Bone Marrow Dosimetry Using 124I-PET

The goal in radioimmunotherapy is to maximize the absorbed dose to target volumes while ensuring that delivery to vulnerable normal organs is within acceptable limits. Typically, for radioimmunotherapy the dose-limiting organ is the red marrow (i.e., the blood-forming cells of the bone marrow). Several methods have been developed for red marrow dosimetry and can generally be divided into image- and blood sample–based approaches. The most commonly used quantitative imaging technique for dosimetry is the conjugate-view method. Anterior and posterior images are acquired with a γ-camera at multiple time points after administration of the radiolabeled antibody. Geometric mean counts are obtained for regions of interest (ROIs) placed over targets of interest. These may then be corrected for attenuation and scatter and converted to activities or activity concentrations (1,2). The resulting time–activity data are used to determine the pharmacokinetics of the antibody in the organs of interest, and the area under the time–activity curve is used as the basis for calculation of radiation dose to tissues, including red marrow. Planar imaging has been used to quantify activity concentration for purposes of dosimetry, particularly for isotopes such as 131I, which can be followed over many days. However, accuracy is limited by the approximate scatter and attenuation corrections generally used and the typically poor target-tissue visualization and delineation on planar images (3). Methods to obtain quantitative SPECT images have and continue to be developed (4), but to our knowledge, their application to bone marrow dosimetry has not been reported. In an alternative approach, blood or plasma activity concentration may be used as a surrogate (with a scaling factor) of the activity concentration in red marrow for agents that do not specifically bind to marrow cellular components or otherwise specifically localize in marrow (5–8). Measurements of blood or plasma activity concentration at multiple times after administration may be used as a basis for red marrow absorbed dose estimation (7). The blood-based method assumes that extracellular fluid in the marrow spaces has the same activity concentration as plasma and, consequently, that the activity concentration ratio of red marrow to plasma is a constant, equal to the fraction of red marrow composed of extracellular fluid (7). Alternatively, the ratio may be expressed with respect to whole blood (8) (i.e., a red marrow–to–blood ratio), for which a value of 0.32–0.36 is typically used (9). Evaluation of this approach was performed in a 7-institution trial in which marrow dose was estimated by a centralized facility using standardized methods and compared with estimates provided by the individual participants. The study showed that independent use of the blood method resulted in red marrow dose estimates with mean and maximum differences of 8% and 30%, respectively (10). However, red marrow absorbed dose as calculated by this approach has not proven to be a good predictor of hematologic toxicity, particularly for nuclides other than 131I (11,12). PET, like γ-camera–based SPECT, can provide quantitative, 3-dimensional images that may be used to study biochemical and physiologic processes in the human body (13,14). However, PET has several physical advantages, including a more accurate attenuation correction that enables calibration of the scanner in terms of the absolute activity concentration in a tissue (i.e., Bq/mL). This advantage is of fundamental importance in accurately determining radiation doses to tissues or organs. In addition, PET provides higher sensitivity and spatial resolution than SPECT or planar γ-camera imaging. The most commonly used PET radionuclide, 18F, has a half-life too short (110 min) to encompass the long retention and slow biokinetic behavior of large molecules such as antibodies. Among the currently available positron emitters, 124I has the longest physical half-life (4.2 d) and PET/CT using 124I-labeled antibodies has been used to successfully image antibody biodistribution over timescales of a week or more after administration (15,16). However, 124I poses several challenges to quantitative PET. The most important of these factors are its low (0.24) positron yield and emission of prompt γ-rays (in coincidence with the positron decay) that have energies within the annihilation energy window (350–650 keV). Despite these difficulties, 124I-PET has been shown to be accurate to within 10% for images acquired in 2-dimensional mode (17–19). In the current study, PET and PET/CT images of patients who had been administered 124I-radiolabeled antibodies were used to investigate the relationship between red marrow and plasma activity concentrations as a function of time after injection. The impact of this relationship on estimated absorbed dose to red marrow was assessed and compared with the conventional plasma-based method. To our knowledge, this is the first time that PET has been used for bone marrow dosimetry.