A phase I feasibility study of multi-modality imaging assessing rapid expansion of marrow fat and decreased bone mineral density in cancer patients

Abstract

Purpose Cancer survivors are at an increased risk for fractures, but lack of effective and economical biomarkers limits quantitative assessments of marrow fat (MF), bone mineral density (BMD) and their relation in response to cytotoxic cancer treatment. We report dual energy CT (DECT) imaging, commonly used for cancer diagnosis, treatment and surveillance, as a novel biomarker of MF and BMD. Methods We validated DECT in pre-clinical and Phase I clinical trials and verified with water-fat MRI (WF-MRI), quantitative CT (QCT) and dual-energy X-ray absorptiometry (DXA). Basis material composition framework was validated using water and small-chain alcohols simulating different components of bone marrow. Histologic validation was achieved by measuring percent adipocyte in cadaver vertebrae and compared with DECT and WF-MRI. For a Phase I trial, sixteen patients with gynecologic malignancies (treated with oophorectomy, radiotherapy or chemotherapy) underwent DECT, QCT, WF-MRI and DXA before and 12 months after treatment. BMD and MF percent and distribution were quantified in lumbar vertebrae and the right femoral neck. Results Measured precision (3 mg/cm3) was sufficient to distinguish test solutions. Adiposity in cadaver bone histology was highly correlated with MF measured using DECT and WF-MRI (r = 0.80 and 0.77, respectively). In the clinical trial, DECT showed high overall correlation (r = 0.77, 95% CI: 0.69, 0.83) with WF-MRI. MF increased significantly after treatment (p<0.002). Chemotherapy and radiation caused greater increases in MF than oophorectomy (p<0.032). L4 BMD decreased 14% by DECT, 20% by QCT, but only by 5% by DXA (p<0.002 for all). At baseline, we observed a statistically significant inverse association between MF and BMD which was dramatically attenuated after treatment. Conclusion Our study demonstrated that DECT, similar to WF-MRI, can accurately measure marrow adiposity. Both imaging modalities show rapid increase in MF following cancer treatment. Our results suggest that MF and BMD cannot be used interchangeably to monitor skeletal health following cancer therapy.

Evaluation of Functional Marrow Irradiation Based on Skeletal Marrow Composition Obtained Using Dual-Energy Computed Tomography

“…A number of imaging studies have been published to estimate RM and YM (20–23). In a clinical study, we previously reported water-fat magnetic resonance imaging (WF-MRI) to visualize and map marrow compositions and its high correlation with DECT derived marrow fat measurements (16,24). Due to technical difficulties, lengthy scanning time, and cost, the use of WF-MRI is mainly confined to small skeletal regions.…”

“…The majority of the patients undergoing HCT receive prior chemotherapy treatment. Because cancer treatment changes marrow fat composition, (16) individual factors including age and prior treatment may influence the distribution of marrow composition in different sites. Thus, if treatment is developed for differential radiation delivery to individual marrow composition, it will have to be individualized ( personalized medicine).…”

“…As the CT scan is part of PET-CT imaging, integration of this process will be easier and cost-effective. However, one may need to verify marrow composition with a gold standard MRI in some skeletal sites, as shown in our previous work (16). Second, although 18 Gy was prescribed to the primary target in this simulation, it is not clear how much dose and fraction should be prescribed for clinical practice.…”

“…Details of this method were reported previously (16,17). Briefly, differences in HU estimates acquired at different x-ray energies are used to infer basis material composition ( H 2 O , K 2 HPO 4 ) for each voxel in the spatially registered CT data sets.…”

“…The biopsy tool used to assess marrow, is limited to specific regions and lacks spatial resolution and the insertion of the needle probably damaged the local region, so that only an average reading was recorded. The water-fat magnetic resonance imaging (WF-MRI) could differentiate marrow composition (16). However, it is inadequate for i) bone tissue imaging, ii) radiation dosimetric and planning purposes, iii) and whole body MRI will be prohibitively expensive and will require very long scan time.…”