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      Current Status and Future Perspectives in Differentiated Thyroid Cancer

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          Abstract

          Thyroid cancer is increasing all over the world. The exact cause of this increase is still debated and there are conflicting reports. Sophisticated molecular studies suggest that environmental chemicals may have effects of thyroid carcinogenesis. The development of powerful molecular biology techniques has enabled targeted next-generation sequencing for detection of mutations in thyroid cancer, and this technique can make a specific diagnosis of thyroid cancer in cytologically indeterminate cases. The initial treatment of well-differentiated thyroid cancer (DTC) is surgery followed by radioiodine remnant ablation. However, further studies are needed to determine the optimal dosage of radioactive iodine for DTC patients with lateral neck metastasis. DTC is an indolent tumor and may cause death even decades later. Thus, long-term follow-up is mandatory. Recently, dynamic risk stratification (DRS) has begun to use stimulated thyroglobulin level at 1 year after the initial treatment and restratified the risk in accordance with the response to the initial treatment. This DRS strategy accurately predicts disease free survival and can be widely used in daily clinical settings. For the iodine refractory metastatic disease, redifferentiation therapy and targeted therapy are two promising alternative treatments. Sorafenib is the first approved agent for the treatment of progressive iodine refractory advanced thyroid cancer in Korea and may be very helpful for radioactive-refractory locally advanced or metastatic DTC. Selumetinib may be an effective redifferentiating agent and could be used within several years.

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          Most cited references57

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          BRAF mutation in thyroid cancer.

          M Xing (2005)
          Genetic alteration is the driving force for thyroid tumorigenesis and progression, based upon which novel approaches to the management of thyroid cancer can be developed. A recent important genetic finding in thyroid cancer is the oncogenic T1799A transversion mutation of BRAF (the gene for the B-type Raf kinase, BRAF). Since the initial report of this mutation in thyroid cancer 2 years ago, rapid advancements have been made. BRAF mutation is the most common genetic alteration in thyroid cancer, occurring in about 45% of sporadic papillary thyroid cancers (PTCs), particularly in the relatively aggressive subtypes, such as the tall-cell PTC. This mutation is mutually exclusive with other common genetic alterations, supporting its independent oncogenic role, as demonstrated by transgenic mouse studies that showed BRAF mutation-initiated development of PTC and its transition to anaplastic thyroid cancer. BRAF mutation is mutually exclusive with RET/PTC rearrangement, and also displays a reciprocal age association with this common genetic alteration in thyroid cancer. The T1799A BRAF mutation occurs exclusively in PTC and PTC-derived anaplastic thyroid cancer and is a specific diagnostic marker for this cancer when identified in cytological and histological specimens. This mutation is associated with a poorer clinicopathological outcome and is a novel independent molecular prognostic marker in the risk evaluation of thyroid cancer. Moreover, preclinical and clinical evaluations of the therapeutic value of novel specific mitogen-activated protein kinase pathway inhibitors in thyroid cancer are anticipated. This newly discovered BRAF mutation may prove to have an important impact on thyroid cancer in the clinic.
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            Increasing incidence of differentiated thyroid cancer in the United States, 1988-2005.

            Studies have reported an increasing incidence of thyroid cancer since 1980. One possible explanation for this trend is increased detection through more widespread and aggressive use of ultrasound and image-guided biopsy. Increases resulting from increased detection are most likely to involve small primary tumors rather than larger tumors, which often present as palpable thyroid masses. The objective of the current study was to investigate the trends in increasing incidence of differentiated (papillary and follicular) thyroid cancer by size, age, race, and sex. Cases of differentiated thyroid cancer (1988-2005) were analyzed using the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) dataset. Trends in incidence rates of papillary and follicular cancer, race, age, sex, primary tumor size ( 4 cm), and SEER stage (localized, regional, distant) were analyzed using joinpoint regression and reported as the annual percentage change (APC). Incidence rates increased for all sizes of tumors. Among men and women of all ages, the highest rate of increase was for primary tumors or =4 cm among men (1988-2005: APC, 3.7) and women (1988-2005: APC, 5.70) and for distant SEER stage disease among men (APC, 3.7) and women (APC, 2.3). The incidence rates of differentiated thyroid cancers of all sizes increased between 1988 and 2005 in both men and women. The increased incidence across all tumor sizes suggested that increased diagnostic scrutiny is not the sole explanation. Other explanations, including environmental influences and molecular pathways, should be investigated.
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              Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study.

              Patients with advanced, incurable thyroid cancer not amenable to surgery or radioactive iodine ((131)I) therapy have few satisfactory therapeutic options. This multi-institutional study assessed the activity and safety of axitinib, an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 in patients with advanced thyroid cancer. Patients with thyroid cancer of any histology that was resistant or not appropriate for (131)I were enrolled onto a single-arm phase II trial to receive axitinib orally (starting dose, 5 mg twice daily). Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors was the primary end point. Secondary end points included duration of response, progression-free survival (PFS), overall survival, safety, and modulation of soluble (s) VEGFR. Sixty patients were enrolled. Partial responses were observed in 18 patients, yielding an ORR of 30% (95% CI, 18.9 to 43.2). Stable disease lasting > or = 16 weeks was reported in another 23 patients (38%). responses were noted in all histologic subtypes. Median PFS was 18.1 months (95% CI, 12.1 to not estimable). Axitinib was generally well tolerated, with the most common grade > or = 3 treatment-related adverse event being hypertension (n = 7; 12%). Eight patients (13%) discontinued treatment because of adverse events. Axitinib selectively decreased sVEGFR-2 and sVEGFR-3 plasma concentrations versus sKIT, demonstrating its targeting of VEGFR. Axitinib is a selective inhibitor of VEGFR with compelling antitumor activity in all histologic subtypes of advanced thyroid cancer.
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                Author and article information

                Journal
                Endocrinol Metab (Seoul)
                Endocrinol Metab (Seoul)
                ENM
                Endocrinology and Metabolism
                Korean Endocrine Society
                2093-596X
                2093-5978
                September 2014
                25 September 2014
                : 29
                : 3
                : 217-225
                Affiliations
                Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
                Author notes
                Corresponding author: Young Kee Shong. Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. Tel: +82-2-3010-3244, Fax: +82-2-3010-6962, ykshong@ 123456amc.seoul.kr
                Article
                10.3803/EnM.2014.29.3.217
                4192824
                26e1baba-a650-435a-b2f4-58b0a9250ebb
                Copyright © 2014 Korean Endocrine Society

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                Categories
                Review Article

                thyroid,thyroid neoplasms,diagnosis,therapy,prognosis
                thyroid, thyroid neoplasms, diagnosis, therapy, prognosis

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