Clinical guidance for radioiodine refractory differentiated thyroid cancer

Prognosis from differentiated thyroid cancer is worse when the disease becomes refractory to radioiodine. Until recently, treatment options have been limited to local therapies such as surgery and radiotherapy, but the recent availability of systemic therapies now provides some potential for disease control. Multitargeted kinase inhibitors (TKIs) including lenvatinib and sorafenib have been shown to improve progression‐free survival in phase III clinical trials, but are also associated with a spectrum of adverse effects. Other TKIs have been utilized as “redifferentiation” agents, increasing sodium iodide symporter expression in metastases and thus restoring radioiodine avidity. Some patients whose disease progresses on initial TKI therapy will still respond to a different TKI and clinical trials currently in progress will clarify the best options for such patients. As these drugs are not inexpensive, care needs to be taken to minimize not only biological but also financial toxicity. In this review, we examine the basic biology of radioiodine refractory disease and discuss optimal treatment approaches, with specific focus on choice and timing of TKI treatment. This clinical field remains fluid, and directions for future research include exploring biomarkers and considering adjuvant TKI use in certain patient groups.     

Clinical Prognostic Score for Predicting Disease Remission with Differentiated Thyroid Cancers

Background: Differentiated thyroid cancer is the most common endocrine malignancy with a generally good prognosis. Knowing long-term outcomes of each patient helps management planning. The study was conducted to develop and validate a clinical prognostic score for predicting disease remission in patients with differentiated thyroid cancer based on patient, tumor and treatment factors. Materials and Methods: A retrospective cohort study of 1,217 differentiated thyroid cancer patients from two tertiary-care hospitals in the Northeast of Thailand was performed. Associations between potential clinical prognostic factors and remission were tested by Cox proportional-hazards analysis in 852 patients (development cohort). The prediction score was created by summation of score points weighted from regression coefficients of independent prognostic factors. Risks of disease remission were estimated and the derived score was then validated in the remaining 365 patients (validation cohort). Results: During the median follow-up time of 58 months, 648 (76.1%) patients in the development cohort had disease remission. Five independent prognostic factors were identified with corresponding score points: duration from thyroid surgery to 131I treatment (0.721), distant metastasis at initial diagnosis (0.801), postoperative serum thyroglobulin level (0.535), anti-thyroglobulin antibodies positivity (0.546), and adequacy of serum TSH suppression (0.293). The total risk score for each patient was calculated and three categories of remission probability were proposed: ≤1.628 points (low risk, 83% remission), 1.629-1.816 points (intermediate risk, 87% remission), and ≥1.817 points (high risk, 93% remission). The concordance (C-index) was 0.761 (95% CI 0.754-0.767). Conclusions: The clinical prognostic scoring model developed to quantify the probability of disease remission can serve as a useful tool in personalized decision making regarding treatment in differentiated thyroid cancer patients.     

Internal radiation therapy: a neglected aspect of nuclear medicine in the molecular era

With increasing evidence, internal radiation therapy, also known as brachytherapy, has become a neglected aspect of nuclear medicine in the molecular era. In this paper, recent developments regarding internal radiation therapy, including developments in radioiodine-131 (¹³¹I) and thyroid, radioimmunotherapy (RIT) for non-Hodgkin lymphoma (NHL), and radiopharmaceuticals for bone metastases. Relevant differences and status of their applications in China were mentioned as well. These molecular mediated internal radiation therapies are gaining increasing importance by providing palliative and curative treatments for an increasing number of diseases and becoming one of the important parts of molecular nuclear medicine.     

分化型甲状腺癌^131I疗效影响因素分析

目的对分化型甲状腺癌（DTC）术后患者实施放射性碘（^131I）清除残余甲状腺（清甲）治疗,分析影响清甲效果的相关因素。方法收集DTC术后接受^131I清甲治疗患者的临床资料。采用BinaryLogistic回归分析和x^2检验,分析患者性别和年龄、DTC的病理学类型和有无转移、甲状腺残余组织大小、血清促甲状腺激素（TSH）水平、甲状腺摄碘率和^131I治疗剂量对清甲疗效的影响。结果共收集183例患者资料,其中一次清甲完全者109例,占59．56％。BinaryLogistic回归分析表明,残余甲状腺大小和^131I治疗剂量分别是影响清甲效果的主要因素（Wald=8．59,P=0．003;Wald=6．40,P=0．011）。x^2检验结果显示,与血清TSH水平≥30uIU／mL患者比较,血清TSH水平〈30uIU／mL患者的清甲效果较差（x^2=7．291,P=0．007）;而血清TSH水平〈60uIU／mL与≥60uIU／mL患者间清甲效果比较,差异无统计学意义（P〉0．05）。结论在分化型甲状腺癌患者的^131I清甲治疗中,残余甲状腺大小和^131I治疗剂量是影响清甲效果的主要因素。血清TSH水平≥30uIU／mL者的清甲疗效较好,而过高的血清TSH水平则并不能使清甲效果进一步提高。     

Analysis of demographic and clinical factors affecting the outcome of radioiodine therapy in patients with hyperthyroidism

Introduction

The influence of demographic and clinical factors on the outcome of ¹³¹I therapy in hyperthyroid patients has been examined, based on a retrospective evaluation of results obtained in patients submitted to ¹³¹I treatment at the Department of Nuclear Medicine and Oncological Endocrinology, Medical University of Lodz (Province Hospital, Zgierz). The goal of the study was to analyse such factors as the age and sex of patients, disease duration, as well as the hormonal status before ¹³¹I application, which could have an influence on the effects of therapy with radioiodine ¹³¹I.

Material and methods

The study involved 500 randomly selected patients with hyperthyroidism, treated with ¹³¹I radioiodine. The following 3 groups were defined: group 1 – patients with multinodular goitre (MNG), n = 200; group 2 – patients with a single autonomous nodule of the thyroid (AFTN), n = 100; group 3 – patients with Graves’ disease (GD), n = 200. The local ethics committee (in the Polish Mother''s Memorial Hospital – Research Institute, Lodz) approved the study.

Results

The obtained results indicate that the efficacy of therapy with ¹³¹I applied in patients with MNG, AFTN and GD does not depend on either patient sex or patient age. The length of antithyroid treatment before ¹³¹I therapy onset does not appear to have any effect on the therapy outcome, and the baseline thyrotropin concentration seems to be significant only in the case of GD.

Conclusions

The analysed demographic factors do not affect the outcome of ¹³¹I therapy in hyperthyroidism.     

Pharmacokinetics and biodistribution of a small radioiodine labeled nerve growth factor fragment

Nerve growth factor (NGF) exerts various actions on neuronal and non-neuronal tissues and has potential therapeutic utility, but difficulties in using the whole protein have stimulated interest in small NGF fragments. We radioiodinated a small cyclic peptide derived from NGF using the Bolton-Hunter method [125I-C(92-96)], and confirmed binding to high affinity NGF receptors by cross-linkage analysis. Pharmacokinetic characteristics in intravenously injected mice were T 1/2 alpha 5.2 min, T 1/2beta 121.3 min, clearance 11.8+/-0.5 ml/min, and volume of distribution 69.7+/-4.6 ml. Dose-proportionate increases in areas-under-curve and peak-concentrations indicated linear pharmacokinetics. Biodistribution data revealed that clinically relevant doses allowed C(92-96) accumulation sufficient to elicit biological responses in receptor expressing organs including the lungs, liver, spleen, and pancreas.     

Measures of Thyroid Function among Belarusian Children and Adolescents Exposed to Iodine-131 from the Accident at the Chernobyl Nuclear Plant

Background: Thyroid dysfunction after exposure to low or moderate doses of radioactive iodine-131 (¹³¹I) at a young age is a public health concern. However, quantitative data are sparse concerning ¹³¹I-related risk of these common diseases.Objective: Our goal was to assess the prevalence of thyroid dysfunction in association with ¹³¹I exposure during childhood (≤ 18 years) due to fallout from the Chernobyl accident.Methods: We conducted a cross-sectional analysis of hypothyroidism, hyperthyroidism, autoimmune thyroiditis (AIT), serum concentrations of thyroid-stimulating hormone (TSH), and autoantibodies to thyroperoxidase (ATPO) in relation to measurement-based ¹³¹I dose estimates in a Belarusian cohort of 10,827 individuals screened for various thyroid diseases.Results: Mean age at exposure (± SD) was 8.2 ± 5.0 years. Mean (median) estimated ¹³¹I thyroid dose was 0.54 (0.23) Gy (range, 0.001–26.6 Gy). We found significant positive associations of ¹³¹I dose with hypothyroidism (mainly subclinical and antibody-negative) and serum TSH concentration. The excess odds ratio per 1 Gy for hypothyroidism was 0.34 (95% CI: 0.15, 0.62) and varied significantly by age at exposure and at examination, presence of goiter, and urban/rural residency. We found no evidence of positive associations with antibody-positive hypothyroidism, hyperthyroidism, AIT, or elevated ATPO.Conclusions: The association between ¹³¹I dose and hypothyroidism in the Belarusian cohort is consistent with that previously reported for a Ukrainian cohort and strengthens evidence of the effect of environmental ¹³¹I exposure during childhood on hypothyroidism, but not other thyroid outcomes.     

^131I治疗甲亢604例近期疗效分析

目的分析^131I治疗甲亢近期临床疗效。方法根据甲状腺质量和最高吸碘率等给予604例甲亢患者个性化^131I治疗,^131I于治疗后1、3、6、12个月随访,对甲亢、Graves眼病、甲亢性心脏病、低钾周期性麻痹、谷丙转氨酶升高、粒细胞减少及甲状腺大小等的转归进行回顾性分析。结果痊愈374例（61．9％）,部分缓解101例（16．8％）,甲减112例（18．5％）,无效17（2．8％）,总有效率为97．2％,治愈率为80．4％。^131I治疗Graves眼病总有效率83．7％,治疗甲亢性心脏病总有效率95．6％,同时可以缓解低钾周期性麻痹症状,改善肝功能,升高粒细胞,缩小甲状腺。结论^131I治疗甲亢及其伴发症安全有效,但要注意甲减等并发症的发生。     

Endogenous expression of the sodium iodide symporter mediates uptake of iodide in murine models of colorectal carcinoma

The sodium iodide symporter (NIS) mediates iodide uptake into the thyroid. Because of this mechanism, differentiated thyroid cancer is susceptible for radioiodine therapy. Functional NIS expression in extrathyroidal tumors has been reported mainly in breast cancer. We screened colorectal tumors for NIS expression and investigated the mechanisms regulating NIS activity. Cell lines were screened for iodide uptake in vitro and NIS expression was evaluated by real‐time RT‐PCR, immunocytochemistry and immunoblotting. Iodide and pertechnetate uptake were evaluated in allograft tumors by biodistribution studies and scintigraphy. Tumors of transgenic mouse models for colorectal cancer harboring mutations in the oncogenes KRAS, β‐catenin or the tumor‐suppressor gene adenomatous‐polyposis coli (APC) were screened for NIS expression by RT‐PCR. In vitro, functional NIS activity was detected in murine CMT93 rectal carcinoma cells and NIS expression was verified on mRNA and protein level. Inhibition of tyrosine kinases increased iodide uptake. Inhibition of tyrosine phosphatases decreased iodide uptake. In vivo, functional NIS expression was preserved in CMT93 tumors and tumor uptake could be enhanced by treatment of mice with tyrosine kinase inhibitors. In transgenic murine models of colorectal cancer, 14% of endogenous tumors expressed elevated levels of NIS mRNA. We conclude that NIS is functionally expressed in a subset of murine colorectal tumors and its activity is regulated by tyrosine phosphorylation. Therefore, with specific tyrosine kinase inhibition, these tumors might be susceptible for radioiodine treatment. Further studies are justified to identify the specific pathways regulating NIS activity and to transfer these findings to human cell lines and tissues. © 2009 UICC     

Graves'病(GD)放射性碘治疗效果的影响因素

 目的  探讨弥漫性毒性甲状腺肿伴甲状腺功能亢进症(Graves' disease, GD)患者首次放射碘治疗效果的影响因素。方法  选择复旦大学附属中山医院行放射碘治疗的GD患者203例,治疗前分别记录其性别、年龄、甲亢病程、是否应用抗甲状腺药物(antithyroid drug, ATD)、ATD应用时间,检测甲状腺激素包括游离三碘甲腺原氨酸(free triiodothyronine, FT3)、游离甲状腺素(free thyroxine, FT4)、促甲状腺激素(thyroid-stimulating hormone, TSH)以及甲状腺相关抗体包括抗甲状腺球蛋白抗体(antithyroglobulin antibody, TGAb)、抗甲状腺过氧化物酶抗体(anti-thyroid peroxidase antibody, TPOAb)、促甲状腺素受体抗体(thyrotrophin receptor antibody, TRAb)。全部患者行甲状腺超声,计算甲状腺体积,行摄碘率检查并记录24 h 131I摄取率,根据甲状腺显像结果给予相应剂量的放射碘口服。结果  放射碘治疗后随访1年,134例(66%)治疗有效(甲功正常和甲减),69例(34%)治疗无效(甲亢)。用非条件Logistic回归分析影响因素发现,单位体积甲状腺放射碘剂量与GD患者放射碘治疗效果独立相关(P＝0.013, OR＝4.225, 95%CI: 1.362~13.016),而性别、年龄、体重指数、甲亢病程、是否ATD治疗、ATD应用时间、FT3、TPOAb、TRAb及24 h摄碘率均与治疗效果无显著相关性。结论  单位体积甲状腺的放射碘剂量直接影响GD患者治疗的效果,患者甲状腺体积较大时建议适当增加治疗剂量。