Oral Oncology 50 (2014) 577–586

Contents lists available at ScienceDirect

Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology

Review

ACR Appropriateness CriteriaÒ thyroid carcinoma
Joseph K. Salama a,⇑, Daniel W. Golden b, Sue S. Yom c, Madhur Kumar Garg d, Joshua Lawson e, Mark W. McDonald f, Harry Quon g, John A. Ridge h, Nabil Saba i, Richard V. Smith j, Francis Worden k, Anamaria Reyna Yeung l, Jonathan J. Beitler m a Duke University, Durham, NC, United States University of Chicago Hospital, Chicago, IL, United States University of California San Francisco, San Francisco, CA, United States d Montefiore Medical Center, Bronx, NY, United States e Lexington Medical Center, West Columbia, SC, United States f Indiana University School of Medicine, Indianapolis, IN, United States g Johns Hopkins University, Baltimore, MD, United States h American College of Surgeons, Fox Chase Cancer Center, Philadelphia, PA, United States i American Society of Clinical Oncology, Emory University, Atlanta, GA, United States j American College of Surgeons, Montefiore Medical Center, Bronx, NY, United States k American Society of Clinical Oncology, University of Michigan, Ann Arbor, Michigan, United States l University of Florida, Gainesville, FL, United States m Emory University School of Medicine, Atlanta, GA, United States b c

a r t i c l e

i n f o

s u m m a r y
The ACR Head and Neck Cancer Appropriateness Criteria Committee reviewed relevant medical literature to provide guidance for those managing patients with thyroid carcinoma. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Thyroid cancer is the most common endocrine malignancy in the United States, most often presenting as a localized palpable nodule. Surgery is the mainstay of treatment for WDTC, with most patients undergoing complete resection of their disease having good outcomes. Following surgery thyroxine supplementation should begin to suppress TSH, which unchecked can stimulate residual disease and/or metastatic progression, Adjuvant treatment with radioactive iodine (RAI) using iodine-131 (131I) is frequently used for diagnostic and therapeutic purposes. The use of EBRT for thyroid cancer has not been tested in well-designed, randomized, controlled trials and should, therefore, be considered on a case-by-case basis. Chemotherapy plays a minimal role in the management of WDTC. Novel biologic agents, such as systemic therapy options, are being actively investigated, and patients with metastatic thyroid cancer that is not iodine avid should be encouraged to enroll in clinical trials exploring novel systemic agents. Ó 2014 American College of Radiology. Published by Elsevier Ltd. All rights reserved.

Keywords: Thyroid cancer Appropriateness Criteria Anaplastic thyroid cancer Medullary thyroid cancer Well differentiated thyroid cancer Radiotherapy thyroid cancer

Introduction/background Thyroid cancer is the most common endocrine malignancy in the United States, where the annual incidence is approximately 37,000 and increasing due to the more frequent diagnosis of early well-differentiated thyroid carcinoma (WDTC) [1]. Annually, approximately 1600 people die from thyroid malignancies [2].
⇑ Corresponding author. Address: American College of Radiology, 1891 Preston White Dr., Reston, VA 20191, United States. E-mail address: joseph.salama@duke.edu (J.K. Salama).

Women represent approximately 75% of newly diagnosed thyroid carcinoma cases. Risk factors for thyroid cancer include exposure to ionizing radiation and a family history of the disease [3,4]. Thyroid cancer spans a spectrum of disease entities from the often curable, well-differentiated histologies (papillary, follicular/ Hürthle cell, and medullary) to the aggressive anaplastic histology that represents only 2% of all thyroid cancer cases but 50% of thyroid cancer-related deaths. Guidelines for the management of thyroid carcinoma have been promulgated and are widely used [5,6]. The overwhelming majority of patients with WDTC will do well with appropriate treatment. The high long-term survivorship

1368-8375/$ - see front matter Ó 2014 American College of Radiology. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.12.004

578

J.K. Salama et al. / Oral Oncology 50 (2014) 577–586

and relative rarity of the disease have frustrated efforts to execute randomized trials, so management recommendations are not guided by conventional modern standards in oncology. Anatomy and physiology of the thyroid gland The thyroid gland is a bilobed organ joined at the isthmus, which is located just inferior to the cricoid cartilage and surrounds the anterior portion of the trachea. The recurrent and superior laryngeal nerves pass near the thyroid gland on their way to the larynx. Four parathyroid glands are usually located near the thyroid gland as well. The physiology of the thyroid gland is unique. Thyrotropinreleasing hormone, produced within the hypothalamus, signals the anterior pituitary to release thyroid-stimulating hormone (TSH). TSH then stimulates the follicular cells within the thyroid gland to release thyroxine, which in turn modulates the body’s metabolic rate. Iodine is required for the production of thyroxine. The production of TSH and thyroxine is tightly regulated by a negative feedback loop within the hypothalamic–thalamic–thyroid axis. TSH can stimulate both normal thyrocytes and WDTC cells. Therefore, TSH suppression is a vital component of treatment for WDTC. The thyroid gland also contains parafollicular C cells that secrete calcitonin, a hormone that helps regulate, but is not mandatory for, calcium homeostasis. Primary lymphatic drainage of the thyroid is to the central neck compartment (level VI), with secondary echelons including the internal jugular chain (levels II–IV), posterior neck (level V), and superior mediastinum (level VII). However, this drainage pattern is inconsistent, and skip metastases directly to the lateral neck compartment have been reported in 620% of cases [7]. Presentation of thyroid carcinoma A thyroid carcinoma most often presents as a localized palpable nodule, although the disease is increasingly detected as an incidental finding resulting from imaging studies conducted to evaluate other conditions. The cancer may present with lateral cervical lymphadenopathy from metastatic disease, compressive symptoms (including respiratory embarrassment and dysphagia), and hoarseness with recurrent laryngeal nerve injury. Fine needle aspiration biopsy represents the appropriate initial diagnostic maneuver, and it readily distinguishes many papillary thyroid carcinomas (PTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC) from benign nodular thyroid disease. A benign follicular adenoma cannot be distinguished from a follicular carcinoma without examination of the lesion margin for vascular or capsular invasion. Hence, a thyroidectomy is required to confirm follicular thyroid cancer (FTC), which represents only about 20% of follicular neoplasms. The follicular variant of papillary carcinoma may also present with what appears to be a follicular neoplasm. The molecular mechanisms of malignant transformation include activating mutations in the RAS–RAF–MEK–ERK pathway in PTC [8], mutations in the RET proto-oncogene in MTC [9], and protein 53 defects in ATC [10]. Thyroid cancers typically spread to distant sites in a characteristic fashion, depending on the histology – PTC to lymph nodes, lungs, and bones; FTC to bones and lungs; and ATC to lymph nodes, lungs, bones, brain, and other sites. As many as 50% of patients with apparently localized PTC harbor lymph node metastases. Few develop a clinically significant progression in nodes. Unlike other FTC, Hürthle cell carcinomas (HCC) may spread to regional lymph nodes. PTC often afflicts children and young adults, but it is a far more threatening malignancy in older individuals. Mortality rises with patient age.

Treatment of thyroid carcinoma Surgery is the mainstay of treatment for WDTC, and the overwhelming majority of patients who undergo complete resection of their clinical disease will do well. Adjuvant treatment with radioactive iodine (RAI) using iodine-131 (131I) is frequently used for diagnostic and therapeutic purposes. MTC, arising from C cells, is characterized by the early dissemination to lymph nodes and does not concentrate iodine. Resection should include a lymphadenectomy, the extent of which remains subject to debate. Most ATCs are unresectable at presentation. Surgical maneuvers (including tracheotomy) are controversial. Distant metastases are common, and chemoradiotherapy alone represents the usual management strategy. WDTC includes PTC (the most common variant of thyroid cancer), FTC (which includes HCC), and MTC. The primary treatment modality for WDTC is surgery. For most WDTCs, a total thyroidectomy is recommended, although there is strong support for a total lobectomy for a substantial group of patients with low-risk disease (age 15–45 years, with no prior radiation, no distant metastases, no cervical nodal disease, no clinical or radiographic extrathyroidal extension, cancer < 4 cm in diameter, and no aggressive variant). Although multiple studies have suggested improved outcomes with a total thyroidectomy compared with a partial thyroidectomy [11–14], controversy persists because the morbidity of bilateral thyroidectomy is higher (particularly with respect to parathyroid injury) even in experienced hands. A series of 1355 patients with PTC or FTC showed a 30-year recurrence rate of 40% after a subtotal thyroidectomy versus 26% after a total or near-total thyroidectomy [13]. Furthermore, a total thyroidectomy is advantageous for several reasons: (1) follow-up screening for recurrence or metastasis is simplified if there is no residual thyroid tissue; (2) postoperative RAI is more effective when there is no residual normal thyroid tissue; and (3) completion thyroidectomy for recurrent disease has a high associated morbidity (due to the resulting total thyroidectomy, with increased risks to the laryngeal nerves and parathyroid glands). Papillary microcarcinoma (4000 patients treated in 23 nonrandomized studies failed to show a benefit in overall survival; however, it did show an improvement in 10-year locoregional recurrence (relative risk 0.31) and an absolute 3% reduction in distant metastases with the addition of RRA [24]. Prior to RAI, administration of recombinant human thyrotropin or thyroid hormone withdrawal should be implemented to improve uptake of 131I in remnant thyroid tissue or residual disease. Patients should also be given instructions for a low-iodine diet. Two recent, large, randomized trials demonstrated similar ablation rates after thyrotropin administration or thyroid hormone withdrawal, with 1 trial suggesting a trend toward increased adverse events with thyroid hormone withdrawal (30% versus 23%, P = .11) [30] and the other trial showing a significantly higher proportion of patients with symptoms of hypothyroidism, deterioration of quality of life, and higher rates of lacrimal gland

dysfunction after thyroid hormone withdrawal [5]. Based on these 2 studies, the use of recombinant human thyrotropin should be considered the preferred method to improve uptake of 131I. If a diagnostic scan is performed prior to therapy, 123I should be administered to prevent stunning (the reduced uptake of subsequent RAI administration due to sublethal radiation damage) of thyroid tissue or residual disease. Alternatively, an empiric treatment dose of 131I can be administered, making sure to obtain a post-treatment diagnostic scan. This should not be done if the results of the scan would change the therapeutic dose, per the American Thyroid Association (ATA) guidelines [31]. The dose for postoperative RAI remains controversial. Most centers use a fixed dose between 30 mCi and 100 mCi, depending on risk factors. A systematic review of 41 retrospective studies, 12 prospective studies, and 6 randomized studies compared the low dose (30 mCi) with the high dose (100 mCi) and found a trend toward improved ablation with the higher dose, although this did not reach significance [32]. Multiple guidelines and recommendations have been released in recent years suggesting the use of ablative doses ranging from 30 mCi to 150 mCi [33]. A recent study of patterns of care in North America showed that approximately 50% of centers treat with 100 mCi, 20% treat with 30–99 mCi, and 14% treat with 629.9 mCi for low-risk PTC [33]. Two recent, large, randomized trials that included patients with pT1-3 and nodenegative or -positive disease demonstrated equivalent rates of remnant ablation with 30 mCi and 100 mCi [5,30]. ATA and National Comprehensive Cancer Network guidelines recommend 30–100 mCi for patients without residual gross disease and 100–200 mCi for patients with a high risk of local recurrence, residual gross disease, or distant metastases [6,31]. These doses are similar to those used at large tertiary referral centers, including lower risk patients (age < 45 years with intrathyroidal tumors < 2 cm) receiving 30–50 mCi, while intermediate-risk patients receive 75–100 mCi for the initial therapy. Only patients with a high risk of local recurrence, residual gross disease, or distant metastases are treated with 130–200 mCi. Whole body and blood dosimetry studies are rarely performed for routine RAI ablation, as the standard 131I doses are well below a dose that may cause toxicity. Hospitalization is no longer required in most states following 131I administration. Toxicity associated with RAI includes transient parotitis, nausea, emesis, and bone marrow suppression. In 2 recent, large, randomized trials [5,30], longer post-treatment hospitalization stays, higher rates of adverse events, and decreased quality of life were significantly associated with a dose of 100 mCi compared with 30 mCi 131I. Bone marrow suppression after a dose of 100 mCi for RRA has been shown to depress white blood cell and platelet counts at 1 year [34]. There is no significant increased risk of infertility, spontaneous abortion, premature delivery, or congenital anomalies in children of women who receive RAI prior to pregnancy [35,36]. To mitigate the potential adverse salivary effects of RAI, the use of pilocarpine [37] and amifostine [38] have been investigated. However, due to the cost and associated side effects, they are not used in standard practice. Most patients are advised to eat hard candies the day following RAI treatment to prevent accumulation of 131I in the salivary glands. In the treatment of extensive metastatic disease, rare side effects include pulmonary fibrosis and an increase in malignancies, including leukemia and solid tumors. Recent evidence shows an increase in RAI use for early-stage (pT1N0) thyroid cancer, with no evidence to support a survival outcome [39]. This trend is of concern, given the known risk for second malignancies, particularly leukemia and salivary gland tumors [39]. Elderly patients should receive aggressive surgery (near-total or total thyroidectomy) followed by RAI if their performance status

580

J.K. Salama et al. / Oral Oncology 50 (2014) 577–586

will tolerate it. A recent analysis of the Surveillance Epidemiology and End Results registry showed that elderly patients are less likely to be treated with surgery or RAI, although multivariable analysis associated both treatment modalities with improved survival [40].

External beam radiotherapy The use of EBRT for thyroid cancer has not been tested in welldesigned, randomized, controlled trials and should, therefore, be considered on a case-by-case basis following surgery and RAI. Indications for use of EBRT postoperatively can include gross residual disease, extracapsular or extrathyroidal extension, recurrent disease or 131I failure, poor iodine avidity, multiple pathologically involved lymph nodes, HCC histology, patient age > 45 years, or high risk on prognostic systems [41]. There has been no report of successfully completed, randomized, controlled trials investigating the role of postoperative adjuvant EBRT. One trial attempted to randomize patients treated with surgery, 131I, and TSH-suppression for pT4 FTC to EBRT for observation [42]. Due to poor accrual, the trial became a prospective cohort study after only 45 of 311 patients had consented to randomization. Of the 47 randomized patients, 26 received EBRT. This trial failed to show a statistically significant local control benefit for EBRT, although there was a trend toward improved complete remission rates (96% versus 86%) and local control (100% versus 97%) with the addition of EBRT. Although there is a lack of prospective randomized data, retrospective evidence supports the use of EBRT in high-risk patients. A retrospective study of 169 patients with pathologic T4 disease who received RAI and TSH suppression therapy found a benefit with EBRT, which improved failure-free survival from 45% to 90% [43]. However, this benefit was limited to patients > 40 years of age with lymph node-positive disease. A similar benefit was not seen with FTC. Another study, in which 105 of 842 patients received EBRT, showed a benefit of EBRT use, with a relative risk of locoregional failure of 0.35 [44]. Although other studies failed to show a benefit to adjuvant EBRT after surgery and RAI, the groups receiving EBRT had unfavorable characteristics [45–48]; therefore, selection bias may have played a role in this outcome. Based on the totality of the evidence, EBRT should be considered particularly for older patients (>40 years) with high-risk PTC or HCC (pathologic T4 or with pathologically involved lymph nodes) after surgery and RAI [49,50]. When administered postoperatively, EBRT treatment volumes for these patients usually include levels II–VII (including upper mediastinal lymph nodes) extending from the angle of the mandible to the tracheal bifurcation with or without the retropharyngeal lymph nodes at a dose of 45–50 Gy. The coverage of elective nodal regions is often recommended, based on small retrospective studies of locoregionally advanced nonanaplastic thyroid cancer that demonstrated significantly improved 5-year locoregional control (89% versus 40%) with the addition of elective field irradiation in the recurrent or postoperative setting with gross residual disease [51]. No difference was seen in acute or late toxicities between the groups. High-risk microscopic regions (i.e., tumor bed, initial thyroid gland volume, adjacent primary nodal group, level VI, or any pathologically involved lymph node levels) are often treated with 60 Gy, while areas of positive margins are treated with 66– 70 Gy. When treated, gross residual disease is often treated at 70 Gy or higher. Conventional treatment fields traditionally consisted of anterior or anteroposterior/posteroanterior fields to below cord tolerance followed by anterior electrons or opposed lateral/oblique fields to the final dose. Interest is being directed at developing techniques to reduce EBRT-related toxicity, in particular intensity-modulated radiotherapy (IMRT). Recent publications have demonstrated the

feasibility of using IMRT to treat patients with thyroid cancer [52,53]. One group showed equivalent survival outcomes with reduced severe late morbidity (2% versus 12%) for 131I postoperative patients when comparing 57 patients treated with IMRT to 74 patients treated with conventional radiotherapy [54]. When gross residual disease is present, some studies have suggested that EBRT may improve locoregional tumor control. For patients with an incomplete surgical resection, the addition of EBRT was shown to improve the 15-year local control from 77% to 89%, although the patients treated with EBRT had larger and more extensive tumors [55]. Another study showed equivalent local control in patients treated with EBRT regardless of the extent of resection [56]. Together, these studies demonstrate the potential effectiveness of EBRT. Risk factors that have been shown to predict for worse response to EBRT include high-risk histologic features [54], gross residual disease [54,57], and lack of iodine avidity [58]. Systemic therapy Chemotherapy plays a minimal role in the management of WDTC. Doxorubicin is currently the only FDA-approved agent for noniodine avid disease [59]. Studies are now elucidating the common genetic alterations in thyroid cancer such as the BRAF gene V600E mutation [60], which may represent targets for novel biologic agents. Similarly, vascular endothelial growth factor (VEGF) is overexpressed in WDTC, which has prompted the study of small molecule tyrosine kinase inhibitors over the past few years. Sorafenib has demonstrated response rates of 15–23% in 3 phase II studies [61–63]. Axitinib and pazopanib have also been evaluated with similar results [64,65]. In a multi-institutional phase II study, levantinib demonstrated a response rate of 50%, with a median progression-free survival (PFS) rate of 13 months, and recently it was compared to a placebo in a large, randomized, phase III trial, the results of which are pending. The results of the DECISION trial – a multi-institutional, randomized, placebo-controlled, phase III trial comparing sorafenib with a placebo – were presented at the 2013 American Society of Clinical Oncology Annual Meeting. In evaluation of the primary endpoint of this study, sorafenib demonstrated an improvement over the placebo in the PFS rate by 5 months, and the majority of adverse events were manageable and nonlife threatening. The objective response rate for sorafenib was 23%, and survival was not improved due to the cross-over effect in the placebo arm. Interestingly, at 400 days 25% of the placebo arm patients did not demonstrate disease progression, begging the question of whom to treat and when. In 1 series of WDTC patients, who were iodine-refractory and FDG-negative, the median PFS rate was 41 months without treatment [66]. Deciding when and to whom to administer targeted therapy may become more evident as data from a subset analysis of this study and future randomized studies evolve. Additional data suggest that targeting molecular phenotypes may also be reasonable. A recent study by Ho et al. [67] demonstrated that radioiodine uptake could be enhanced by selumetinib in advanced thyroid cancer patients. Similarly, vemurafenib may induce clinical responses in patients harboring BRAF mutations (see Variants 1–3). Well-differentiated thyroid cancer – medullary thyroid cancer MTC is a neuroendocrine tumor of the parafollicular C cells, which produce calcitonin. Approximately 80% of MTC cases are sporadic, although some are familial, arising from multiple endocrine neoplasia type 2 (MEN2) syndrome. The management of patients with MEN2 syndrome should include familial screening and evaluation for aprophylactic thyroidectomy. Further discussion is beyond the scope of this review. At the time of diagnosis,

J.K. Salama et al. / Oral Oncology 50 (2014) 577–586 Variant 1 T1a N0 M0 papillary thyroid carcinoma: 40-year-old woman. Treatment Total lobectomy (hemithyroidectomy) Total thyroidectomy Thyroglobulin suppression with levothyroxine Postoperative Adjuvant Radioactive Iodine (RRA or RAI) 30 mCi with thyrotropin stimulation 100 mCi with thyrotropin stimulation 30 mCi with thyroid hormone withdrawal 100 mCi with thyroid hormone withdrawal Postoperative external beam radiotherapy Postoperative chemotherapy Adjuvant concurrent chemoradiotherapy Rating 8 8 9 Comments Variant 3 T4a N1a M0 papillary thyroid carcinoma: 65-year-old man. Treatment Total lobectomy (hemithyroidectomy) Total thyroidectomy Thyroglobulin suppression with levothyroxine Postoperative Adjuvant Radioactive Iodine (RRA or RAI) 30 mCi with thyrotropin stimulation 100 mCi with thyrotropin stimulation 30 mCi with thyroid hormone withdrawal 100 mCi with thyroid hormone withdrawal Postoperative External Beam Radiotherapy 3D-CRT IMRT Treat thyroid bed first echelon LN’s only Treat thyroid bed and entire elective neck Postoperative chemotherapy Adjuvant concurrent chemoradiotherapy Rating 1 9 9

581

Comments

3 1 2 1 1 1 1

1 8 1 7 5 8 5 8 1 1

Rating scale: 1, 2, 3 usually not appropriate; 4, 5, 6 may be appropriate; 7, 8, 9 usually appropriate.

approximately 50% of patients with MTC have clinically detectable cervical lymph node metastases. All patients with sporadic MTC should be offered germline RET oncogene testing, given that approximately 6–7% of unselected patients with MTC have a germline mutation [68,69]. The primary management for MTC is surgical resection with a lymphadenectomy. Prior to surgery, all patients with MTC should be evaluated for pheochromocytoma, or, to rule out pheochromocytoma, they should be tested for a negative RET proto-oncogene mutation and have a negative family history for MTC. Staging is based on size, extrathyroidal extension, lymph node status, and metastases. There is no role for RAI, as MTC is not iodine avid. Thyroxine should be started immediately following surgery with the goal of maintaining euthyroidism. There is no role for suppression of serum thyrotropin, because parafollicular C cells do not respond to TSH. EBRT is recommended postoperatively for patients with gross residual disease to obtain local control. In a series of 21 patients treated postoperatively with gross residual disease, local control was 20%, which is poor but demonstrates that local control can be achieved in a subset of patients [70]. The use of adjuvant EBRT for microscopic disease is less clear. There have been no reports of a consistent survival benefit with the use of adjuvant EBRT, likely due to microscopic disease outside of the neck. However, local control improves with the use of EBRT [70–73]. In 1 series of 40 patients with high-risk features, including gross residual disease,

Rating scale: 1, 2, 3 usually not appropriate; 4, 5, 6 may be appropriate; 7, 8, 9 usually appropriate.

positive lymph nodes, or extracapsular extension, the use of postoperative adjuvant EBRT (median 40 Gy) significantly improved 10-year local–regional control (86% versus 52%) [70]. In another series of 51 patients with elevated postoperative calcitonin, 24 were treated with EBRT; local control was 71% versus 41% favoring EBRT, although this was not statistically significant [71]. Additionally, a series of 34 patients with stage IVa-c disease treated with EBRT (median 60 Gy) showed a local control rate of 87%, confirming the role for adjuvant EBRT in locally extensive disease [73]. The recommended dose for EBRT is 56 Gy to cervical lymph nodes, 66 Gy to areas concerning microscopic residual disease, and >70 Gy for gross disease. Patients are followed with regular serum calcitonin and carcinoembryonic antigen measurements to detect recurrence. In the recurrent setting, EBRT should be considered after the surgical resection of a locoregional recurrence or for palliation of a symptomatic distant metastasis. Therefore, when locoregional control is important, consideration should be given for EBRT use. Metastatic MTC is difficult to treat. Chemotherapy provides minimal benefit. Recently, the FDA approved vandetanib for the treatment of symptomatic or progressive MTC in patients with

Variant 2 T1b N0 M0 papillary thyroid carcinoma: 60-year-old man. Treatment Total lobectomy (hemithyroidectomy) Total thyroidectomy Thyroglobulin suppression with levothyroxine Postoperative Adjuvant Radioactive Iodine (RRA or RAI) 30 mCi with thyrotropin stimulation 100 mCi with thyrotropin stimulation 30 mCi with thyroid hormone withdrawal 100 mCi with thyroid hormone withdrawal Postoperative external beam radiotherapy Postoperative chemotherapy Adjuvant concurrent chemoradiotherapy Rating 3 9 9 Comments

5 7 4 6 1 1 1

Depends on final pathology and post-treatment evaluation Many patients will not require this high of a dose Associated with worse side effects than thyrotropin stimulation Depends on final pathology and post-treatment evaluation. Many patients may not require this high of a dose. Associated with worse side effects than thyrotropin stimulation

Rating scale: 1, 2, 3 usually not appropriate; 4, 5, 6 may be appropriate; 7, 8, 9 usually appropriate.

582

J.K. Salama et al. / Oral Oncology 50 (2014) 577–586

unresectable, locally advanced, or metastatic disease. Vandetanib is the first drug approved for this indication. Approval was based on the results of a double-blind trial, in which patients were randomized 2:1 to vandetanib (300 mg/d orally) versus a placebo. The primary objective was to demonstrate improvement in PFS with vandetanib compared with the placebo. Other endpoints included evaluation of the overall survival and objective response rates. The PFS analysis showed a marked improvement for patients randomized to vandetanib (hazard ratio = 0.35; 95% confidence interval, 0.24–0.53; P40 Gy [94]. Treatment fields should include the thyroid or thyroid bed and adjacent lymph node echelons in the neck and mediastinum. There are no data to support treating the entire neck and mediastinum. Dose fractionation schemes are variable, but 60 Gy in 1.5 Gy fractions twice daily is an appropriate and accepted fractionation scheme. For patients with poor performance status or metastatic disease, a palliative regimen of 20 Gy in 4-Gy fractions or 30 Gy in 3-Gy fractions should be considered to slow local progression. Some groups treat with 20 Gy in 4-Gy fractions, with a second course of 20 Gy 4 weeks later in patients who show a response to treatment. As with other thyroid cancer variants, IMRT is being actively explored as a method to reduce toxicity and improve the therapeutic ratio. One retrospective study compared toxicity in patients treated with either IMRT or 3-D conformal EBRT [96]. No difference in toxicity was reported, which was attributed to the wide field coverage used for IMRT. Overall, for locally advanced ATC, aggressive combined modality therapy (surgery if localized to the thyroid, chemotherapy, and radiation) has been attempted with mixed results. However, given the locally aggressive nature of ATC, aggressive local therapy is recommended to prevent or delay death by local progression (see Variants 5 and 6).

584

J.K. Salama et al. / Oral Oncology 50 (2014) 577–586 constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 2003;63(7):1454–7. Elisei R, Cosci B, Romei C, et al. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year followup study. J Clin Endocrinol Metab 2008;93(3):682–7. Ito T, Seyama T, Mizuno T, et al. Unique association of p53 mutations with undifferentiated but not with differentiated carcinomas of the thyroid gland. Cancer Res 1992;52(5):1369–71. Bilimoria KY, Bentrem DJ, Ko CY, et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg 2007;246(3):375–81. discussion 381–374. Hay ID, Grant CS, Bergstralh EJ, Thompson GB, van Heerden JA, Goellner JR. Unilateral total lobectomy: is it sufficient surgical treatment for patients with AMES low-risk papillary thyroid carcinoma? Surgery 1998;124(6):958–64. discussion 964–956. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97(5):418–28. DeGroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 1990;71(2):414–24. Harach HR, Franssila KO, Wasenius VM. Occult papillary carcinoma of the thyroid. A ‘‘normal’’ finding in Finland. A systematic autopsy study. Cancer 1985;56(3):531–8. Avram AM, Fig LM, Frey KA, Gross MD, Wong KK. Preablation 131-I scans with SPECT/CT in postoperative thyroid cancer patients: what is the impact on staging? J Clin Endocrinol Metab 2013;98(3):1163–71. Hay ID, Grant CS, Taylor WF, McConahey WM. Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 1987;102(6):1088–95. Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 1988;104(6):947–53. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 1993;114(6):1050–7. discussion 1057– 1058. Pasieka JL, Zedenius J, Auer G, et al. Addition of nuclear DNA content to the AMES risk-group classification for papillary thyroid cancer. Surgery 1992;112(6):1154–9. discussion 1159–1160. Alevizaki C, Molfetas M, Samartzis A, et al. Iodine 131 treatment for differentiated thyroid carcinoma in patients with end stage renal failure: dosimetric, radiation safety, and practical considerations. Hormones (Athens) 2006;5(4):276–87. Grigsby PW, Siegel BA, Baker S, Eichling JO. Radiation exposure from outpatient radioactive iodine (131I) therapy for thyroid carcinoma. JAMA 2000;283(17):2272–4. Wong JB, Kaplan MM, Meyer KB, Pauker SG. Ablative radioactive iodine therapy for apparently localized thyroid carcinoma. A decision analytic perspective. Endocrinol Metab Clin North Am 1990;19(3):741–60. Sawka AM, Thephamongkhol K, Brouwers M, Thabane L, Browman G, Gerstein HC. Clinical review 170: a systematic review and metaanalysis of the effectiveness of radioactive iodine remnant ablation for welldifferentiated thyroid cancer. J Clin Endocrinol Metab 2004;89(8):3668–76. Hay ID, Thompson GB, Grant CS, et al. Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940–1999): temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients. World J Surg 2002;26(8):879–85. Sawka AM, Brierley JD, Tsang RW, et al. An updated systematic review and commentary examining the effectiveness of radioactive iodine remnant ablation in well-differentiated thyroid cancer. Endocrinol Metab Clin North Am 2008;37(2):457–80. x. Sacks W, Fung CH, Chang JT, Waxman A, Braunstein GD. The effectiveness of radioactive iodine for treatment of low-risk thyroid cancer: a systematic analysis of the peer-reviewed literature from 1966 to April 2008. Thyroid 2010;20(11):1235–45. Jonklaas J, Sarlis NJ, Litofsky D, et al. Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid 2006;16(12):1229–42. Maxon 3rd HR, Englaro EE, Thomas SR, et al. Radioiodine-131 therapy for welldifferentiated thyroid cancer – a quantitative radiation dosimetric approach: outcome and validation in 85 patients. J Nucl Med 1992;33(6):1132–6. Mallick U, Harmer C, Yap B, et al. Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer. N Engl J Med 2012;366(18):1674–85. Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19(11):1167–214. Hackshaw A, Harmer C, Mallick U, Haq M, Franklyn JA. 131I activity for remnant ablation in patients with differentiated thyroid cancer: a systematic review. J Clin Endocrinol Metab 2007;92(1):28–38. Tuttle RM, Leboeuf R, Martorella AJ. Papillary thyroid cancer: monitoring and therapy. Endocrinol Metab Clin North Am 2007;36(3):753–78. vii. Molinaro E, Leboeuf R, Shue B, et al. Mild decreases in white blood cell and platelet counts are present one year after radioactive iodine remnant ablation. Thyroid 2009;19(10):1035–41. Sarkar SD, Beierwaltes WH, Gill SP, Cowley BJ. Subsequent fertility and birth histories of children and adolescents treated with 131I for thyroid cancer. J Nucl Med 1976;17(6):460–4.

Metastatic thyroid cancer Management of metastatic thyroid cancer depends on the histologic variant. Patients with metastatic WDTC may still benefit from local control, given the ability of RAI to eradicate distant disease. Patients with tumors that do not uptake iodine have a worse prognosis. When managing patients with extracervical metastases from thyroid cancer, the goals should be to improve survival, palliate symptoms, prevent morbidity, and limit treatment-related toxicity [97]. If the tumor remains iodine-avid, RAI should be attempted with a dose of 150–200 mCi [31]. Patients with pulmonary metastases should receive a dose of 150 mCi to reduce the risk of pulmonary toxicity. One series of 444 patients, 295 of whom had iodine-avid metastatic disease, showed a 43% rate of resolution of iodine-avid metastases [98]. The 10-year survival rate was 92% for the group with resolution of RAI avidity compared with 19% in disease that did not completely resolve. EBRT should be used to palliate local symptoms that are not amenable to RAI or require rapid relief. Lesion positron emission tomography (PET) avidity is inversely correlated with iodine avidity; therefore, PET-avid lesions should be treated with EBRT, as they do not respond to 131I therapy [99]. Dose regimens of 8 Gy in a single fraction, 20 Gy in 5 fractions, 30 Gy in 10 fractions, or 37.5 Gy in 15 fractions are all appropriate. Novel biologic agents, such as systemic therapy options, are being actively investigated. The tyrosine kinase inhibitor axitinib has shown a 30% overall response rate in incurable thyroid cancer of any histology [65], and thalidomide has shown activity in rapidly progressive metastatic thyroid cancer [100]. Patients with metastatic thyroid cancer that is not iodine avid should be encouraged to enroll in clinical trials that further explore novel systemic agents (see Variants 7 and 8). Summary  For WDTC, surgery and often adjuvant RAI are common components of therapy.  The role of radiotherapy is less well defined and is often decided on a case-by-case basis.  Systemic therapeutic options, particularly with targeted therapies, are being actively investigated.  ATCs usually require a multimodality approach, typically with concurrent chemotherapy and radiation. Conflict of interest statement Sue S. Yom, MD, PhD – Clinical trial support from Genentech. References
[1] Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA 2006;295(18):2164–7. [2] Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 2009;59(4):225–49. [3] Schneider AB, Sarne DH. Long-term risks for thyroid cancer and other neoplasms after exposure to radiation. Nat Clin Pract Endocrinol Metab 2005;1(2):82–91. [4] Pal T, Vogl FD, Chappuis PO, et al. Increased risk for nonmedullary thyroid cancer in the first degree relatives of prevalent cases of nonmedullary thyroid cancer: a hospital-based study. J Clin Endocrinol Metab 2001;86(11):5307–12. [5] Schlumberger M, Catargi B, Borget I, et al. Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med 2012;366(18):1663–73. [6] NCCN Clinical Practice Guidelines in Oncology. Thyroid carcinoma. Version 3.2012; 2012. [7] Machens A, Holzhausen HJ, Dralle H. Skip metastases in thyroid cancer leaping the central lymph node compartment. Arch Surg 2004;139(1):43–5. [8] Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for [27] [23] [9]

[10]

[11] [12]

[13] [14]

[15]

[16]

[17]

[18] [19]

[20]

[21]

[22]

[24]

[25]

[26]

[28] [29]

[30] [31]

[32]

[33] [34]

[35]

J.K. Salama et al. / Oral Oncology 50 (2014) 577–586 [36] Fard-Esfahani A, Hadifar M, Fallahi B, et al. Radioiodine treatment complications to the mother and child in patients with differentiated thyroid carcinoma. Hell J Nucl Med 2009;12(1):37–40. [37] Almeida JP, Kowalski LP. Pilocarpine used to treat xerostomia in patients submitted to radioactive iodine therapy: a pilot study. Braz J Otorhinolaryngol 2010;76(5):659–62. [38] Bohuslavizki KH, Klutmann S, Jenicke L, et al. Salivary gland protection by S2-(3-aminopropylamino)-ethylphosphorothioic acid (amifostine) in highdose radioiodine treatment: results obtained in a rabbit animal model and in a double-blind multi-arm trial. Cancer Biother Radiopharm 1999;14(5):337–47. [39] Iyer NG, Morris LG, Tuttle RM, Shaha AR, Ganly I. Rising incidence of second cancers in patients with low-risk (T1N0) thyroid cancer who receive radioactive iodine therapy. Cancer 2011;117(19):4439–46. [40] Park HS, Roman SA, Sosa JA. Treatment patterns of aging Americans with differentiated thyroid cancer. Cancer 2010;116(1):20–30. [41] Brierley JD, Tsang RW. External beam radiation therapy for thyroid cancer. Endocrinol Metab Clin North Am 2008;37(2):497–509. xi. [42] Biermann M, Pixberg M, Riemann B, et al. Clinical outcomes of adjuvant external-beam radiotherapy for differentiated thyroid cancer – results after 874 patient-years of follow-up in the MSDS-trial. Nuklearmedizin 2009;48(3):89–98. quiz N15. [43] Farahati J, Reiners C, Stuschke M, et al. Differentiated thyroid cancer. Impact of adjuvant external radiotherapy in patients with perithyroidal tumor infiltration (stage pT4). Cancer 1996;77(1):172–80. [44] Chow SM, Law SC, Mendenhall WM, et al. Papillary thyroid carcinoma: prognostic factors and the role of radioiodine and external radiotherapy. Int J Radiat Oncol Biol Phys 2002;52(3):784–95. [45] Samaan NA, Schultz PN, Hickey RC, et al. The results of various modalities of treatment of well differentiated thyroid carcinomas: a retrospective review of 1599 patients. J Clin Endocrinol Metab 1992;75(3):714–20. [46] Lin JD, Tsang NM, Huang MJ, Weng HF. Results of external beam radiotherapy in patients with well differentiated thyroid carcinoma. Jpn J Clin Oncol 1997;27(4):244–7. [47] Rosa Pelizzo M, Toniato A, Boschin IM, et al. Locally advanced differentiated thyroid carcinoma: a 35-year mono-institutional experience in 280 patients. Nucl Med Commun 2005;26(11):965–8. [48] Staunton MD. Thyroid cancer: a multivariate analysis on influence of treatment on long-term survival. Eur J Surg Oncol 1994;20(6):613–21. [49] Lenio PT. External irradiation in treatment of papillary carcinoma of the thyroid. Am J Surg 1976;131(3):281–3. [50] Simpson WJ, Carruthers JS. The role of external radiation in the management of papillary and follicular thyroid cancer. Am J Surg 1978;136(4):457–60. [51] Kim TH, Chung KW, Lee YJ, et al. The effect of external beam radiotherapy volume on locoregional control in patients with locoregionally advanced or recurrent nonanaplastic thyroid cancer. Radiat Oncol 2010;5:69. [52] Rosenbluth BD, Serrano V, Happersett L, et al. Intensity-modulated radiation therapy for the treatment of nonanaplastic thyroid cancer. Int J Radiat Oncol Biol Phys 2005;63(5):1419–26. [53] Urbano TG, Clark CH, Hansen VN, et al. Intensity Modulated Radiotherapy (IMRT) in locally advanced thyroid cancer: acute toxicity results of a phase I study. Radiother Oncol 2007;85(1):58–63. [54] Schwartz DL, Lobo MJ, Ang KK, et al. Postoperative external beam radiotherapy for differentiated thyroid cancer: outcomes and morbidity with conformal treatment. Int J Radiat Oncol Biol Phys 2009;74(4):1083–91. [55] Tubiana M, Haddad E, Schlumberger M, Hill C, Rougier P, Sarrazin D. External radiotherapy in thyroid cancers. Cancer 1985;55(9 Suppl.):2062–71. [56] Terezakis SA, Lee KS, Ghossein RA, et al. Role of external beam radiotherapy in patients with advanced or recurrent nonanaplastic thyroid cancer: Memorial Sloan-kettering Cancer Center experience. Int J Radiat Oncol Biol Phys 2009;73(3):795–801. [57] O’Connell ME, A’Hern RP, Harmer CL. Results of external beam radiotherapy in differentiated thyroid carcinoma: a retrospective study from the Royal Marsden Hospital. Eur J Cancer 1994;30A(6):733–9. [58] Simpson WJ, Panzarella T, Carruthers JS, Gospodarowicz MK, Sutcliffe SB. Papillary and follicular thyroid cancer: impact of treatment in 1578 patients. Int J Radiat Oncol Biol Phys 1988;14(6):1063–75. [59] Gottlieb JA, Hill Jr CS. Chemotherapy of thyroid cancer with adriamycin. Experience with 30 patients. N Engl J Med 1974;290(4):193–7. [60] Mathur A, Moses W, Rahbari R, et al. Higher rate of BRAF mutation in papillary thyroid cancer over time: a single-institution study. Cancer 2011;117(19):4390–5. [61] Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol 2009;27(10):1675–84. [62] Ahmed M, Barbachano Y, Riddell A, et al. Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population. Eur J Endocrinol 2011;165(2):315–22. [63] Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol 2008;26(29):4714–9. [64] Bible KC, Suman VJ, Molina JR, et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol 2010;11(10):962–72. [65] Cohen EE, Rosen LS, Vokes EE, et al. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol 2008;26(29):4708–13.

585

[66] Schreinemakers JM, Vriens MR, Munoz-Perez N, et al. Fluorodeoxyglucosepositron emission tomography scan-positive recurrent papillary thyroid cancer and the prognosis and implications for surgical management. World J Surg Oncol 2012;10:192. [67] Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 2013;368(7):623–32. [68] Wohllk N, Cote GJ, Bugalho MM, et al. Relevance of RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 1996;81(10):3740–5. [69] Eng C, Mulligan LM, Smith DP, et al. Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf) 1995;43(1):123–7. [70] Brierley J, Tsang R, Simpson WJ, Gospodarowicz M, Sutcliffe S, Panzarella T. Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Thyroid 1996;6(4):305–10. [71] Fersht N, Vini L, A’Hern R, Harmer C. The role of radiotherapy in the management of elevated calcitonin after surgery for medullary thyroid cancer. Thyroid 2001;11(12):1161–8. [72] Nguyen TD, Chassard JL, Lagarde P, et al. Results of postoperative radiation therapy in medullary carcinoma of the thyroid: a retrospective study by the French Federation of Cancer Institutes – the Radiotherapy Cooperative Group. Radiother Oncol 1992;23(1):1–5. [73] Schwartz DL, Rana V, Shaw S, et al. Postoperative radiotherapy for advanced medullary thyroid cancer–local disease control in the modern era. Head Neck 2008;30(7):883–8. [74] Wells Jr SA, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, doubleblind phase III trial. J Clin Oncol 2012;30(2):134–41. [75] Schoffski P, Elisei R, Muller S, et al. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline. ASCO Meeting Abstracts 2012;30(15_Suppl.):5508. [76] Kebebew E, Greenspan FS, Clark OH, Woeber KA, McMillan A. Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer 2005;103(7):1330–5. [77] Tan RK, Finley 3rd RK, Driscoll D, Bakamjian V, Hicks Jr WL, Shedd DP. Anaplastic carcinoma of the thyroid: a 24-year experience. Head Neck 1995;17(1):41–7. discussion 47–48. [78] Tennvall J, Lundell G, Wahlberg P, et al. Anaplastic thyroid carcinoma: three protocols combining doxorubicin, hyperfractionated radiotherapy and surgery. Br J Cancer 2002;86(12):1848–53. [79] Haigh PI, Ituarte PH, Wu HS, et al. Completely resected anaplastic thyroid carcinoma combined with adjuvant chemotherapy and irradiation is associated with prolonged survival. Cancer 2001;91(12):2335–42. [80] Heron DE, Karimpour S, Grigsby PW. Anaplastic thyroid carcinoma: comparison of conventional radiotherapy and hyperfractionation chemoradiotherapy in two groups. Am J Clin Oncol 2002;25(5):442–6. [81] De Crevoisier R, Baudin E, Bachelot A, et al. Combined treatment of anaplastic thyroid carcinoma with surgery, chemotherapy, and hyperfractionated accelerated external radiotherapy. Int J Radiat Oncol Biol Phys 2004;60(4):1137–43. [82] Nel CJ, van Heerden JA, Goellner JR, et al. Anaplastic carcinoma of the thyroid: a clinicopathologic study of 82 cases. Mayo Clin Proc 1985;60(1):51–8. [83] Chen J, Tward JD, Shrieve DC, Hitchcock YJ. Surgery and radiotherapy improves survival in patients with anaplastic thyroid carcinoma: analysis of the surveillance, epidemiology, and end results 1983–2002. Am J Clin Oncol 2008;31(5):460–4. [84] Pierie JP, Muzikansky A, Gaz RD, Faquin WC, Ott MJ. The effect of surgery and radiotherapy on outcome of anaplastic thyroid carcinoma. Ann Surg Oncol 2002;9(1):57–64. [85] McIver B, Hay ID, Giuffrida DF, et al. Anaplastic thyroid carcinoma: a 50-year experience at a single institution. Surgery 2001;130(6):1028–34. [86] Foote RL, Molina JR, Kasperbauer JL, et al. Enhanced survival in locoregionally confined anaplastic thyroid carcinoma: a single-institution experience using aggressive multimodal therapy. Thyroid 2011;21(1):25–30. [87] Besic N, Auersperg M, Us-Krasovec M, Golouh R, Frkovic-Grazio S, Vodnik A. Effect of primary treatment on survival in anaplastic thyroid carcinoma. Eur J Surg Oncol 2001;27(3):260–4. [88] Busnardo B, Daniele O, Pelizzo MR, et al. A multimodality therapeutic approach in anaplastic thyroid carcinoma: study on 39 patients. J Endocrinol Invest 2000;23(11):755–61. [89] Junor EJ, Paul J, Reed NS. Anaplastic thyroid carcinoma: 91 patients treated by surgery and radiotherapy. Eur J Surg Oncol 1992;18(2):83–8. [90] Troch M, Koperek O, Scheuba C, et al. High efficacy of concomitant treatment of undifferentiated (anaplastic) thyroid cancer with radiation and docetaxel. J Clin Endocrinol Metab 2010;95(9):E54–57. [91] Wong CS, Van Dyk J, Simpson WJ. Myelopathy following hyperfractionated accelerated radiotherapy for anaplastic thyroid carcinoma. Radiother Oncol 1991;20(1):3–9. [92] Simpson WJ. Anaplastic thyroid carcinoma: a new approach. Can J Surg 1980;23(1):25–7. [93] Mitchell G, Huddart R, Harmer C. Phase II evaluation of high dose accelerated radiotherapy for anaplastic thyroid carcinoma. Radiother Oncol 1999;50(1):33–8.

586

J.K. Salama et al. / Oral Oncology 50 (2014) 577–586 [98] Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006;91(8):2892–9. [99] Wang W, Larson SM, Tuttle RM, et al. Resistance of [18f]-fluorodeoxyglucoseavid metastatic thyroid cancer lesions to treatment with high-dose radioactive iodine. Thyroid 2001;11(12):1169–75. [100] Ain KB, Lee C, Williams KD. Phase II trial of thalidomide for therapy of radioiodine-unresponsive and rapidly progressive thyroid carcinomas. Thyroid 2007;17(7):663–70.

[94] Wang Y, Tsang R, Asa S, Dickson B, Arenovich T, Brierley J. Clinical outcome of anaplastic thyroid carcinoma treated with radiotherapy of once- and twicedaily fractionation regimens. Cancer 2006;107(8):1786–92. [95] Kim JH, Leeper RD. Treatment of locally advanced thyroid carcinoma with combination doxorubicin and radiation therapy. Cancer 1987;60(10):2372–5. [96] Bhatia A, Rao A, Ang KK, et al. Anaplastic thyroid cancer: clinical outcomes with conformal radiotherapy. Head Neck 2010;32(7):829–36. [97] Haugen BR, Kane MA. Approach to the thyroid cancer patient with extracervical metastases. J Clin Endocrinol Metab 2010;95(3):987–93.