R. Hobbs

Human Biodistribution and Radiation Dosimetry of 82Rb

Prior estimates of radiation-absorbed doses from 82Rb, a frequently used PET perfusion tracer, yielded discrepant results. We reevaluated 82Rb dosimetry using human in vivo biokinetic measurements. Methods: Ten healthy volunteers underwent dynamic PET/CT (6 contiguous table positions, each with separate 82Rb infusion). Source organ volumes of interest were delineated on the CT images and transferred to the PET images to obtain time-integrated activity coefficients. Radiation doses were estimated using OLINDA/EXM 1.0. Results: The highest mean absorbed organ doses (μGy/MBq) were observed for the kidneys (5.81), heart wall (3.86), and lungs (2.96). Mean effective doses were 1.11 ± 0.22 and 1.26 ± 0.20 μSv/MBq using the tissue-weighting factors of the International Commission on Radiological Protection (ICRP), publications 60 and 103, respectively. Conclusion: Our current 82Rb dosimetry suggests reasonably low radiation exposure. On the basis of this study, a clinical 82Rb injection of 2 × 1,480 MBq (80 mCi) would result in a mean effective dose of 3.7 mSv using the weighting factors of the ICRP 103—only slightly above the average annual natural background exposure in the United States (3.1 mSv).

Three-Dimensional Radiobiologic Dosimetry: Application of Radiobiologic Modeling to Patient-Specific 3-Dimensional Imaging-Based Internal Dosimetry

Phantom-based and patient-specific imaging-based dosimetry methodologies have traditionally yielded mean organ-absorbed doses or spatial dose distributions over tumors and normal organs. In this work, radiobiologic modeling is introduced to convert the spatial distribution of absorbed dose into biologically effective dose and equivalent uniform dose parameters. The methodology is illustrated using data from a thyroid cancer patient treated with radioiodine. Methods: Three registered SPECT/CT scans were used to generate 3-dimensional images of radionuclide kinetics (clearance rate) and cumulated activity. The cumulated activity image and corresponding CT scan were provided as input into an EGSnrc-based Monte Carlo calculation: The cumulated activity image was used to define the distribution of decays, and an attenuation image derived from CT was used to define the corresponding spatial tissue density and composition distribution. The rate images were used to convert the spatial absorbed dose distribution to a biologically effective dose distribution, which was then used to estimate a single equivalent uniform dose for segmented volumes of interest. Equivalent uniform dose was also calculated from the absorbed dose distribution directly. Results: We validate the method using simple models; compare the dose-volume histogram with a previously analyzed clinical case; and give the mean absorbed dose, mean biologically effective dose, and equivalent uniform dose for an illustrative case of a pediatric thyroid cancer patient with diffuse lung metastases. The mean absorbed dose, mean biologically effective dose, and equivalent uniform dose for the tumor were 57.7, 58.5, and 25.0 Gy, respectively. Corresponding values for normal lung tissue were 9.5, 9.8, and 8.3 Gy, respectively. Conclusion: The analysis demonstrates the impact of radiobiologic modeling on response prediction. The 57% reduction in the equivalent dose value for the tumor reflects a high level of dose nonuniformity in the tumor and a corresponding reduced likelihood of achieving a tumor response. Such analyses are expected to be useful in treatment planning for radionuclide therapy.

Bortezomib-induced enzyme-targeted radiation therapy in herpesvirus-associated tumors

We investigated the possibility of using a pharmacologic agent to modulate viral gene expression to target radiotherapy to tumor tissue. In a mouse xenograft model, we had previously shown targeting of [125I]2′-fluoro-2′-deoxy-β-D-5-iodouracil-arabinofuranoside ([125I]FIAU) to tumors engineered to express the Epstein-Barr virus thymidine kinase (EBV-TK). Here we extend those results to targeting of a therapeutic radiopharmaceutical [131I]FIAU to slow or stop tumor growth or to achieve tumor regression. These outcomes were achieved in xenografts with tumors that constitutively expressed the EBV-TK. With naturally infected EBV tumor cell lines (Burkitts lymphoma and gastric carcinoma), activation of viral gene expression by pretreatment with bortezomib was required. Marked changes in tumor growth could also be achieved in naturally infected Kaposis sarcoma herpesvirus tumors after pretreatment with bortezomib. Bortezomib-induced enzyme-targeted radiation therapy illustrates the possibility of pharmacologically modulating tumor gene expression to result in targeted radiotherapy.

124I PET-Based 3D-RD Dosimetry for a Pediatric Thyroid Cancer Patient: Real-Time Treatment Planning and Methodologic Comparison

Patient-specific 3-dimensional radiobiologic dosimetry (3D-RD) was used for 131I treatment planning for an 11-y-old girl with differentiated papillary thyroid cancer, heavy lung involvement, and cerebral metastases. 124I PET was used for pharmacokinetics. Calculation of the recommended administered activity, based on lung toxicity constraints, was performed in real time (i.e., during the data-acquisition interval). The results were available to the physician in time to influence treatment; these estimates were compared with conventional dosimetry methodologies. In subsequent, retrospective analyses, the 3D-RD calculations were expanded to include additional tumor dose estimates, and the conventional methodologies were reexamined to reveal the causes of the differences observed. A higher recommended administered activity than by an S-value–based method with a favorable clinical outcome was obtained. This approach permitted more aggressive treatment while adhering to patient-specific lung toxicity constraints. A retrospective analysis of the conventional methodologies with appropriate corrections yielded absorbed dose estimates consistent with 3D-RD.

Three-dimensional imaging-based radiobiological dosimetry.

Targeted radionuclide therapy holds promise as a new treatment for cancer. Advances in imaging are making it possible for researchers to evaluate the spatial distribution of radioactivity in tumors and normal organs over time. Matched anatomical imaging, such as combined single-photon emission computed tomography/computed tomography and positron emission tomography/computed tomography, has also made it possible to obtain tissue density information in conjunction with the radioactivity distribution. Coupled with sophisticated iterative reconstruction algorithms, these advances have made it possible to perform highly patient-specific dosimetry that also incorporates radiobiological modeling. Such sophisticated dosimetry techniques are still in the research investigation phase. Given the attendant logistical and financial costs, a demonstrated improvement in patient care will be a prerequisite for the adoption of such highly-patient specific internal dosimetry methods.

Radioimmunotherapy of Breast Cancer Metastases with α-Particle Emitter 225Ac: Comparing Efficacy with 213Bi and 90Y

alpha-Particles are suitable to treat cancer micrometastases because of their short range and very high linear energy transfer. alpha-Particle emitter (213)Bi-based radioimmunotherapy has shown efficacy in a variety of metastatic animal cancer models, such as breast, ovarian, and prostate cancers. Its clinical implementation, however, is challenging due to the limited supply of (225)Ac, high technical requirement to prepare radioimmunoconjugate with very short half-life (T(1/2) = 45.6 min) on site, and prohibitive cost. In this study, we investigated the efficacy of the alpha-particle emitter (225)Ac, parent of (213)Bi, in a mouse model of breast cancer metastases. A single administration of (225)Ac (400 nCi)-labeled anti-rat HER-2/neu monoclonal antibody (7.16.4) completely eradicated breast cancer lung micrometastases in approximately 67% of HER-2/neu transgenic mice and led to long-term survival of these mice for up to 1 year. Treatment with (225)Ac-7.16.4 is significantly more effective than (213)Bi-7.16.4 (120 microCi; median survival, 61 days; P = 0.001) and (90)Y-7.16.4 (120 microCi; median survival, 50 days; P < 0.001) as well as untreated control (median survival, 41 days; P < 0.0001). Dosimetric analysis showed that (225)Ac-treated metastases received a total dose of 9.6 Gy, significantly higher than 2.0 Gy from (213)Bi and 2.4 Gy from (90)Y. Biodistribution studies revealed that (225)Ac daughters, (221)Fr and (213)Bi, accumulated in kidneys and probably contributed to the long-term renal toxicity observed in surviving mice. These data suggest (225)Ac-labeled anti-HER-2/neu monoclonal antibody could significantly prolong survival in HER-2/neu-positive metastatic breast cancer patients.

A bone marrow toxicity model for 223Ra alpha-emitter radiopharmaceutical therapy

Ra-223, an α-particle emitting bone-seeking radionuclide, has recently been used in clinical trials for osseous metastases of prostate cancer. We investigated the relationship between absorbed fraction-based red marrow dosimetry and cell level-dosimetry using a model that accounts for the expected localization of this agent relative to marrow cavity architecture. We show that cell level-based dosimetry is essential to understanding potential marrow toxicity. The GEANT4 software package was used to create simple spheres representing marrow cavities. Ra-223 was positioned on the trabecular bone surface or in the endosteal layer and simulated for decay, along with the descendants. The interior of the sphere was divided into cell-size voxels and the energy was collected in each voxel and interpreted as dose cell histograms. The average absorbed dose values and absorbed fractions were also calculated in order to compare those results with previously published values. The absorbed dose was predominantly deposited near the trabecular surface. The dose cell histogram results were used to plot the percentage of cells that received a potentially toxic absorbed dose (2 or 4 Gy) as a function of the average absorbed dose over the marrow cavity. The results show (1) a heterogeneous distribution of cellular absorbed dose, strongly dependent on the position of the cell within the marrow cavity; and (2) that increasing the average marrow cavity absorbed dose, or equivalently, increasing the administered activity resulted in only a small increase in potential marrow toxicity (i.e. the number of cells receiving more than 4 or 2 Gy), for a range of average marrow cavity absorbed doses from 1 to 20 Gy. The results from the trabecular model differ markedly from a standard absorbed fraction method while presenting comparable average dose values. These suggest that increasing the amount of radioactivity may not substantially increase the risk of toxicity, a result unavailable to the absorbed fraction method of dose calculation.

Extension of the biological effective dose to the MIRD schema and possible implications in radionuclide therapy dosimetry

In dosimetry-based treatment planning protocols, patients with rapid clearance of the radiopharmaceutical require a larger amount of initial activity than those with slow clearance to match the absorbed dose to the critical organ. As a result, the dose-rate to the critical organ is higher in patients with rapid clearance and may cause unexpected toxicity compared to patients with slow clearance. In order to account for the biological impact of different dose-rates, radiobiological modeling is beginning to be applied to the analysis of radionuclide therapy patient data. To date, the formalism used for these analyses is based on kinetics derived from activity in a single organ, the target. This does not include the influence of other source organs to the dose and dose-rate to the target organ. As a result, only self-dose irradiation in the target organ contributes to the dose-rate. In this work, the biological effective dose (BED) formalism has been extended to include the effect of multiple source organ contributions to the net dose-rate in a target organ. The generalized BED derivation has been based on the Medical Internal Radionuclide Dose Committee (MIRD) schema assuming multiple source organs following exponential effective clearance of the radionuclide. A BED-based approach to determine the largest safe dose to critical organs has also been developed. The extended BED formalism is applied to red marrow dosimetry, as well as kidney dosimetry considering the cortex and the medulla separately, since both those organs are commonly dose limiting in radionuclide therapy. The analysis shows that because the red marrow is an early responding tissue (high alpha/beta), it is less susceptible to unexpected toxicity arising from rapid clearance of high levels of administered activity in the marrow or in the remainder of the body. In kidney dosimetry, the study demonstrates a complex interplay between clearance of activity in the cortex and the medulla, as well as the initial activity ratio and the S value ratio between the two. In some scenarios, projected BED based on both the cortex and the medulla is a more appropriate constraint on the administered activity than the BED based on the cortex only. Furthermore, different fractionated regimens were considered to reduce renal toxicity. The MIRD-based BED formalism is expected to be useful for patient-specific adjustments of activity and to facilitate the investigation of dose-toxicity correlations with respect to dose-rate and tissue repair mechanism.

Dose-finding Study of 153Sm-EDTMP in Patients With Poor-prognosis Osteosarcoma

Samarium‐153 ethylenediaminetetramethylene phosphonic acid (153Sm‐EDTMP) has been used to treat patients with high‐risk osteosarcoma. The purpose of the current study was to determine the maximally tolerated dose of 153Sm‐EDTMP that permits hematopoietic recovery within 6 weeks.

Three-dimensional radiobiological dosimetry (3D-RD) with 124I PET for 131I therapy of thyroid cancer

Radioiodine therapy of thyroid cancer was the first and remains among the most successful radiopharmaceutical (RPT) treatments of cancer although its clinical use is based on imprecise dosimetry. The positron emitting radioiodine, 124I, in combination with positron emission tomography (PET)/CT has made it possible to measure the spatial distribution of radioiodine in tumors and normal organs at high resolution and sensitivity. The CT component of PET/CT has made it simpler to match the activity distribution to the corresponding anatomy. These developments have facilitated patient-specific dosimetry (PSD), utilizing software packages such as three-dimensional radiobiological dosimetry (3D-RD), which can account for individual patient differences in pharmacokinetics and anatomy. We highlight specific examples of such calculations and discuss the potential impact of 124I PET/CT on thyroid cancer therapy.