Spotlight on the Association of Radioactive Iodine Treatment With Cancer Mortality in Patients With Hyperthyroidism is Keeping the Highest Risk From Antithyroid Drugs in the Blind Spot.

July 1, 2019, JAMA Internal Medicine released online an article authored by Kitahara et al entitled "Association of radioactive iodine treatment with cancer mortality in patients with hyperthyroidism." The Altmetric Attention Score, a global indicator of interest from lay public and colleagues, skyrocketed to 223 by July 7, placing the article in the top 5% of all scored reports. The overall perception of death from cancer risk associated with I is inflated and not supported by evidence. As co-authors of this article, we offer previously unpublished data and analysis that (1) disputes clinical significance of the associated risk from I and (2) shows, again, that antithyroid drugs carry a statistically significant and a much more obvious cancer death risk.

MIRD Pamphlet No. 26: Joint EANM/MIRD Guidelines for Quantitative 177Lu SPECT Applied for Dosimetry of Radiopharmaceutical Therapy.

The accuracy of absorbed dose calculations in personalized internal radionuclide therapy is directly related to the accuracy of the activity (or activity concentration) estimates obtained at each of the imaging time points. MIRD Pamphlet no. 23 presented a general overview of methods that are required for quantitative SPECT imaging. The present document is next in a series of isotope-specific guidelines and recommendations that follow the general information that was provided in MIRD 23. This paper focuses on (177)Lu (lutetium) and its application in radiopharmaceutical therapy.

MIRD pamphlet No. 24: Guidelines for quantitative 131I SPECT in dosimetry applications.

The reliability of radiation dose estimates in internal radionuclide therapy is directly related to the accuracy of activity estimates obtained at each imaging time point. The recently published MIRD pamphlet no. 23 provided a general overview of quantitative SPECT imaging for dosimetry. The present document is the first in a series of isotope-specific guidelines that will follow MIRD 23 and focuses on one of the most commonly used therapeutic radionuclides, (131)I. The purpose of this document is to provide guidance on the development of protocols for quantitative (131)I SPECT in radionuclide therapy applications that require regional (normal organs, lesions) and 3-dimensional dosimetry.

Uncertainties in estimating health risks associated with exposure to ionising radiation.

The information for the present discussion on the uncertainties associated with estimation of radiation risks and probability of disease causation was assembled for the recently published NCRP Report No. 171 on this topic. This memorandum provides a timely overview of the topic, given that quantitative uncertainty analysis is the state of the art in health risk assessment and given its potential importance to developments in radiation protection. Over the past decade the increasing volume of epidemiology data and the supporting radiobiology findings have aided in the reduction of uncertainty in the risk estimates derived. However, it is equally apparent that there remain significant uncertainties related to dose assessment, low dose and low dose-rate extrapolation approaches (e.g. the selection of an appropriate dose and dose-rate effectiveness factor), the biological effectiveness where considerations of the health effects of high-LET and lower-energy low-LET radiations are required and the transfer of risks from a population for which health effects data are available to one for which such data are not available. The impact of radiation on human health has focused in recent years on cancer, although there has been a decided increase in the data for noncancer effects together with more reliable estimates of the risk following radiation exposure, even at relatively low doses (notably for cataracts and cardiovascular disease). New approaches for the estimation of hereditary risk have been developed with the use of human data whenever feasible, although the current estimates of heritable radiation effects still are based on mouse data because of an absence of effects in human studies. Uncertainties associated with estimation of these different types of health effects are discussed in a qualitative and semi-quantitative manner as appropriate. The way forward would seem to require additional epidemiological studies, especially studies of low dose and low dose-rate occupational and perhaps environmental exposures and for exposures to x rays and high-LET radiations used in medicine. The development of models for more reliably combining the epidemiology data with experimental laboratory animal and cellular data can enhance the overall risk assessment approach by providing biologically refined data to strengthen the estimation of effects at low doses as opposed to the sole use of mathematical models of epidemiological data that are primarily driven by medium/high doses. NASA's approach to radiation protection for astronauts, although a unique occupational group, indicates the possible applicability of estimates of risk and their uncertainty in a broader context for developing recommendations on: (1) dose limits for occupational exposure and exposure of members of the public; (2) criteria to limit exposures of workers and members of the public to radon and its short-lived decay products; and (3) the dosimetric quantity (effective dose) used in radiation protection.

MIRD pamphlet No. 23: quantitative SPECT for patient-specific 3-dimensional dosimetry in internal radionuclide therapy.

In internal radionuclide therapy, a growing interest in voxel-level estimates of tissue-absorbed dose has been driven by the desire to report radiobiologic quantities that account for the biologic consequences of both spatial and temporal nonuniformities in these dose estimates. This report presents an overview of 3-dimensional SPECT methods and requirements for internal dosimetry at both regional and voxel levels. Combined SPECT/CT image-based methods are emphasized, because the CT-derived anatomic information allows one to address multiple technical factors that affect SPECT quantification while facilitating the patient-specific voxel-level dosimetry calculation itself. SPECT imaging and reconstruction techniques for quantification in radionuclide therapy are not necessarily the same as those designed to optimize diagnostic imaging quality. The current overview is intended as an introduction to an upcoming series of MIRD pamphlets with detailed radionuclide-specific recommendations intended to provide best-practice SPECT quantification-based guidance for radionuclide dosimetry.

Updated mortality analysis of radiation workers at Rocketdyne (Atomics International), 1948-2008.

Updated analyses of mortality data are presented on 46,970 workers employed 1948-1999 at Rocketdyne (Atomics International). Overall, 5,801 workers were involved in radiation activities, including 2,232 who were monitored for intakes of radionuclides, and 41,169 workers were engaged in rocket testing or other non-radiation activities. The worker population is unique in that lifetime occupational doses from all places of employment were sought, updated and incorporated into the analyses. Further, radiation doses from intakes of 14 different radionuclides were calculated for 16 organs or tissues using biokinetic models of the International Commission on Radiation Protection (ICRP). Because only negligible exposures were received by the 247 workers monitored for radiation activities after 1999, the mean dose from external radiation remained essentially the same at 13.5 mSv (maximum 1 Sv) as reported previously, as did the mean lung dose from external and internal radiation combined at 19.0 mSv (maximum 3.6 Sv). An additional 9 years of follow-up, from December 31,1999 through 2008, increased the person-years of observation for the radiation workers by 21.7% to 196,674 (mean 33.9 years) and the number of cancer deaths by 50% to 684. Analyses included external comparisons with the general population and the computation of standardized mortality ratios (SMRs) and internal comparisons using proportional hazards models and the computation of relative risks (RRs). A low SMR for all causes of death (SMR 0.82; 95% CI 0.78-0.85) continued to indicate that the Rocketdyne radiation workers were healthier than the general population and were less likely to die. The SMRs for all cancers taken together (SMR 0.88; 95% CI 0.81-0.95), lung cancer (SMR 0.87; 95% CI 0.76-1.00) and leukemia other than chronic lymphocytic leukemia (CLL) (SMR 1.04; 95% 0.67-1.53) were not significantly elevated. Cox regression analyses revealed no significant dose-response trends for any cancer. For all cancers excluding leukemia, the RR at 100 mSv was estimated as 0.98 (95% CI 0.82-1.17), and for all leukemia other than CLL it was 1.06 (95% CI 0.50-2.23). Uranium was the primary radionuclide contributing to internal exposures, but no significant increases in lung and kidney disease were seen. The extended follow-up reinforces the findings in the previous study in failing to observe a detectable increase in cancer deaths associated with radiation, but strong conclusions still cannot be drawn because of small numbers and relatively low career doses. Larger combined studies of early workers in the United States using similar methodologies are warranted to refine and clarify radiation risks after protracted exposures.

MIRD Pamphlet No. 22 (abridged): radiobiology and dosimetry of alpha-particle emitters for targeted radionuclide therapy.

The potential of alpha-particle emitters to treat cancer has been recognized since the early 1900s. Advances in the targeted delivery of radionuclides and radionuclide conjugation chemistry, and the increased availability of alpha-emitters appropriate for clinical use, have recently led to patient trials of radiopharmaceuticals labeled with alpha-particle emitters. Although alpha-emitters have been studied for many decades, their current use in humans for targeted therapy is an important milestone. The objective of this work is to review those aspects of the field that are pertinent to targeted alpha-particle emitter therapy and to provide guidance and recommendations for human alpha-particle emitter dosimetry.

MIRD pamphlet No. 20: the effect of model assumptions on kidney dosimetry and response--implications for radionuclide therapy.

UNLABELLED: 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 (166)Ho-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.

State of the art in nuclear medicine dose assessment.

Basic calculational methods and models used in dose assessment for internal emitters in nuclear medicine are discussed in this overview. Methods for quantification of activity in clinical and preclinical studies also are discussed, and we show how to implement them in currently available dose calculational models. Current practice of the use of internal emitters in therapy also is briefly presented here. Some of the future challenges for dose assessment in nuclear medicine are discussed, including application of patient-specific dose calculational methods and the need for significant advances in radiation biology.

Kinetic modeling in support of radionuclide dose assessment.

In this review, we trace the origins of mathematical modeling methods and pay particular attention to radiotracer applications. Nuclear medicine has been advanced greatly by the efforts of the Society of Nuclear Medicine's Medical Internal Radiation Dose Committee. Well-developed mathematical methods and tools have been created in support of a wide range of applications. Applications of mathematical modeling extend well beyond biology and medicine and are essential to analysis is a wide range of fields that rely on numerical predictions, eg, weather, economic, and various gaming applications. We start with the discovery of radioactivity and radioactive transformations and illustrate selected applications in biology, physiology, and pharmacology. We discuss compartment models as tools used to frame the context of specific problems. A definition of terms, methods, and examples of particular problems follows. We present models of different applications with varying complexity depending on the features of the particular system and function being analyzed. Commonly used analysis tools and methods are described, followed by established models which describe dosimetry along gastrointestinal and urinary excretory pathways, ending finally with a brief discussion of bone marrow dose. We conclude pointing to more recent, promising methods, not yet widely used in dosimetry applications, which aim at coupling pharmacokinetic data with other patient data to correlate patient outcome (benefits and risk) with the type, amount, kind and timing of the therapy the patient received.

Factors associated with elevated serum concentrations of anti-TPO antibodies in subjects with and without diffuse goitre. Results from the Ukrainian-American Cohort Study of thyroid cancer and other thyroid diseases following the Chornobyl accident.

OBJECTIVES: To examine factors associated with the prevalence of elevated anti-thyroid peroxidase antibodies (ATPO) among iodine-deficient adolescents and young adults and test whether associations vary according to the presence of diffuse goitre. DESIGN: Subjects were members of the Ukrainian-American Cohort Study exposed to the Chornobyl accident whose (131)I thyroid dose estimates were below 0.2 Gy. MEASUREMENTS: The odds ratios (ORs) for ATPO above 60 U/ml were estimated using logistic regression models for a number of factors in the total population (N = 5133), and separately for thyroid disease-free subjects (N = 3875), those with diffuse goitre (N = 921), and diffuse goitre without autoimmune thyroiditis (AIT; N = 883). RESULTS: Elevated ATPO was found in 9.9% of the total population and ORs were significantly higher in females, older individuals, those examined in earlier calendar years, residents of Kyiv and Chernihiv oblasts, subjects with a family history of thyroid disease, higher thyroid ultrasound volume, suppressed or elevated TSH, blood collection in March to May, very low thyroglobulin (Tg), and shorter serum storage time. When thyroid disease-free subjects and those with diffuse goitre were compared, there were few differences in antibody prevalence, and after excluding individuals with AIT, the only difference was an increased prevalence of elevated ATPO at low urinary iodine in those with goitre alone. CONCLUSIONS: Although a number of factors are associated with the prevalence of elevated ATPO in our study group, with the exception of urinary iodine these factors are independent of goitre, and differences between thyroid disease-free subjects and those with diffuse goitre are largely due to AIT.

Mortality among Rocketdyne workers who tested rocket engines, 1948-1999.

OBJECTIVE: The objective of this study was to evaluate potential health risks associated with testing rocket engines. METHODS: A retrospective cohort mortality study was conducted of 8372 Rocketdyne workers employed 1948 to 1999 at the Santa Susana Field Laboratory (SSFL). Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) were calculated for all workers, including those employed at specific test areas where particular fuels, solvents, and chemicals were used. Dose-response trends were evaluated using Cox proportional hazards models. RESULTS: SMRs for all cancers were close to population expectations among SSFL workers overall (SMR = 0.89; CI = 0.82-0.96) and test stand mechanics in particular (n = 1651; SMR = 1.00; CI = 0.86-1.16), including those likely exposed to hydrazines (n = 315; SMR = 1.09; CI = 0.75-1.52) or trichloroethylene (TCE) (n = 1111; SMR = 1.00; CI = 0.83-1.19). Nonsignificant associations were seen between kidney cancer and TCE, lung cancer and hydrazines, and stomach cancer and years worked as a test stand mechanic. No trends over exposure categories were statistically significant. CONCLUSION: Work at the SSFL rocket engine test facility or as a test stand mechanic was not associated with a significant increase in cancer mortality overall or for any specific cancer.

Mortality among radiation workers at Rocketdyne (Atomics International), 1948-1999.

A retrospective cohort mortality study was conducted of workers engaged in nuclear technology development and employed for at least 6 months at Rocketdyne (Atomics International) facilities in California, 1948-1999. Lifetime occupational doses were derived from company records and linkages with national dosimetry data sets. International Commission on Radiation Protection (ICRP) biokinetic models were used to estimate radiation doses to 16 organs or tissues after the intake of radionuclides. Standardized mortality ratios (SMRs) compared the observed numbers of deaths with those expected in the general population of California. Cox proportional hazards models were used to evaluate dose-response trends over categories of cumulative radiation dose, combining external and internal organ-specific doses. There were 5,801 radiation workers, including 2,232 monitored for radionuclide intakes. The mean dose from external radiation was 13.5 mSv (maximum 1 Sv); the mean lung dose from external and internal radiation combined was 19.0 mSv (maximum 3.6 Sv). Vital status was determined for 97.6% of the workers of whom 25.3% (n = 1,468) had died. The average period of observation was 27.9 years. All cancers taken together (SMR 0.93; 95% CI 0.84-1.02) and all leukemia excluding chronic lymphocytic leukemia (CLL) (SMR 1.21; 95% CI 0.69-1.97) were not significantly elevated. No SMR was significantly increased for any cancer or for any other cause of death. The Cox regression analyses revealed no significant dose-response trends for any cancer. For all cancers excluding leukemia, the RR at 100 mSv was estimated as 1.00 (95% CI 0.81-1.24), and for all leukemia excluding CLL it was 1.34 (95% CI 0.73-2.45). The nonsignificant increase in leukemia (excluding CLL) was in accord with expectation from other radiation studies, but a similar nonsignificant increase in CLL (a malignancy not found to be associated with radiation) tempers a causal interpretation. Radiation exposure has not caused a detectable increase in cancer deaths in this population, but results are limited by small numbers and relatively low career doses.

A comprehensive dose reconstruction methodology for former rocketdyne/atomics international radiation workers.

Incomplete radiation exposure histories, inadequate treatment of internally deposited radionuclides, and failure to account for neutron exposures can be important uncertainties in epidemiologic studies of radiation workers. Organ-specific doses from lifetime occupational exposures and radionuclide intakes were estimated for an epidemiologic study of 5,801 Rocketdyne/Atomics International (AI) radiation workers engaged in nuclear technologies between 1948 and 1999. The entire workforce of 46,970 Rocketdyne/AI employees was identified from 35,042 Kardex work histories cards, 26,136 electronic personnel listings, and 14,189 radiation folders containing individual exposure histories. To obtain prior and subsequent occupational exposure information, the roster of all workers was matched against nationwide dosimetry files from the Department of Energy, the Nuclear Regulatory Commission, the Landauer dosimetry company, the U.S. Army, and the U.S. Air Force. Dosimetry files of other worker studies were also accessed. Computation of organ doses from radionuclide intakes was complicated by the diversity of bioassay data collected over a 40-y period (urine and fecal samples, lung counts, whole-body counts, nasal smears, and wound and incident reports) and the variety of radionuclides with documented intake including isotopes of uranium, plutonium, americium, calcium, cesium, cerium, zirconium, thorium, polonium, promethium, iodine, zinc, strontium, and hydrogen (tritium). Over 30,000 individual bioassay measurements, recorded on 11 different bioassay forms, were abstracted. The bioassay data were evaluated using ICRP biokinetic models recommended in current or upcoming ICRP documents (modified for one inhaled material to reflect site-specific information) to estimate annual doses for 16 organs or tissues taking into account time of exposure, type of radionuclide, and excretion patterns. Detailed internal exposure scenarios were developed and annual internal doses were derived on a case-by-case basis for workers with committed equivalent doses indicated by screening criteria to be greater than 10 mSv to the organ with the highest internal dose. Overall, 5,801 workers were monitored for radiation at Rocketdyne/AI: 5,743 for external exposure and 2,232 for internal intakes of radionuclides; 41,169 workers were not monitored for radiation. The mean cumulative external dose based on Rocketdyne/AI records alone was 10.0 mSv, and the dose distribution was highly skewed with most workers experiencing low cumulative doses and only a few with high doses (maximum 500 mSv). Only 45 workers received greater than 200 mSv while employed at Rocketdyne/AI. However, nearly 32% (or 1,833) of the Rocketdyne/AI workers had been monitored for radiation at other nuclear facilities and incorporation of these doses increased the mean dose to 13.5 mSv (maximum 1,005 mSv) and the number of workers with >200 mSv to 69. For a small number of workers (n=292), lung doses from internal radionuclide intakes were relatively high (mean 106 mSv; maximum 3,560 mSv) and increased the overall population mean dose to 19.0 mSv and the number of workers with lung dose>200 mSv to 109. Nearly 10% of the radiation workers (584) were monitored for neutron exposures (mean 1.2 mSv) at Rocketdyne/AI, and another 2% were monitored for neutron exposures elsewhere. Interestingly, 1,477 workers not monitored for radiation at Rocketdyne/AI (3.6%) were found to have worn dosimeters at other nuclear facilities (mean external dose of 2.6 mSv, maximum 188 mSv). Without considering all sources of occupational exposure, an incorrect characterization of worker exposure would have occurred with the potential to bias epidemiologic results. For these pioneering workers in the nuclear industry, 26.5% of their total occupational dose (collective dose) was received at other facilities both prior to and after employment at Rocketdyne/AI. In addition, a small number of workers monitored for internal radionuclides contributed disproportionately to the number of workers with high lung doses. Although nearly 12% of radiation workers had been monitored for neutron exposures during their career, the cumulative dose levels were small in comparison with other external and internal exposure. Risk estimates based on nuclear worker data must be interpreted cautiously if internally deposited radionuclides and occupational doses received elsewhere are not considered.

The importance of patient-specific radiation dose calculations for the administration of radionuclides in therapy.

This paper advocates patient-specific approaches to radiation dose calculations for radionuclides used in therapy and outlines strategies for implementing such approaches. The use of a simple approaches to radionuclide therapy, e.g. a single amount of activity for all patients or the same amount of activity administered per unit body weight do not permit the optimization of individual patient therapy. While limitations in current models and logistic problems prevent dose calculations of the quality currently enjoyed with external radiation therapy approaches, improvements can be made, and models are constantly evolving. Specific suggestions regarding the extension of current models, and of the use of new models which use image data from individual patients, are discussed in the context of allowing radiotherapy with internal emitters to employ the kind of patient-specific approaches that are used in other therapeutic modalities, which are clearly in the patients' best interests.