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，图像引导的保留骨髓强度调制放射治疗（IG-BMS-IMRT），是否可以降低接受化疗和盆腔放射治疗（CRT）患者的血液学毒性（HT）。放射诱导的高温疗法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。次要目标是确定骨髓（BM）亚区域的功能特性，并验证一种新的MRI技术来量化BM脂肪含量。具体目的是：（SA1）检测IG-BMS-IMRT是否会降低接受放化疗的宫颈癌患者的HT；（SA2）确定模型发现辐射剂量增加导致高温升高的“关键”BM分区的功能特性；和（SA3）验证骨髓标本MR脂肪定量技术的技术和生化特性。我们的主要假设是，与历史对照相比，IG-BMS-IMRT将导致急性HT的相对减少50%。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。我们将获得基线18F-3'-氟-3'-脱氧- l -胸腺嘧啶正电子发射断层扫描（FLT-PET）和定量脂肪部分MRI扫描，以确定活跃的BM亚区。我们将根据先前开发的协议对BM进行分割，然后将其用作IMRT计划期间的主要避免结构。活性BM的剂量学限值是根据我们以前开发的毒性模型得出的。我们将获得治疗中和治疗后脂肪部分MRI扫描来量化BM亚区变化。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，验证FLT示踪剂摄取和FF变化在“关键”区域比非“关键”BM次区域更大的假设。对于目标2，我们将测试MR脂肪分数估计值在不同的方案条件下是否稳定，以及它们是否与脂肪含量的生化和组织学分析相关。该项目的最终结果将决定IG-BMS-IMRT是否具有强大的生理基础和对毒性的临床显著影响，并将决定该方法是否应该与传统RT相比进入III期试验。

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.