Distribution Atlas of Proliferating Bone Marrow in Non-Small Cell Lung Cancer Patients Measured by FLT-PET/CT Imaging, With Potential Applicability in Radiation Therapy Planning

Purpose

Proliferating bone marrow is exquisitely sensitive to ionizing radiation. Knowledge of its distribution could improve radiation therapy planning to minimize unnecessary marrow exposure and avoid consequential prolonged myelosuppression. [18F]-Fluoro-3-deoxy-3-L-fluorothymidine (FLT)–positron emission tomography (PET) is a novel imaging modality that provides detailed quantitative images of proliferating tissues, including bone marrow. We used FLT-PET imaging in cancer patients to produce an atlas of marrow distribution with potential clinical utility.

Methods and Materials

The FLT-PET and fused CT scans of eligible patients with non-small cell lung cancer (no distant metastases, no prior cytotoxic exposure, no hematologic disorders) were reviewed. The proportions of skeletal FLT activity in 10 predefined bony regions were determined and compared according to age, sex, and recent smoking status.

Results

Fifty-one patients were studied: 67% male; median age 68 (range, 31-87) years; 8% never smokers; 70% no smoking in the preceding 3 months. Significant differences in marrow distribution occurred between sex and age groups. No effect was detected from smoking in the preceding 3 months. Using the mean percentages of FLT uptake per body region, we created an atlas of the distribution of functional bone marrow in 4 subgroups defined by sex and age.

Conclusions

This atlas has potential utility for estimating the distribution of active marrow in adult cancer patients to guide radiation therapy planning. However, because of interindividual variation it should be used with caution when radiation therapy risks ablating large proportions of active marrow; in such cases, individual FLT-PET scans may be required.

Introduction

Active bone marrow is exquisitely sensitive to ionizing radiation exposure, and knowledge of the distribution of proliferating marrow in patients is of real-world, clinical importance in radiation oncology. Before the advent of [18F]-fluoro-3-deoxy-3-l-fluorothymidine positron emission tomography (FLT-PET), no imaging modality was available with the potential to accurately demonstrate proliferative marrow distribution. Historically, suboptimal estimates of the volume and location of active bone marrow have come from pathologic studies, radiolabeled iron infusions, magnetic resonance imaging, and scintigraphic imaging of the distribution of Technetium sulfur colloid 1, 2, 3, 4, 5, 6, 7, 8, 9. However, the validity and reliability of these results were limited by technical difficulties or assumptions in the calculations: for example, whole-body imaging with Technetium sulfur colloid suffers from lower resolution and represents reticuloendothelial distribution rather than true proliferating marrow. Despite the limitations of these techniques, estimates of the distribution of bone marrow by age have been published, demonstrating marked differences between newborns and adults 10, 11. To date, these published works have been the only sources of information available to radiation oncologists when considering the amount of functional marrow that will be irradiated during a planned course of radiation therapy.

None of the published data give useful information with regard to the variation in the distribution of functional bone marrow that may exist between adults. The most comprehensive information published to date was derived from cadaveric studies performed by Japanese pathologists in 1963, who estimated the volume and distribution of active marrow by age and sex in Japanese cadavers (5). These studies were relatively crude, using a combination of histopathology and weighing of material derived from boiled bones, with no real indication of the functional proliferation of the marrow. The new modality of FLT-PET offers a non-invasive method that can directly image proliferation in tissue with greater quantitative potential than historical imaging techniques. The tracer, FLT, is incorporated into the synthesis of new DNA during the proliferation of cells, and the uptake of FLT is proportional to amount of proliferating marrow as part of the hematopoietic system. [18F]-Fluoro-3-deoxy-3-l-fluorothymidine–PET has great potential for directly visualizing functional marrow distribution in living patients and for observing changes in marrow proliferation caused by both disease states and myelotoxic therapies. Our group has previously reported on the use of FLT-PET to determine the distribution of proliferative bone marrow in a small heterogeneous group of 13 oncology patients (12), and we have recently reported the ability of FLT-PET to document changes in bone marrow activity after chemotherapy (13).

In the present study, we expand upon our earlier findings and report on our investigation of FLT-PET as a tool to image the distribution of proliferating bone marrow in patients with non-myeloid malignancies and without prior cytotoxic therapy exposure. The primary objective of this study was to describe and assess the distribution of hematopoiesis (as reflected by FLT-PET activity) throughout the skeleton, according to age, sex, and recent smoking status within the preceding 3 months. The secondary objective was to create standardized atlases of proliferative marrow in this cohort of adult patients, to function as a unique tool to guide radiation therapy planning when bone marrow toxicity is a clinical concern.