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Thyroid Disorders The Management of Medullary Thyroid Carcinoma in the Era of Targeted Therapy Brian Ng-Cheng-Hin and Kate L Newbold 1. NIHR Royal Marsden Hospital and Institute of Cancer Research BRC, London, UK. Abstract Medullary thyroid cancer (MTC) is a rare cancer comprising approximately 5% of all thyroid cancers. The majority arises sporadically but around 25% are hereditary forming part of the Multiple Endocrine Neoplasia (MEN) type 2 syndromes. The initial management is surgical, the extent of resection determined by radiological stage, presence of and specific REarranged during Transfection (RET) oncogene mutation and level of serum calcitonin. External beam radiotherapy may be utilised in the adjuvant setting to improve local control rates. Conventional cytotoxic agents remain essentially futile in the management of advanced MTC with response rates of around 15-20% at best. Over the last decade, alongside a greater understanding of the molecular pathogenesis of MTC we have seen the development of small molecule agents including tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFRs) and RET with activity in advanced MTC. This review will examine the evidence for this therapeutic approach, when to consider initiating and how to manage toxicities arising from such therapies in the treatment of advanced MTC. Keywords Medullary thyroid cancer, targeted therapy, kinase inhibitors Disclosure: Kate L Newbold has received honoraria for speaking and advisory board membership for Astra-Zeneca, Genzyme and Eisai. Brian Ng-Cheng-Hin has nothing to disclose in relation to this article. No funding was received for the publication of this article. This work was undertaken in The Royal Marsden NHS Foundation Trust who received a proportion of its funding from the NHS Executive; the views expressed in this publication are those of the authors and not necessarily those of the NHS Executive. We acknowledge the support of the National Institute for Health Research Royal Marsden Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 19 January 2016 Accepted: 9 February 2016 Citation: European Endocrinology, 2016;12(1):39–43 Correspondence: Kate L Newbold, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton. Surrey SM2 5PT, UK E: kate.newbold@rmh.nhs.uk. Medullary Thyroid Cancer (MTC) is a rare cancer of the thyroid parafollicular or ‘C’ cells, and is estimated to make up around 5–10% of all thyroid cancers. 1 MTC was first described in 1906 by Jacquet as a thyroid tumour with amyloid, but the term MTC and its histological description of a solid non-follicular tumour with amyloid features was coined by Hazard et al., in 1959. 2,3 Parafollicular C cells originate from the neural crest and so in keeping with their neuroendocrine origin, MTC secretes calcitonin (Ct), serotonin, chromogranin A and expresses carcinoembryonic antigen (CEA). Serum levels of Ct and CEA are used as tumour markers to aid diagnosis, monitor disease progression and assess response to treatment. 75% of MTCs are sporadic and the remaining 15% are hereditary as part of the Multiple Endocrine Neoplasia (MEN) type 2 syndrome and the familial MTC (FMTC). 4,5 The MEN syndrome arises from a germline mutation in the REarranged during Transfection (RET) oncogene. The MEN type 2 syndromes can be subcategorised into MEN2A and MEN2B according to clinical features. MEN2A is comprised of MTC, hyperparathyroidism and phaeochromocytoma whereas MEN2B consists of MTC, phaeochromocytoma, mucosal neuromas and a marfanoid habitus. FMTC is thought to be part of the spectrum of MEN2A. Patients have FMTC when they harbour a germline RET mutation but do not display the other phenotypic characteristics of MEN2A. Patients may present with a solitary thyroid nodule or with palpable cervical neck nodes. Symptoms can result from pressure effects of TOU CH MED ICA L MEDIA the disease such as dysphagia, dyspnoea, hoarseness and coughing. Ct secretion by the tumour may cause systemic symptoms such as flushing and diarrhoea. Not uncommonly, on direct questioning, patients will have suffered from irritable bowel symptoms for years. At diagnosis, lymph nodes metastases are found in around 60–70%, with 7-20% having distant metastatic disease and over 20% will die from their metastatic disease. 6–8 Overall, the prognosis of MTC is good but is dependent on the stage; with reported 10-year overall survival of 95% with localised disease, 75% with regional disease and falling to 40% in those presenting with distant metastases. 7 Current Standard Management Early Stage Medullary Thyroid Cancer Treatment of localised disease is surgical with total thyroidectomy and selective lymphadenectomy. Thorough pre-operative staging together with serum Ct levels are critical to the decision making for the extent of neck dissection and lymphadenectomy required. Debate continues as to the role and extent of elective dissection of the radiologically negative neck. Patients with distant metastases or serum Ct levels suggestive of distant metastatic disease may be offered a more conservative local surgical approach. The American Thyroid Association guidelines provide useful background for these decisions. 8 39