A Critical Assessment of the Linear No-Threshold Hypothesis: Its Validity and Applicability for Use in Risk Assessment and Radiation Protection.

The Society of Nuclear Medicine and Molecular Imaging convened a task group to examine the evidence for the risk of carcinogenesis from low-dose radiation exposure and to assess evidence in the scientific literature related to the overall validity of the linear no-threshold (LNT) hypothesis and its applicability for use in risk assessment and radiation protection. In the low-dose and dose-rate region, the group concluded that the LNT hypothesis is invalid as it is not supported by the available scientific evidence and, instead, is actually refuted by published epidemiology and radiation biology. The task group concluded that the evidence does not support the use of LNT either for risk assessment or radiation protection in the low-dose and dose-rate region.

Reducing the incidence of 131I-induced sialadenitis: the role of pilocarpine.

UNLABELLED: The goal of this study was to reduce the salivary symptoms of pain and xerostomia caused by 131I therapy for papillary and follicular thyroid carcinoma. METHODS: In a single-blind controlled prospective study of 60 patients, we investigated whether pilocarpine, 5 mg orally every 8 h for 1 wk after 131I therapy, would reduce salivary symptoms. All patients received 8 mg of dexamethasone and 100 mg of dolasetron mesylate orally 2 h before therapy and every 12 h for another 5 doses after 131I ingestion. In addition, for a week after therapy all drank 2,400 mL of nondairy liquid per day and had sugar-free gum or candy in their mouths at all times when awake for a week and, for the first 3 nights, every 3 h after retiring. All brushed their mouths out every 3 h while awake and also for the first 3 nights after 131I therapy. Symptoms and signs were followed by frequent telephone calls over the first week and every 8-12 wk thereafter, a physical examination within the first 10 d after therapy, and a clinic visit 6-8 mo after therapy. Statistical comparisons were by chi2 analysis. RESULTS: The 2 patient groups were not statistically different in age, sex, type of thyroid cancer, or 131I activity administered (P > 0.05). There were no statistical differences between the groups in the prevalence of sialadenitis, stomatitis, xerostomia, or dysgeusia over the next 6 mo (P > 0.05). CONCLUSION: Under the conditions of the study, pilocarpine did not reduce the occurrence of radiation sialadenitis or stomatitis. The occurrence, however, was lower than had previously been reported in the literature, possibly because of the concurrent stringent application of physiologic sialogogues (candy, gum, fluids), dexamethasone, and dolasetron mesylate, a serotonin receptor antagonist.

The BEIR VII Estimates of Low-Dose Radiation Health Risks Are Based on Faulty Assumptions and Data Analyses: A Call for Reassessment.

The 2006 National Academy of Sciences Biologic Effects of Ionizing Radiation (BEIR) VII report is a well-recognized and frequently cited source on the legitimacy of the linear no-threshold (LNT) model-a model entailing a linear and causal relationship between ionizing radiation and human cancer risk. Linearity means that all radiation causes cancer and explicitly excludes a threshold below which radiogenic cancer risk disappears. However, the BEIR VII committee has erred in the interpretation of its selected literature; specifically, the in vitro data quoted fail to support LNT. Moreover, in vitro data cannot be considered as definitive proof of cancer development in intact organisms. This review is presented to stimulate a critical reevaluation by a BEIR VIII committee to reassess the validity, and use, of LNT and its derived policies.

Comparison of outcomes after (123)I versus (131)I pre-ablation imaging before radioiodine ablation in differentiated thyroid carcinoma.

UNLABELLED: Detection of residual tissue after thyroidectomy for papillary or follicular thyroid carcinoma may be performed using diagnostic imaging with either (123)I or (131)I. The former is often preferred to avoid "stunning"-defined as a reduction in uptake of the therapeutic dose of (131)I caused by some form of cell damage from the diagnostic dosage of the radionuclide. Stunning could potentially reduce the therapeutic efficacy of (131)I given to ablate a post-thyroidectomy remnant. This study examines the outcomes of ablative (131)I therapy after diagnostic studies with either (123)I or (131)I to determine if the diagnostic dosages of these radionuclides used in our Thyroid Cancer Center reduce the efficacy of (131)I given for remnant ablation. METHODS: Fifty patients with nonmetastatic papillary or follicular carcinoma of the thyroid received total thyroidectomy; this was followed by thyroid hormone withdrawal to achieve a serum thyroid-stimulating hormone level in excess of 30 microIU/mL. They were divided prospectively into 2 groups. Group 1 had diagnostic imaging with 14.8 MBq of (123)I followed by thyroid remnant ablation with 3.7 GBq of (131)I. Group 2 had empiric ablation with the same 3.7-GBq (131)I dosage, but the preceding diagnostic scan was performed with 74 MBq of (131)I. Comparisons of equivalence of the 2 population samples and of the post-ablation outcomes were evaluated by chi(2) analysis. Successful ablation required a negative follow-up thyroid scan 6-8 mo after ablation and also an undetectable serum thyroglobulin level in the absence of antithyroglobulin antibodies. RESULTS: There was no significant difference between the 2 groups demographically, in tumor burden or stage, or in the post-thyroidectomy ablation rate (group 1, 81%; group 2, 74%; P > 0.05). CONCLUSION: If thyroid remnant stunning occurs due to 74 MBq (131)I used as a diagnostic agent before (131)I ablation, it has no significant clinical correlate, as it yields the same ablation rate as that which occurs after 14.8 MBq of (123)I used for imaging.

Bone mineral density (BMD) assessment of central skeletal sites from peripheral BMD and ultrasonographic measurements: an improved solution employing age and weight in type 3 regression.

The objective of this study was to develop a method whereby bone mineral density measurements of the heel and finger, as well as ultrasonographic measurements of calcaneal sound transmission, could identify individuals with a diagnosis of osteoporosis or osteopenia by the World Health Organization criteria for these diagnoses in the central skeleton (i.e., the lumbar spine (LS) and hip [femoral neck] [FN]). Two hundred and forty-four women in a university hospital laboratory setting had dual-energy X-ray absorptiometry measurements of bone mineral density (BMD) in the calcaneus, finger, hip, and spine, and quantitative ultrasound of the calcaneus. Regression equations were developed to predict central bone mineral T-scores from T-scores of peripheral measurements, adjusted by age and weight. Equations were validated by predicting the cut point for osteopenia at the lumbar spine and hip (T-score=-1.0). Ninety-five percent confidence intervals of the mean predicted LS or FN T-score from each peripheral site included -1.0. We conclude that our derived regression equations (taking into account interaction of peripheral BMD with patient age and weight) are useful for predicting T-scores in the central skeleton. This approach reduces the potential for misdiagnosis, which can result if one uses unadjusted peripheral T-scores, which are only moderately correlated with the central measurements of BMD.

Teletherapy and radiopharmaceutical therapy of painful bone metastases.

Bone pain from metastatic disease is most common in cancers of the breast, prostate, and lung. Despite the World Health organization algorithm for treating such pain, the outcomes are not often satisfactory. In 2005, there will be 3 radiopharmaceuticals available in the United States that can reduce or relieve bone pain caused by osteoblastic metastases with apparently equal efficacy. Phosphorus-32 as sodium phosphate, strontium-89 ( 89Sr) as the chloride, and samarium-153 lexidronam may all be given intravenously (and 32P also orally) in patients where bone scintigraphy demonstrates a metastatic lesion causing the patient's bone pain. Side effects are usually mild and include pancytopenia with leukocyte and platelet nadirs at approximately 50% of baseline, and a mild-to-moderate, but brief, increase in pain ("flare") in approximately 10% of patients. At least 1 of these radiotracers, 89Sr, has the availability to reduce the incidence of new bone metastases as well, but, given alone, none prolong life. In a few studies in which 89Sr has been combined with chemotherapy, prolongation of patient survival has been demonstrated. Many questions remain as to the optimization of use of this group of radiopharmaceuticals, including whether combinations of radiopharmaceuticals with each other, with bisphosphonates or with chemotherapy can improve the therapeutic outcomes even more.

Radiopharmaceuticals for the palliation of painful bone metastases.

Metastatic bone pain is prevalent in advanced cancer, and, despite a plethora of available therapies, effective palliation remains a clinical challenge. Bone-seeking radiopharmaceuticals are an often-overlooked but valuable analgesic option for select patients. These agents work by binding to hydroxyapatite at the tumor-bone interface of osteoblastic lesions, delivering therapeutic doses of radiation to closely circumscribed tissue regions. They have been shown to reduce pain and improve quality of life. Their safety, simplicity, convenience of administration, and cost-effectiveness make them suitable for hospice and palliative care settings.

The US national isotope program: current status and strategy for future success.

Since their introduction in the 1940s, peaceful use of stable isotopes and radioisotopes in the United States has expanded continuously. Today, new isotopes for diagnostic and therapeutic uses are not being developed, critical isotopes for national security are in short supply, and demand for isotopes critical to homeland security exceeds supply. While commercial suppliers, both domestic and foreign, can only meet specific needs, the nation needs a consistent, reliable supply of radioactive and stable isotopes for research, medical, security, and space power applications. The national isotope infrastructure, defined as both facilities and trained staff at national laboratories and universities, is in danger of being lost due to chronic underfunding. With the specific recommendations given herein, the US Department of Energy may realign and refocus its Isotope Program to provide a framework for a successful National Isotope Program.

Prevalence of adverse events to radiopharmaceuticals from 2007 to 2011.

UNLABELLED: We studied the changing patterns of radiopharmaceutical use and the incidence of adverse events (AEs) to PET radiopharmaceuticals, non-PET radiopharmaceuticals, and adjunctive nonradioactive pharmaceuticals in nuclear medicine from 2007 to 2011. METHODS: Fifteen academic institutions submitted quarterly reports of radiopharmaceutical use and AEs covering 2007-2011. RESULTS: 1,024,177 radiopharmaceutical administrations were monitored: 207,281 diagnostic PET, 803,696 diagnostic non-PET, and 13,200 therapeutic. In addition, 112,830 adjunctive nonradioactive pharmaceutical administrations were monitored. The annual use of bone scintigraphy and radiotracer therapies was unchanged. PET radiopharmaceutical use increased from 17% to 26% of diagnostic procedures (P < 0.01). The incidence of radiopharmaceutical AEs was 2.1/10(5) administrations, with no hospitalizations or deaths. CONCLUSION: From 2007 to 2011, PET studies increased, and therapeutic radiopharmaceutical use and bone scintigraphy were unchanged. Over 2 decades, the incidence of AEs has remained stable at 2.1-2.3/10(5) dosages.

The AEC/NRC 30 mCi rule: regulatory origins and clinical consequences for 131I remnant ablative doses.

BACKGROUND: Clinical and historical uncertainty exists surrounding the regulations of the Atomic Energy Commission/Nuclear Regulatory Commission (AEC/NRC) requiring patient hospitalization when (131)I activities exceed 30 mCi. This review investigates the sometimes disturbing regulatory and clinical origins and consequences of the use of this low, 30 mCi dose as a prescription for thyroid remnant ablation. SUMMARY: As early as in the 1940s, activities of (131)I between 30 and 200 mCi, often fractionated, were employed. The AEC deliberated from 1947 to the early 1960s before imposing as a license condition the requirement of hospitalizing patients until they contained <30 mCi of any byproduct material. The written AEC record throughout these years contains no supportive data to suggest safety issues requiring hospitalization at this activity level of (131)I. Yet the techniques for making the necessary calculations for determining radiation safety were available at this time. Declarations on the subject by nongovernmental bodies were misinterpreted as confirming such hospitalization as a legal requirement. The 30 mCi license condition was codified into NRC regulations in 1987 and was subsequently removed in 1997. Without any data, these U.S. regulatory agencies caused significant expense, inconvenience, and fear, affecting thyroid cancer patients and their families. This 30 mCi regulatory activity limit morphed, by a fortunate coincidence, into an acceptable ablative activity before there were solid confirmatory data. Studies on this 30 mCi ablative dose indicate that this activity was never associated with radiation health and safety issues, and was never more effective than higher ablative doses but led slightly more often to the need for a second (131)I dose. Nevertheless, the available data generally support the American Thyroid Association and Society of Nuclear Medicine and Molecular Imaging Guidelines, which indicate, without a treatment activity preference, that 30-100 mCi of (131)I provide adequate ablation. Follow-up data on the rates of recurrences, deaths, and second primary malignancies within this range of doses are unavailable. CONCLUSIONS: This history of unjustified governmental action and blind acceptance must remind the medical/radiation safety community to require solid data before ever again adopting baseless requirements. The 30 mCi dose should have never been employed as a requirement for hospitalization.

Radioiodine: the classic theranostic agent.

Radioiodine has the distinction of being the first theranostic agent in our armamentarium. Millennia were required to discover that the agent in orally administered seaweed and its extracts, which had been shown to cure neck swelling due to thyromegaly, was iodine, first demonstrated to be a new element in 1813. Treatment of goiter with iodine began at once, but its prophylactic value to prevent a common form of goiter took another century. After Enrico Fermi produced the first radioiodine, (128)I, in 1934, active experimentation in the United States and France delineated the crucial role of iodine in thyroid metabolism and disease. (130)I and (131)I were first employed to treat thyrotoxicosis by 1941, and thyroid cancer in 1943. After World War II, (131)I became widely available at a reasonable price for diagnostic testing and therapy. The rectilinear scanner of Cassen and Curtis (Science 1949;110:94-95), and a dedicated gamma camera invented by Anger (Nature 1952;170:200-201), finally permitted the diagnostic imaging of thyroid disease, with (131)I again the radioisotope of choice, although there were short-lived attempts to employ (125)I and (132)I for this purpose. (123)I was first produced in 1949 but did not become widely available until about 1982, 10 years after a production technique eliminated high-energy (124)I contamination. I continues to be the radioiodine of choice for the diagnosis of benign thyroid disease, whereas (123)I and (131)I are employed in the staging and detection of functioning thyroid cancer. (124)I, a positron emitter, can produce excellent anatomically correlated images employing positron emission tomography/computed tomography equipment and has the potential to enhance heretofore imperfect dosimetric studies in determining the appropriate administered activity to ablate/treat thyroid cancer. Issues of acceptable measuring error in thyroid cancer dosimetry and the role in (131)I therapy of tumor heterogeneity, tumor hypoxia, and kinetics must be overcome, and long-term outcome studies following (131)I given based on this new dosimetry must be completed before the nuclear medicine community will be able to predictably cure our thyroid cancer patients with this technology.

The problem of the patient with thyroglobulin elevation but negative iodine scintigraphy: the TENIS syndrome.

The available data upon which to act in caring for patients with functioning thyroid cancer and thyroglobulin elevation/negative iodine scintigraphy (TENIS) are imperfect, almost never coming from randomized, blinded studies. When the serum thyroglobulin exceeds 2-10 ng/mL, one should use the latest imaging equipment available to find metastatic disease, especially in areas in which it is potentially resectable, ie, neck, bone, and occasionally brain, and collaborate with an experienced surgeon in removing such metastases. If one cannot locate operable metastases and/or tumor location remains elusive, empiric high-dose (131)I therapy, preceded by dosimetry, should be considered. There are no randomized studies to prove that this treatment prolongs life, although there is definite evidence of cell killing, because the serum thyroglobulin level frequently diminishes after radioiodine therapy. In selected cases External beam radiotherapy will be helpful when the tumor has been located but cannot be fully removed, for example, with invasion of the trachea, spine, or muscles. There are several tyrosine kinase inhibitors that have shown some effectiveness against the TENIS syndrome, but these should ideally be used in the context of a clinical trial. Tyrosine kinase inhibitor drugs should be preferred to conventional chemotherapy at this time; data on lenalidominde have only appeared in abstract form. The return of NIS function, to permit functioning thyroid cancer with the TENIS syndrome to again concentrate therapeutic amounts of (131)I, remains an elusive goal, with few drugs showing real promise. Gene therapy to restore the function of the NIS gene and enhance cellular immunomodulatory and tumor suppressive activity has not yet succeeded clinically. Physicians caring for patients with the TENIS syndrome are urged to enter them into clinical therapeutic studies whenever possible.