Abstract and Introduction
Background: The modern era of radioiodine (I-131) theranostics for metastatic differentiated thyroid cancer requires us to rationalize the role of traditional empiric prescription in nonmalignant thyroid disease. We currently practice empiric I-131 prescription for treatment of hyperthyroidism. This study aims to assess outcomes after treatment of hyperthyroidism by empiric I-131 prescription at our centre, evaluate factors that impact on outcomes and prescribing practice, and gain insight into whether there is a place for theranostically-guided prescription in hyperthyroidism.
Patients and Methods: A retrospective review was undertaken of all patients with Graves' disease, toxic multinodular goitre (MNG) and toxic adenoma treated with I-131 between 2016 and 2021. Associations between clinical or scintigraphic variables and remission (euthyroid or hypothyroid) or persistence of hyperthyroidism at follow-up were performed using standard t test as well as Pearson's product correlation.
Results: Of 146 patients with a mean follow-up of 13.6 months, 80.8% achieved remission of hyperthyroidism. This was highest in toxic nodules (90.1%), compared with Graves' disease (73.8%) and toxic MNG (75.5%). In patients with Graves' disease, higher administered activity was associated with remission (p = .035). There was a weak inverse correlation between the Tc-99m pertechnetate uptake vs prescribed activity in Graves' disease (r = −0.33; p = .009). Only one patient (0.7%) had an I-131 induced flare of thyrotoxicosis.
Conclusion: Traditional empiric I-131 prescription is a safe and effective treatment of hyperthyroidism and suitable for most patients. However, there may be a role for personalized I-131 prescription by theranostic guidance in selected patients with high thyroid hyperactivity.
Scientific progress in radioiodine (I-131) theranostics presents an ethical conundrum: given our limited resources, should hyperthyroidism be treated with the same personalized finesse as metastatic differentiated thyroid cancer? Intuitively, the answer should be "yes"; however, the daily realities of a resource-limited clinic might skew our response to "perhaps."
Hyperthyroidism is common, with a population prevalence of the combined aetiologies of Graves' disease, toxic adenoma and toxic multinodular goitre of up to 1.2%. The sequelae of uncontrolled hyperthyroidism include osteoporosis, atrial fibrillation, as well as risk of miscarriage and pregnancy complications. Hence, noninvasive definitive treatment with radioactive iodine is often undertaken.[1,2]
I-131 for treatment of hyperthyroidism has been empirically prescribed for over 70 years. This traditional practice of empiric prescription neglects a fundamental radiobiologic perspective, resulting in today's lack of consensus recommendation regarding administered activity, with both fixed and dosimetric approaches described.[1–4] Prescription of a fixed or "ablative" activity, has been shown to be effective in relieving hyperthyroidism at the expense of high rates of hypothyroidism. Dosimetrically guided I-131 prescription, commonly with Marinelli's formula, uses patient-specific parameters such as gland size and radioiodine kinetics to prescribe intended mean radiation absorbed doses (Gy) depending on aetiology and treatment intent.[5,6] A personalized dosimetric approach is most in keeping with the "as low as reasonable achievable (ALARA)" radiation safety principle and the prospect of achieving euthyroidism is attractive. However, personalized predictive dosimetry i.e., theranostics, is resource intensive and has not yet been shown to be superior to empiric prescription to achieve long-term euthyroidism.[7,8] Limitations in the theranostic approach include uncertainties in simulated iodine kinetics, gland size measurements and lack of agreement in the literature about dose(Gy)-response thresholds, with a recent meta-analysis highlighting the heterogeneity in absorbed doses ranging from 55 to 407Gy. This meta-analysis suggested a thyroid absorbed dose threshold of 150 Gy to achieve euthyroidism (38% of patients) and/or hypothyroidism (74% of patients). A dose–response relationship was identified where a higher absorbed dose of 300 Gy was associated with the highest response rate to achieve either euthyroidism or hypothyroidism (88% of patients).
It is standard practice in most institutions for physicians to prescribe empiric I-131 activities based on clinical circumstances, gland size and thyroid scintigraphy.[10,11] However, assessment of thyroid activity by scintigraphy using technetium-99m (Tc-99m) pertechnetate has been challenging due to its different kinetics and imaging characteristics to I-131.[6,12]
Our institution has I-131 theranostic expertise for metastatic differentiated thyroid cancer. To date we have not yet applied theranostics to I-131 treatment of hyperthyroidism, which has been prescribed empirically in line with American Thyroid Association (ATA) guidelines, limited to a maximum of 15 mCi (555MBq) due to local outpatient regulatory requirements. Our centre bases empiric prescription on disease aetiology, 20-min Tc-99m pertechnetate uptake measurement, gland size (where available) and clinical context, for example, if the referring endocrinologist and patient specifically request an "ablative" treatment a higher activity will generally be prescribed. This study aims to interrogate our local practice and evaluate the outcomes of patients treated in our centre with empirically prescribed I-131 for hyperthyroidism. In doing so, we hope to gain insight into factors that impact the efficacy of our empirically prescribed I-131 with a goal to improve future local practice. We would also like to identify a subset of patients for whom the resource-intensive process of theranostically guided I-131 activity prescription should be considered.
Patients and Methods
A retrospective chart review of all patients treated with I-131 for hyperthyroidism at a single public tertiary referral centre between January 2016 and June 2021 was performed. A standard data collection proforma was used to collect clinical information from request cards, progress notes stored on the radiology reporting database and the hospital electronic medical record. Information obtained included patient age at time of treatment, sex, aetiology of hyperthyroidism, thyroid scintigraphy results, antithyroid drug treatment, and thyroid function tests before treatment. Available thyroid scintigraphy studies using technetium-99m (Tc-99m) pertechnetate were reviewed to confirm diagnosis.
All thyroid scintigraphy and uptake calculations performed in our centre conformed to standard protocol. Static images were taken of the thyroid at 20 min post intravenous administration of Tc-99m pertechnetate, using Siemens gamma cameras Symbia T16 and Intevo Bold (Siemens Healthcare). The 20-min percentage thyroid pertechnetate uptake was calculated, taking into consideration residual activity within the injection syringe.
An activity of I-131 was then empirically prescribed by a nuclear medicine physician after reviewing the thyroid scintigraphy results and a detailed consultation with the patient including formal consent process. Empiric I-131 activity prescription generally ranged from 5 to 15 mCi (185-555MBq). The empiric prescription was determined depending on aetiology of hyperthyroidism, scintigraphic appearances and 20-min uptake of Tc-99m pertechnetate, gland size and clinical context.
Follow-up data was obtained from the local electronic medical record, as well as available correspondence from private referrers.
The study was part of the Royal Melbourne Hospital Quality Assurance process and was favourably evaluated by the Office for Research, approval number QA2021027.
The primary endpoint of the study was the thyroid status outcome, either hyperthyroidism remission or persistence after treatment with I-131. Remission was defined as either euthyroidism or hypothyroidism at time of follow-up. Persistence of hyperthyroidism pertained to patients who continued to require antithyroid drug (ATD) therapy or had thyroid-stimulating hormone (TSH) suppression (in the absence of thyroid hormone replacement) at the time of follow-up.
Continuous variables are presented as mean ± standard deviation (SD) or range where appropriate. Univariate analysis with paired t test was used to test for an association between clinical or scintigraphic variables (age, sex, follow-up time, anti-thyroid drug treatment parameters, pretreatment thyroid function test results, percentage pertechnetate uptake, activity of I-131 administered) and the thyroid status outcome. Multivariate analysis was performed using binomial regression including only those variables which were significant in the univariate analysis or clinically relevant. Pearson's product correlation coefficient was used to test for association between the 20-min Tc-99m pertechnetate uptake and activity of I-131 prescribed. These statistical tests were performed using R (R Core Team, 2021). A p-value < .05 was considered statistically significant.
In an attempt to identify a dose(Gy)-response relationship, we performed a dosimetric sub-analysis on our cohort of Graves' disease. We applied the following equation described by the European Association of Nuclear Medicine (EANM) Therapy Committee to approximate the thyroid mean absorbed dose:
where A$A$ (MBq) is the prescribed I-131 activity, Ē (Gy.g/MBq.day) is the mean energy deposited per decay of radioiodine for a given thyroid size, M is the thyroid mass (g) and τ (day) is the thyroid I-131 Residence Time also known as the Time Integrated Activity Coefficient. We applied population averages for Graves' disease thyroid mass and its Residence Time obtained by meta-analyses of published data (Supporting Information Data). Tissue density was assumed to be 1.04 g/ml. This dosimetric sub-analysis was not performed for toxic adenoma or multinodular goitre due to the widely variable thyroid sizes which preclude reliable analysis.
Clin Endocrinol. 2022;97(1):124-129. © 2022 Blackwell Publishing