Purpose: Previously, we showed successful imaging of xenografts that express the prostatespecific membrane antigen (PSMA) using small-animal positron emission tomography (PET) and the radiolabeled PSMA inhibitor]methyl-L-cysteine. Herein, we extend that work by preparing and testing a PSMA inhibitor of the same class labeled with fluorine-18. High radiopharmaceutical uptake was also seen in kidneys and bladder; however, washout of radioactivity from these organs was faster than from the PIP tumors. The maximum PIP tumor uptake was 8.16 F 2.55% injected dose per gram, achieved at 60 min after injection, which decreased to 4.69 F 0.89 at 120 min. The PIP tumor to muscle ratio was 20 at 120 min after injection. Based on the mouse biodistribution, the dose-limiting organ is the kidneys (human estimated absorbed dose: 0.05 mGy/MBq; 0.2 rad/mCi). Conclusion: [

MarylandPhantom-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.Key Words: dosimetry; radiobiology; 3D-ID; patient-specific dosimetry; treatment planning The tools and methodologies for performing radionuclide dosimetry for therapeutic nuclear medicine applications have evolved over the past 2 decades such that current research focuses on patient-specific 3-dimensional (3D) image or voxel-based approaches (1,2). In this work, we describe an extension of this methodology that incorporates radiobiologic modeling to account for the spatial distribution of absorbed dose and the effect of dose rate on biologic response. The methodology is incorporated into a software package, called 3D-RD, for 3D radiobiologic dosimetry.Patient-specific 3D imaging-based internal dosimetry is a methodology in which the patient's own anatomy and spatial distribution of radioactivity over time are factored into an absorbed dose calculation that provides as o...

Targeted radionuclide therapy holds promise as a new treatment against cancer. Advances in imaging are making it possible to evaluate the spatial distribution of radioactivity in tumors and normal organs over time. Matched anatomical imaging such as combined SPECT/CT and PET/CT have also made it possible to obtain tissue density information in conjunction with the radioactivity distribution. Coupled with sophisticated iterative reconstruction algorithims, 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.

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 α/β), 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 a) sebastien.baechler@chuv.ch. 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. NIH Public Access

BACKGROUND: 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. METHODS: Patients with recurrent or refractory osteosarcoma with bone metastases were enrolled in this study. Subjects were treated with increasing doses of 153Sm‐EDTMP, beginning with 1.0 millicuries (mCi)/kg and followed initially with 40% increment dose level escalations, using a continual reassessment method for dose escalation and de‐escalation with a target dose–limiting toxicity (DLT) rate of 30%. Complete blood counts were monitored weekly, and the primary DLT was defined as failure to achieve an absolute neutrophil count >750/mm3 and a platelet count >75,000/mm3 within 6 weeks of treatment. In addition to assessing toxicity, dosimetry measurements were made to estimate the radiation dose delivered to target lesions. RESULTS: The maximally tolerated dose of 153Sm‐EDTMP was 44.8 megabecquerel (MBq)/kg (1.21 mCi/kg). DLTs were confined to hematologic toxicities, particularly delayed platelet recovery in 2 patients treated at a dose of 51.8 MBq/kg (1.4 mCi/kg). Grade 2 and 3 pulmonary toxicity (graded according to the National Cancer Institute Common Toxicity Criteria [version 3.0]) as reported in 2 patients (at administered activities of 44.8 MBq/kg and 51.8 MBq/kg) was attributable to progressive pulmonary disease. No other significant nonhematologic toxicities were observed. CONCLUSIONS: Patients with osteosarcoma who have previously been heavily treated with chemotherapy can be safely administered 153Sm‐EDTMP with rapid hematologic recovery. The data from the current study support the development of a future trial to assess the efficacy of combining targeted radiotherapy with cytotoxic chemotherapy as a treatment option for patients with high‐risk osteosarcoma. Cancer 2009. © 2009 American Cancer Society.