Lionel G. Bouchet

MIRD pamphlet no. 20: The effect of model assumptions on kidney dosimetry and response - Implications for radionuclide therapy

Renal toxicity associated with small-molecule radionuclide therapy has been shown to be dose-limiting for many clinical studies. Strategies for maximizing dose to the target tissues while sparing normal critical organs based on absorbed dose and biologic response parameters are commonly used in external-beam therapy. However, radiopharmaceuticals passing though the kidneys result in a differential dose rate to suborgan elements, presenting a significant challenge in assessing an accurate dose–response relationship that is predictive of toxicity in future patients. We have modeled the multiregional internal dosimetry of the kidneys combined with the biologic response parameters based on experience with brachytherapy and external-beam radiation therapy to provide an approach for predicting radiation toxicity to the kidneys. Methods: The multiregion kidney dosimetry model of MIRD pamphlet no. 19 has been used to calculate absorbed dose to regional structures based on preclinical and clinical data. Using the linear quadratic model for radiobiologic response, we computed regionally based surviving fractions for the kidney cortex and medulla in terms of their concentration ratios for several examples of radiopharmaceutical uptake and clearance. We used past experience to illustrate the relationship between absorbed dose and calculated biologically effective dose (BED) with radionuclide-induced nephrotoxicity. Results: Parametric analysis for the examples showed that high dose rates associated with regions of high activity concentration resulted in the greatest decrease in tissue survival. Higher dose rates from short-lived radionuclides or increased localization of radiopharmaceuticals in radiosensitive kidney subregions can potentially lead to greater whole-organ toxicity. This finding is consistent with reports of kidney toxicity associated with early peptide receptor radionuclide therapy and 166Ho-phosphonate clinical investigations. Conclusion: Radionuclide therapy dose–response data, when expressed in terms of biologically effective dose, have been found to be consistent with external-beam experience for predicting kidney toxicity. Model predictions using both the multiregion kidney and linear quadratic models may serve to guide the investigator in planning and optimizing future clinical trials of radionuclide therapy.

Protection by DMSO against Cell Death Caused by Intracellularly Localized Iodine-125, Iodine-131 and Polonium-210

Abstract Bishayee, A., Rao, D. V., Bouchet, L. G., Bolch, W. E. and Howell, R. W. Protection by DMSO against Cell Death Caused by Intracellularly Localized Iodine-125, Iodine-131 and Polonium-210. The mechanisms by which DNA-incorporated radionuclides impart lethal damage to mammalian cells were investigated by examining the capacity of dimethyl sulfoxide (DMSO) to protect against lethal damage to Chinese hamster V79 cells caused by unbound tritium (3H2O), DNA-incorporated 125I- and 131I-iododeoxyuridine (125IdU, 131IdU), and cytoplasmically localized 210Po citrate. The radionuclides 3H and 131I emit low- and medium-energy β particles, respectively, 125I is a prolific Auger electron emitter, and 210Po emits 5.3 MeV α particles. Cells were radiolabeled and maintained at 10.5°C for 72 h in the presence of different concentrations of DMSO (5–12.5% v/v), and the surviving fraction compared to that of unlabeled controls was determined. DMSO afforded no protection against the lethal effects of the high-LET α particles emitted by 210Po. Protection against lethal damage caused by unbound 3H, 131IdU and 125IdU depended on the concentration of DMSO in the culture medium. Ten percent DMSO provided maximum protection in all cases. The dose modification factors obtained at 10% DMSO for 3H2O, 131IdU, 125IdU and 210Po citrate were 2.9 ± 0.01, 2.3 ± 0.5, 2.6 ± 0.2 and 0.95 ± 0.07, respectively. These results indicate that the toxicity of Auger electron and β-particle emitters incorporated into the DNA of mammalian cells is largely radical-mediated and is therefore indirect in nature. This is also the case for the low-energy β particles emitted by 3H2O. In contrast, α particles impart lethal damage largely by direct effects. Finally, calculations of cellular absorbed doses indicate that β-particle emitters are substantially more toxic when incorporated into the DNA of mammalian cells than when they are localized extracellularly.

Voxeldose: A Computer Program for 3-D Dose Calculation in Therapeutic Nuclear Medicine

A computer program, VoxelDose, was developed to calculate patient specific 3-D-dose maps at the voxel level. The 3-D dose map is derived in three steps: (i) The SPECT acquisitions are reconstructed using a filtered back projection method, with correction for attenuation and scatter; (ii) the 3-D cumulated activity map is generated by integrating the SPECT data; and (iii) a 3-D dose map is computed by convolution (using the Fourier Transform) of the cumulated activity map and corresponding MIRD voxel S values. To validate the VoxelDose software, a Liqui-Phil abdominal phantom with four simulated organ inserts and one spherical tumor (radius 4.2 cm) was filled with known activity concentrations of 111In. Four cylindrical calibration tubes (from 3.7 to 102 kBq/mL) were placed on the phantom. Thermoluminescent mini-dosimeters (mini-TLDs) were positioned on the surface of the organ inserts. Percent differences between the known and measured activity concentrations were determined to be 12.1 (tumor), 1.8 (spleen), 1.4, 8.1 (right and left kidneys), and 38.2% (liver), leading to percent differences between the calculated and TLD measured doses of 41, 16, 3, 5, and 62%. Large differences between the measured and calculated dose in the tumor and the liver may be attributed to several reasons, such as the difficulty in precisely associating the position of the TLD to a voxel and limits of the quantification method (mainly the scatter correction and partial volume effect). Further investigations should be performed to better understand the impact of each effect on the results and to improve absolute quantification. For all other organs, activity concentration measurements and dose calculations agree well with the known activity concentrations.

Isotropic beam bouquets for shaped beam linear accelerator radiosurgery

In stereotactic radiosurgery and radiotherapy treatment planning, the steepest dose gradient is obtained by using beam arrangements with maximal beam separation. We propose a treatment plan optimization method that optimizes beam directions from the starting point of a set of isotropically convergent beams, as suggested by Webb. The optimization process then individually steers each beam to the best position, based on beams-eye-view (BEV) critical structure overlaps with the target projection and the targets projected cross sectional area at each beam position. This final optimized beam arrangement maintains a large angular separation between adjacent beams while conformally avoiding critical structures. As shown by a radiosurgery plan, this optimization method improves the critical structure sparing properties of an unoptimized isotropic beam bouquet, while maintaining the same degree of dose conformity and dose gradient. This method provides a simple means of designing static beam radiosurgery plans with conformality indices that are within established guidelines for radiosurgery planning, and with dose gradients that approach those achieved in conventional radiosurgery planning.