Image-guided bone marrow-sparing IMRT for cervical cancer

描述（由申请人提供）：拟议研究的主要目的是测试一种新技术，图像引导的骨髓保留调强放疗（IG-BMS-IMRT），是否可以减少接受同步化疗和盆腔放疗（CRT）的患者的血液学毒性（HT）。放射诱导的HT是一个重要的临床问题，限制了盆腔恶性肿瘤患者化疗的强度。次要目的是确定骨髓（BM）亚区的功能特性，并验证一种新的MRI技术，以量化BM脂肪含量。具体目标是：（SA 1）测试IG-BMS-IMRT是否会降低接受放化疗的宫颈癌患者的HT;（SA 2）确定模型发现增加的辐射剂量导致HT增加的“关键”BM亚区的功能特性;（SA 3）验证骨髓样本中MR脂肪定量技术的技术和生物化学特性。我们的主要假设是，IG-BMS-IMRT将导致急性HT相对减少50%，与历史对照相比。我们将在50例患者的前瞻性II期多机构临床试验中检验这一假设，主要终点为急性HT。我们将采集基线18 F-3 '-氟-3'-脱氧-L-胸苷正电子发射断层扫描（FLT-PET）和定量脂肪分数MRI扫描，以识别活动性BM亚区。我们将根据先前开发的协议分割BM，然后将其用作IMRT计划期间的主要避免结构。活性BM的剂量限制来自我们开发的先前毒性模型。我们将获得治疗中期和治疗后的脂肪分数MRI扫描，以量化BM亚区的变化。作为二次分析，我们将使用先前开发的基于高维数据分析和可变形图像配准的技术来检验以下假设：与非“关键”BM子区域相比，“关键”BM子区域中的FLT示踪剂摄取和FF变化更大。对于目标2，我们将测试MR脂肪分数估计值在不同的协议条件下是否稳定，以及它们是否与脂肪含量的生化和组织学测定相关。该项目的最终结果将确定IG-BMS-IMRT是否具有强大的生理学原理和对毒性的临床显著影响，并将确定该方法是否应与传统RT相比进入III期试验。 公共卫生相关性：在这个项目中，我们将测试一种现代放射技术（调强放射治疗（IMRT））是否可以减少接受化疗和放射治疗的宫颈癌患者的血液毒性，该技术旨在保留功能性骨髓亚区，通过18 F-3 '-氟-3'-脱氧-L-胸苷正电子发射断层扫描（FLT-PET）和定量磁共振脂肪分数成像（IDEAL）的组合进行鉴定。我们还进行了二次分析，以测试特定骨髓亚区的功能特性，以验证骨髓成像的IDEAL技术。这项研究很重要，因为辐射诱导的血液毒性是盆腔恶性肿瘤患者最佳化疗的障碍，因此保留骨髓的IMRT技术将具有广泛的适用性。

DESCRIPTION (provided by applicant): The primary objective of the proposed research is to test whether a novel technique, image-guided bone marrow-sparing intensity modulated radiation therapy (IG-BMS-IMRT), can reduce hematologic toxicity (HT) in patients receiving concurrent chemotherapy and pelvic radiation therapy (CRT). Radiation-induced HT is a significant clinical problem limiting the intensity of chemotherapy that can be delivered in patients with pelvic malignancies. Secondary objectives are to determine the functional properties of bone marrow (BM) subregions and to validate a novel MRI technique to quantify BM fat content. The specific aims are: (SA1) to test whether IG-BMS-IMRT will reduce HT for cervical cancer patients undergoing chemoradiotherapy; (SA2) to determine the functional properties of "critical" BM subregions in which models have found that increased radiation dose leads to increased HT; and (SA3) to validate the technical and biochemical properties of MR fat quantification techniques in bone marrow specimens. Our main hypothesis is that IG-BMS-IMRT will lead to a relative reduction of acute HT of 50% compared to historical controls. We will test this hypothesis in a prospective phase II multi-institutional clinical trial of 50 patients, with the primary endpoint of acute HT. We will acquire baseline 18F-3'-fluoro-3'-deoxy-L-thymidine positron emission tomography (FLT-PET) and quantitative fat fraction MRI scans to identify active BM subregions. We will segment the BM based on a previously developed protocol, then use this as a primary avoidance structure during IMRT planning. Dosimetric limits on active BM are derived from previous toxicity models we developed. We will obtain mid- and post-treatment fat fraction MRI scans to quantify changes in BM subregions. As a secondary analysis, we will test the hypothesis that FLT tracer uptake and changes in FF are greater in "critical" compared to non-"critical" BM subregions, using previously developed techniques based on high-dimensional data analysis and deformable image registration. For aim 2, we will test whether MR fat fraction estimates are stable under varying protocol conditions, and whether they correlate with biochemical and histological assays of fat content. The end result of this project will determine whether IG-BMS-IMRT has a strong physiologic rationale and clinically significant impact on toxicity, and will determine whether this approach should move forward to a phase III trial versus conventional RT. PUBLIC HEALTH RELEVANCE: In this project, we will test whether a modern radiation technique (intensity modulated radiation therapy (IMRT)) designed to spare functional bone marrow subregions, identified by a combination of 18F-3'-fluoro-3'- deoxy-L-thymidine positron emission tomography (FLT-PET) and quantitative magnetic resonance fat fraction imaging (IDEAL), can reduce hematologic toxicity in cervical cancer patients undergoing chemotherapy and radiation. We also perform secondary analysis to test functional properties of specific bone marrow subregions to validate the IDEAL technique for bone marrow imaging. The study is important because radiation-induced hematologic toxicity is a barrier to optimal chemotherapy delivery in general for patients with pelvic malignancies, so bone marrow-sparing IMRT techniques would have wide applicability.