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      Updates on the Management of Advanced, Metastatic, and Radioiodine Refractory Differentiated Thyroid Cancer

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          Abstract

          Differentiated thyroid cancer (DTC) accounts for 95% of all thyroid cancers and is generally an indolent tumor, treated effectively with surgery, radioactive iodine, and thyroid-stimulating hormone suppressive therapy. However, 5–10% of patients have advanced disease, with aerodigestive tract invasion, distant metastases, or radioiodine refractory disease, with poor prognosis. This review focuses on the approaches for treating advanced DTC, including management of gross extra-thyroidal extension, recurrent loco-regional or distant metastatic disease, the role of external beam radiation therapy and systemic treatment. Locally ablative treatment modalities, including surgery, radiation therapy, and thermal ablation are evolving and can be used in selected patients. In recent years, new therapeutic agents with molecular targets have become available and two multi-kinase inhibitors, Sorafenib and Lenvatinib, have been licensed for iodine refractory DTC showing an advantage in terms of progression-free survival, although an impact on overall survival has not been proven yet. Management of advanced thyroid cancer can be challenging but a multidisciplinary approach can significantly improve outcomes for this patient population.

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          Most cited references40

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          Thyroid cancer

          Thyroid cancer is the fifth most common cancer in women in the USA, and an estimated over 62 000 new cases occurred in men and women in 2015. The incidence continues to rise worldwide. Differentiated thyroid cancer is the most frequent subtype of thyroid cancer and in most patients the standard treatment (surgery followed by either radioactive iodine or observation) is effective. Patients with other, more rare subtypes of thyroid cancer-medullary and anaplastic-are ideally treated by physicians with experience managing these malignancies. Targeted treatments that are approved for differentiated and medullary thyroid cancers have prolonged progression-free survival, but these drugs are not curative and therefore are reserved for patients with progressive or symptomatic disease.
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            Patient age is significantly related to the progression of papillary microcarcinoma of the thyroid under observation.

            We showed previously that subclinical low-risk papillary thyroid microcarcinoma (PTMC) could be observed without immediate surgery. Patient age is an important prognostic factor of clinical papillary thyroid carcinoma (PTC). In this study, we investigated how patient age influences the observation of low-risk PTMC.
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              Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study.

              Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35-68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=-0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient's response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. National Cancer Institute, supported in part by NCI CA15083 and CM62205. Copyright © 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                20 November 2017
                2017
                : 8
                : 312
                Affiliations
                [1] 1Clinical Oncology, Royal Marsden NHS Foundation Trust , London, United Kingdom
                [2] 2Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center , Catania, Italy
                Author notes

                Edited by: Michele Caraglia, Università degli Studi della Campania “Luigi Vanvitelli”Caserta, Italy

                Reviewed by: Marco Centanni, Sapienza Università di Roma, Italy; Marialuisa Appetecchia, Istituti Fisioterapici Ospitalieri (IRCCS), Italy

                *Correspondence: Kate Newbold, Kate.Newbold@ 123456icr.ac.uk

                Specialty section: This article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2017.00312
                5702018
                29209273
                f4d9bb0f-9ef3-4a07-b95a-f05d4242845f
                Copyright © 2017 Tumino, Frasca and Newbold.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 26 July 2017
                : 27 October 2017
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 57, Pages: 7, Words: 5590
                Categories
                Endocrinology
                Mini Review

                Endocrinology & Diabetes
                thyroid cancer,radioiodine refractory,kinase inhibitors,redifferentiation,distant metastasis

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