MRI-Guided Radiotherapy and Biomarkers for Prostate Cancer

描述（申请人提供）：对接受放射治疗（RT）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，有一些证据支持前列腺中肿瘤负荷最大的区域是放疗后持续疾病风险最高的区域。我们建议采用一种新的方法，将高剂量的消融性放疗送到影像学研究确定的肿瘤体积。多参数MRI，特别是动态对比增强磁共振成像（DCE-MRI）在肿瘤区域的体内三维定位方面非常有前景。我们开发了一种基于无监督模式识别技术的DCE-MRI分析新方法。我们的初步数据表明，该技术在检测肿瘤存在/不存在方面是敏感的，其结果可以直接转化为放射治疗计划系统，以定制放射剂量递送。这种放射治疗技术被称为点阵极端消融剂量（LEAD）放射治疗，包括通过DCE- MRI定义区域和邻近的正常前列腺点阵框架，形成圆柱形的高剂量放射。我们建议进行一项单臂I期临床试验，在标准剂量（每天2.0 Gy）之前，以12-14 Gy的单剂量给药，再增加76 Gy。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，包括在密集肿瘤中由于快速细胞杀伤而降低肿瘤间质液压力。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束RT组件的效果。通过使用直径较小（6- 7mm）的剂量瓶，而不是试图覆盖肿瘤的全部范围，正常组织将更容易幸免。随着越来越多的男性在更年轻的年龄出现前列腺癌，寿命更长，需要确保在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，这对疾病的临床管理至关重要。在本提案中，我们还旨在开发一种方法，通过ArtemisTM系统（Eigen Inc., Grass Valley, California）将DCE-MRI肿瘤图融合到实时经直肠超声图像中，从定向活检中获得生物标志物。指数病变活检的生物标志物将与前列腺其他部位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影响放疗期间患者的预后奠定基础。

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.