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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-SBIB-V (56))
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Vikram, Bhadrasain
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Wyss, Jeffrey C; Carmona, Ruben; Karunamuni, Roshan A et al. (2016) [(18)F]Fluoro-2-deoxy-2-d-glucose versus 3'-deoxy-3'-[(18)F]fluorothymidine for defining hematopoietically active pelvic bone marrow in gynecologic patients. Radiother Oncol 118:72-8
MacEwan, Iain J; Glembotski, Nicholas E; D'Lima, Darryl et al. (2014) Proton density water fraction as a biomarker of bone marrow cellularity: validation in ex vivo spine specimens. Magn Reson Imaging 32:1097-101
Carmona, Ruben; Pritz, Jakub; Bydder, Mark et al. (2014) Fat composition changes in bone marrow during chemotherapy and radiation therapy. Int J Radiat Oncol Biol Phys 90:155-63
Liau, Joy; Shiehmorteza, Masoud; Girard, Olivier M et al. (2013) Evaluation of MRI fat fraction in the liver and spine pre and post SPIO infusion. Magn Reson Imaging 31:1012-6