliminary data suggest that the technique is sensitive in detecting the presence/absence of tumor and its results can be directly translated to the RT planning system for tailored radiation dose delivery. The RT technique, deemed Lattice Extreme Ablative Dose (LEAD) RT, involves the creation of high doses shaped in cylinders through the DCE- MRI defined region(s) and adjacent apparently normal prostate in a lattice framework. We propose a single- arm phase I clinical trial for LEAD RT delivery in a single fraction of 12-14 Gy prior to standard fractions (2.0 Gy per day) for an additional 76 Gy. The hypothesized benefits of the approach are induction of tumor endothelial cell death and possibly bystander effects including reduced tumor interstitial fluid pressure in densely populated tumors due to rapid cell kill. We also hypothesize that the resulting improved oxygenation of the tumor tissue will enhance the effect of the standard external beam RT component. By using dose cylinders with small diameters (6-7 mm) and not attempting to cover the full extent of the tumor, normal tissues will be more easily spared. As more men are presenting with prostate cancer at younger ages and are living longer, the need to ensure complete tumor cell eradication after RT, while keeping normal tissue toxicity and complications low is of paramount importance for the clinical management of the disease. In this proposal we also aim to develop an approach for obtaining biomarkers from directed biopsies using DCE-MRI tumor maps fused to real-time transrectal ultrasound images via the ArtemisTM system (Eigen Inc., Grass Valley, California). Biomarkers from biopsies from the index lesion(s) will be compared to those from tumor in other areas of the prostate. We will establish a novel approach to assessing biomarkers in these aggressive areas versus other tumor regions, which will better set the stage for identifying how molecular abnormalities dictate patient outcome during radiotherapy. PUBLIC HEALTH RELEVANCE: We propose to use a novel method for delivery of an ablative radiation dose to define by imaging. tumor area in the prostate. By using concentrated dose cylinders with small diameter normal tissues will be more easily spared while potentially eradicating the tumor cells successfully. We will determine the feasibility and toxicity of the approach in a Phase I clinical trial.