Variations in Radioiodine Therapy in Europe: Decision-Making after Total Thyroidectomy.

The role of radioiodine therapy (RIT) (used as ablation therapy or adjuvant therapy) following total thyroidectomy for differentiated thyroid cancer (DTC) changed. Major revisions of the American Thyroid Association (ATA) Guidelines in 2015 resulted in significant differences in treatment recommendations in comparison to the European Association of Nuclear Medicine (EANM) 2008 guidelines. Recently, we presented the effects on daily practice for RIT among Swiss Nuclear Medicine centres. We now performed a study at the European level and hypothesized that there is also considerable variability among European experts. We performed a decision-tree-based analysis of management strategies from all members of the EANM thyroid committee to map current practice among experts. We collected data on whether or not RIT is administered, on which criteria these decisions are based and collected details on treatment activities and patient preparation. Our study shows discrepancies for low-risk DTC, where "follow-up only" is recommended by some experts, while RIT with significant doses is used by other experts. E.g., for pT1b tumours without evidence of metastases, the level of agreement for the use of RIT is as low as 50%. If RIT is administered, activities of I-131 range from 1.1 GBq to 3.0 GBq. In other constellations (e.g., pT1a), experts diverge from current clinical guidelines as up to 75% administer RIT in certain cases. For intermediate and high-risk patients, RIT is generally recommended. However, dosing and treatment preparation (rhTSH vs. thyroid hormone withdrawal) vary distinctly. In comparison to the Swiss study, the general level of agreement is higher among the European experts. The recently proposed approach on the use of RIT, based on integrated post-surgery assessment (Martinique article) and results of ongoing prospective randomized studies are likely to reduce uncertainty in approaching RIT treatment. In certain constellations, consensus identified among European experts might be helpful in formulating future guidelines.

Real-World Efficacy and Safety of Multi-Tyrosine Kinase Inhibitors in Radioiodine Refractory Thyroid Cancer.

Background: The management of patients with locally advanced or metastatic differentiated thyroid cancer (DTC) that is refractory to radioiodine (RAI) remains a therapeutic challenge. The multi-tyrosine kinase inhibitors (TKIs) sorafenib and lenvatinib have been approved based on phase 3 clinical trials. Patients and Methods: We aimed at describing the efficacy and safety of TKI treatment of RAI-refractory DTC in a real-world setting at six German referral centers. One hundred and one patients with locally advanced or metastatic RAI-refractory DTC treated with sorafenib, lenvatinib, and/or pazopanib were included. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated by using the Kaplan-Meier method. Results: Ninety-seven of 101 patients had progressive disease before TKI initiation. The median PFS for first-line treatment with sorafenib (n = 33), lenvatinib (n = 53), and pazopanib (n = 15) was 9 (95% confidence interval 5.2-12.8), 12 (4.4-19.6), and 12 months (4.4-19.6), respectively. The median OS for first-line treatment was 37 (10-64) for sorafenib, 47 (15.5-78.5) for lenvatinib, and 34 months (20.2-47.8) for pazopanib. Serious complications (e.g., hemorrhage, acute coronary syndrome, and thrombosis/venous thromboembolism) occurred in 16 out of 75 (21%) patients taking lenvatinib, in 3 out of 42 (7%) patients taking sorafenib, and in 3 out of 24 (13%) patients taking pazopanib. Conclusions: Sorafenib, lenvatinib, and pazopanib are effective treatment options in the majority of patients with RAI-refractory DTC. The PFS and six-month survival rate in patients treated with lenvatinib und pazopanib appear to compare favorably with sorafenib in the first-line treatment setting. However, a more advanced disease stage at treatment initiation in sorafenib- and pazopanib-treated patients in the era before TKI-approval and the retrospective nature of this study precludes a direct comparison of TKIs.

Questions and Controversies in the Clinical Application of Tyrosine Kinase Inhibitors to Treat Patients with Radioiodine-Refractory Differentiated Thyroid Carcinoma: Expert Perspectives.

Notwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue.

Differentiated thyroid cancer patients potentially benefitting from postoperative I-131 therapy: a review of the literature of the past decade.

BACKGROUND: Since the last major review of literature on the benefit of I-131 therapy, the continued debate on postoperative radioiodine treatment (RIT) in differentiated thyroid carcinoma (DTC) has led to a number of further studies being published on this topic. AIM: The aim of the present paper is to report the results of an updated structured review of the literature pertaining to the prognostic benefits of postoperative RIT in DTC in terms of recurrence-free and disease-specific survival. METHODS: A systematic search of the literature was performed using the Medline and Cochrane Library database. The search period started in August 2007 and ended on December 6, 2017. Search terms used included "differentiated thyroid cancer" and "radioiodine therapy" amended by specific terms for recurrence/disease-free survival or overall and/or cancer-specific survival. Included in the search were systematic reviews, randomized clinical trials, or cohort studies consisting of both patients who underwent postoperative RIT and patients treated by surgery alone. RESULTS: Eleven retrospective cohort studies met the defined inclusion criteria and were included in the present review. Results of the studies were mixed, with some showing a benefit of RIT even in microcarcinoma whereas others showed no benefit at all. CONCLUSION: Literature published in the last decade offers data that support adjuvant postoperative RIT in DTC patients with a tumor diameter exceeding 1 cm. Therefore, at least until randomized prospective studies prove otherwise, the prescription of adjuvant I-131 treatment to all DTC patients with a primary tumor diameter exceeding 1 cm remains a reasonable option.

Controversies, Consensus, and Collaboration in the Use of 131I Therapy in Differentiated Thyroid Cancer: A Joint Statement from the American Thyroid Association, the European Association of Nuclear Medicine, the Society of Nuclear Medicine and Molecular Imaging, and the European Thyroid Association.

BACKGROUND: Publication of the 2015 American Thyroid Association (ATA) management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer was met with disagreement by the extended nuclear medicine community with regard to some of the recommendations related to the diagnostic and therapeutic use of radioiodine (131I). Because of these concerns, the European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging declined to endorse the ATA guidelines. As a result of these differences in opinion, patients and clinicians risk receiving conflicting advice with regard to several key thyroid cancer management issues. SUMMARY: To address some of the differences in opinion and controversies associated with the therapeutic uses of 131I in differentiated thyroid cancer constructively, the ATA, the European Association of Nuclear Medicine, the Society of Nuclear Medicine and Molecular Imaging, and the European Thyroid Association each sent senior leadership and subject-matter experts to a two-day interactive meeting. The goals of this first meeting were to (i) formalize the dialogue and activities between the four societies; (ii) discuss indications for 131I adjuvant treatment; (iii) define the optimal prescribed activity of 131I for adjuvant treatment; and (iv) clarify the definition and classification of 131I-refractory thyroid cancer. CONCLUSION: By fostering an open, productive, and evidence-based discussion, the Martinique meeting restored trust, confidence, and a sense of collegiality between individuals and organizations that are committed to optimal thyroid disease management. The result of this first meeting is a set of nine principles (The Martinique Principles) that (i) describe a commitment to proactive, purposeful, and inclusive interdisciplinary cooperation; (ii) define the goals of 131I therapy as remnant ablation, adjuvant treatment, or treatment of known disease; (iii) describe the importance of evaluating postoperative disease status and multiple other factors beyond clinicopathologic staging in 131I therapy decision making; (iv) recognize that the optimal administered activity of 131I adjuvant treatment cannot be definitely determined from the published literature; and (v) acknowledge that current definitions of 131I-refractory disease are suboptimal and do not represent definitive criteria to mandate whether 131I therapy should be recommended.

EANM Dosimetry Committee series on standard operational procedures for pre-therapeutic dosimetry II. Dosimetry prior to radioiodine therapy of benign thyroid diseases.

The EANM Dosimetry Committee Series "Standard Operational Procedures for Pre-Therapeutic Dosimetry" (SOP) provides advice to scientists and clinicians on how to perform patient-specific absorbed dose assessments. This particular SOP describes how to tailor the therapeutic activity to be administered for radioiodine therapy of benign thyroid diseases such as Graves' disease or hyperthyroidism. Pretherapeutic dosimetry is based on the assessment of the individual (131)I kinetics in the target tissue after the administration of a tracer activity. The present SOP makes proposals on the equipment to be used and guides the user through the measurements. Time schedules for the measurement of the fractional (131)I uptake in the diseased tissue are recommended and it is shown how to calculate from these datasets the therapeutic activity necessary to administer a predefined target dose in the subsequent therapy. Potential sources of error are pointed out and the inherent uncertainties of the procedures depending on the number of measurements are discussed. The theoretical background and the derivation of the listed equations from compartment models of the iodine kinetics are explained in a supplementary file published online only.

Radioiodine for remnant ablation and therapy of metastatic disease.

Radioiodine is considered an effective and low-risk therapy modality of advanced differentiated thyroid cancer. For patients without lymph-node or distant metastases and low stages of the primary tumor, debate is ongoing about the necessity of thyroid remnant tissue ablation in an adjuvant setting. On the basis of evidence from retrospective studies, and until results of ongoing controlled prospective randomized trials become available, (131)I ablation of remnant thyroid tissue in patients with primary tumors >1 cm is advisable. For thyroid remnant ablation, individual dosimetry is not obligatory. By contrast, the effectiveness of (131)I therapy of locally advanced and/or metastatic disease can be improved by individual dosimetry. For practical reasons, an approach delivering the maximal possible radiation dose to the tumor without exceeding a critical blood dose of approximately 2 Gy seems advantageous. The availability of recombinant human TSH (rhTSH) has improved the quality of life of patients and reduces the radiation exposure of healthy nonthyroid tissue compared with TSH stimulation through levothyroxine withdrawal. In patients with distant metastases, rhTSH stimulation is possible only in off-label use, from which especially elderly and frail patients may benefit, as they most severely suffer from hypothyroidism caused by thyroid hormone withdrawal.

Dosimetry and thyroid cancer: the individual dosage of radioiodine.

Adjuvant therapy of differentiated thyroid cancer with radioactive iodine ((131)I) is a standard procedure for the ablation of remnant thyroid tissue following surgery and for the treatment of iodine-avid metastases. Presently, there are two dosimetric concepts for the treatment of thyroid cancer using radioiodine: a) the bone marrow dose limited approach and b) lesion-based dosimetry. Both concepts and their clinical applications are described. In addition, the use of (124)I as a diagnostic and dosimetric agent is discussed. Treatment of children and adolescents with radioiodine requires special precautions; individualized approaches in this setting are reviewed. The limitations of treatments aiming at high absorbed doses are addressed as well as the doses to normal organs. Finally, new concepts for further elaborating the potential of thyroid cancer treatment using (131)I are introduced.

Potency and tolerance of calcitonin stimulation with high-dose calcium versus pentagastrin in normal adults.

OBJECTIVE: The objectives of the study was to compare pentagastrin- and calcium-stimulated serum human calcitonin (hCT) levels for nonsmoking healthy adults without evidence of thyroid disorders and determine reference ranges of basal and pentagastrin- and calcium-stimulated serum hCT levels. DESIGN: This was a healthy volunteer study including within-group and intergroup comparisons. SETTING: The study was conducted at a tertiary referral center. SUBJECTS: Subjects included 50 healthy, nonsmoking volunteers (25 female; aged 22-57 yr) without evidence of thyroid abnormality. INTERVENTIONS: hCT was measured using a calcitonin two-site automated chemiluminescent immunometric assay (the most common hCT assay in clinical practice) in serum samples obtained before and 2, 5, and 15 min after iv stimulation using pentagastrin, 0.5 microg/kg body weight, or calcium gluconate, 2.5 mg/kg. MAIN OUTCOME MEASURES: Reference ranges for basal, unstimulated, and pentagastrin- or calcium-stimulated hCT and pentagastrin and calcium tolerability in healthy adults were measured. RESULTS: The 95th percentile basal hCT values did not differ between males and females (5.0 vs. 5.7 pg/ml). The 95th percentile maximal stimulated hCT values rose distinctly after pentagastrin (peak men, 37.8 pg/ml; women, 26.2 pg/ml) and even more so after calcium (peak men, 131.1 pg/ml, women, 90.2 pg/ml). No hCT increase was detected in four of 25 men and 12 of 25 women after pentagastrin vs. none of 24 men and two of 18 women after calcium. Calcium was associated with fewer and less intense adverse effects than was pentagastrin. CONCLUSION: High-dose calcium is a more potent and better-tolerated hCT stimulator than is pentagastrin. The reference ranges for basal and stimulated hCT established via automated chemiluminescent assay were lower than those reported for other assays.

Changing trends of incidence and prognosis of thyroid carcinoma in lower Franconia, Germany, from 1981-1995.

BACKGROUND: A population-based registry (PBR) in Lower Frankonia in southern Germany was conducted to evaluate the changes of incidence and prognosis of thyroid carcinoma (TC) in this area. METHODS: The study comprised 476 patients with differentiated thyroid carcinoma (DTC) from Lower Franconia (1.3 x 10(6) inhabitants) registered between 1981 and 1995 at the Regional Tumor Center. The incidence was assessed with respect to gender, age, histology, tumor stage, lymph node involvement and distant metastases in 5-year intervals (1981-1985, 1986-1990, and 1991-1995). RESULTS: An increasing rate of papillary thyroid carcinoma PTC and a decreasing rate of follicular thyroid carcinoma (FTC) were observed over the three time periods (1981-1985, 1986-1990, and 1991-1995). The overall incidence revealed no significant change with time for both females from 3.22 to 3.25 and 3.73 and males (1.07 to 1.54 and 1.69) between the three time periods. There was a significant improvement in outcome of patients with DTC with respect to life expectancy. CONCLUSIONS: Iodine prophylaxis does influence the distribution of the histologic types of thyroid cancer and leads to an increase in the ratio of papillary versus follicular carcinoma. Our study supports the hypothesis that the benefits of correcting iodine deficency outweigh the risks of iodine supplementation.