Richard B. Sparks

Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma.

UNLABELLED Radiation dosimetry studies were performed in patients with non-Hodgkins lymphoma (NHL) treated with 90Y Zevalin (90yttrium ibritumomab tiuxetan, IDEC-Y2B8) on a Phase III open-label prospectively randomized multicenter trial. The trial was designed to evaluate the efficacy and safety of 90Y Zevalin radioimmunotherapy compared to rituximab (Rituxan, MabThera) immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed NHL. An important secondary objective was to determine if radiation dosimetry prior to 90Y Zevalin administration is required for safe treatment in this patient population. METHODS Patients randomized into the Zevalin arm were given a tracer dose of 5 mCi (185 MBq) (111)In Zevalin (111indium ibritumomab tiuxetan) on Day 0, evaluated with dosimetry, and then administered a therapeutic dose of 0.4 mCi/kg (15 MBq/kg) 90Y Zevalin on Day 7. Both Zevalin doses were preceded by an infusion of 250 mg/m(2) rituximab to clear peripheral B-cells and improve Zevalin biodistribution. Following administration of (111)In Zevalin, serial anterior and posterior whole-body scans were acquired and blood samples were obtained. Residence times for 90Y were estimated for major organs, and the MIRDOSE3 computer software program was used to calculate organ-specific and total body radiation absorbed dose. Patients randomized into the rituximab arm received a standard course of rituximab immunotherapy (375 mg/m(2) weekly x 4). RESULTS In a prospectively defined 90 patient interim analysis, the overall response rate was 80% for Zevalin vs. 44% for rituximab. For all patients with Zevalin dosimetry data (N=72), radiation absorbed doses were estimated to be below the protocol-defined upper limits of 300 cGy to red marrow and 2000 cGy to normal organs. The median estimated radiation absorbed doses were 71 cGy to red marrow (range: 18-221 cGy), 216 cGy to lungs (94-457 cGy), 532 cGy to liver (range: 234-1856 cGy), 848 cGy to spleen (range: 76-1902 cGy), 15 cGy to kidneys (0.27-76 cGy) and 1484 cGy to tumor (range: 61-24274 cGy). Toxicity was primarily hematologic, transient, and reversible. The severity of hematologic nadir did not correlate with estimates of effective half-life (half-life) or residence time of 90Y in blood, or radiation absorbed dose to the red marrow or total body. CONCLUSION 90Y Zevalin administered to NHL patients at non-myeloablative maximum tolerated doses delivers acceptable radiation absorbed doses to uninvolved organs. Lack of correlation between dosimetric or pharmacokinetic parameters and the severity of hematologic nadir suggest that hematologic toxicity is more dependent on bone marrow reserve in this heavily pre-treated population. Based on these findings, it is safe to administer 90Y Zevalin in this defined patient population without pre-treatment (111)In-based radiation dosimetry.

Radiation absorbed dose to the embryo/fetus from radiopharmaceuticals.

Radiation protection practice requires the knowledge of estimated absorbed radiation doses to aid in the understanding of the potential detriment of various exposures. In nuclear medicine, the radiation doses to the internal organs of the subject are commonly calculated using the MIRD methods and equations. The absorbed dose to the embryo or fetus has long been an area of concern. The recent release of the pregnant female phantom series, and its incorporation into the MIRDOSE 3 computer software, has made possible the estimation of absorbed doses from radionuclides in the body to the fetus in early pregnancy and at 3, 6, and 9 mo gestation. A survey of several major medical institutions was made to determine the radiopharmaceuticals which might be given, whether intentionally or not, to women of childbearing years. Biokinetic data for these radiopharmaceuticals were gathered from various documents and other resources, and the absorbed doses to the embryo and fetus at these different stages of gestation from radiations originating within the mothers organs were estimated. In addition, information about activity distributed within the placenta and fetus was included where quantitative data were available. These absorbed dose estimates can be used to evaluate the risk associated with the use of different radiopharmaceuticals so that a more informed evaluation of the risks and benefits of the different procedures may be made. Further research is needed into the mechanisms and quantitative aspects of the placental transfer of many radiopharmaceuticals.

Phase I, First-in-Human Study of BMS747158, a Novel 18F-Labeled Tracer for Myocardial Perfusion PET: Dosimetry, Biodistribution, Safety, and Imaging Characteristics After a Single Injection at Rest

18F-labeled BMS747158 is a novel myocardial perfusion imaging tracer that targets mitochondrial complex 1. The objectives of this phase I study were to evaluate radiation dosimetry, biodistribution, human safety, tolerability, and early elimination of 18F activity in urine after injection of a single dose of the tracer at rest in healthy subjects. Methods: Thirteen healthy subjects were injected with 170–244 MBq (4.6–6.6 mCi) of BMS747158 intravenously. Dynamic PET was obtained over the heart for 10 min, followed by sequential whole-body imaging for 5 h. Blood samples and urinary excretion were collected for up to 8 h. Heart rate, electrocardiogram, and blood pressure were monitored before and during imaging. The residence times were determined from multiexponential regression of organ region-of-interest data normalized by injected dose. Absorbed dose estimates for all target organs were determined using MIRD schema with OLINDA/EXM software. Results: The organ receiving the largest mean absorbed dose was the kidneys at 0.066 mSv/MBq (0.24 rem/mCi), followed by the heart wall at 0.048 mSv/MBq (0.18 rem/mCi). The mean effective dose was 0.019 mSv/MBq (0.072 rem/mCi). The heart exhibited high and sustained retention of BMS747158 from the earliest images through approximately 5 h after injection. There were no drug-related adverse events, and the tracer was well tolerated in all subjects. Mean urinary excretion was 4.83 percentage injected dose (range, 0.64–12.41 percentage injected dose). Conclusion: These preliminary data suggest that 18F-labeled BMS747158 appears to be well tolerated and has a unique potential for myocardial perfusion PET.

Placental transfer of radiopharmaceuticals and dosimetry in pregnancy

The calculation of radiation dose estimates to the fetus is often important in nuclear medicine. To obtain the best estimates of radiation dose to the fetus, the best biological and physical models should be employed. In this paper the most recent data available on the placental crossover of many radiopharmaceuticals are presented. This information was used with standard kinetic models describing the maternal distribution and retention and with the best available physical models to obtain fetal dose estimates for these radiopharmaceuticals at all stages of pregnancy (presented in a separate paper). The literature yielded information on placental crossover of 15 radiopharmaceuticals, from animal or human data. From these data, radiation dose estimates were developed in early pregnancy and at 3, 6, and 9 mo gestation for these radiopharmaceuticals, as well as for many others used in nuclear medicine (the latter considering only maternal organ contributions to fetal dose).

Radiation dosimetry results from a phase II trial of Ibritumomab Tiuxetan (Zevalin™) radioimmunotherapy for patients with non-Hodgkin's lymphoma and mild thrombocytopenia

This was a 30-patient Phase II trial of reduced-dose (90)Y ibritumomab tiuxetan (Zevalin) RIT for patients with low-grade, follicular, or transformed B-cell NHL and mild thrombocytopenia. Patients were given an imaging dose of (111)In-labeled ibritumomab tiuxetan for dosimetry measurements. One week later, patients were administered a therapeutic dose of 0.3 mCi/kg (11 MBq/kg) (90)Y ibritumomab tiuxetan. Both (111)In- and (90)Y-labeled ibritumomab tiuxetan doses were preceded by an infusion of 250 mg/m(2) rituximab (Rituxan, MabThera) an unlabeled chimeric anti-CD20 antibody, to clear peripheral blood B cells and improve biodistribution of the radiolabeled antibody. For all 30 patients, normal organ and red marrow radiation absorbed doses were well below protocol-defined limits of 2000 cGy and 300 cGy, respectively. Median radiation absorbed doses were 48 cGy to red marrow (range: 6.5-95 cGy), 393 cGy to liver (range: 92-1581 cGy), 522 cGy to spleen (range: 165-1711 cGy), 162 cGy to lungs (41-295 cGy), and 14 cGy to kidneys (0.03-65 cGy). Though most correlative analyses were negative, certain analyses demonstrated a statistically significant correlation between the severity or duration of thrombocytopenia and pharmacokinetic or dosimetric parameters. These correlations were not consistent across the total patient population, and therefore, could not be exploited to predict hematologic toxicity.

Biodistribution and Radiation Dosimetry of LMI1195: First-in-Human Study of a Novel 18F-Labeled Tracer for Imaging Myocardial Innervation

A novel 18F-labeled ligand for the norepinephrine transporter (N-[3-bromo-4-(3-18F-fluoro-propoxy)-benzyl]-guanidine [LMI1195]) is in clinical development for mapping cardiac nerve terminals in vivo using PET. Human safety, whole-organ biodistribution, and radiation dosimetry of LMI1195 were evaluated in a phase 1 clinical trial. Methods: Twelve healthy subjects at 3 clinical sites were injected intravenously with 150–250 MBq of LMI1195. Dynamic PET images were obtained over the heart for 10 min, followed by sequential whole-body images for approximately 5 h. Blood samples were obtained, and heart rate, electrocardiogram, and blood pressure were monitored before and during imaging. Residence times were determined from multiexponential regression of organ region-of-interest data normalized by administered activity (AA). Radiation dose estimates were calculated using OLINDA/EXM. Myocardial, lung, liver, and blood-pool standardized uptake values were determined at different time intervals. Results: No adverse events due to LMI1195 were seen. Blood radioactivity cleared quickly, whereas myocardial uptake remained stable and uniform throughout the heart over 4 h. Liver and lung activity cleared relatively rapidly, providing favorable target-to-background ratios for cardiac imaging. The urinary bladder demonstrated the largest peak uptake (18.3% AA), followed by the liver (15.5% AA). The mean effective dose was 0.026 ± 0.0012 mSv/MBq. Approximately 1.6% AA was seen in the myocardium initially, remaining above 1.5% AA (decay-corrected) through 4 h after injection. The myocardium-to-liver ratio was approximately unity initially, increasing to more than 2 at 4 h. Conclusion: These preliminary data suggest that LMI1195 is well tolerated and yields a radiation dose comparable to that of other commonly used PET radiopharmaceuticals. The kinetics of myocardial and adjacent organ activity suggest that cardiac imaging should be possible with acceptable patient radiation dose.

The need for better methods to determine release criteria for patients administered radioactive material.

In current NRC regulations, three options exist that may be used to determine release criteria for patients administered radioactive materials. Absorbed dose estimates may he based on administered activity, measured dose rate, or on patient. Specific calculations. All of these methods proposed by the NRC can lead to overestimation of the dose equivalent to others due to their oversimplified nature. The primary oversimplifications are the use of a point source methodology and using the measured surface entrance dose rate to determine whole body dose. In order to show the inaccuracy of these oversimplifications for 131I, results using Monte Carlo radiation transport analysis with simplified anthropomorphic mathematical phantoms were determined. These results were then compared to actual patient measurements and the results of point source analysis. The measurement data were taken from 49 131I radioinummotherapy patients. The point source calculations were performed using well established methodologies and using the same assumptions as in the NRC regulations for patient release criteria. Monte Carlo results were obtained by implementing two simplified 70 kg anthropomorphic phantoms and performing radiation transport simulation. The activity in the “patient” phantom was assumed to be localized in the abdominal region to correspond to the activity localization seen in the radioimmunotherapy patients who were measured. Dose equivalents per unit cumulated activities were determined for 131I using the various methods. The relationship between measured dose equivalent per unit cumulated activity and whole body dose equivalent per unit cumulated activity was also investigated using Monte Carlo analysis. The point source method as implemented by the NRC yields an estimated dose equivalent per unit cumulated activity of 1.6 × 10−8 mSv MBq−1 S−1 at 1 m (2.2 × 10−4 rem mCi−1 h−1 at 1 m), and the Monte Carlo based method yielded a whole body dose equivalent per unit cumulated activity in the target phantom of 6.8 × 10−9 mSv MBq−1 s−1 (9.0 × 10−5 rem mCi−1 h−1) for abdominal localization of activity in the source phantom. The measurements of the radioinummotherapy patients yielded an average result of 1.0 × 10−8 mSv MBq−1 s−1 (1.3 × 10−4 rem mCi−1 h−1). When corrected for the difference between measured surface dose equivalent and whole body dose equivalent as determined by Monte Carlo analysis, these measurements represent a whole body dose equivalent per unit cumulated activity of about 6.2 × 10−9 mSv MBq−1 s−1 (8.1 × 10−5 rem mCi−1 h−1). Based on these results, the current NRC dose-based methodology for the release of patients administered radioactive materials signiflcantly overestimates the dose equivalent to others from 131I therapy patients.

(S)-4-(3-18F-Fluoropropyl)-l-Glutamic Acid: An 18F-Labeled Tumor-Specific Probe for PET/CT Imaging—Dosimetry

The glutamic acid derivative (S)-4-(3-18F-Fluoropropyl)-l-glutamic acid (18F-FSPG, alias BAY 94-9392), a new PET tracer for the detection of malignant diseases, displayed promising results in non–small cell lung cancer patients. The aim of this study was to provide dosimetry estimates for 18F-FSPG based on human whole-body PET/CT measurements. Methods: 18F-FSPG was prepared by a fully automated 2-step procedure and purified by a solid-phase extraction method. PET/CT scans were obtained for 5 healthy volunteers (mean age, 59 y; age range, 51–64 y; 2 men, 3 women). Human subjects were imaged for up to 240 min using a PET/CT scanner after intravenous injection of 299 ± 22.5 MBq of 18F-FSPG. Image quantification, time–activity data modeling, estimation of normalized number of disintegrations, and production of dosimetry estimates were performed using the RADAR (RAdiation Dose Assessment Resource) method for internal dosimetry and in general concordance with the methodology and principles as presented in the MIRD 16 document. Results: Because of the renal excretion of the tracer, the absorbed dose was highest in the urinary bladder wall and kidneys, followed by the pancreas and uterus. The individual organ doses (mSv/MBq) were 0.40 ± 0.058 for the urinary bladder wall, 0.11 ± 0.011 for the kidneys, 0.077 ± 0.020 for the pancreas, and 0.030 ± 0.0034 for the uterus. The calculated effective dose was 0.032 ± 0.0034 mSv/MBq. Absorbed dose to the bladder and the effective dose can be reduced significantly by frequent bladder-voiding intervals. For a 0.75-h voiding interval, the bladder dose was reduced to 0.10 ± 0.012 mSv/MBq, and the effective dose was reduced to 0.015 ± 0.0010 mSv/MBq. Conclusion: On the basis of the distribution and biokinetic data, the determined radiation dose for 18F-FSPG was calculated to be 9.5 ± 1.0 mSv at a patient dose of 300 MBq, which is of similar magnitude to that of 18F-FDG (5.7 mSv). The effective dose can be reduced to 4.5 ± 0.30 mSv (at 300 MBq), with a bladder-voiding interval of 0.75 h.

Radioactivity Appearing At Landfills In Household Trash Of Nuclear Medicine Patients: Much Ado About Nothing?

The U.S. NRC in 1997 removed its arbitrary 1.11 GBq (30 mCi) rule, which had been in existence for almost 50 y, and now many more patients receiving radionuclide therapy in nuclear medicine can be treated as outpatients. However, another problem has the potential to limit the short-lived reality of outpatient treatment unless nuclear medicine practitioners and the health physics community gets involved. Radioactive articles in the household trash of nuclear medicine patients are appearing at solid waste landfills that have installed radiation monitors to prevent the entry of any detectable radioactivity, and alarms are going off around the country. These monitors are set to alarm at extremely low activity levels. Some states may actually hold licensees responsible if a patient’s radioactive household trash is discovered in a solid waste stream; this is another major reason [along with continued use of the 1.11 GBq (30 mCi) rule] why many licensees are still not releasing their radionuclide therapy patients. This is in spite of the fact that the radioactivity contained in released nuclear medicine therapy patients, let alone the much lower activity level contained in their potentially radioactive household wastes, poses a minimal hazard to the public health and safety or to the environment. Currently, there are no regulations governing the disposal of low-activity, rapidly-decaying radioactive materials found in the household trash of nuclear medicine patients, the performance of landfill radiation monitors, or the necessity of spectrometry equipment. Resources are, therefore, being unnecessarily expended by regulators and licensees in responding to radiation monitor alarms that are caused by these unregulated short-lived materials that may be mixed with municipal trash. Recommendations are presented that would have the effect of modifying the existing landfill regulations and practices so as to allow the immediate disposal of such wastes.

A Phase I–II, Open-Label, Multicenter Trial to Determine the Dosimetry and Safety of 99mTc-Sestamibi in Pediatric Subjects

Myocardial perfusion imaging has long been used off label by practitioners attending for children with cardiac aliments. To provide clinicians with evidence-based dosage recommendation, a phase I–II, open-label, nonrandomized, multicenter trial was therefore designed using 99mTc-sestamibi in pediatric subjects (registered under www.clinicaltrials.gov identifier no. NCT00162045). Methods: Safety and pharmacokinetic data were collected from 78 subjects using either a 1-d imaging protocol (3.7–7.4 MBq/kg, followed by 11.1 MBq/kg) or a 2-d protocol (7.4 MBq/kg for both rest and stress). Anterior and posterior planar images were collected at 15 min, 1.5 h, 4 h, and 8 h. Blood and urine samples were collected at predetermined times. Results: Subjects included 39 children (mean age ± SD, 8.5 ± 2.04 y) and 39 adolescents (mean age ± SD, 13.6 ± 1.39 y). Mean estimated organ-absorbed doses to the upper large intestine, small intestine, gallbladder wall, and lower large intestines were 0.082, 0.043, 0.042, and 0.035 mSv/MBq, respectively. All patients tolerated the radiotracer without serious adverse effects. Significant differences were observed in the liver, upper large intestine contents, and small intestine contents between rest and stress imaging. The effective dose equivalent and effective dose averages were lower in adolescents than younger children (0.011 and 0.019 mSv/MBq, respectively; P < 0.0001). Percentage injected doses (%IDs) corrected for radioactive decay in all dosimetry-evaluable subjects at 15 min and 4 h were 1.9% and 1.2% in the myocardium. Similarly in the lungs, the %ID for all dosimetry-evaluable subjects was 4.9% at 15 min after injection. At rest, the %ID in the liver decreased from a maximum of about 26% at 15 min to less than 9% at 90 min. With stress, values decreased from 15% to 7%, respectively. Conclusion: The estimates of radiation dosimetry, pharmacokinetic parameters, and safety profile in this study population are similar to published studies based on body-mass extrapolations from studies in adults. As such, applying current 99mTc-sestamibi dosing regimens for 1- and 2-d protocols based on those extrapolations will result in the expected radiation dose in children and adolescents.