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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/pdqcis/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-pdqcis-lrg.png" alt="Cover of PDQ Cancer Information Summaries" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>PDQ Cancer Information Summaries [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK65719_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK65719_dtls__"><div>Bethesda (MD): <a href="http://www.cancer.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Cancer Institute (US)</a>; 2002-.</div></div><div class="half_rhythm"></div><div class="bk_noprnt"><form method="get" action="/books/n/pdqcis/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK65719_"><span class="title" itemprop="name">Thyroid Cancer Treatment (Adult) (PDQ®)</span></h1><div class="subtitle whole_rhythm">Health Professional Version</div><p class="contrib-group"><span itemprop="author">PDQ Adult Treatment Editorial Board</span>.</p><p class="small">Published online: February 18, 2022.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p id="CDR0000062913__418">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult thyroid cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.</p><p id="CDR0000062913__419">This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p></div><div id="CDR0000062913__1"><h2 id="_CDR0000062913__1_">General Information About Thyroid Cancer</h2><p id="CDR0000062913__574">Thyroid cancer includes the following four main types:</p><ul id="CDR0000062913__575"><li class="half_rhythm"><div>Papillary.</div></li><li class="half_rhythm"><div>Follicular.</div></li><li class="half_rhythm"><div>Medullary.</div></li><li class="half_rhythm"><div>Anaplastic.</div></li></ul><p id="CDR0000062913__421">For clinical management of
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the patient, thyroid cancer is generally divided into the following two categories:[<a class="bk_pop" href="#CDR0000062913_rl_1_1">1</a>]
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</p><ol id="CDR0000062913__617"><li class="half_rhythm"><div>Differentiated thyroid cancer, which includes well-differentiated tumors, poorly differentiated tumors, and undifferentiated tumors (papillary, follicular, or anaplastic).</div></li><li class="half_rhythm"><div>Medullary thyroid cancer. </div></li></ol><p id="CDR0000062913__627">Well-differentiated tumors (papillary and follicular thyroid cancer) are highly treatable and usually curable. Poorly differentiated and undifferentiated thyroid tumors (anaplastic thyroid cancer) are less common, aggressive, metastasize early, and have a poorer prognosis. Medullary thyroid cancer is a neuroendocrine cancer that has an intermediate prognosis. </p><p id="CDR0000062913__423">The
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thyroid gland may occasionally be the site of other primary tumors, including
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sarcomas, lymphomas, epidermoid carcinomas, and teratomas. The thyroid may also be the site
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of metastasis from other cancers, particularly of the lung, breast, and kidney.
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</p><div id="CDR0000062913__304"><h3>Incidence and Mortality</h3><p id="CDR0000062913__243">Estimated new cases and deaths from thyroid cancer in the United States in 2022:[<a class="bk_pop" href="#CDR0000062913_rl_1_2">2</a>]</p><ul id="CDR0000062913__244"><li class="half_rhythm"><div>New cases: 43,800.</div></li><li class="half_rhythm"><div>Deaths: 2,230.</div></li></ul><p id="CDR0000062913__312">Thyroid
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cancer affects women more often than men and usually occurs in
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people aged 25 to 65 years. The incidence of this malignancy has
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|
been increasing over the last decade. Thyroid cancer commonly presents
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as a so-called <i>cold nodule</i>. It is detected as a palpable thyroid gland during a physical exam and evaluated with iodine I 131 scans; scintigraphy shows that the isotope is not taken up in an area of the gland. The overall incidence of cancer in a cold nodule is 12% to
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15%, but it is higher in people younger than 40 years and in people with calcifications present on preoperative ultrasonography.[<a class="bk_pop" href="#CDR0000062913_rl_1_3">3</a>,<a class="bk_pop" href="#CDR0000062913_rl_1_4">4</a>]</p></div><div id="CDR0000062913__424"><h3>Anatomy</h3><p id="CDR0000062913__747">Thyroid gland tissue envelops the upper trachea just below the thyroid and cricoid cartilages that make up the larynx. The gland has an isthmus and often asymmetric right and left lobes; usually four parathyroid glands lie posteriorly. When swallowing, the thyroid may be felt to rise with the larynx—most commonly in the presence of a disease process. </p><div id="CDR0000062913__842" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Anatomy%20of%20the%20thyroid%20and%20parathyroid%20glands&p=BOOKS&id=578124_CDR0000719086.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000719086.jpg" alt="Anatomy of the thyroid and parathyroid glands; drawing shows the thyroid gland at the base of the throat near the trachea. An inset shows the front and back views. The front view shows that the thyroid is shaped like a butterfly, with the right lobe and left lobe connected by a thin piece of tissue called the isthmus. The back view shows the four pea-sized parathyroid glands. The larynx is also shown." class="tileshop" title="Click on image to zoom" /></a></div><div class="caption"><p>Anatomy of the thyroid and parathyroid glands.</p></div></div></div><div id="CDR0000062913__313"><h3>Risk Factors</h3><p id="CDR0000062913__314">Patients with a history of radiation therapy administered in infancy or childhood for
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benign conditions of the head and neck (such as
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enlarged thymus, tonsils, or adenoids; or acne) have an increased risk of cancer and
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other abnormalities of the thyroid gland. In this group of patients,
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malignancies of the thyroid gland appear as early as 5 years
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after radiation therapy and may appear 20 or more years later.[<a class="bk_pop" href="#CDR0000062913_rl_1_5">5</a>] Radiation exposure as a consequence of nuclear fallout has also been associated with a high risk of thyroid cancer, especially in children.[<a class="bk_pop" href="#CDR0000062913_rl_1_6">6</a>-<a class="bk_pop" href="#CDR0000062913_rl_1_8">8</a>] </p><p id="CDR0000062913__549">Other risk
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factors for thyroid cancer include the following:[<a class="bk_pop" href="#CDR0000062913_rl_1_9">9</a>]</p><ul id="CDR0000062913__315"><li class="half_rhythm"><div>Family history of thyroid disease or multiple endocrine neoplasia (MEN) syndrome.</div></li><li class="half_rhythm"><div><i>RET</i> gene mutation.[<a class="bk_pop" href="#CDR0000062913_rl_1_2">2</a>,<a class="bk_pop" href="#CDR0000062913_rl_1_10">10</a>]</div></li><li class="half_rhythm"><div>A history of goiter.</div></li><li class="half_rhythm"><div>Female gender.</div></li><li class="half_rhythm"><div>Asian race.</div></li></ul></div><div id="CDR0000062913__426"><h3>Diagnostic and Staging Evaluation</h3><p id="CDR0000062913__427">The following tests and procedures may be used in the diagnosis and staging of thyroid cancer:</p><ul id="CDR0000062913__428"><li class="half_rhythm"><div>Physical exam and history.</div></li><li class="half_rhythm"><div>Laryngoscopy.</div></li><li class="half_rhythm"><div>Blood hormone studies.</div></li><li class="half_rhythm"><div>Blood chemistry studies.</div></li><li class="half_rhythm"><div>Ultrasound exam.</div></li><li class="half_rhythm"><div>Computed tomography scan.</div></li><li class="half_rhythm"><div>Fine-needle aspiration biopsy of the thyroid.</div></li><li class="half_rhythm"><div>Surgical excision.</div></li></ul></div><div id="CDR0000062913__316"><h3>Prognostic Factors for Well-Differentiated Thyroid Cancer</h3><p id="CDR0000062913__317"> Age appears to be the
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single most important prognostic factor.[<a class="bk_pop" href="#CDR0000062913_rl_1_11">11</a>] The prognosis for differentiated
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carcinoma (papillary or follicular) without
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extracapsular extension or vascular invasion is better for patients younger than 40 years.[<a class="bk_pop" href="#CDR0000062913_rl_1_11">11</a>-<a class="bk_pop" href="#CDR0000062913_rl_1_15">15</a>]</p><p id="CDR0000062913__580">Patients considered at low risk according to age, metastases, extent, and size risk criteria include women younger than 50 years and men younger
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than 40 years without evidence of distant metastases. The low-risk group also includes older patients with primary papillary tumors smaller than 5
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cm without evidence of gross extrathyroidal
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invasion, and older patients with follicular cancer without major capsular invasion or blood
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vessel invasion.[<a class="bk_pop" href="#CDR0000062913_rl_1_13">13</a>] Using these criteria, a retrospective study of 1,019
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patients showed that the 20-year survival rate was 98% for low-risk patients and
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50% for high-risk patients.[<a class="bk_pop" href="#CDR0000062913_rl_1_13">13</a>]</p><p id="CDR0000062913__536">A
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retrospective surgical series of 931 previously untreated patients with
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differentiated thyroid cancer found that age older than 45 years, follicular histology, primary tumor larger than 4
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cm (T2–T3), extrathyroidal extension (T4), and distant metastases were adverse prognostic factors.[<a class="bk_pop" href="#CDR0000062913_rl_1_16">16</a>,<a class="bk_pop" href="#CDR0000062913_rl_1_17">17</a>] Favorable prognostic factors included female gender, multifocality, and
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regional lymph node involvement.[<a class="bk_pop" href="#CDR0000062913_rl_1_16">16</a>]
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Other studies, however, have shown that regional lymph node involvement had no
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effect [<a class="bk_pop" href="#CDR0000062913_rl_1_18">18</a>,<a class="bk_pop" href="#CDR0000062913_rl_1_19">19</a>] or had an adverse effect on survival.[<a class="bk_pop" href="#CDR0000062913_rl_1_14">14</a>,<a class="bk_pop" href="#CDR0000062913_rl_1_15">15</a>,<a class="bk_pop" href="#CDR0000062913_rl_1_20">20</a>] </p><p id="CDR0000062913__910">Another retrospective series of 1,807 patients found that the presence of distant metastases was most predictive of survival, followed by age.[<a class="bk_pop" href="#CDR0000062913_rl_1_21">21</a>] An age cutoff of 55 years was identified as most predictive of survival. This led to an international multi-institutional validation of age 55 years as a cutoff for risk stratification in the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system for well-differentiated thyroid cancer. This analysis of 9,484 patients was responsible for the change in age cutoff from 45 years to 55 years in the <i>AJCC Cancer Staging Manual</i>, 8th edition, using AJCC/UICC staging for well-differentiated thyroid cancer.[<a class="bk_pop" href="#CDR0000062913_rl_1_22">22</a>] </p><p id="CDR0000062913__630"> The prognostic significance of lymph node status is controversial. Use of sentinel lymph node biopsy may aid in identifying patients with occult metastases who might benefit from central neck dissection.[<a class="bk_pop" href="#CDR0000062913_rl_1_23">23</a>]</p><p id="CDR0000062913__430">Diffuse, intense
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immunostaining for vascular endothelial growth factor in patients with
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papillary cancer has been associated with a high rate of local recurrence and
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distant metastases.[<a class="bk_pop" href="#CDR0000062913_rl_1_24">24</a>] An elevated serum thyroglobulin level correlates
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strongly with recurrent tumor when found in patients with differentiated
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thyroid cancer during postoperative evaluations.[<a class="bk_pop" href="#CDR0000062913_rl_1_25">25</a>,<a class="bk_pop" href="#CDR0000062913_rl_1_26">26</a>] Serum thyroglobulin
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levels are most sensitive when patients are hypothyroid and have elevated serum
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thyroid-stimulating hormone levels.[<a class="bk_pop" href="#CDR0000062913_rl_1_27">27</a>] Expression of the tumor suppressor
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gene <i>p53</i> has also been associated with an adverse prognosis for patients with
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thyroid cancer.[<a class="bk_pop" href="#CDR0000062913_rl_1_28">28</a>]</p><p id="CDR0000062913__631">(Refer to the <a href="#CDR0000062913__492">Clinical Features and Prognosis </a> section of the Medullary Thyroid Cancer section and the <a href="#CDR0000062913__519">Clinical Features and Prognosis</a> section of the Anaplastic Thyroid Cancer section of this summary for more information about prognosis.)</p></div><div id="CDR0000062913__320"><h3>Related Summaries</h3><p id="CDR0000062913__321">Other PDQ summaries containing information related to thyroid cancer include the following: </p><ul id="CDR0000062913__322"><li class="half_rhythm"><div>
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<a href="/books/n/pdqcis/CDR0000062890/">Genetics of Endocrine and Neuroendocrine Neoplasias</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/pdqcis/CDR0000790382/">Childhood Thyroid Cancer Treatment</a>
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</div></li><li class="half_rhythm"><div>
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<a href="/books/n/pdqcis/CDR0000800107/">Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment</a>
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</div></li></ul></div><div id="CDR0000062913_rl_1"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062913_rl_1_1">LiVolsi VA: Pathology of thyroid disease. In: Falk SA: Thyroid Disease: Endocrinology, Surgery, Nuclear Medicine, and Radiotherapy. Lippincott-Raven, 1997, pp 127-175.</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_2">American Cancer Society: Cancer Facts and Figures 2022. American Cancer Society, 2022. <a href="https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2022/2022-cancer-facts-and-figures.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed October 7, 2022.</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_3">Tennvall J, Biörklund A, Möller T, et al.: Is the EORTC prognostic index of thyroid cancer valid in differentiated thyroid carcinoma? Retrospective multivariate analysis of differentiated thyroid carcinoma with long follow-up. Cancer 57 (7): 1405-14, 1986. [<a href="https://pubmed.ncbi.nlm.nih.gov/3948123" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3948123</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_4">Khoo ML, Asa SL, Witterick IJ, et al.: Thyroid calcification and its association with thyroid carcinoma. Head Neck 24 (7): 651-5, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12112538" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12112538</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_5">Carling T, Udelsman R: Thyroid tumors. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 1457-72.</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_6">Pacini F, Vorontsova T, Molinaro E, et al.: Prevalence of thyroid autoantibodies in children and adolescents from Belarus exposed to the Chernobyl radioactive fallout. Lancet 352 (9130): 763-6, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9737280" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9737280</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_7">Cardis E, Kesminiene A, Ivanov V, et al.: Risk of thyroid cancer after exposure to 131I in childhood. J Natl Cancer Inst 97 (10): 724-32, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15900042" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15900042</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_8">Tronko MD, Howe GR, Bogdanova TI, et al.: A cohort study of thyroid cancer and other thyroid diseases after the chornobyl accident: thyroid cancer in Ukraine detected during first screening. J Natl Cancer Inst 98 (13): 897-903, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16818853" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16818853</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_9">Iribarren C, Haselkorn T, Tekawa IS, et al.: Cohort study of thyroid cancer in a San Francisco Bay area population. Int J Cancer 93 (5): 745-50, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11477590" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11477590</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_10">Salvatore G, Giannini R, Faviana P, et al.: Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma. J Clin Endocrinol Metab 89 (10): 5175-80, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15472223" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15472223</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_11">Mazzaferri EL: Treating differentiated thyroid carcinoma: where do we draw the line? Mayo Clin Proc 66 (1): 105-11, 1991. [<a href="https://pubmed.ncbi.nlm.nih.gov/1988750" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1988750</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_12">Grant CS, Hay ID, Gough IR, et al.: Local recurrence in papillary thyroid carcinoma: is extent of surgical resection important? Surgery 104 (6): 954-62, 1988. [<a href="https://pubmed.ncbi.nlm.nih.gov/3194847" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3194847</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_13">Sanders LE, Cady B: Differentiated thyroid cancer: reexamination of risk groups and outcome of treatment. Arch Surg 133 (4): 419-25, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9565123" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9565123</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_14">Staunton MD: Thyroid cancer: a multivariate analysis on influence of treatment on long-term survival. Eur J Surg Oncol 20 (6): 613-21, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7995409" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7995409</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_15">Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97 (5): 418-28, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7977430" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7977430</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_16">Shah JP, Loree TR, Dharker D, et al.: Prognostic factors in differentiated carcinoma of the thyroid gland. Am J Surg 164 (6): 658-61, 1992. [<a href="https://pubmed.ncbi.nlm.nih.gov/1463119" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1463119</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_17">Andersen PE, Kinsella J, Loree TR, et al.: Differentiated carcinoma of the thyroid with extrathyroidal extension. Am J Surg 170 (5): 467-70, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7485734" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7485734</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_18">Coburn MC, Wanebo HJ: Prognostic factors and management considerations in patients with cervical metastases of thyroid cancer. Am J Surg 164 (6): 671-6, 1992. [<a href="https://pubmed.ncbi.nlm.nih.gov/1463122" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1463122</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_19">Voutilainen PE, Multanen MM, Leppäniemi AK, et al.: Prognosis after lymph node recurrence in papillary thyroid carcinoma depends on age. Thyroid 11 (10): 953-7, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11716043" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11716043</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_20">Sellers M, Beenken S, Blankenship A, et al.: Prognostic significance of cervical lymph node metastases in differentiated thyroid cancer. Am J Surg 164 (6): 578-81, 1992. [<a href="https://pubmed.ncbi.nlm.nih.gov/1463103" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1463103</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_21">Nixon IJ, Kuk D, Wreesmann V, et al.: Defining a Valid Age Cutoff in Staging of Well-Differentiated Thyroid Cancer. Ann Surg Oncol 23 (2): 410-5, 2016. [<a href="/pmc/articles/PMC4959904/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4959904</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26215199" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26215199</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_22">Nixon IJ, Wang LY, Migliacci JC, et al.: An International Multi-Institutional Validation of Age 55 Years as a Cutoff for Risk Stratification in the AJCC/UICC Staging System for Well-Differentiated Thyroid Cancer. Thyroid 26 (3): 373-80, 2016. [<a href="/pmc/articles/PMC4790212/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4790212</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26914539" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26914539</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_23">Cunningham DK, Yao KA, Turner RR, et al.: Sentinel lymph node biopsy for papillary thyroid cancer: 12 years of experience at a single institution. Ann Surg Oncol 17 (11): 2970-5, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20552407" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20552407</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_24">Lennard CM, Patel A, Wilson J, et al.: Intensity of vascular endothelial growth factor expression is associated with increased risk of recurrence and decreased disease-free survival in papillary thyroid cancer. Surgery 129 (5): 552-8, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11331447" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11331447</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_25">van Herle AJ, van Herle KA: Thyroglobulin in benign and malignant thyroid disease. In: Falk SA: Thyroid Disease: Endocrinology, Surgery, Nuclear Medicine, and Radiotherapy. Lippincott-Raven, 1997, pp 601-618.</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_26">Ruiz-Garcia J, Ruiz de Almodóvar JM, Olea N, et al.: Thyroglobulin level as a predictive factor of tumoral recurrence in differentiated thyroid cancer. J Nucl Med 32 (3): 395-8, 1991. [<a href="https://pubmed.ncbi.nlm.nih.gov/2005446" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2005446</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_27">Duren M, Siperstein AE, Shen W, et al.: Value of stimulated serum thyroglobulin levels for detecting persistent or recurrent differentiated thyroid cancer in high- and low-risk patients. Surgery 126 (1): 13-9, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10418587" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10418587</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_1_28">Godballe C, Asschenfeldt P, Jørgensen KE, et al.: Prognostic factors in papillary and follicular thyroid carcinomas: p53 expression is a significant indicator of prognosis. Laryngoscope 108 (2): 243-9, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9473076" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9473076</span></a>]</div></li></ol></div></div><div id="CDR0000062913__6"><h2 id="_CDR0000062913__6_">Cellular Classification of Thyroid Cancer</h2><p id="CDR0000062913__7">In thyroid cancer, cell type is an important determinant of prognosis and treatment. The thyroid has two cell types: follicular cells and parafollicular C cells. The management of thyroid cancer depends on the cell of origin and how well the integrity of the cell type is maintained. The four main types of thyroid cancer are divided into the following two categories for clinical management:[<a class="bk_pop" href="#CDR0000062913_rl_6_1">1</a>]
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</p><h4><span class="title">Differentiated (follicular cell) thyroid cancers.</span></h4><ol id="CDR0000062913__911"><li class="half_rhythm"><div>Well-differentiated.<ol id="CDR0000062913__912" class="lower-alpha"><li class="half_rhythm"><div>Papillary thyroid carcinoma.</div></li><li class="half_rhythm"><div>Follicular thyroid carcinoma.<ul id="CDR0000062913__913"><li class="half_rhythm"><div>Hürthle cell carcinoma, a variant of follicular carcinoma with a poorer prognosis.[<a class="bk_pop" href="#CDR0000062913_rl_6_2">2</a>,<a class="bk_pop" href="#CDR0000062913_rl_6_3">3</a>]</div></li></ul></div></li></ol></div></li><li class="half_rhythm"><div>Poorly differentiated.</div></li><li class="half_rhythm"><div>Undifferentiated.<ul id="CDR0000062913__914"><li class="half_rhythm"><div>Anaplastic thyroid carcinoma.</div></li></ul></div></li></ol><h4><span class="title">Parafollicular C cell thyroid cancers.</span></h4><ol id="CDR0000062913__915"><li class="half_rhythm"><div> Medullary thyroid carcinoma.</div></li></ol><h4><span class="title">Other types (not derived from thyroid cells).</span></h4><ol id="CDR0000062913__916"><li class="half_rhythm"><div>Lymphoma.</div></li><li class="half_rhythm"><div>Sarcoma.</div></li><li class="half_rhythm"><div>Carcinosarcoma.</div></li></ol><div id="CDR0000062913_rl_6"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062913_rl_6_1">LiVolsi VA: Pathology of thyroid disease. In: Falk SA: Thyroid Disease: Endocrinology, Surgery, Nuclear Medicine, and Radiotherapy. Lippincott-Raven, 1997, pp 127-175.</div></li><li><div class="bk_ref" id="CDR0000062913_rl_6_2">Kushchayeva Y, Duh QY, Kebebew E, et al.: Comparison of clinical characteristics at diagnosis and during follow-up in 118 patients with Hurthle cell or follicular thyroid cancer. Am J Surg 195 (4): 457-62, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18070728" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18070728</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_6_3">Mills SC, Haq M, Smellie WJ, et al.: Hürthle cell carcinoma of the thyroid: Retrospective review of 62 patients treated at the Royal Marsden Hospital between 1946 and 2003. Eur J Surg Oncol 35 (3): 230-4, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/18722077" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18722077</span></a>]</div></li></ol></div></div><div id="CDR0000062913__14"><h2 id="_CDR0000062913__14_">Stage Information for Thyroid Cancer</h2><div id="CDR0000062913__298"><h3>Definitions of TNM</h3><p id="CDR0000062913__301">The American Joint Committee on Cancer has designated staging by the TNM (tumor, node, metastasis)
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classification to define thyroid cancer.[<a class="bk_pop" href="#CDR0000062913_rl_14_1">1</a>,<a class="bk_pop" href="#CDR0000062913_rl_14_2">2</a>] Definitions of TNM stages for each type of thyroid cancer are described in the following sections of this summary:</p><ul id="CDR0000062913__632"><li class="half_rhythm"><div><a href="#CDR0000062913__441">Stage information for papillary and follicular thyroid cancer</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062913__500">Stage information for medullary thyroid cancer</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062913__523">Stage information for anaplastic thyroid cancer</a>.</div></li></ul></div><div id="CDR0000062913_rl_14"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062913_rl_14_1">Tuttle RM, Morris LF, Haugen BR, et al.: Thyroid--Differentiated and Anaplastic Carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 873-90.</div></li><li><div class="bk_ref" id="CDR0000062913_rl_14_2">Rosen Je, Lloyd RV, Brierley JD, et al.: Thyroid--Medullary. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 891-901.</div></li></ol></div></div><div id="CDR0000062913__555"><h2 id="_CDR0000062913__555_">Treatment Option Overview for Thyroid Cancer</h2><p id="CDR0000062913__753">Standard treatment options for thyroid cancer are described in <a class="figpopup" href="/books/NBK65719.23/table/CDR0000062913__754/?report=objectonly" target="object" rid-figpopup="figCDR0000062913754" rid-ob="figobCDR0000062913754">Table 1</a>.</p><div id="CDR0000062913__754" class="table"><h3><span class="title">Table 1. Standard Treatment Options for Thyroid Cancer</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65719.23/table/CDR0000062913__754/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062913__754_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Type of Thyroid Cancer</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Disease Status</th><th colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">Standard Treatment Options </th></tr></thead><tbody><tr><td colspan="1" rowspan="6" style="vertical-align:top;">Papillary and follicular</td><td colspan="1" rowspan="6" style="vertical-align:top;">Localized/regional</td><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__637">Surgery</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062913__639">–Total thyroidectomy</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062913__917">–Lobectomy</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__920">RAI therapy</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__941">Thyroid-suppression therapy</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__943">EBRT</a>
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</td></tr><tr><td colspan="1" rowspan="8" style="vertical-align:top;">Papillary and follicular</td><td colspan="1" rowspan="8" style="vertical-align:top;">Metastatic </td><td colspan="2" rowspan="1" style="vertical-align:top;">
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<b>Iodine-sensitive:</b>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="/books/NBK65719.23/#CDR0000062913__695">RAI therapy</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="/books/NBK65719.23/#CDR0000062913__695">Thyroid-suppression therapy</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<b>Iodine-resistant:</b>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__696">Thyroid-suppression therapy</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__698">Targeted therapy</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__702">Surgery</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__704">EBRT</a>
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</td></tr><tr><td colspan="1" rowspan="4" style="vertical-align:top;">Recurrent papillary and follicular thyroid cancer</td><td colspan="1" rowspan="4" style="vertical-align:top;"></td><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__676">Surgery with or without postoperative RAI therapy</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__681">Targeted therapy</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__686">EBRT</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__712">Chemotherapy</a>
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</td></tr><tr><td colspan="1" rowspan="4" style="vertical-align:top;">Medullary thyroid cancer</td><td colspan="1" rowspan="2" style="vertical-align:top;">Localized disease</td><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__721">Total thyroidectomy</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__723">EBRT</a>
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</td></tr><tr><td colspan="1" rowspan="2" style="vertical-align:top;">Locally advanced and metastatic disease</td><td colspan="2" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062913__782">Targeted therapy</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__732">Palliative chemotherapy</a>
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</td></tr><tr><td colspan="1" rowspan="3" style="vertical-align:top;">Anaplastic thyroid cancer</td><td colspan="1" rowspan="3" style="vertical-align:top;"></td><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__528">Surgery</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__530">EBRT</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062913__532">Systemic therapy</a>
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</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastases; EBRT = external-beam radiation therapy; RAI = radioactive iodine.</p></div></dd></dl></div></div></div></div><div id="CDR0000062913__435"><h2 id="_CDR0000062913__435_">Papillary and Follicular Thyroid Cancer</h2><div id="CDR0000062913__437"><h3>Clinical Features and Prognosis</h3><p id="CDR0000062913__438">The clinical features and prognosis of well-differentiated thyroid tumors vary by stage.</p><p id="CDR0000062913__597">Most papillary cancers have some follicular elements. These follicular elements may outnumber the papillary formations, but they do not
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change the prognosis. </p><p id="CDR0000062913__598">Follicular adenomas, which are characterized by their lack of invasion through
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the capsule into the surrounding thyroid tissue, must be distinguished from follicular thyroid carcinoma. While follicular cancer has a good prognosis, it
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is less favorable than that of papillary carcinoma. The 10-year survival is better for
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patients with follicular carcinoma without vascular invasion than it is for
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patients with vascular invasion.</p><p id="CDR0000062913__599">Papillary carcinomas metastasize more frequently to regional lymph nodes than
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to distant sites. Follicular carcinomas more commonly invade blood vessels and metastasize hematogenously to the lungs and to the bone rather than through the
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lymphatic system. When metastases occur, treatment with radioiodine is initially effective, but prognosis worsens as resistance to radioiodine ensues.
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</p><p id="CDR0000062913__633">Staging and prognosis of papillary and follicular thyroid cancer are determined by the age and site of the disease. The clinical features and prognoses for papillary thyroid cancer include the following:</p><ul id="CDR0000062913__439"><li class="half_rhythm"><div><b>Stage I papillary or follicular thyroid cancer </b>is localized to the thyroid gland in patients aged 55 years or older. In those younger than 55 years, the cancer may have spread to nearby tissues and lymph nodes but not to other parts of the body. In as many as 50% of the cases, papillary thyroid cancer is multifocal.
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</div></li><li class="half_rhythm"><div><b>Stage II papillary or follicular thyroid cancer</b> is defined by either of the following descriptions: (1) patients are younger than 55 years and the tumor has spread from the thyroid to distant parts of the body, or (2) patients are aged 55 years or older: and the tumor is confined to or has limited invasion outside of the thyroid, with or without lymph node involvement, but without spread to distant parts of the body. Stage II is the most advanced stage possible in a patient younger than 55 years. </div></li><li class="half_rhythm"><div><b>Stage III papillary or follicular thyroid cancer</b> is only possible in patients aged 55 years or older. The thyroid tumor demonstrates extension into surrounding soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve. There may or may not be lymph node involvement, but there is no distant spread to other parts of the body. </div></li><li class="half_rhythm"><div><b> Stage IVA papillary or follicular thyroid cancer</b> is only applicable for patients aged 55 years or older. The thyroid tumor demonstrates extension into surrounding soft tissues that includes either prevertebral fascia or encases the carotid artery or mediastinal vessels. There may or may not be lymph node involvement, but there is no distant spread to other parts of the body.</div></li><li class="half_rhythm"><div>
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<b>Stage IVB papillary or follicular thyroid cancer</b> is only applicable for patients aged 55 years or older. It is defined by the presence of distant spread to other parts of the body. The lungs and bones are the most frequent sites of distant spread. </div></li></ul><p id="CDR0000062913__440">Hürthle cell carcinoma is a variant of follicular carcinoma with a similar prognosis and is treated in the same way as equivalent stage non-Hürthle cell follicular carcinoma.[<a class="bk_pop" href="#CDR0000062913_rl_435_1">1</a>]</p></div><div id="CDR0000062913__441"><h3>Stage Information for Papillary and Follicular Thyroid Cancer</h3><div id="CDR0000062913__883" class="table"><h3><span class="title">Table 2. Definitions of Differentiated TNM Stage I for Papillary and Follicular Thyroid Carcinoma<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65719.23/table/CDR0000062913__883/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062913__883_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Stage</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">T<sup>b</sup>NM</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Description</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Illustration</th></tr></thead><tbody><tr><td colspan="4" rowspan="1" style="vertical-align:top;">
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<b>Age at diagnosis is <55 years:</b>
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</td></tr><tr><td colspan="1" rowspan="20" style="vertical-align:top;">I</td><td colspan="1" rowspan="20" style="vertical-align:top;">Any T, Any N, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">TX = Primary tumor cannot be assessed.</td><td colspan="1" rowspan="20" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000779383&p=BOOKS&id=578124_CDR0000779383.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000779383.jpg" alt="Stage I papillary and follicular thyroid cancer in patients younger than 55 years; drawing shows cancer in the thyroid gland. Also shown are the larynx and trachea." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T0 = No evidence of primary tumor.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T1 = Tumor ≤2 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1a = Tumor ≤1 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1b = Tumor >1 cm but ≤2 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T2 = Tumor >2 cm but ≤4 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T3 = Tumor >4 cm limited to the thyroid, or gross extrathyroidal extension invading only strap muscles.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3a = Tumor >4 cm limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3b = Gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles) from a tumor of any size.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T4 = Includes gross extrathyroidal extension beyond the strap muscles.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T4a = Gross extrathyroidal extension invading subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve from a tumor of any size.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T4b = Gross extrathyroidal extension invading prevertebral fascia or encasing the carotid artery or mediastinal vessels from a tumor of any size.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">NX = Regional lymph nodes cannot be assessed.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N0a = One or more cytologically or histologically confirmed benign lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N0b = No radiologic or clinical evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N1 = Metastasis to regional nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1a = Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1b = Metastasis to unilateral, bilateral, or contralateral cervical neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="4" rowspan="1" style="vertical-align:top;">
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<b>Age at diagnosis is ≥55 years: </b>
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</td></tr><tr><td colspan="1" rowspan="8" style="vertical-align:top;">I</td><td colspan="1" rowspan="4" style="vertical-align:top;">T1, N0/NX, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T1 = Tumor ≤2 cm in greatest dimension, limited to the thyroid.</td><td colspan="1" rowspan="8" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000779378&p=BOOKS&id=578124_CDR0000779378.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000779378.jpg" alt="Stage I papillary and follicular thyroid cancer in patients 55 years and older; drawing shows cancer in the thyroid gland and the tumor is 4 centimeters or smaller. An inset shows 4 centimeters is about the size of a walnut. Also shown are the larynx and trachea." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">NX = Regional lymph nodes cannot be assessed.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="4" style="vertical-align:top;">T2, N0/NX, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T2 = Tumor >2 cm but ≤4 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">NX = Regional lymph nodes cannot be assessed.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastasis.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Reprinted with permission from AJCC: Thyroid--Differentiated and Anaplastic Carcinoma. In: Amin, MB, Edge Sb, Greene FL et al., eds.: <i>AJCC Cancer Staging Manual</i>. 8th ed. New York, NY: Springer, 2017, pp 873–90. </p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>b</sup>All categories may be subdivided: (s) solitary tumor and (m) multifocal tumor (the largest determines the classification).</p></div></dd></dl></div></div></div><div id="CDR0000062913__884" class="table"><h3><span class="title">Table 3. Definitions of Differentiated TNM Stage II for Papillary and Follicular Thyroid Carcinoma<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65719.23/table/CDR0000062913__884/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062913__884_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Stage</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">T<sup>b</sup>NM</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Description</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Illustration</th></tr><tr><th colspan="4" rowspan="1" style="text-align:left;vertical-align:top;">Age at diagnosis is <55 years:</th></tr></thead><tbody><tr><td colspan="1" rowspan="2" style="vertical-align:top;">II</td><td colspan="1" rowspan="2" style="vertical-align:top;">Any T, Any N, M1</td><td colspan="1" rowspan="1" style="vertical-align:top;">Any T = See descriptions in <a class="figpopup" href="/books/NBK65719.23/table/CDR0000062913__883/?report=objectonly" target="object" rid-figpopup="figCDR0000062913883" rid-ob="figobCDR0000062913883">Table 2</a>. </td><td colspan="1" rowspan="2" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000781921&p=BOOKS&id=578124_CDR0000781921.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000781921.jpg" alt="Stage II papillary and follicular thyroid cancer in patients younger than 55 years; drawing shows other parts of the body where thyroid cancer may spread, including the lung and bone. An inset shows cancer cells spreading from the thyroid gland, through the blood and lymph system, to another part of the body where metastatic cancer has formed." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Any N = See descriptions in <a class="figpopup" href="/books/NBK65719.23/table/CDR0000062913__883/?report=objectonly" target="object" rid-figpopup="figCDR0000062913883" rid-ob="figobCDR0000062913883">Table 2</a>.</td></tr><tr><td colspan="4" rowspan="1" style="vertical-align:top;">
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<b>Age at diagnosis is ≥55 years:</b>
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</td></tr><tr><td colspan="1" rowspan="16" style="vertical-align:top;">II</td><td colspan="1" rowspan="7" style="vertical-align:top;">T1, N1, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T1 = Tumor ≤2 cm in greatest dimension, limited to the thyroid.</td><td colspan="1" rowspan="16" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000779381&p=BOOKS&id=578124_CDR0000779381.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000779381.jpg" alt="Stage II papillary and follicular thyroid cancer (1) in patients 55 years and older; drawing shows cancer in the thyroid gland and nearby lymph nodes. The tumor is 4 centimeters or smaller. An inset shows 4 centimeters is about the size of a walnut. Also shown are the larynx and trachea." class="tileshop" title="Click on image to zoom" /></a></div>
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000790804&p=BOOKS&id=578124_CDR0000790804.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000790804.jpg" alt="Stage II papillary and follicular thyroid cancer (2) in patients 55 years and older; drawing shows cancer in the thyroid gland and the tumor is larger than 4 centimeters. An inset shows 4 centimeters is about the size of a walnut. Also shown are the lymph nodes, larynx, and trachea." class="tileshop" title="Click on image to zoom" /></a></div>
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000790805&p=BOOKS&id=578124_CDR0000790805.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000790805.jpg" alt="Stage II papillary and follicular thyroid cancer (3) in patients 55 years and older; drawing shows cancer in the thyroid gland and nearby muscles in the neck. Also shown are the larynx and trachea." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"> –T1a = Tumor ≤1 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1b = Tumor >1 cm but ≤2 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N1 = Metastasis to regional nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1a = Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1b = Metastasis to unilateral, bilateral, or contralateral cervical neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="5" style="vertical-align:top;">T2, N1, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T2 = Tumor >2 cm but ≤4 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N1 = Metastasis to regional nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1a = Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1b = Metastasis to unilateral, bilateral, or contralateral cervical neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="4" style="vertical-align:top;">T3a/T3b, Any N, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">–T3a = Tumor >4 cm limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3b = Gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles) from a tumor of any size.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Any N = See descriptions in <a class="figpopup" href="/books/NBK65719.23/table/CDR0000062913__883/?report=objectonly" target="object" rid-figpopup="figCDR0000062913883" rid-ob="figobCDR0000062913883">Table 2</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastasis.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Reprinted with permission from AJCC: Thyroid--Differentiated and Anaplastic Carcinoma. In: Amin, MB, Edge Sb, Greene FL et al., eds.: <i>AJCC Cancer Staging Manual</i>. 8th ed. New York, NY: Springer, 2017, pp 873–90. </p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>b</sup>All categories may be subdivided: (s) solitary tumor and (m) multifocal tumor (the largest determines the classification).</p></div></dd></dl></div></div></div><div id="CDR0000062913__885" class="table"><h3><span class="title">Table 4. Definitions of Differentiated TNM Stage III for Papillary and Follicular Thyroid Carcinoma<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65719.23/table/CDR0000062913__885/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062913__885_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Stage </th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">T<sup>b</sup>NM</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Description</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Illustration</th></tr></thead><tbody><tr><td colspan="4" rowspan="1" style="vertical-align:top;">
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<b>Age at diagnosis is ≥55 years:</b>
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</td></tr><tr><td colspan="1" rowspan="3" style="vertical-align:top;">III</td><td colspan="1" rowspan="3" style="vertical-align:top;">T4a, Any N, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;"> –T4a = Gross extrathyroidal extension invading subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve from a tumor of any size.</td><td colspan="1" rowspan="3" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000779382&p=BOOKS&id=578124_CDR0000779382.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000779382.jpg" alt="Stage III papillary and follicular thyroid cancer in patients 55 years and older; drawing shows cancer that has spread from the thyroid gland to the esophagus, the trachea, the larynx, and the left recurrent laryngeal nerve. Also shown is the right recurrent laryngeal nerve." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Any N = See descriptions in <a class="figpopup" href="/books/NBK65719.23/table/CDR0000062913__883/?report=objectonly" target="object" rid-figpopup="figCDR0000062913883" rid-ob="figobCDR0000062913883">Table 2</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastasis.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Reprinted with permission from AJCC: Thyroid--Differentiated and Anaplastic Carcinoma. In: Amin, MB, Edge Sb, Greene FL et al., eds.: <i>AJCC Cancer Staging Manual</i>. 8th ed. New York, NY: Springer, 2017, pp 873–90. </p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>b</sup>All categories may be subdivided: (s) solitary tumor and (m) multifocal tumor (the largest determines the classification).</p></div></dd></dl></div></div></div><div id="CDR0000062913__886" class="table"><h3><span class="title">Table 5. Definitions of Differentiated TNM Stages IVA and IVB for Papillary and Follicular Thyroid Carcinoma<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65719.23/table/CDR0000062913__886/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062913__886_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Stage</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">T<sup>b</sup>NM</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Description</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Illustration</th></tr></thead><tbody><tr><td colspan="4" rowspan="1" style="vertical-align:top;">
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<b>Age at diagnosis is ≥55 years: </b>
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</td></tr><tr><td colspan="1" rowspan="3" style="vertical-align:top;">IVA</td><td colspan="1" rowspan="3" style="vertical-align:top;">T4b, Any N, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;"> –T4b = Gross extrathyroidal extension invading prevertebral fascia or encasing the carotid artery or mediastinal vessels from a tumor of any size.</td><td colspan="1" rowspan="3" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000780089&p=BOOKS&id=578124_CDR0000780089.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000780089.jpg" alt="Stage IVA papillary and follicular thyroid cancer in patients 55 years and older; drawing shows cancer has (a) spread to tissue in front of the spine, (b) surrounded the common carotid artery, and (c) surrounded the blood vessels in the area between the lungs. Also shown are the thyroid gland, trachea, and lymph nodes." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Any N = See descriptions in <a class="figpopup" href="/books/NBK65719.23/table/CDR0000062913__883/?report=objectonly" target="object" rid-figpopup="figCDR0000062913883" rid-ob="figobCDR0000062913883">Table 2</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="3" style="vertical-align:top;">IVB</td><td colspan="1" rowspan="3" style="vertical-align:top;">Any T, Any N, M1</td><td colspan="1" rowspan="1" style="vertical-align:top;">Any T = See descriptions in <a class="figpopup" href="/books/NBK65719.23/table/CDR0000062913__883/?report=objectonly" target="object" rid-figpopup="figCDR0000062913883" rid-ob="figobCDR0000062913883">Table 2</a>. </td><td colspan="1" rowspan="3" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000780092&p=BOOKS&id=578124_CDR0000780092.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000780092.jpg" alt="Stage IVB papillary and follicular thyroid cancer in patients 55 years and older; drawing shows other parts of the body where thyroid cancer may spread, including the lung and bone. An inset shows cancer cells spreading from the thyroid, through the blood and lymph system, to another part of the body where metastatic cancer has formed." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Any N = See descriptions in <a class="figpopup" href="/books/NBK65719.23/table/CDR0000062913__883/?report=objectonly" target="object" rid-figpopup="figCDR0000062913883" rid-ob="figobCDR0000062913883">Table 2</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M1 = Distant metastasis.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastasis.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Reprinted with permission from AJCC: Thyroid--Differentiated and Anaplastic Carcinoma. In: Amin, MB, Edge Sb, Greene FL et al., eds.: <i>AJCC Cancer Staging Manual</i>. 8th ed. New York, NY: Springer, 2017, pp 873–90. </p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>b</sup>All categories may be subdivided: (s) solitary tumor and (m) multifocal tumor (the largest determines the classification).</p></div></dd></dl></div></div></div><div id="CDR0000062913__887" class="table"><h3><span class="title">Table 6. Definitions of Anaplastic TNM Stages IVA, IVB, and IVC for Papillary and Follicular Thyroid Carcinoma<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65719.23/table/CDR0000062913__887/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062913__887_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Stage</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">T<sup>b</sup>NM</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Description</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Illustration</th></tr></thead><tbody><tr><td colspan="1" rowspan="11" style="vertical-align:top;">IVA</td><td colspan="1" rowspan="11" style="vertical-align:top;">T1–T3a, N0/NX, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T1 = Tumor ≤2 cm in greatest dimension, limited to the thyroid.</td><td colspan="1" rowspan="11" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000782401&p=BOOKS&id=578124_CDR0000782401.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000782401.jpg" alt="Stage IVA anaplastic thyroid cancer; drawing shows cancer in the thyroid gland. The lymph nodes are also shown." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1a = Tumor ≤1 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1b = Tumor >1 cm but ≤2 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T2 = Tumor >2 cm but ≤4 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T3 = Tumor >4 cm limited to the thyroid, or gross extrathyroidal extension invading only strap muscles.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3a = Tumor >4 cm limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N0a = One or more cytologically or histologically confirmed benign lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N0b = No radiologic or clinical evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">NX = Regional lymph nodes cannot be assessed.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis</td></tr><tr><td colspan="1" rowspan="18" style="vertical-align:top;">IVB</td><td colspan="1" rowspan="10" style="vertical-align:top;">T1–T3a, N1, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T1 = Tumor ≤2 cm in greatest dimension, limited to the thyroid.</td><td colspan="1" rowspan="18" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000782402&p=BOOKS&id=578124_CDR0000782402.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000782402.jpg" alt="Stage IVB anaplastic thyroid cancer (1); drawing shows cancer in the thyroid gland and nearby lymph nodes." class="tileshop" title="Click on image to zoom" /></a></div>
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000790836&p=BOOKS&id=578124_CDR0000790836.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000790836.jpg" alt="Stage IVB anaplastic thyroid cancer (2); drawing shows cancer in the thyroid gland and nearby muscles in the neck. The lymph nodes are also shown." class="tileshop" title="Click on image to zoom" /></a></div>
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000790838&p=BOOKS&id=578124_CDR0000790838.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000790838.jpg" alt="Stage IVB anaplastic thyroid cancer (3); drawing shows cancer in the thyroid gland and in the esophagus, the trachea, the larynx, the left recurrent laryngeal nerve, and the tissue in front of the spine (inset). Cancer has also surrounded the common carotid artery and the blood vessels in the area between the lungs. Also shown is the right recurrent laryngeal nerve." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1a = Tumor ≤1 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1b = Tumor >1 cm but ≤2 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T2 = Tumor >2 cm but ≤4 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T3 = Tumor >4 cm limited to the thyroid, or gross extrathyroidal extension invading only strap muscles.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3a = Tumor >4 cm limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N1 = Metastasis to regional nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1a = Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1b = Metastasis to unilateral, bilateral, or contralateral cervical neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="3" style="vertical-align:top;">T3b, Any N, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;"> –T3b = Gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles) from a tumor of any size.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Any N = See descriptions in <a class="figpopup" href="/books/NBK65719.23/table/CDR0000062913__883/?report=objectonly" target="object" rid-figpopup="figCDR0000062913883" rid-ob="figobCDR0000062913883">Table 2</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="5" style="vertical-align:top;">T4, Any N, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T4 = Includes gross extrathyroidal extension beyond the strap muscles.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T4a = Gross extrathyroidal extension invading subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve from a tumor of any size.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T4b = Gross extrathyroidal extension invading prevertebral fascia or encasing the carotid artery or mediastinal vessels from a tumor of any size.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Any N = See descriptions in <a class="figpopup" href="/books/NBK65719.23/table/CDR0000062913__883/?report=objectonly" target="object" rid-figpopup="figCDR0000062913883" rid-ob="figobCDR0000062913883">Table 2</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="3" style="vertical-align:top;">IVC</td><td colspan="1" rowspan="3" style="vertical-align:top;">Any T, Any N, M1, </td><td colspan="1" rowspan="1" style="vertical-align:top;">Any T = See descriptions in <a class="figpopup" href="/books/NBK65719.23/table/CDR0000062913__883/?report=objectonly" target="object" rid-figpopup="figCDR0000062913883" rid-ob="figobCDR0000062913883">Table 2</a>.</td><td colspan="1" rowspan="3" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000780096&p=BOOKS&id=578124_CDR0000780096.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000780096.jpg" alt="Stage IVC anaplastic thyroid cancer; drawing shows other parts of the body where thyroid cancer may spread, including the lung and bone. An inset shows cancer cells spreading from the thyroid, through the blood and lymph system, to another part of the body where metastatic cancer has formed." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Any N = See descriptions in <a class="figpopup" href="/books/NBK65719.23/table/CDR0000062913__883/?report=objectonly" target="object" rid-figpopup="figCDR0000062913883" rid-ob="figobCDR0000062913883">Table 2</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M1 = Distant metastasis.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastasis.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Reprinted with permission from AJCC: Thyroid--Differentiated and Anaplastic Carcinoma. In: Amin, MB, Edge Sb, Greene FL et al., eds.: <i>AJCC Cancer Staging Manual</i>. 8th ed. New York, NY: Springer, 2017, pp 873–90. </p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>b</sup>All categories may be subdivided: (s) solitary tumor and (m) multifocal tumor (the largest determines the classification).</p></div></dd></dl></div></div></div></div><div id="CDR0000062913__443"><h3>Standard Treatment Options for Papillary and Follicular Thyroid Cancer</h3><div id="CDR0000062913__748"><h4>Localized/regional papillary and follicular thyroid cancer</h4><p id="CDR0000062913__445">Surgery is the therapy of choice for all primary lesions. Surgical options
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include total thyroidectomy or lobectomy. The choice of procedure is
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influenced mainly by the age of the patient and the size of the nodule.
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Survival results with the two procedures are similar for early-stage disease, with differences in the rates
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of surgical complications and local recurrences.[<a class="bk_pop" href="#CDR0000062913_rl_435_2">2</a>-<a class="bk_pop" href="#CDR0000062913_rl_435_8">8</a>]</p><div id="CDR0000062913__444"><h5>Standard treatment options for localized/regional papillary and follicular thyroid cancer</h5><p id="CDR0000062913__736">Standard treatment options for localized/regional papillary and follicular thyroid cancer include the following:</p><ol id="CDR0000062913__447"><li class="half_rhythm"><div>
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|
<a href="#CDR0000062913__637">Surgery.</a>
|
|
<ul id="CDR0000062913__636"><li class="half_rhythm"><div>
|
|
<a href="#CDR0000062913__639">Total thyroidectomy.</a>
|
|
</div></li><li class="half_rhythm"><div>
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|
<a href="#CDR0000062913__917">Lobectomy.</a>
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|
</div></li></ul>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<a href="#CDR0000062913__920">Radioactive iodine (RAI) therapy.</a>
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|
</div></li><li class="half_rhythm"><div><a href="#CDR0000062913__941">Thyroid-suppression therapy</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062913__943">External-beam radiation therapy (EBRT)</a>.</div></li></ol><div id="CDR0000062913__637"><h5>Surgery</h5><p id="CDR0000062913__638">The objective of surgery is to completely remove the primary tumor, while minimizing treatment-related morbidity, and to guide postoperative treatment with RAI. The goal of RAI is to ablate the remnant thyroid tissue to improve the specificity of thyroglobulin assays, which allows the detection of persistent disease by follow-up whole-body scanning. For patients undergoing RAI, removal of all normal thyroid tissue is an important surgical objective. Additionally, for accurate long-term surveillance, RAI whole-body scanning and measurement of serum thyroglobulin are affected by residual, normal thyroid tissue, and in these situations, near total or total thyroidectomy is required. This approach facilitates follow-up thyroid scanning.</p><div id="CDR0000062913__639"><h5>Total thyroidectomy</h5><p id="CDR0000062913__640">Total thyroidectomy is often used because of the high
|
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incidence of multicentric involvement of both lobes of the gland and the
|
|
possibility of dedifferentiation of any residual tumor to the anaplastic cell
|
|
type. </p><p id="CDR0000062913__641">Evidence (total thyroidectomy):</p><ol id="CDR0000062913__642"><li class="half_rhythm"><div>From the National Cancer Data Base (NCDB) registry of 52,173 patients, 43,227 (82.9%) underwent total thyroidectomy, and 8,946 (17.1%) underwent lobectomy. [<a class="bk_pop" href="#CDR0000062913_rl_435_9">9</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810035/" class="def">Level of evidence C1</a>] <ul id="CDR0000062913__643"><li class="half_rhythm"><div>For a papillary thyroid cancer tumor that measured less than 1 cm, the extent of surgery did not impact recurrence (<i>P</i> = .24) or survival (<i>P</i> = .83).</div></li><li class="half_rhythm"><div>For tumors that measured 1 cm or larger, lobectomy resulted in higher risk of recurrence (<i>P</i> = .04) and death (<i>P</i> = .009).</div></li><li class="half_rhythm"><div>To minimize the influence of larger tumors, 1-cm to 2-cm lesions were examined separately. Lobectomy resulted in a higher risk of recurrence (<i>P</i> = .04) and death (<i>P</i> = .04).</div></li><li class="half_rhythm"><div>Total thyroidectomy resulted in lower recurrence rates and improved survival for patients with papillary thyroid cancer tumors that measured 1 cm or larger compared with lobectomy.</div></li></ul></div></li><li class="half_rhythm"><div>In a pattern-of-care study that used the NCDB registry from 1985 to 2003, 57,243 papillary thyroid cancer patients with tumors measuring 1 cm or larger underwent total thyroidectomy or lobectomy. Trends in the extent of surgery were examined for patients with papillary thyroid cancer over two decades. Logistic regression was used to identify factors that predict the use of total thyroidectomy compared with lobectomy.[<a class="bk_pop" href="#CDR0000062913_rl_435_10">10</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810035/" class="def">Level of evidence C1</a>] <ul id="CDR0000062913__749"><li class="half_rhythm"><div>Use of total thyroidectomy increased from 70.8% in 1985 to 90.4% in 2003 (<i>P</i> < .0001). </div></li><li class="half_rhythm"><div>Patients treated at high-volume medical facilities or academic centers were more likely to undergo total thyroidectomy than were patients examined at low-volume medical facilities or community hospitals (<i>P</i> < .0001).</div></li></ul></div></li></ol></div><div id="CDR0000062913__917"><h5>Lobectomy</h5><p id="CDR0000062913__918">Thyroid lobectomy alone may be sufficient treatment for small (<1 cm), low-risk, unifocal, intrathyroidal papillary carcinomas in the absence of previous head and neck irradiation or radiologically or clinically involved cervical nodal metastases. This procedure is associated with a lower incidence of
|
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complications, but approximately 5% to 10% of patients will have a recurrence
|
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in the thyroid after a lobectomy.[<a class="bk_pop" href="#CDR0000062913_rl_435_11">11</a>]</p><p id="CDR0000062913__919">Abnormal regional lymph nodes are biopsied at the time of
|
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surgery. Recognized involved nodes are removed at initial surgery, but
|
|
selective node removal can be performed, and radical neck dissection is usually not
|
|
required.
|
|
This
|
|
results in a decreased recurrence rate but has not been shown to improve
|
|
survival.
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|
Follicular thyroid cancer commonly metastasizes to lungs and bone. When a remnant lobe remains, use of iodine I 131 as ablative therapy is compromised because the radioiodine will be preferentially taken up by the remnant normal tissue rather than by the tumor. </p></div></div><div id="CDR0000062913__920"><h5>Radioactive iodine (RAI) therapy</h5><p id="CDR0000062913__921">Studies have shown that a postoperative course of therapeutic
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|
(ablative) doses of radioiodine 131I results in a decreased recurrence rate among high-risk patients with papillary
|
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and follicular carcinomas.[<a class="bk_pop" href="#CDR0000062913_rl_435_5">5</a>] RAI may be given in addition to exogenous thyroid
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hormone but is not considered routine.[<a class="bk_pop" href="#CDR0000062913_rl_435_12">12</a>] RAI treatment is optimal after total thyroidectomy with minimal thyroid remnant. With a large thyroid remnant, a low thyroglobulin level cannot be achieved, which increases the chance of requiring multiple doses of RAI.</p><p id="CDR0000062913__922">Consideration of RAI for remnant ablation is based on pathological risk features including the following:</p><ul id="CDR0000062913__923"><li class="half_rhythm"><div>The size of the primary tumor.</div></li><li class="half_rhythm"><div>The presence of lymphovascular invasion.</div></li><li class="half_rhythm"><div>Capsule invasion.</div></li><li class="half_rhythm"><div>The number of involved lymph nodes.</div></li></ul><p id="CDR0000062913__924">RAI may be given with one of two methods of thyroid-stimulating hormone (TSH/thyrotropin) stimulation: </p><ul id="CDR0000062913__925"><li class="half_rhythm"><div>Withdrawal of thyroid hormone.</div></li><li class="half_rhythm"><div>Administration of recombinant human thyrotropin (rhTSH).</div></li></ul><p id="CDR0000062913__926">Administered rhTSH maintains quality of life and reduces the radiation dose delivered to the body compared with thyroid hormone withdrawal.[<a class="bk_pop" href="#CDR0000062913_rl_435_13">13</a>] Patients presenting with papillary
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thyroid microcarcinomas (tumors <10 mm), which are considered to be very low risk, have an excellent prognosis when
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treated surgically. Additional therapy with 131I would not be expected to
|
|
improve the prognosis.[<a class="bk_pop" href="#CDR0000062913_rl_435_14">14</a>]</p><p id="CDR0000062913__927">The role of RAI in low-risk patients is not clear because disease-free survival (DFS) or overall survival (OS) benefits have not been demonstrated. </p><p id="CDR0000062913__928">Evidence (surgery with or without RAI):</p><ol id="CDR0000062913__929"><li class="half_rhythm"><div>One study reviewed 1,298 low-risk patients from the French Thyroid Cancer Registry.[<a class="bk_pop" href="#CDR0000062913_rl_435_15">15</a>] Patients were identified as having low-risk papillary or follicular cancer as they are defined by the American Thyroid Association and the European Thyroid Association criteria, which include the following:<ul id="CDR0000062913__930"><li class="half_rhythm"><div>Complete tumor resection.</div></li><li class="half_rhythm"><div>Multifocal tumors 1 cm or smaller confined to the thyroid. </div></li><li class="half_rhythm"><div>Tumors larger than 1 cm but no larger than 4 cm confined to the thyroid. </div></li><li class="half_rhythm"><div> No lymph node involvement or distant metastatic disease.</div></li></ul></div></li></ol><p id="CDR0000062913__931">Of the 1,298 patients, 911 patients received RAI after surgery, and 387 patients did not receive RAI after surgery. The follow-up period was 10.3 years. </p><ul id="CDR0000062913__932"><li class="half_rhythm"><div>In multivariate analyses, there were no differences in OS (<i>P</i> = .243) or DFS (<i>P</i> = .2659), according to RAI use.[<a class="bk_pop" href="#CDR0000062913_rl_435_15">15</a>]</div></li></ul><p id="CDR0000062913__933">Long-term complications of RAI using 131I include the following:</p><ul id="CDR0000062913__934"><li class="half_rhythm"><div>Second malignancies.</div></li><li class="half_rhythm"><div>Sialadenitis.</div></li><li class="half_rhythm"><div>Lacrimal and salivary gland dysfunction.</div></li></ul><p id="CDR0000062913__935">Options for reducing the amount of radiation exposure by reducing the amount of RAI in each dose and giving RAI in combination with rhTSH injections have been explored for low-risk thyroid cancer patients.</p><p id="CDR0000062913__936">Evidence (thyroid hormone withdrawal or use of rhTSH with 131I):</p><ol id="CDR0000062913__937"><li class="half_rhythm"><div>A phase III, randomized, noninferiority study of patients with low-risk thyroid cancer using a comparison of two thyrotropin-stimulation methods (thyroid hormone withdrawal or use of rhTSH) and two doses of 131I (1.1 GBq [30 mCi] and 3.7 GBq [100 mCi]) using a 2 × 2 factorial design was reviewed.[<a class="bk_pop" href="#CDR0000062913_rl_435_16">16</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810035/" class="def">Level of evidence C1</a>]<ul id="CDR0000062913__938"><li class="half_rhythm"><div>Equivalent thyroid ablation rates between high- and low-dose 131I at 6 to 10 months after administration of 131I were recorded.</div></li><li class="half_rhythm"><div>Patients with more advanced T stage (T1–T3, N0–1) and with less than a total thyroidectomy were included with a lower overall ablation rate of 85%.</div></li></ul></div></li><li class="half_rhythm"><div>Another phase III, randomized, noninferiority study of patients with low-risk thyroid cancer using a comparison of two thyrotropin-stimulation methods (thyroid hormone withdrawal or use of rhTSH) and two doses of 131I (1.1 GBq [30 mCi] and 3.7 GBq [100 mCi]) using a 2 × 2 factorial design was reviewed. The inclusion criteria consisted of a low-risk, homogeneous cohort in which all of the patients underwent total thyroidectomy, and had pathological TNM stage pT1 (≤1 cm) and N1 or NX, pT1 (>1–2 cm) and any N, or pT2, N0 without thyroid capsule extension/distant metastases.[<a class="bk_pop" href="#CDR0000062913_rl_435_17">17</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810035/" class="def">Level of evidence C1</a>]<ul id="CDR0000062913__939"><li class="half_rhythm"><div>Thyroid ablation rates were equivalent between high- and low-dose 131I at 6 to 10 months after administration of 131I.</div></li><li class="half_rhythm"><div>Complete thyroid ablation rate was 92%.</div></li><li class="half_rhythm"><div>Patients undergoing thyroid hormone withdrawal had more symptoms of hypothyroidism associated with deterioration in quality of life compared with the rhTSH group.</div></li></ul></div></li></ol><p id="CDR0000062913__940">Neither study assessed the effect of low-dose RAI on long-term recurrences or survival. The studies also did not address whether RAI could be safely omitted in specific low-risk groups. </p></div><div id="CDR0000062913__941"><h5>Thyroid-suppression therapy</h5><p id="CDR0000062913__942">After thyroid surgery, all patients, except those undergoing lobectomy, will require thyroid hormone replacement therapy. For patients who have undergone thyroidectomy, supratherapeutic doses of thyroid hormone are routinely administered to suppress TSH levels. The degree of TSH suppression recommended depends on the risk of recurrence and the comorbidities of the patient. Studies have suggested that TSH suppression improves progression-free survival (PFS), but there is no definitive evidence that it improves OS.[<a class="bk_pop" href="#CDR0000062913_rl_435_18">18</a>,<a class="bk_pop" href="#CDR0000062913_rl_435_19">19</a>]</p></div><div id="CDR0000062913__943"><h5>External-beam radiation therapy (EBRT) </h5><p id="CDR0000062913__944">EBRT is typically reserved for palliative treatment of unresectable or metastatic papillary or follicular thyroid cancer. In some cases, it may be appropriate to treat with EBRT in the adjuvant setting if there is confirmed or suspected microscopic residual disease that is confirmed or suspected to be refractory to RAI. There are no randomized trials to guide the selection of patients who might benefit from treatment with EBRT. The decision to use EBRT is based on retrospective data and clinical judgment.[<a class="bk_pop" href="#CDR0000062913_rl_435_20">20</a>] </p></div></div></div><div id="CDR0000062913__472"><h4>Metastatic papillary and follicular thyroid cancer</h4><p id="CDR0000062913__473">Total thyroidectomy is still recommended as the initial treatment for metastatic papillary or follicular thyroid cancer. RAI is the second treatment and is given to ablate the remnant thyroid and treat the metastatic disease. If a thyroidectomy is not done, then RAI is not a treatment option for the patient. The most common sites of distant metastases are the lungs and bones. Treatment of distant
|
|
metastases is usually not curative but may produce significant palliation.
|
|
Genomic testing to identify actionable mutations such as <i>RET</i> and <i>NTRK</i> fusions should be considered for patients with advanced progressive disease. Standard treatment options for iodine-sensitive and iodine-resistant metastatic papillary and follicular thyroid cancer are described below. </p><p id="CDR0000062913__474">
|
|
<b>Standard treatment options for iodine-sensitive thyroid cancer</b>
|
|
</p><p id="CDR0000062913__738">Standard treatment options for iodine-sensitive thyroid cancer include the following:</p><ol id="CDR0000062913__695"><li class="half_rhythm"><div>RAI therapy: Metastases that demonstrate uptake of this isotope may be ablated
|
|
by therapeutic doses of 131I.</div></li><li class="half_rhythm"><div>Thyroid-suppression therapy.</div></li></ol><p id="CDR0000062913__476">
|
|
<b>Standard treatment options for iodine-resistant thyroid cancer</b>
|
|
</p><p id="CDR0000062913__739">Standard treatment options for iodine-resistant thyroid cancer include the following:</p><ol id="CDR0000062913__477"><li class="half_rhythm"><div>
|
|
<a href="#CDR0000062913__696">Thyroid-suppression therapy.</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<a href="#CDR0000062913__698">Targeted therapy.</a>
|
|
<ul id="CDR0000062913__1079"><li class="half_rhythm"><div><a href="#CDR0000062913__1080">Tyrosine kinase inhibitors</a>. </div></li></ul>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<a href="#CDR0000062913__702">Surgery.</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<a href="#CDR0000062913__704">EBRT.</a>
|
|
</div></li></ol><div id="CDR0000062913__696"><h5>Thyroid-suppression therapy</h5><p id="CDR0000062913__697">TSH suppression with thyroxine is effective in many
|
|
lesions that are not sensitive to 131I.</p></div><div id="CDR0000062913__698"><h5>Targeted therapy</h5><div id="CDR0000062913__1080"><h5>Tyrosine kinase inhibitors</h5><div id="CDR0000062913__1081"><h5>Sorafenib</h5><p id="CDR0000062913__1082">Sorafenib is an orally active multitargeted tyrosine kinase inhibitor. </p><p id="CDR0000062913__1083">Evidence (sorafenib):</p><ol id="CDR0000062913__1084"><li class="half_rhythm"><div>A phase III randomized, double-blind, placebo-controlled study (<a href="https://www.cancer.gov/clinicaltrials/NCT00984282" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">DECISION</a> [<a href="https://clinicaltrials.gov/show/NCT00984282" title="Study NCT00984282" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT00984282</a>]) evaluated the activity of sorafenib in patients with progressive, iodine-refractory, differentiated thyroid cancer.[<a class="bk_pop" href="#CDR0000062913_rl_435_21">21</a>] In the trial, 417 patients with locally advanced or metastatic RAI−refractory thyroid cancer (papillary, follicular [including Hürthle cell], and poorly differentiated, not anaplastic tumors, defined as beyond well-differentiated tumors or those well-differentiated tumors that become resistant to radioiodine treatment) whose disease had progressed within the past 14 months were randomly assigned to receive sorafenib (400 mg twice a day) or placebo. Patients who received previous chemotherapy, thalidomide, or targeted therapy were excluded.[<a class="bk_pop" href="#CDR0000062913_rl_435_21">21</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810025/" class="def">Level of evidence B1</a>]<ul id="CDR0000062913__1085"><li class="half_rhythm"><div> The median PFS in the sorafenib group was 10.8 months versus 5.8 months in the placebo group (hazard ratio [HR] 0.59; 95% confidence interval [CI], 0.45–0.76, <i>P </i>< .0001). </div></li><li class="half_rhythm"><div> OS was not significantly improved (HR, 0.80; 95% CI, 0.54–1.19, <i>P</i> = .14, one-sided <i>P</i>-value), but the median OS had not been reached at the time of primary analysis data cutoff, and crossover was allowed. </div></li><li class="half_rhythm"><div> Objective response rate (all partial responses) was 12.2% in the sorafenib group compared with 0.5% in the placebo group. </div></li><li class="half_rhythm"><div>Median time-to-progression was 11.1 months in the sorafenib group compared with 5.7 months in the placebo group (HR, 0.56; 95% CI, 0.43–0.72, <i>P</i> < .001). </div></li><li class="half_rhythm"><div> Adverse events occurred in 98.6% of patients treated with sorafenib and 87.6% of patients treated with placebo. The most common adverse events in the sorafenib group were hand-foot skin reactions (76.3%), diarrhea (68.6%), alopecia (67.1%), and rash or desquamation (50.2%). Most events were grade 1 or 2. Seven squamous cell carcinomas of the skin occurred in the sorafenib group.</div></li></ul></div></li></ol></div><div id="CDR0000062913__1086"><h5>Lenvatinib</h5><p id="CDR0000062913__1087">Lenvatinib is an orally active, multitargeted tyrosine kinase inhibitor. </p><p id="CDR0000062913__1088">Evidence (lenvatinib):</p><ol id="CDR0000062913__1089"><li class="half_rhythm"><div> A phase III, randomized, double-blind, placebo-controlled study (<a href="https://www.cancer.gov/clinicaltrials/NCT01321554" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SELECT</a> [<a href="https://clinicaltrials.gov/show/NCT01321554" title="Study NCT01321554" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT01321554</a>]) evaluated the activity of lenvatinib in patients with progressive, iodine-refractory, differentiated thyroid cancer.[<a class="bk_pop" href="#CDR0000062913_rl_435_22">22</a>] In this trial, 261 patients were randomly assigned to receive lenvatinib (24 mg every day), and 131 patients were randomly assigned to receive placebo. Eligible patients had differentiated thyroid cancer (including papillary, follicular, poorly differentiated, and Hürthle cell carcinomas), RAI-refractory disease, and evidence of radiological progression within the previous 13 months. At disease progression, patients in the placebo group could receive open-label lenvatinib.[<a class="bk_pop" href="#CDR0000062913_rl_435_22">22</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810025/" class="def">Level of evidence B1</a>]<ol id="CDR0000062913__1090" class="lower-alpha"><li class="half_rhythm"><div> The primary endpoint was PFS, and secondary endpoints were OS, response rate, and safety.</div></li><li class="half_rhythm"><div>The median PFS in the lenvatinib group was 18.3 months versus 3.6 months in the placebo group (HR<sub>progression or death</sub>, 0.21; 99% CI, 0.14–0.31; <i>P</i> < .001). A PFS difference was observed in patients with all histologic types of thyroid cancer enrolled in this trial. </div></li><li class="half_rhythm"><div> There was no significant difference in OS between the two groups (HR <sub>death</sub>, 0.73; 95% CI, 0.50–1.07; <i>P</i> = .10), even with the crossover design of the study. </div></li><li class="half_rhythm"><div> Objective response rate was 64.8% in the lenvatinib group versus 1.5% in the placebo group (odds ratio [OR], 28.87; 95% CI, 12.46–66.86; <i>P</i> < .001). </div></li><li class="half_rhythm"><div>Treatment-related adverse events (all grades) occurred in 97.3% of patients in the lenvatinib group and 59.5% of patients in the placebo group.<ul id="CDR0000062913__1091"><li class="half_rhythm"><div>Grade 3 or higher adverse events were observed in 75.9% of patients who received lenvatinib and 9.9% of patients who received placebo.</div></li><li class="half_rhythm"><div>The most common adverse events in the lenvatinib group were hypertension (67.8%), diarrhea (59.4%), fatigue (59%), decreased appetite (50.2%), decreased weight (46.4%), and nausea (41%).</div></li><li class="half_rhythm"><div>Discontinuation of the study drug because of adverse events occurred in 14.2% of patients who received lenvatinib and 2.3% of patients who received placebo.</div></li><li class="half_rhythm"><div>In the lenvatinib group, 6 of 20 deaths occurring during the treatment period were considered drug related.</div></li></ul></div></li></ol></div></li></ol></div></div></div><div id="CDR0000062913__702"><h5>Surgery</h5><p id="CDR0000062913__703">Resection of limited metastases, especially symptomatic metastases, should be considered when the tumor has no uptake of 131I.</p></div><div id="CDR0000062913__704"><h5>EBRT</h5><p id="CDR0000062913__705">EBRT is considered for patients with localized lesions that are
|
|
unresponsive to 131I.[<a class="bk_pop" href="#CDR0000062913_rl_435_23">23</a>]</p></div><div id="CDR0000062913__565"><h5>Treatment options under clinical evaluation for metastatic papillary and follicular thyroid cancer</h5><p id="CDR0000062913__566">Patients unresponsive to 131I should also be considered candidates for
|
|
clinical trials testing new approaches to this disease. </p><ul id="CDR0000062913__711"><li class="half_rhythm"><div>Chemotherapy has been reported to produce
|
|
occasional complete responses of long duration.[<a class="bk_pop" href="#CDR0000062913_rl_435_24">24</a>-<a class="bk_pop" href="#CDR0000062913_rl_435_26">26</a>]</div></li><li class="half_rhythm"><div>Clinical trials evaluating new treatment approaches to this disease should be considered for patients with radioiodine-refractory papillary or follicular thyroid cancer. Oral inhibitors targeting specific activating point mutations are under clinical evaluation, as are new immunotherapy approaches.[<a class="bk_pop" href="#CDR0000062913_rl_435_27">27</a>-<a class="bk_pop" href="#CDR0000062913_rl_435_29">29</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810033/" class="def">Level of evidence B4</a>]</div></li></ul></div></div><div id="CDR0000062913__668"><h4>Recurrent papillary and follicular thyroid cancer</h4><p id="CDR0000062913__669">Approximately 10% to 30% of
|
|
patients thought to be disease free after initial treatment will develop
|
|
recurrence and/or metastases. Of these patients, approximately 80% develop recurrence
|
|
with disease in the neck alone, and 20% develop recurrence with distant metastases. The most
|
|
common site of distant metastasis is the lung. In a single series of 289
|
|
patients who developed recurrences after initial surgery, 16% died of cancer at
|
|
a median time of 5 years after recurrence.[<a class="bk_pop" href="#CDR0000062913_rl_435_5">5</a>]</p><p id="CDR0000062913__670">The prognosis for patients
|
|
with clinically detectable recurrences is generally poor, regardless of cell
|
|
type.[<a class="bk_pop" href="#CDR0000062913_rl_435_30">30</a>] Patients who recur with local or regional tumor
|
|
detected only by 131I scan have a better prognosis.[<a class="bk_pop" href="#CDR0000062913_rl_435_31">31</a>] </p><p id="CDR0000062913__691">The selection of
|
|
further treatment depends on many factors, including the following:</p><ul id="CDR0000062913__671"><li class="half_rhythm"><div>Cell type.</div></li><li class="half_rhythm"><div>Uptake of
|
|
131I.</div></li><li class="half_rhythm"><div>Previous treatment.</div></li><li class="half_rhythm"><div>Site of recurrence.</div></li><li class="half_rhythm"><div>Individual patient
|
|
considerations.</div></li><li class="half_rhythm"><div>Presence of an activating <i>RET</i> or <i>NTRK</i> fusion.
|
|
</div></li></ul><p id="CDR0000062913__672">Patients treated for differentiated thyroid cancer are followed carefully
|
|
with physical examinations, serum quantitative thyroglobulin levels, and radiologic studies based
|
|
on individual risk for recurrent disease.[<a class="bk_pop" href="#CDR0000062913_rl_435_32">32</a>]</p><p id="CDR0000062913__752">
|
|
<b>Standard treatment options for recurrent papillary and follicular thyroid cancer</b>
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</p><p id="CDR0000062913__742">Standard treatment options for recurrent papillary and follicular thyroid cancer include the following:</p><ol id="CDR0000062913__675"><li class="half_rhythm"><div><a href="#CDR0000062913__676">Surgery with or without postoperative RAI</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062913__681">Targeted therapy</a>.<ul id="CDR0000062913__1010"><li class="half_rhythm"><div><a href="#CDR0000062913__1011">Tyrosine kinase inhibitors</a>. </div></li><li class="half_rhythm"><div><a href="#CDR0000062913__1028">RET kinase inhibitors</a>. </div></li><li class="half_rhythm"><div><a href="#CDR0000062913__1040">NTRK inhibitors</a>. </div></li></ul></div></li><li class="half_rhythm"><div><a href="#CDR0000062913__686">EBRT</a>.</div></li><li class="half_rhythm"><div>
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<a href="#CDR0000062913__712">Chemotherapy.</a>
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</div></li></ol><div id="CDR0000062913__676"><h5>Surgery with or without postoperative RAI therapy</h5><p id="CDR0000062913__677">Surgery with or without 131I ablation can be useful in
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controlling local recurrences, regional node metastases, or occasionally,
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metastases at other localized sites.[<a class="bk_pop" href="#CDR0000062913_rl_435_33">33</a>] Approximately 50% of the patients
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who undergo surgery for recurrent tumors can be rendered free of disease with a second
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operation.[<a class="bk_pop" href="#CDR0000062913_rl_435_30">30</a>] Local and regional recurrences detected by 131I scan and not
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clinically apparent can be treated with 131I ablation and have an excellent
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prognosis.[<a class="bk_pop" href="#CDR0000062913_rl_435_34">34</a>]</p><p id="CDR0000062913__678">Up to 25% of recurrences and metastases from well-differentiated thyroid cancer
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may not show 131I uptake. For these patients, other standard imaging techniques such as ultrasonography, computed tomography, magnetic resonance imaging, and positron emission tomography scans may detect recurrent or metastatic disease.</p><p id="CDR0000062913__680">Patients unresponsive to 131I should also be considered candidates for clinical trials testing new approaches to treating this disease.</p></div><div id="CDR0000062913__681"><h5>Targeted therapy</h5><div id="CDR0000062913__1011"><h5>Tyrosine kinase inhibitors</h5><div id="CDR0000062913__1012"><h5>Sorafenib</h5><p id="CDR0000062913__1013">Sorafenib is an orally active, multitargeted tyrosine kinase inhibitor. It has been approved by the U.S. Food and Drug Administration (FDA) as a treatment option when recurrent disease does not
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concentrate 131I or disease recurs after 131I ablation.</p><p id="CDR0000062913__1014">Evidence (sorafenib):</p><ol id="CDR0000062913__1015"><li class="half_rhythm"><div>A phase III, randomized, double-blind, placebo-controlled study (<a href="https://www.cancer.gov/clinicaltrials/NCT00984282" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">DECISION</a> [<a href="https://clinicaltrials.gov/show/NCT00984282" title="Study NCT00984282" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT00984282</a>]) evaluated the activity of sorafenib in patients with progressive, iodine-refractory, differentiated thyroid cancer.[<a class="bk_pop" href="#CDR0000062913_rl_435_21">21</a>] In the trial, 417 patients with locally advanced or metastatic RAI-refractory thyroid cancer (papillary, follicular [including Hürthle cell], and poorly differentiated tumors) whose disease had progressed within the past 14 months were randomly assigned to receive sorafenib (400 mg twice a day) or placebo. Patients who received previous chemotherapy, thalidomide, or targeted therapy were excluded.[<a class="bk_pop" href="#CDR0000062913_rl_435_21">21</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810025/" class="def">Level of evidence B1</a>]<ul id="CDR0000062913__1016"><li class="half_rhythm"><div>The median PFS in the sorafenib group was 10.8 months versus 5.8 months in the placebo group (HR, 0.59; 95% CI, 0.45–0.76; <i>P</i> < .001). </div></li><li class="half_rhythm"><div>OS was not significantly improved (HR, 0.80; 95% CI, 0.54–1.19; <i>P</i> = .14, one-sided <i>P</i>-value), but the median OS had not been reached at the time of primary analysis data cutoff, and crossover was allowed. </div></li><li class="half_rhythm"><div>Objective response rates (all partial responses) were 12.2% in the sorafenib group compared with 0.5% in the placebo group. </div></li><li class="half_rhythm"><div>Median time-to-progression was 11.1 months in the sorafenib group compared with 5.7 months in the placebo group (HR, 0.56; 95% CI, 0.43–0.72; <i>P </i>< .001). </div></li><li class="half_rhythm"><div>Adverse events occurred in 98.6% of patients treated with sorafenib and 87.6% of patients treated with placebo. The most common adverse events in the sorafenib group were hand-foot skin reactions (76.3%), diarrhea (68.6%), alopecia (67.1%), and rash or desquamation (50.2%). Most events were grade 1 or 2. Seven squamous cell carcinomas of the skin occurred in the sorafenib group.</div></li></ul></div></li></ol></div><div id="CDR0000062913__1017"><h5>Lenvatinib</h5><p id="CDR0000062913__1018">Lenvatinib is an orally active, multitargeted tyrosine kinase inhibitor.</p><p id="CDR0000062913__1019">Evidence (lenvatinib):</p><ol id="CDR0000062913__1020"><li class="half_rhythm"><div>A phase III, randomized, double-blind, placebo-controlled study (<a href="https://www.cancer.gov/clinicaltrials/NCT01321554" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SELECT</a> [<a href="https://clinicaltrials.gov/show/NCT01321554" title="Study NCT01321554" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT01321554</a>]) evaluated the activity of lenvatinib in patients with progressive, iodine-refractory, differentiated thyroid cancer.[<a class="bk_pop" href="#CDR0000062913_rl_435_22">22</a>] In this trial, 261 patients were randomly assigned to receive lenvatinib (24 mg every day), and 131 patients were randomly assigned to receive placebo. Eligible patients had differentiated thyroid cancer (including papillary, follicular, poorly differentiated, and Hürthle cell carcinomas), RAI-refractory disease, and evidence of radiological progression within the previous 13 months. At disease progression, patients in the placebo group could receive open-label lenvatinib.[<a class="bk_pop" href="#CDR0000062913_rl_435_22">22</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810025/" class="def">Level of evidence B1</a>]<ol id="CDR0000062913__1021" class="lower-alpha"><li class="half_rhythm"><div> The primary endpoint was PFS, and secondary endpoints were OS, response rate, and safety.</div></li><li class="half_rhythm"><div>The median PFS in the lenvatinib group was 18.3 months versus 3.6 months in the placebo group (HR<sub>progression or death</sub>, 0.21; 99% CI, 0.14–0.31; <i>P</i> < .001). A PFS difference was observed in patients with all histologic types of thyroid cancer enrolled in this trial. </div></li><li class="half_rhythm"><div> There was no significant difference in OS between the two groups (HR<sub>death</sub>, 0.73; 95% CI, 0.50–1.07; <i>P</i> = .10), even with the crossover design of the study. </div></li><li class="half_rhythm"><div> Objective response rate was 64.8% in the lenvatinib group versus 1.5% in the placebo group (OR, 28.87; 95% CI, 12.46–66.86; <i>P</i> < .001). </div></li><li class="half_rhythm"><div>Treatment-related adverse events (all grades) occurred in 97.3% of patients in the lenvatinib group and 59.5% of patients in the placebo group.<ul id="CDR0000062913__1022"><li class="half_rhythm"><div>Grade 3 or higher adverse events were observed in 75.9% of patients who received lenvatinib and 9.9% of patients who received placebo.</div></li><li class="half_rhythm"><div>The most frequent adverse events in the lenvatinib group were hypertension (67.8%), diarrhea (59.4%), fatigue (59%), decreased appetite (50.2%), decreased weight (46.4%), and nausea (41%).</div></li><li class="half_rhythm"><div>Discontinuation of study drug because of adverse events occurred in 14.2% of patients who received lenvatinib and 2.3% of patients who received placebo.</div></li><li class="half_rhythm"><div>In the lenvatinib group, 6 of 20 deaths occurring during the treatment period were considered to be drug-related.</div></li></ul></div></li></ol></div></li></ol></div><div id="CDR0000062913__1023"><h5>Cabozantinib</h5><p id="CDR0000062913__1024">Cabozantinib is an orally bioavailable tyrosine kinase inhibitor of c-MET and vascular endothelial growth factor receptor-2 (VEGFR-2).</p><p id="CDR0000062913__1025">Evidence (cabozantinib):</p><ol id="CDR0000062913__1026"><li class="half_rhythm"><div> A phase III, randomized, double blind, placebo-controlled study (<a href="https://www.cancer.gov/clinicaltrials/NCT03690388" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COSMIC-311</a> [<a href="https://clinicaltrials.gov/show/NCT03690388" title="Study NCT03690388" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT03690388</a>]), was conducted to evaluate the efficacy of cabozantinib in patients aged 16 years and older with RAI-refractory differentiated thyroid cancer. Objective response rate was the primary endpoint in the first 100 randomly assigned patients (the <i>objective response rate intention-to-treat [OITT] population</i>), and PFS was the primary endpoint in all randomly assigned patients (the <i>intention-to-treat [ITT] population</i>).[<a class="bk_pop" href="#CDR0000062913_rl_435_35">35</a>]<ul id="CDR0000062913__1027"><li class="half_rhythm"><div>Of 187 patients, 63% had received previous therapy with lenvatinib, 60% had received previous therapy with sorafenib, and 24% had received previous therapy with both lenvatinib and sorafenib. Most patients (76%) had experienced disease progression while receiving sorafenib or lenvatinib.</div></li><li class="half_rhythm"><div> In the OITT population, 15% of patients (99% CI, 5.8%–29.3%) in the cabozantinib group had a confirmed partial response, and median duration of response had not been reached at the data cutoff.</div></li><li class="half_rhythm"><div> In the ITT population, after a median follow-up of 6.2 months, patients who received cabozantinib showed significant improvement in PFS compared with patients who received placebo (median not reached [96% CI, 5.7–not estimable (NE)] vs. 1.9 months [1.8–3.6]) (HR, 0.22; 96% CI, 0.13–0.36; <i>P</i> < .0001). Median OS was not reached in either ITT group (95% CI, NE–NE) (HR, 0.54; 95% CI, 0.27–1.11). The 6-month OS rate was 85% (95% CI, 75%–91%) in the cabozantinib group and 73% (58.4%–83.7%) in the placebo group.</div></li><li class="half_rhythm"><div> Grade 3 to 4 treatment-related adverse events occurred in 57% of patients who received cabozantinib and 26% of patients who received placebo, and included palmar-plantar erythrodysesthesia (10%), hypertension (11%), fatigue (8%), diarrhea (7%), and hypocalcemia (7%). Serious treatment-related adverse events occurred in 20 of 125 patients (16%) in the cabozantinib group and 1 of 62 patients (2%) in the placebo group. There were no treatment-related deaths.</div></li><li class="half_rhythm"><div>In August 2021, the FDA reviewed a new drug application for the use of cabozantinib in patients with differentiated thyroid cancer who are aged 12 years and older because there are no standard of care treatments for this population after anti-VEGFR therapy. </div></li></ul></div></li></ol></div></div><div id="CDR0000062913__1028"><h5>RET kinase inhibitors</h5><div id="CDR0000062913__1029"><h5>Selpercatinib</h5><p id="CDR0000062913__1030">Selpercatinib is an orally active, highly selective, small-molecule RET kinase inhibitor.</p><p id="CDR0000062913__1031">Evidence (selpercatinib):</p><ol id="CDR0000062913__1032"><li class="half_rhythm"><div>A phase I/II trial (<a href="https://www.cancer.gov/clinicaltrials/NCT03157128" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">LIBRETTO-001</a> [<a href="https://clinicaltrials.gov/show/NCT03157128" title="Study NCT03157128" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT03157128</a>]) evaluated the safety and efficacy of selpercatinib in adolescent and adult patients with any solid tumor type harboring an activating <i>RET</i> alteration. The primary endpoint was an objective response (complete response or partial response). Patients with <i>RET</i> fusion–positive thyroid cancer had radioiodine-refractory disease and received at least one previous systemic therapy other than radioiodine. Nineteen patients with <i>RET</i> fusion–positive thyroid cancer were enrolled; 13 patients had papillary thyroid cancer, 3 had poorly differentiated thyroid cancer, 1 had anaplastic thyroid cancer, and 1 had Hürthle cell thyroid cancer. Ninety-five percent of patients with <i>RET</i> fusion–positive thyroid cancer received the phase II dose of 160 mg twice daily.[<a class="bk_pop" href="#CDR0000062913_rl_435_36">36</a>]<ol id="CDR0000062913__1033" class="lower-alpha"><li class="half_rhythm"><div> The objective response rate was 79% (95% CI, 54%−94%).[<a class="bk_pop" href="#CDR0000062913_rl_435_36">36</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810037/" class="def">Level of evidence C2</a>] </div></li><li class="half_rhythm"><div> At 1 year, 71% of responses were ongoing (95% CI, 39%−88%) and 64% of patients were progression-free.</div></li><li class="half_rhythm"><div>Treatment-related adverse events (any grade) occurred in 94% of patients.<ul id="CDR0000062913__1034"><li class="half_rhythm"><div> Grade 3 adverse events were observed in 28% of patients, and grade 4 adverse events were observed in 2% of patients.</div></li><li class="half_rhythm"><div> The most frequent adverse events were dry mouth (46%), hypertension (43%), diarrhea (38%), fatigue (38%), increased aspartate aminotransferase (AST) level (35%), nausea (35%), and constipation (35%).</div></li><li class="half_rhythm"><div> Thirty percent of patients had dose reductions because of treatment-related adverse events, and 2% of patients discontinued the drug because of adverse events.</div></li></ul></div></li></ol></div></li></ol></div><div id="CDR0000062913__1035"><h5>Pralsetinib</h5><p id="CDR0000062913__1036">Pralsetinib is an oral RET-targeted therapy. In December 2020, the FDA approved pralsetinib for patients aged 12 years and older and for adults with advanced or metastatic <i>RET</i>-mutant medullary thyroid cancer (MTC) or <i>RET</i> fusion–positive RAI-refractory differentiated thyroid cancer. </p><p id="CDR0000062913__1039">Evidence (pralsetinib):</p><ol id="CDR0000062913__1037"><li class="half_rhythm"><div> A phase I/II, multicenter, open-label study (<a href="https://www.cancer.gov/clinicaltrials/NCT03037385" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ARROW</a> [<a href="https://clinicaltrials.gov/show/NCT03037385" title="Study NCT03037385" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT03037385</a>]) evaluated the efficacy and safety of pralsetinib.[<a class="bk_pop" href="#CDR0000062913_rl_435_37">37</a>]<ul id="CDR0000062913__1038"><li class="half_rhythm"><div> At data cutoff, 147 patients had <i>RET</i>-mutant MTC and 22 patients had <i>RET</i> fusion–positive differentiated thyroid cancer. A total of 142 patients with <i>RET</i>-mutant MTC or <i>RET</i> fusion–positive differentiated thyroid cancer initiated the phase II dose of pralsetinib at 400 mg once daily.</div></li><li class="half_rhythm"><div> There were 61 patients with <i>RET</i>-mutant MTC who had previously received cabozantinib, vandetanib, or both, and 23 patients were treatment-naïve. </div></li><li class="half_rhythm"><div> In patients with <i>RET</i> fusion–positive differentiated thyroid cancer, the overall response rate was 89% (95% CI, 52%–100%), all of which were partial responses. Duration of response was not reached after a median follow-up of 9.5 months. Median PFS was not reached (95% CI, NE), with an estimated 1-year PFS rate of 81% after a median follow-up of 12.9 months. Median OS was also not reached, with an estimated 1-year OS rate of 91% (95% CI, 74%–100%) after a median follow-up of 15.8 months. </div></li><li class="half_rhythm"><div> The most frequent all-cause adverse events were anemia (45%), musculoskeletal pain (45%), constipation (44%), increased AST (42%), and hypertension (40%). Grade 3 to 4 treatment-related adverse events included hypertension (17%), neutropenia (13%), lymphopenia (12%), and anemia (10%). Serious adverse events were reported in 15% of patients; the most frequently reported serious adverse event was pneumonitis (4%).</div></li></ul></div></li></ol></div></div><div id="CDR0000062913__1040"><h5>NTRK inhibitors</h5><div id="CDR0000062913__1041"><h5>Larotrectinib</h5><p id="CDR0000062913__1042">Larotrectinib is a potent and highly selective small-molecule inhibitor of the TRKA, TRKB, and TRKC proteins.</p><p id="CDR0000062913__1043">Evidence (larotrectinib):</p><ol id="CDR0000062913__1044"><li class="half_rhythm"><div>An expanded pooled efficacy analysis included 159 patients with <i>TRK</i> fusion−positive cancers treated with larotrectinib and a safety analysis included 260 patients treated with larotrectinib regardless of <i>TRK</i> fusion status.[<a class="bk_pop" href="#CDR0000062913_rl_435_38">38</a>]<ol id="CDR0000062913__1045" class="lower-alpha"><li class="half_rhythm"><div> For the 24 patients with thyroid cancer, the overall response rate was 79% (95% CI, 58%−93%). The median duration of response was NE (14.8 months−NE).[<a class="bk_pop" href="#CDR0000062913_rl_435_38">38</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810037/" class="def">Level of evidence C2</a>]</div></li><li class="half_rhythm"><div> Of the 260 patients in the safety analysis, 13% had grade 3 treatment-related adverse events and fewer than 1% had grade 4 treatment-related adverse events. <ul id="CDR0000062913__1046"><li class="half_rhythm"><div> The most common grade 3 or 4 treatment-related adverse events were increased alanine aminotransferase (3%), anemia (2%), and decreased neutrophil count (2%).</div></li><li class="half_rhythm"><div> Doses were reduced in 8% of patients with <i>TRK</i> fusion-positive cancer because of adverse events. The drug was discontinued in 2% of 260 patients because of treatment-related adverse events.</div></li></ul></div></li></ol></div></li></ol></div><div id="CDR0000062913__1047"><h5>Entrectinib</h5><p id="CDR0000062913__1048">Entrectinib is a potent small-molecule inhibitor of the TRKA, TRKB, TRKC, ROS1, and ALK proteins.</p><p id="CDR0000062913__1049">Evidence (entrectinib):</p><ol id="CDR0000062913__1050"><li class="half_rhythm"><div>A pooled analysis of three phase I/II trials was conducted to evaluate the efficacy and safety of entrectinib in patients with metastatic or locally advanced or unresectable <i>NTRK</i> fusion−positive solid tumors. The efficacy analysis included 54 adult patients with advanced or metastatic <i>NTRK</i> fusion−positive solid tumors.[<a class="bk_pop" href="#CDR0000062913_rl_435_39">39</a>]<ol id="CDR0000062913__1051" class="lower-alpha"><li class="half_rhythm"><div> The objective response rate was 57% (95% CI, 34.2%−70.8%). Seven percent of patients had a complete response, and 50% of patients had a partial response.[<a class="bk_pop" href="#CDR0000062913_rl_435_39">39</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810037/" class="def">Level of evidence C2</a>]</div></li><li class="half_rhythm"><div>The median duration of response was 10 months (95% CI, 7.1−NE), and the median PFS was 11 months (95% CI, 8−14.9).</div></li><li class="half_rhythm"><div> For the five patients with thyroid cancer, the overall response rate was 20% (95% CI, 1%−72%).</div></li><li class="half_rhythm"><div> In the overall safety population (n = 355), the most frequently reported treatment-related adverse events were dysgeusia (41%), fatigue (28%), dizziness (26%), constipation (23%), and diarrhea (22%). <ul id="CDR0000062913__1052"><li class="half_rhythm"><div>The most common grade 3 or 4 treatment-related adverse events were increased weight (5%) and anemia (5%). </div></li></ul></div></li></ol></div></li></ol></div></div></div><div id="CDR0000062913__686"><h5>EBRT</h5><p id="CDR0000062913__687">EBRT or intraoperative radiation therapy can be
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useful in controlling symptoms related to local tumor recurrences.[<a class="bk_pop" href="#CDR0000062913_rl_435_40">40</a>]</p></div><div id="CDR0000062913__712"><h5>Chemotherapy</h5><p id="CDR0000062913__713">Systemic
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chemotherapy can be considered. Chemotherapy has been reported to produce
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occasional objective responses, usually of short duration.[<a class="bk_pop" href="#CDR0000062913_rl_435_26">26</a>,<a class="bk_pop" href="#CDR0000062913_rl_435_31">31</a>]</p></div><div id="CDR0000062913__688"><h5>Treatment options under clinical evaluation for recurrent papillary and follicular thyroid cancer</h5><p id="CDR0000062913__689">Clinical trials evaluating new treatment approaches to this disease should be considered for patients with recurrent papillary or follicular thyroid cancer. Oral inhibitors targeting specific activating point mutations are under clinical evaluation, as are new immunotherapy approaches.[<a class="bk_pop" href="#CDR0000062913_rl_435_27">27</a>-<a class="bk_pop" href="#CDR0000062913_rl_435_29">29</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810033/" class="def">Level of evidence B4</a>] </p></div></div></div><div id="CDR0000062913__TrialSearch_435_sid_5"><h3>Current Clinical Trials</h3><p id="CDR0000062913__TrialSearch_435_22">Use our <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/advanced-search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div><div id="CDR0000062913_rl_435"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062913_rl_435_1">Haigh PI, Urbach DR: The treatment and prognosis of Hürthle cell follicular thyroid carcinoma compared with its non-Hürthle cell counterpart. Surgery 138 (6): 1152-7; discussion 1157-8, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16360403" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16360403</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_2">Carling T, Udelsman R: Thyroid tumors. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 1457-72.</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_3">Grant CS, Hay ID, Gough IR, et al.: Local recurrence in papillary thyroid carcinoma: is extent of surgical resection important? Surgery 104 (6): 954-62, 1988. [<a href="https://pubmed.ncbi.nlm.nih.gov/3194847" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3194847</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_4">Cady B, Rossi R: An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 104 (6): 947-53, 1988. [<a href="https://pubmed.ncbi.nlm.nih.gov/3194846" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3194846</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_5">Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97 (5): 418-28, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7977430" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7977430</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_6">Staunton MD: Thyroid cancer: a multivariate analysis on influence of treatment on long-term survival. Eur J Surg Oncol 20 (6): 613-21, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7995409" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7995409</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_7">Tollefsen HR, Shah JP, Huvos AG: Follicular carcinoma of the thyroid. Am J Surg 126 (4): 523-8, 1973. [<a href="https://pubmed.ncbi.nlm.nih.gov/4743837" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 4743837</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_8">Edis AJ: Surgical treatment for thyroid cancer. Surg Clin North Am 57 (3): 533-42, 1977. [<a href="https://pubmed.ncbi.nlm.nih.gov/867221" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 867221</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_9">Bilimoria KY, Bentrem DJ, Ko CY, et al.: Extent of surgery affects survival for papillary thyroid cancer. Ann Surg 246 (3): 375-81; discussion 381-4, 2007. [<a href="/pmc/articles/PMC1959355/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1959355</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17717441" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17717441</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_10">Bilimoria KY, Bentrem DJ, Linn JG, et al.: Utilization of total thyroidectomy for papillary thyroid cancer in the United States. Surgery 142 (6): 906-13; discussion 913.e1-2, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/18063075" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18063075</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_11">Hay ID, Grant CS, Bergstralh EJ, et al.: Unilateral total lobectomy: is it sufficient surgical treatment for patients with AMES low-risk papillary thyroid carcinoma? Surgery 124 (6): 958-64; discussion 964-6, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9854569" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9854569</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_12">Beierwaltes WH, Rabbani R, Dmuchowski C, et al.: An analysis of "ablation of thyroid remnants" with I-131 in 511 patients from 1947-1984: experience at University of Michigan. J Nucl Med 25 (12): 1287-93, 1984. [<a href="https://pubmed.ncbi.nlm.nih.gov/6502251" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6502251</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_13">Hänscheid H, Lassmann M, Luster M, et al.: Iodine biokinetics and dosimetry in radioiodine therapy of thyroid cancer: procedures and results of a prospective international controlled study of ablation after rhTSH or hormone withdrawal. J Nucl Med 47 (4): 648-54, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16595499" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16595499</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_14">Hay ID, Grant CS, van Heerden JA, et al.: Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period. Surgery 112 (6): 1139-46; discussion 1146-7, 1992. [<a href="https://pubmed.ncbi.nlm.nih.gov/1455316" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1455316</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_15">Schvartz C, Bonnetain F, Dabakuyo S, et al.: Impact on overall survival of radioactive iodine in low-risk differentiated thyroid cancer patients. J Clin Endocrinol Metab 97 (5): 1526-35, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22344193" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22344193</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_16">Schlumberger M, Catargi B, Borget I, et al.: Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med 366 (18): 1663-73, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22551127" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22551127</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_17">Mallick U, Harmer C, Yap B, et al.: Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer. N Engl J Med 366 (18): 1674-85, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22551128" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22551128</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_18">Pujol P, Daures JP, Nsakala N, et al.: Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer. J Clin Endocrinol Metab 81 (12): 4318-23, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8954034" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8954034</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_19">Cooper DS, Specker B, Ho M, et al.: Thyrotropin suppression and disease progression in patients with differentiated thyroid cancer: results from the National Thyroid Cancer Treatment Cooperative Registry. Thyroid 8 (9): 737-44, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9777742" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9777742</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_20">Giuliani M, Brierley J: Indications for the use of external beam radiation in thyroid cancer. Curr Opin Oncol 26 (1): 45-50, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24225415" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24225415</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_21">Brose MS, Nutting CM, Jarzab B, et al.: Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 384 (9940): 319-28, 2014. [<a href="/pmc/articles/PMC4366116/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4366116</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24768112" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24768112</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_22">Schlumberger M, Tahara M, Wirth LJ, et al.: Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372 (7): 621-30, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25671254" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25671254</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_23">Simpson WJ, Carruthers JS: The role of external radiation in the management of papillary and follicular thyroid cancer. Am J Surg 136 (4): 457-60, 1978. [<a href="https://pubmed.ncbi.nlm.nih.gov/707725" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 707725</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_24">Gottlieb JA, Hill CS, Ibanez ML, et al.: Chemotherapy of thyroid cancer. An evaluation of experience with 37 patients. Cancer 30 (3): 848-53, 1972. [<a href="https://pubmed.ncbi.nlm.nih.gov/5075365" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 5075365</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_25">Harada T, Nishikawa Y, Suzuki T, et al.: Bleomycin treatment for cancer of the thyroid. Am J Surg 122 (1): 53-7, 1971. [<a href="https://pubmed.ncbi.nlm.nih.gov/5091855" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 5091855</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_26">Shimaoka K, Schoenfeld DA, DeWys WD, et al.: A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56 (9): 2155-60, 1985. [<a href="https://pubmed.ncbi.nlm.nih.gov/3902203" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3902203</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_27">Sherman SI, Wirth LJ, Droz JP, et al.: Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med 359 (1): 31-42, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18596272" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18596272</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_28">Jin Y, Van Nostrand D, Cheng L, et al.: Radioiodine refractory differentiated thyroid cancer. Crit Rev Oncol Hematol 125: 111-120, 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/29650270" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29650270</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_29">Naoum GE, Morkos M, Kim B, et al.: Novel targeted therapies and immunotherapy for advanced thyroid cancers. Mol Cancer 17 (1): 51, 2018. [<a href="/pmc/articles/PMC5817719/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5817719</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29455653" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29455653</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_30">Goretzki PE, Simon D, Frilling A, et al.: Surgical reintervention for differentiated thyroid cancer. Br J Surg 80 (8): 1009-12, 1993. [<a href="https://pubmed.ncbi.nlm.nih.gov/8402050" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8402050</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_31">De Besi P, Busnardo B, Toso S, et al.: Combined chemotherapy with bleomycin, adriamycin, and platinum in advanced thyroid cancer. J Endocrinol Invest 14 (6): 475-80, 1991. [<a href="https://pubmed.ncbi.nlm.nih.gov/1723086" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1723086</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_32">Ross DS: Long-term management of differentiated thyroid cancer. Endocrinol Metab Clin North Am 19 (3): 719-39, 1990. [<a href="https://pubmed.ncbi.nlm.nih.gov/2261913" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2261913</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_33">Pak H, Gourgiotis L, Chang WI, et al.: Role of metastasectomy in the management of thyroid carcinoma: the NIH experience. J Surg Oncol 82 (1): 10-8, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12501164" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12501164</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_34">Coburn M, Teates D, Wanebo HJ: Recurrent thyroid cancer. Role of surgery versus radioactive iodine (I131) Ann Surg 219 (6): 587-93; discussion 593-5, 1994. [<a href="/pmc/articles/PMC1243200/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1243200</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/8203968" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8203968</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_35">Brose MS, Robinson B, Sherman SI, et al.: Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 22 (8): 1126-1138, 2021. [<a href="https://pubmed.ncbi.nlm.nih.gov/34237250" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34237250</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_36">Wirth LJ, Sherman E, Robinson B, et al.: Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N Engl J Med 383 (9): 825-835, 2020. [<a href="https://pubmed.ncbi.nlm.nih.gov/32846061" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32846061</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_37">Subbiah V, Hu MI, Wirth LJ, et al.: Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. Lancet Diabetes Endocrinol 9 (8): 491-501, 2021. [<a href="https://pubmed.ncbi.nlm.nih.gov/34118198" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34118198</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_38">Hong DS, DuBois SG, Kummar S, et al.: Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol 21 (4): 531-540, 2020. [<a href="/pmc/articles/PMC7497841/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7497841</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32105622" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32105622</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_39">Doebele RC, Drilon A, Paz-Ares L, et al.: Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol 21 (2): 271-282, 2020. [<a href="/pmc/articles/PMC7461630/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7461630</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31838007" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31838007</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_435_40">Vikram B, Strong EW, Shah JP, et al.: Intraoperative radiotherapy in patients with recurrent head and neck cancer. Am J Surg 150 (4): 485-7, 1985. [<a href="https://pubmed.ncbi.nlm.nih.gov/4051112" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 4051112</span></a>]</div></li></ol></div></div><div id="CDR0000062913__132"><h2 id="_CDR0000062913__132_">Medullary Thyroid Cancer (MTC)</h2><div id="CDR0000062913__714"><h3>Sporadic and Hereditary MTC</h3><p id="CDR0000062913__715">MTC occurs in two forms,
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sporadic and hereditary. In the sporadic form, the tumor is usually unilateral.
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In the hereditary form, the tumor is almost always bilateral. In addition, the
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hereditary form may be associated with benign or malignant tumors of other
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endocrine organs, commonly referred to as the multiple endocrine neoplasia
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(MEN) syndromes types 2A and 2B (MEN2A or MEN2B).
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These syndromes are associated with pheochromocytoma of the adrenal
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gland and parathyroid hyperplasia.</p><p id="CDR0000062913__716">Approximately 25% of reported cases of MTC are hereditary.
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Hereditary MTC syndromes include MEN2A, which is
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the most common, MEN2B, and hereditary non-MEN syndromes. (Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000062890/">Genetics of Endocrine and Neuroendocrine Neoplasias</a> for more information.) Any patient with a
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hereditary variant is screened for other associated endocrine tumors,
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particularly parathyroid hyperplasia and pheochromocytoma. Medullary carcinoma usually secretes
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calcitonin, a hormonal marker for the tumor, and may be detectable in blood
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even when the tumor is clinically occult. Determining the level of calcitonin
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is useful for diagnostic purposes and for following the results of treatment.</p><p id="CDR0000062913__717">Patients with MTC (whether hereditary or sporadic) are
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tested for <i>RET</i> mutations, and if the mutations are positive, family members will
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also be tested. Family members may be screened for calcitonin elevation and for the <i>RET</i>
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proto-oncogene mutation to identify other individuals at risk for developing
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hereditary MTC. Because a modest elevation of calcitonin may lead to a false-positive diagnosis of medullary carcinoma, DNA testing for the <i>RET</i> mutation is
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the optimal approach. Family members who are gene carriers may choose to undergo
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prophylactic thyroidectomy at an early age.[<a class="bk_pop" href="#CDR0000062913_rl_132_1">1</a>,<a class="bk_pop" href="#CDR0000062913_rl_132_2">2</a>]</p></div><div id="CDR0000062913__492"><h3>Clinical Features and Prognosis</h3><p id="CDR0000062913__493">MTC comprises 3% to 4% of all thyroid cancers.
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These tumors usually present as a hard mass in the neck or thyroid, often associated
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with lymphadenopathy.[<a class="bk_pop" href="#CDR0000062913_rl_132_3">3</a>] MTC can also be diagnosed by fine-needle aspiration biopsy. Cytology
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typically reveals hypercellular tumors with spindle-shaped cells and poor
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adhesion.[<a class="bk_pop" href="#CDR0000062913_rl_132_4">4</a>] Metastases to regional lymph nodes
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are found in about 50% of the cases.</p><p id="CDR0000062913__692">The overall survival rates of patients with MTC is 86% at 5 years and 65% at 10 years.</p><p id="CDR0000062913__693">Prognosis depends on the following:[<a class="bk_pop" href="#CDR0000062913_rl_132_5">5</a>]</p><ul id="CDR0000062913__694"><li class="half_rhythm"><div>Extent of disease at
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presentation.</div></li><li class="half_rhythm"><div>Presence or absence of regional lymph node metastases.</div></li><li class="half_rhythm"><div>Completeness of the surgical resection.</div></li></ul><p id="CDR0000062913__621">Poor prognostic
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factors include the following:[<a class="bk_pop" href="#CDR0000062913_rl_132_4">4</a>,<a class="bk_pop" href="#CDR0000062913_rl_132_6">6</a>,<a class="bk_pop" href="#CDR0000062913_rl_132_7">7</a>]</p><ul id="CDR0000062913__622"><li class="half_rhythm"><div>Advanced age.</div></li><li class="half_rhythm"><div>Advanced stage.</div></li><li class="half_rhythm"><div>Previous neck surgery.</div></li><li class="half_rhythm"><div>Associated MEN2B.</div></li></ul></div><div id="CDR0000062913__500"><h3>Stage Information for MTC</h3><p id="CDR0000062913__501">Several staging systems have been employed to correlate extent of disease with
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long-term survival in MTC. The clinical staging system of
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the American Joint Committee on Cancer correlates survival to size of the primary tumor (T), presence or absence
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of lymph node involvement (N), and presence or absence of distant metastasis (M).
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Patients with the best prognosis are those who are diagnosed with the hereditary form of MTC after a positive screening for a <i>RET</i> mutation.[<a class="bk_pop" href="#CDR0000062913_rl_132_8">8</a>]</p><div id="CDR0000062913__889" class="table"><h3><span class="title">Definitions of Differentiated TNM Stage I for MTC<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65719.23/table/CDR0000062913__889/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062913__889_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Stage</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">TNM</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Description</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Illustration</th></tr></thead><tbody><tr><td colspan="1" rowspan="7" style="vertical-align:top;">I</td><td colspan="1" rowspan="7" style="vertical-align:top;">T1, N0, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T1 = Tumor ≤2 cm in greatest dimension limited to the thyroid.</td><td colspan="1" rowspan="7" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000779386&p=BOOKS&id=578124_CDR0000779386.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000779386.jpg" alt="Stage I medullary thyroid cancer; drawing shows cancer in the thyroid gland and the tumor is 2 centimeters or smaller. An inset shows 2 centimeters is about the size of a peanut. Also shown are the larynx and trachea." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1a = Tumor ≤1 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1b = Tumor >1 cm but ≤2 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N0a = One or more cytologically or histologically confirmed benign lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N0b = No radiologic or clinical evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastasis; MTC = medullary thyroid cancer.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Reprinted with permission from AJCC: Thyroid--Medullary. In: Amin MB, Edge SB, Greene FL, et al., eds.: <i>AJCC Cancer Staging Manual</i>. 8th ed. New York, NY: Springer, 2017, pp 891–901.</p></div></dd></dl></div></div></div><div id="CDR0000062913__890" class="table"><h3><span class="title">Definitions of Differentiated TNM Stage II for MTC<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65719.23/table/CDR0000062913__890/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062913__890_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Stage</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">TNM</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Description</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Illustration</th></tr></thead><tbody><tr><td colspan="1" rowspan="12" style="vertical-align:top;">II</td><td colspan="1" rowspan="5" style="vertical-align:top;">T2, N0, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T2 = Tumor >2 cm but ≤4 cm in greatest dimension limited to the thyroid.</td><td colspan="1" rowspan="12" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000779390&p=BOOKS&id=578124_CDR0000779390.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000779390.jpg" alt="Stage II medullary thyroid cancer; drawing shows (a) cancer in the thyroid gland and the tumor is larger than 2 centimeters and (b) cancer has spread to nearby muscles in the neck. An inset shows 2 centimeters is about the size of a peanut. Also shown are the larynx and trachea." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N0a = One or more cytologically or histologically confirmed benign lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N0b = No radiologic or clinical evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="7" style="vertical-align:top;">T3, N0, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T3 = Tumor >4 cm or with extrathyroidal extension.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3a = Tumor >4 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3b = Tumor of any size with gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles).</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N0a = One or more cytologically of histologically confirmed benign lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N0b = No radiologic or clinical evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastasis; MTC = medullary thyroid cancer.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Reprinted with permission from AJCC: Thyroid--Medullary. In: Amin MB, Edge SB, Greene FL, et al., eds.: <i>AJCC Cancer Staging Manual</i>. 8th ed. New York, NY: Springer, 2017, pp 891–901.</p></div></dd></dl></div></div></div><div id="CDR0000062913__891" class="table"><h3><span class="title">Definitions of Differentiated TNM Stage III for MTC<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65719.23/table/CDR0000062913__891/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062913__891_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Stage</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">TNM</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Description</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Illustration</th></tr></thead><tbody><tr><td colspan="1" rowspan="9" style="vertical-align:top;">III</td><td colspan="1" rowspan="9" style="vertical-align:top;">T1–3, N1a, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T1 = Tumor ≤2 cm in greatest dimension limited to the thyroid.</td><td colspan="1" rowspan="9" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000779393&p=BOOKS&id=578124_CDR0000779393.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000779393.jpg" alt="Stage III medullary thyroid cancer; drawing shows cancer in the thyroid gland and in nearby lymph nodes. Also shown are the trachea and larynx." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1a = Tumor ≤1 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1b = Tumor >1 cm but ≤2 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T2 = Tumor >2 cm but ≤4 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T3 = Tumor >4 cm or with extrathyroidal extension.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3a = Tumor >4 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3b = Tumor of any size with gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles).</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N1a = Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastasis; MTC = medullary thyroid cancer.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Reprinted with permission from AJCC: Thyroid--Medullary. In: Amin MB, Edge SB, Greene FL, et al., eds.: <i>AJCC Cancer Staging Manual</i>. 8th ed. New York, NY: Springer, 2017, pp 891–901.</p></div></dd></dl></div></div></div><div id="CDR0000062913__892" class="table"><h3><span class="title">Definitions of Differentiated TNM Stages IVA, IVB, and IVC for MTC<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65719.23/table/CDR0000062913__892/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062913__892_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Stage</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">TNM</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Description</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Illustration</th></tr></thead><tbody><tr><td colspan="1" rowspan="18" style="vertical-align:top;">IVA</td><td colspan="1" rowspan="9" style="vertical-align:top;">T4a, Any N, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">–T4a = Moderately advanced disease; tumor of any size with gross extrathyroidal extension into the nearby tissues of the neck, including subcutaneous soft tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve.</td><td colspan="1" rowspan="18" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000780091&p=BOOKS&id=578124_CDR0000780091.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000780091.jpg" alt="Stage IVA medullary thyroid cancer; drawing shows cancer in the thyroid gland and in the larynx, the esophagus, the left recurrent laryngeal nerve, the trachea, and a lymph node on one side of the neck. Also shown is the right recurrent laryngeal nerve." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">NX = Regional lymph nodes cannot be assessed.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N0a = One or more cytologically or histologically confirmed benign lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N0b = No radiologic or clinical evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N1 = Metastasis to regional nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1a = Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1b = Metastasis to unilateral, bilateral, or contralateral cervical neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="9" style="vertical-align:top;">T1–3, N1b, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T1 = Tumor ≤2 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1a = Tumor ≤1 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1b = Tumor >1 cm but ≤2 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T2 = Tumor >2 cm but ≤4 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T3 = Tumor >4 cm or with extrathyroidal extension.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3a = Tumor >4 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3b = Tumor of any size with gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles).</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1b = Metastasis to unilateral, bilateral, or contralateral cervical neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="3" style="vertical-align:top;">IVB</td><td colspan="1" rowspan="3" style="vertical-align:top;">T4b, Any N, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T4b = Very advanced disease; tumor of any size with extension toward the spine or into nearby large blood vessels, gross extrathyroidal extension invading the prevertebral fascia, or encasing the carotid artery or mediastinal vessels.</td><td colspan="1" rowspan="3" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000780093&p=BOOKS&id=578124_CDR0000780093.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000780093.jpg" alt="Stage IVB medullary thyroid cancer; drawing shows cancer has (a) spread from the thyroid gland to tissue in front of the spine and to the spine (inset), (b) surrounded the common carotid artery, and (c) surrounded the blood vessels in the area between the lungs. Also shown are the lymph nodes and trachea." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Any N = See descriptions in this table, Stage IVA.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="14" style="vertical-align:top;">IVC</td><td colspan="1" rowspan="14" style="vertical-align:top;">Any T, Any N, M1</td><td colspan="1" rowspan="1" style="vertical-align:top;">TX = Primary tumor cannot be assessed.</td><td colspan="1" rowspan="14" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000780095&p=BOOKS&id=578124_CDR0000780095.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000780095.jpg" alt="Stage IVC medullary thyroid cancer; drawing shows other parts of the body where thyroid cancer may spread, including the lung and liver. An inset shows cancer cells spreading from the thyroid, through the blood and lymph system, to another part of the body where metastatic cancer has formed." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T0 = No evidence of primary tumor.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T1 = Tumor ≤2 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1a = Tumor ≤1 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1b = Tumor >1 cm but ≤2 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T2 = Tumor >2 cm but ≤4 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T3 = Tumor >4 cm or with extrathyroidal extension.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3a = Tumor >4 cm in greatest dimension limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3b = Tumor of any size with gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles).</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T4 = Advanced disease.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T4a = Moderately advanced disease; tumor of any size with gross extrathyroidal extension into the nearby tissues of the neck, including subcutaneous soft tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T4b = Very advanced disease; tumor of any size with extension toward the spine or into nearby large blood vessels, gross extrathyroidal extension invading the prevertebral fascia, or encasing the carotid artery or mediastinal vessels.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Any N = See descriptions in this table, Stage IVA, T4a, Any N, M0.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M1 = Distant metastasis.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastasis; MTC = medullary thyroid cancer.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Reprinted with permission from AJCC: Thyroid--Medullary. In: Amin MB, Edge SB, Greene FL, et al., eds.: <i>AJCC Cancer Staging Manual</i>. 8th ed. New York, NY: Springer, 2017, pp 891–901.</p></div></dd></dl></div></div></div></div><div id="CDR0000062913__503"><h3>Standard Treatment Options for MTC</h3><div id="CDR0000062913__718"><h4>Localized disease</h4><p id="CDR0000062913__743">Standard treatment options for localized MTC include the following:</p><ol id="CDR0000062913__719"><li class="half_rhythm"><div><a href="#CDR0000062913__721">Total thyroidectomy.</a>
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</div></li><li class="half_rhythm"><div>
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<a href="#CDR0000062913__723">External-beam radiation therapy (EBRT).</a>
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</div></li></ol><p id="CDR0000062913__720">Radioactive iodine is not used in the treatment of patients with MTC.
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</p><div id="CDR0000062913__721"><h5>Total thyroidectomy</h5><p id="CDR0000062913__722">Patients with MTC are treated with a total
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thyroidectomy unless there is evidence of distant metastasis. In patients
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with clinically palpable MTC, the incidence of
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microscopically positive nodes is more than 75%. Routine central and bilateral
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modified neck dissections are generally done.[<a class="bk_pop" href="#CDR0000062913_rl_132_9">9</a>] When cancer is confined to
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the thyroid gland, the prognosis is excellent.</p></div><div id="CDR0000062913__723"><h5>EBRT</h5><p id="CDR0000062913__724">EBRT has been used for palliation of locally recurrent
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tumors without evidence that it provides any survival advantage.[<a class="bk_pop" href="#CDR0000062913_rl_132_10">10</a>]</p></div></div><div id="CDR0000062913__725"><h4>Locally advanced and metastatic disease</h4><p id="CDR0000062913__744">Standard treatment options for locally advanced and metastatic MTC include the following:</p><ol id="CDR0000062913__746"><li class="half_rhythm"><div><a href="#CDR0000062913__782">Targeted therapy</a>.<ul id="CDR0000062913__1053"><li class="half_rhythm"><div><a href="#CDR0000062913__1054">Tyrosine kinase inhibitors</a>. </div></li><li class="half_rhythm"><div><a href="#CDR0000062913__1065">RET kinase inhibitors</a>. </div></li></ul></div></li><li class="half_rhythm"><div>
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<a href="#CDR0000062913__732">Palliative chemotherapy.</a>
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</div></li></ol><div id="CDR0000062913__782"><h5>Targeted therapy</h5><div id="CDR0000062913__1054"><h5>Tyrosine kinase inhibitors</h5><div id="CDR0000062913__1092"><h5>Vandetanib</h5><p id="CDR0000062913__1093">Vandetanib is an oral inhibitor of rearranged during transfection (RET) receptor kinase, vascular endothelial growth factor receptor (VEGFR), and epidermal growth-factor receptor.</p><p id="CDR0000062913__1094">Evidence (vandetanib):</p><ol id="CDR0000062913__1095"><li class="half_rhythm"><div>Vandetanib has been evaluated in a placebo-controlled, prospective trial (<a href="https://www.cancer.gov/clinicaltrials/NCT00410761" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT00410761</a>) in 331 patients with locally advanced and metastatic disease with a 2:1 ratio in assignment to the study drug.[<a class="bk_pop" href="#CDR0000062913_rl_132_11">11</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810025/" class="def">Level of evidence B1</a>]<ul id="CDR0000062913__1096"><li class="half_rhythm"><div> With a median follow-up of 24 months, progression-free survival (PFS) favored vandetanib (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.31–0.69; <i>P</i> < .001), with a median PFS estimated at 30.5 months for vandetanib versus 19.3 months for placebo.</div></li><li class="half_rhythm"><div>Overall survival (OS) was not different at 24 months. Longer follow-up will be required because all but 47 patients were alive at the time of analysis, and there was a crossover to the study drug on progression from placebo, making analysis of OS problematic.</div></li><li class="half_rhythm"><div> Vandetanib has significant side effects, including diarrhea, rash, hypertension, and QT prolongation. Quality of life was not formally assessed in this trial.</div></li></ul></div></li></ol></div><div id="CDR0000062913__1097"><h5>Cabozantinib</h5><p id="CDR0000062913__1098">Cabozantinib is an oral tyrosine kinase inhibitor of RET receptor kinase, hepatocyte growth factor receptor MET, and VEGFR-2.</p><p id="CDR0000062913__1099">Evidence (cabozantinib):</p><ol id="CDR0000062913__1100"><li class="half_rhythm"><div>Cabozantinib has been evaluated in a randomized, double-blind, placebo-controlled, phase III trial (<a href="https://www.cancer.gov/clinicaltrials/NCT00704730" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EXAM</a> [<a href="https://clinicaltrials.gov/show/NCT00704730" title="Study NCT00704730" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT00704730</a>]) in 330 patients with metastatic MTC and radiographic progression of disease. Patients were randomly assigned in a 2:1 ratio to receive cabozantinib (140 mg per day) or placebo. Patients who received placebo were not permitted to cross
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over to cabozantinib.[<a class="bk_pop" href="#CDR0000062913_rl_132_12">12</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810025/" class="def">Level of evidence B1</a>]<ul id="CDR0000062913__1101"><li class="half_rhythm"><div> The primary endpoint of the study was PFS, and additional outcome measures were response rate, OS, and safety.</div></li><li class="half_rhythm"><div>Estimated median PFS was 11.2 months in the cabozantinib group and 4.0 months in the placebo group (HR, 0.28; 95% CI, 0.19‒0.40; <i>P</i> < .001). A difference in PFS was observed across all subgroups and was independent of previous tyrosine kinase inhibitor treatment and <i>RET</i> mutation status.</div></li><li class="half_rhythm"><div> During a planned interim analysis of OS, no statistically significant difference was observed between the two groups (HR, 0.98; 95% CI, 0.63‒1.52).</div></li><li class="half_rhythm"><div> Objective response rate was 28% in the cabozantinib group (all partial responses) and 0% in the placebo group (<i>P</i> < .001). The median estimated duration of response was 14.6 months (95% CI, 11.1‒17.5 months). Responses were observed regardless of <i>RET</i> mutation status.</div></li><li class="half_rhythm"><div>The most common cabozantinib-associated adverse events (all grades) included diarrhea (63.1%), palmar-plantar erythrodysesthesia (50%), decreased weight (47.7%), decreased appetite (45.8%), nausea (43%), and fatigue (40.7%)</div></li><li class="half_rhythm"><div>Grade 3 or 4 adverse events were reported in 69% of patients in the cabozantinib group and 33% of patients in the placebo group.</div></li><li class="half_rhythm"><div>Adverse events resulted in treatment discontinuation in 16% of patients who received cabozantinib and in 8% of patients who received placebo.</div></li></ul></div></li></ol></div></div><div id="CDR0000062913__1065"><h5>RET kinase inhibitors </h5><div id="CDR0000062913__1066"><h5>Selpercatinib</h5><p id="CDR0000062913__1067">Selpercatinib is an orally active, highly selective, small-molecule RET kinase inhibitor.</p><p id="CDR0000062913__1068">Evidence (selpercatinib):</p><ol id="CDR0000062913__1069"><li class="half_rhythm"><div>A phase I/II trial (<a href="https://www.cancer.gov/clinicaltrials/NCT03157128" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">LIBRETTO-001</a> [<a href="https://clinicaltrials.gov/show/NCT03157128" title="Study NCT03157128" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT03157128</a>]) evaluated the safety and efficacy of selpercatinib in adolescent and adult patients with any solid tumor type harboring an activating <i>RET</i> alteration. The primary endpoint was an objective response (complete response or partial response). The trial enrolled 55 patients with <i>RET</i>-mutant MTC who were previously treated with vandetanib, cabozantinib, or both; and 88 patients with <i>RET</i>-mutant MTC who were not previously treated with vandetanib or cabozantinib. Eighty two percent of previously treated patients received the recommended phase II dose of 160 mg twice daily, and 98% of previously untreated patients received 160 mg twice daily.[<a class="bk_pop" href="#CDR0000062913_rl_132_13">13</a>]<ol id="CDR0000062913__1070" class="lower-alpha"><li class="half_rhythm"><div>For patients with <i>RET</i>-mutant MTC who were previously treated with vandetanib or cabozantinib:<ul id="CDR0000062913__1071"><li class="half_rhythm"><div> The objective response rate was 69% (95% CI, 55%−81%); 9% of patients had a complete response, and 60% of patients had a partial response. </div></li><li class="half_rhythm"><div> At 1 year, 86% of responses were ongoing (95% CI, 67%−95%), and 100% of patients were progression-free.</div></li></ul></div></li><li class="half_rhythm"><div>For patients with <i>RET</i>-mutant MTC who were not previously treated with vandetanib or cabozantinib:
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<ul id="CDR0000062913__1072"><li class="half_rhythm"><div> The objective response rate was 73% (95% CI, 62%−82%); 11% of patients had a complete response, and 61% of patients had a partial response.[<a class="bk_pop" href="#CDR0000062913_rl_132_13">13</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810037/" class="def">Level of evidence C2</a>]</div></li><li class="half_rhythm"><div> At 1 year, 91% of responses were ongoing (95% CI, 72%−97%), and 92% of patients were progression-free.</div></li></ul></div></li><li class="half_rhythm"><div>Treatment-related adverse events (any grade) occurred in 94% of patients.<ul id="CDR0000062913__1073"><li class="half_rhythm"><div> Grade 3 adverse events were observed in 28% of patients, and grade 4 adverse events were observed in 2% of patients.</div></li><li class="half_rhythm"><div> The most frequent adverse events were dry mouth (46%), hypertension (43%), diarrhea (38%), fatigue (38%), increased aspartate aminotransferase (AST) level (35%), nausea (35%), and constipation (35%).</div></li><li class="half_rhythm"><div>Thirty percent of patients had dose reductions because of treatment-related adverse events, and 2% of patients discontinued the drug because of adverse events.</div></li></ul></div></li></ol></div></li></ol></div><div id="CDR0000062913__1074"><h5>Pralsetinib</h5><p id="CDR0000062913__1075">Pralsetinib is an oral RET-targeted therapy. In December 2020, the U.S. Food and Drug Administration approved pralsetinib for patients aged 12 years and older and for adults with advanced or metastatic <i>RET</i>-mutant MTC or <i>RET</i> fusion–positive RAI-refractory differentiated thyroid cancer. </p><p id="CDR0000062913__1076">Evidence (pralsetinib):</p><ol id="CDR0000062913__1077"><li class="half_rhythm"><div>A phase I/II, multicenter, open-label study (<a href="https://www.cancer.gov/clinicaltrials/NCT03037385" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ARROW</a> [<a href="https://clinicaltrials.gov/show/NCT03037385" title="Study NCT03037385" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT03037385</a>]) evaluated the efficacy and safety of pralsetinib.[<a class="bk_pop" href="#CDR0000062913_rl_132_14">14</a>]<ul id="CDR0000062913__1078"><li class="half_rhythm"><div> At data cutoff, 147 patients had <i>RET</i>-mutant MTC, and 22 patients had <i>RET</i> fusion–positive differentiated thyroid cancer. A total of 142 patients with <i>RET</i>-mutant MTC or <i>RET</i> fusion–positive differentiated thyroid cancer initiated the phase II dose of pralsetinib 400 mg once daily.</div></li><li class="half_rhythm"><div> There were 61 patients with <i>RET</i>-mutant MTC who had previously received cabozantinib, vandetanib, or both, and 23 patients were treatment-naïve. </div></li><li class="half_rhythm"><div> In patients with <i>RET</i>-mutant MTC previously treated with cabozantinib, vandetanib, or both, the overall response rate was 60% (95% CI, 46%–73%), with a complete response in one patient (2%). Median duration of response was not reached after a median follow-up of 11.2 months. Median PFS was not reached (95% CI, 19.1–NE), with an estimated 1-year PFS rate of 75% (95% CI, 63%–86%) after a median follow-up of 14.9 months. Median OS was also not reached (95% CI, NE), with an estimated 1-year OS rate of 89% (95% CI, 87%–91%) after a median follow-up of 16.5 months. </div></li><li class="half_rhythm"><div> In patients with treatment-naïve MTC, the overall response rate was 71% (95% CI, 48%–89%) with a complete response in one patient (5%). Median duration of response was not reached, with a median follow-up of 10.8 months. Median PFS was not reached (95% CI, NE) with an estimated PFS rate of 81% (95% CI, 63%–98%) after a median follow-up of 15.1 months. Median OS was also not reached (95% CI, NE), with an estimated 1-year OS rate of 91% (95% CI, 78%–100%) after a median follow-up of 18.5 months. </div></li><li class="half_rhythm"><div> The most frequent all-cause adverse events were anemia (45%), musculoskeletal pain (45%), constipation (44%), increased AST (42%), and hypertension (40%). Grade 3 to 4 treatment-related adverse events included hypertension (17%), neutropenia (13%), lymphopenia (12%) ,and anemia (10%). Serious adverse events were reported in 15% of patients; the most frequently reported serious adverse event was pneumonitis (4%).</div></li></ul></div></li></ol></div></div></div><div id="CDR0000062913__732"><h5>Palliative chemotherapy</h5><p id="CDR0000062913__733">Palliative chemotherapy has been reported to produce occasional responses in
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patients with metastatic disease.[<a class="bk_pop" href="#CDR0000062913_rl_132_15">15</a>-<a class="bk_pop" href="#CDR0000062913_rl_132_18">18</a>] No single drug regimen can be
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considered standard. Some patients with distant metastases will experience
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prolonged survival and can be managed expectantly until they become
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symptomatic.</p></div></div></div><div id="CDR0000062913__TrialSearch_132_sid_6"><h3>Current Clinical Trials</h3><p id="CDR0000062913__TrialSearch_132_22">Use our <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/advanced-search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div><div id="CDR0000062913_rl_132"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062913_rl_132_1">Lips CJ, Landsvater RM, Höppener JW, et al.: Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 331 (13): 828-35, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7915822" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7915822</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_2">Decker RA, Peacock ML, Borst MJ, et al.: Progress in genetic screening of multiple endocrine neoplasia type 2A: is calcitonin testing obsolete? Surgery 118 (2): 257-63; discussion 263-4, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7638742" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7638742</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_3">Soh EY, Clark OH: Surgical considerations and approach to thyroid cancer. Endocrinol Metab Clin North Am 25 (1): 115-39, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8907683" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8907683</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_4">Giuffrida D, Gharib H: Current diagnosis and management of medullary thyroid carcinoma. Ann Oncol 9 (7): 695-701, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9739433" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9739433</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_5">Carling T, Udelsman R: Thyroid tumors. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 1457-72.</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_6">Saad MF, Ordonez NG, Rashid RK, et al.: Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients. Medicine (Baltimore) 63 (6): 319-42, 1984. [<a href="https://pubmed.ncbi.nlm.nih.gov/6503683" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6503683</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_7">Bergholm U, Bergström R, Ekbom A: Long-term follow-up of patients with medullary carcinoma of the thyroid. Cancer 79 (1): 132-8, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/8988737" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8988737</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_8">Colson YL, Carty SE: Medullary thyroid carcinoma. Am J Otolaryngol 14 (2): 73-81, 1993 Mar-Apr. [<a href="https://pubmed.ncbi.nlm.nih.gov/8097904" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8097904</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_9">Moley JF, DeBenedetti MK: Patterns of nodal metastases in palpable medullary thyroid carcinoma: recommendations for extent of node dissection. Ann Surg 229 (6): 880-7; discussion 887-8, 1999. [<a href="/pmc/articles/PMC1420836/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1420836</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/10363903" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10363903</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_10">Brierley JD, Tsang RW: External radiation therapy in the treatment of thyroid malignancy. Endocrinol Metab Clin North Am 25 (1): 141-57, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8907684" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8907684</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_11">Wells SA, Robinson BG, Gagel RF, et al.: Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 30 (2): 134-41, 2012. [<a href="/pmc/articles/PMC3675689/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3675689</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22025146" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22025146</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_12">Elisei R, Schlumberger MJ, Müller SP, et al.: Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 31 (29): 3639-46, 2013. [<a href="/pmc/articles/PMC4164813/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4164813</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24002501" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24002501</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_13">Wirth LJ, Sherman E, Robinson B, et al.: Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N Engl J Med 383 (9): 825-835, 2020. [<a href="https://pubmed.ncbi.nlm.nih.gov/32846061" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32846061</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_14">Subbiah V, Hu MI, Wirth LJ, et al.: Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. Lancet Diabetes Endocrinol 9 (8): 491-501, 2021. [<a href="https://pubmed.ncbi.nlm.nih.gov/34118198" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34118198</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_15">Shimaoka K, Schoenfeld DA, DeWys WD, et al.: A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56 (9): 2155-60, 1985. [<a href="https://pubmed.ncbi.nlm.nih.gov/3902203" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3902203</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_16">De Besi P, Busnardo B, Toso S, et al.: Combined chemotherapy with bleomycin, adriamycin, and platinum in advanced thyroid cancer. J Endocrinol Invest 14 (6): 475-80, 1991. [<a href="https://pubmed.ncbi.nlm.nih.gov/1723086" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1723086</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_17">Wu LT, Averbuch SD, Ball DW, et al.: Treatment of advanced medullary thyroid carcinoma with a combination of cyclophosphamide, vincristine, and dacarbazine. Cancer 73 (2): 432-6, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/8293411" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8293411</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_132_18">Orlandi F, Caraci P, Berruti A, et al.: Chemotherapy with dacarbazine and 5-fluorouracil in advanced medullary thyroid cancer. Ann Oncol 5 (8): 763-5, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7826911" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7826911</span></a>]</div></li></ol></div></div><div id="CDR0000062913__139"><h2 id="_CDR0000062913__139_">Anaplastic Thyroid Cancer</h2><div id="CDR0000062913__519"><h3>Clinical Features and Prognosis</h3><p id="CDR0000062913__520">Undifferentiated (anaplastic) carcinoma is a highly malignant cancer of
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the thyroid. It grows rapidly and extends to structures beyond the thyroid. It typically presents as a hard, ill-defined mass, often with
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extension into the structures surrounding the thyroid. Anaplastic
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thyroid cancer must be carefully distinguished from lymphoma, which can have a similar presentation. This tumor
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usually occurs in an older age group and is characterized by extensive local
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invasion and rapid progression.[<a class="bk_pop" href="#CDR0000062913_rl_139_1">1</a>]</p><p id="CDR0000062913__734">Five-year survival with this tumor is poor.
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Death is usually from uncontrolled local cancer in the neck, usually within
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months of diagnosis.</p></div><div id="CDR0000062913__523"><h3>Stage Information for Anaplastic Thyroid Cancer</h3><p id="CDR0000062913__524">All patients with anaplastic thyroid cancer are considered to have stage IV disease. </p><div id="CDR0000062913__945" class="table"><h3><span class="title">Table 7. Definitions of TNM Stages for Anaplastic Thyroid Cancer<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65719.23/table/CDR0000062913__945/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062913__945_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Stage</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">T<sup>b</sup>NM</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Description</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Illustration</th></tr></thead><tbody><tr><td colspan="1" rowspan="9" style="vertical-align:top;">IVA</td><td colspan="1" rowspan="9" style="vertical-align:top;">T1–T3a, N0/NX, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T1 = Tumor ≤2 cm in greatest dimension, limited to the thyroid.</td><td colspan="1" rowspan="9" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000782401&p=BOOKS&id=578124_CDR0000782401.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000782401.jpg" alt="Stage IVA anaplastic thyroid cancer; drawing shows cancer in the thyroid gland. The lymph nodes are also shown." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1a = Tumor ≤1 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1b = Tumor >1 cm but ≤2 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T2 = Tumor >2 cm but ≤4 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T3 = Tumor >4 cm limited to the thyroid, or gross extrathyroidal extension invading only strap muscles.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3a = Tumor >4 cm limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">NX = Regional lymph nodes cannot be assessed.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="24" style="vertical-align:top;">IVB</td><td colspan="1" rowspan="10" style="vertical-align:top;">T1–T3a, N1, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T1 = Tumor ≤2 cm in greatest dimension, limited to the thyroid.</td><td colspan="1" rowspan="24" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000782402&p=BOOKS&id=578124_CDR0000782402.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000782402.jpg" alt="Stage IVB anaplastic thyroid cancer (1); drawing shows cancer in the thyroid gland and nearby lymph nodes." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1a = Tumor ≤1 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1b = Tumor >1 cm but ≤2 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T2 = Tumor >2 cm but ≤4 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T3 = Tumor >4 cm limited to the thyroid, or gross extrathyroidal extension invading only strap muscles.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3a = Tumor >4 cm limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N1 = Metastasis to regional nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1a = Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1b = Metastasis to unilateral, bilateral, or contralateral lateral neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="9" style="vertical-align:top;">T3b, Any N, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">–T3b = Gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles) from a tumor of any size.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">NX = regional lymph nodes cannot be assessed.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N0a = One or more cytologically or histologically confirmed benign lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N0b = No radiologic or clinical evidence of locoregional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N1 = Metastasis to regional nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1a = Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1b = Metastasis to unilateral, bilateral, or contralateral lateral neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="5" style="vertical-align:top;">T4, Any N, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T4 = Includes gross extrathyroidal extension beyond the strap muscles.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T4a = Gross extrathyroidal extension invading subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve from a tumor of any size.
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T4b = Gross extrathyroidal extension invading prevertebral fascia or encasing the carotid artery or mediastinal vessels from a tumor of any size.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Any N = See descriptions in this table, Stage IVB, T3b, Any N, M0.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="14" style="vertical-align:top;">IVC</td><td colspan="1" rowspan="14" style="vertical-align:top;">Any T, Any N, M1 </td><td colspan="1" rowspan="1" style="vertical-align:top;">TX = Primary tumor cannot be assessed.</td><td colspan="1" rowspan="14" style="vertical-align:top;">
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<div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20CDR0000780096&p=BOOKS&id=578124_CDR0000780096.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK65719.23/bin/CDR0000780096.jpg" alt="Stage IVC anaplastic thyroid cancer; drawing shows other parts of the body where thyroid cancer may spread, including the lung and bone. An inset shows cancer cells spreading from the thyroid, through the blood and lymph system, to another part of the body where metastatic cancer has formed." class="tileshop" title="Click on image to zoom" /></a></div>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T0 = No evidence of primary tumor.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T1 = Tumor ≤2 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1a = Tumor ≤1 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T1b = Tumor >1 cm but ≤2 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T2 = Tumor >2 cm but ≤4 cm in greatest dimension, limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T3 = Tumor >4 cm limited to the thyroid, or gross extrathyroidal extension invading only strap muscles.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3a = Tumor >4 cm limited to the thyroid.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T3b = Gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles) from a tumor of any size.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T4 = Includes gross extrathyroidal extension beyond the strap muscles.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T4a = Gross extrathyroidal extension invading subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve from a tumor of any size.
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–T4b = Gross extrathyroidal extension invading prevertebral fascia or encasing the carotid artery or mediastinal vessels from a tumor of any size.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Any N = See descriptions in this table, Stage IVB, T3b, Any N, M0.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M1 = Distant metastasis.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastasis.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Reprinted with permission from AJCC: Thyroid--Differentiated and Anaplastic Carcinoma. In: Amin, MB, Edge Sb, Greene FL et al., eds.: <i>AJCC Cancer Staging Manual</i>. 8th ed. New York, NY: Springer, 2017, pp 873–90. </p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>b</sup>All categories may be subdivided: (s) solitary tumor and (m) multifocal tumor (the largest determines the classification).</p></div></dd></dl></div></div></div></div><div id="CDR0000062913__525"><h3>Standard Treatment Options for Anaplastic Thyroid Cancer</h3><p id="CDR0000062913__745">Standard treatment options for anaplastic thyroid cancer include the following:</p><ol id="CDR0000062913__527"><li class="half_rhythm"><div><a href="#CDR0000062913__528">Surgery</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062913__530">External-beam radiation therapy (EBRT)</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062913__532">Systemic therapy</a>.</div></li></ol><div id="CDR0000062913__528"><h4>Surgery</h4><p id="CDR0000062913__529"> If the disease is confined to the local area, which is rare, total thyroidectomy is warranted to
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reduce symptoms caused by the tumor mass.[<a class="bk_pop" href="#CDR0000062913_rl_139_2">2</a>,<a class="bk_pop" href="#CDR0000062913_rl_139_3">3</a>] Tracheostomy is frequently necessary.</p></div><div id="CDR0000062913__530"><h4>EBRT</h4><p id="CDR0000062913__531">EBRT may be used in patients who are not surgical candidates or whose tumor cannot be surgically
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excised.
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</p></div><div id="CDR0000062913__532"><h4>Systemic Therapy</h4><p id="CDR0000062913__533">Anaplastic thyroid cancer is not responsive to iodine I 131 therapy.
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Treatment with individual anticancer drugs has been reported to produce partial
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remissions in some patients. Approximately 30% of patients achieve a partial
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remission with doxorubicin.[<a class="bk_pop" href="#CDR0000062913_rl_139_4">4</a>] The combination of doxorubicin plus cisplatin
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appears to be more active than doxorubicin alone and has been reported to
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produce more complete responses.[<a class="bk_pop" href="#CDR0000062913_rl_139_5">5</a>]</p><p id="CDR0000062913__735">The combination of chemotherapy plus radiation therapy in patients after complete
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resection may provide prolonged survival but has not been compared with any one
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modality alone.[<a class="bk_pop" href="#CDR0000062913_rl_139_6">6</a>,<a class="bk_pop" href="#CDR0000062913_rl_139_7">7</a>]</p><p id="CDR0000062913__950">An estimated 25% of anaplastic thyroid cancers harbor an activating <i>BRAF</i> (V600E) mutation.[<a class="bk_pop" href="#CDR0000062913_rl_139_8">8</a>] </p><p id="CDR0000062913__951">Evidence (dabrafenib and trametinib):</p><ol id="CDR0000062913__952"><li class="half_rhythm"><div>A phase II trial of BRAF and MEK inhibitors, dabrafenib and trametinib, included 16 patients with <i>BRAF</i> (V600E)–mutated anaplastic thyroid cancer.[<a class="bk_pop" href="#CDR0000062913_rl_139_9">9</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810037/" class="def">Level of evidence C2</a>] <ul id="CDR0000062913__953"><li class="half_rhythm"><div>There was a 69% confirmed overall response rate, with median duration of response, progression-free survival (PFS), and overall survival (OS) not reached. </div></li><li class="half_rhythm"><div>Twelve-month estimates were 90% for duration of response, 79% for PFS, and 80% for OS. </div></li></ul></div></li></ol><p id="CDR0000062913__954">On the basis of this data, the combination of dabrafenib and trametinib was approved by the U.S. Food and Drug Administration for the treatment of unresectable or metastatic <i>BRAF</i> (V600E)–mutated anaplastic thyroid cancer. Molecular testing for this mutation is advised for patients with anaplastic thyroid cancer. </p></div></div><div id="CDR0000062913__TrialSearch_139_sid_7"><h3>Current Clinical Trials</h3><p id="CDR0000062913__TrialSearch_139_22">Use our <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/advanced-search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div><div id="CDR0000062913_rl_139"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062913_rl_139_1">Neff RL, Farrar WB, Kloos RT, et al.: Anaplastic thyroid cancer. Endocrinol Metab Clin North Am 37 (2): 525-38, xi, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18502341" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18502341</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_139_2">Goldman JM, Goren EN, Cohen MH, et al.: Anaplastic thyroid carcinoma: long-term survival after radical surgery. J Surg Oncol 14 (4): 389-94, 1980. [<a href="https://pubmed.ncbi.nlm.nih.gov/7442263" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7442263</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_139_3">Aldinger KA, Samaan NA, Ibanez M, et al.: Anaplastic carcinoma of the thyroid: a review of 84 cases of spindle and giant cell carcinoma of the thyroid. Cancer 41 (6): 2267-75, 1978. [<a href="https://pubmed.ncbi.nlm.nih.gov/657091" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 657091</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_139_4">Carling T, Udelsman R: Thyroid tumors. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 1457-72.</div></li><li><div class="bk_ref" id="CDR0000062913_rl_139_5">Shimaoka K, Schoenfeld DA, DeWys WD, et al.: A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56 (9): 2155-60, 1985. [<a href="https://pubmed.ncbi.nlm.nih.gov/3902203" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3902203</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_139_6">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 91 (12): 2335-42, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11413523" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11413523</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_139_7">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 60 (4): 1137-43, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15519785" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15519785</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_139_8">Forbes SA, Beare D, Boutselakis H, et al.: COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res 45 (D1): D777-D783, 2017. [<a href="/pmc/articles/PMC5210583/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5210583</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27899578" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27899578</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062913_rl_139_9">Subbiah V, Kreitman RJ, Wainberg ZA, et al.: Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer. J Clin Oncol 36 (1): 7-13, 2018. [<a href="/pmc/articles/PMC5791845/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5791845</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29072975" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29072975</span></a>]</div></li></ol></div></div><div id="CDR0000062913__203"><h2 id="_CDR0000062913__203_">Changes to This Summary (02/18/2022)</h2><p id="CDR0000062913__204">The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.</p><p id="CDR0000062913__1008">
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<b>
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<a href="#CDR0000062913__1">General Information About Thyroid Cancer</a>
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</b>
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</p><p id="CDR0000062913__1009">Updated <a href="#CDR0000062913__243">statistics</a> with estimated new cases and deaths for 2022 (cited American Cancer Society as reference 2).</p><p id="CDR0000062913__1102">
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<b>
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<a href="#CDR0000062913__435">Papillary and Follicular Thyroid Cancer</a>
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</b>
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</p><p id="CDR0000062913__1103">Added <a href="#CDR0000062913__1023">Cabozantinib</a> as a new subsection.</p><p id="CDR0000062913__1104">Added <a href="#CDR0000062913__1035">Pralsetinib</a> as a new subsection.</p><p id="CDR0000062913__1105">
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<b>
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<a href="#CDR0000062913__132">Medullary Thyroid Cancer (MTC)</a>
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</b>
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</p><p id="CDR0000062913__1106">Added <a href="#CDR0000062913__1074">Pralsetinib</a> as a new subsection.</p><p id="CDR0000062913__disclaimerHP_3">This summary is written and maintained by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/adult-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Adult Treatment Editorial Board</a>, which is
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editorially independent of NCI. The summary reflects an independent review of
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the literature and does not represent a policy statement of NCI or NIH. More
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information about summary policies and the role of the PDQ Editorial Boards in
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maintaining the PDQ summaries can be found on the <a href="#CDR0000062913__AboutThis_1">About This PDQ Summary</a> and <a href="https://www.cancer.gov/publications/pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ® Cancer Information for Health Professionals</a> pages.
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</p></div><div id="CDR0000062913__AboutThis_1"><h2 id="_CDR0000062913__AboutThis_1_">About This PDQ Summary</h2><div id="CDR0000062913__AboutThis_2"><h3>Purpose of This Summary</h3><p id="CDR0000062913__AboutThis_3">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult thyroid cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.</p></div><div id="CDR0000062913__AboutThis_4"><h3>Reviewers and Updates</h3><p id="CDR0000062913__AboutThis_5">This summary is reviewed regularly and updated as necessary by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/adult-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Adult Treatment Editorial Board</a>, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p><p id="CDR0000062913__AboutThis_22"> Board members review recently published articles each month to determine whether an article should:</p><ul id="CDR0000062913__AboutThis_6"><li class="half_rhythm"><div>be discussed at a meeting,</div></li><li class="half_rhythm"><div>be cited with text, or</div></li><li class="half_rhythm"><div>replace or update an existing article that is already cited.</div></li></ul><p id="CDR0000062913__AboutThis_7">Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.</p><p>The lead reviewers for Thyroid Cancer Treatment (Adult) are:</p><ul><li class="half_rhythm"><div>Andrea Bonetti, MD (Azienda ULSS 9 of the Veneto Region)</div></li><li class="half_rhythm"><div>Ann W. Gramza, MD (Georgetown Lombardi Comprehensive Cancer Center)</div></li><li class="half_rhythm"><div>Minh Tam Truong, MD (Boston University Medical Center)</div></li><li class="half_rhythm"><div>Jaydira del Rivero, MD (National Cancer Institute)</div></li></ul><p id="CDR0000062913__AboutThis_9">Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.</p></div><div id="CDR0000062913__AboutThis_10"><h3>Levels of Evidence</h3><p id="CDR0000062913__AboutThis_11">Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a <a href="/books/n/pdqcis/CDR0000062796/">formal evidence ranking system</a> in developing its level-of-evidence designations.</p></div><div id="CDR0000062913__AboutThis_12"><h3>Permission to Use This Summary</h3><p id="CDR0000062913__AboutThis_13">PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”</p><p id="CDR0000062913__AboutThis_14">The preferred citation for this PDQ summary is:</p><p id="CDR0000062913__AboutThis_15">PDQ® Adult Treatment Editorial Board. PDQ Thyroid Cancer Treatment (Adult). Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: <a href="https://www.cancer.gov/types/thyroid/hp/thyroid-treatment-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.cancer.gov/types/thyroid/hp/thyroid-treatment-pdq</a>. Accessed <MM/DD/YYYY>. [PMID: 26389164]</p><p id="CDR0000062913__AboutThis_16">Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in <a href="https://visualsonline.cancer.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Visuals Online</a>, a collection of over 2,000 scientific images.
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</p></div><div id="CDR0000062913__AboutThis_17"><h3>Disclaimer</h3><p id="CDR0000062913__AboutThis_18">Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the <a href="https://www.cancer.gov/about-cancer/managing-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Managing Cancer Care</a> page.</p></div><div id="CDR0000062913__AboutThis_20"><h3>Contact Us</h3><p id="CDR0000062913__AboutThis_21">More information about contacting us or receiving help with the Cancer.gov website can be found on our <a href="https://www.cancer.gov/contact" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Contact Us for Help</a> page. Questions can also be submitted to Cancer.gov through the website’s <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>.</p></div></div></div></div>
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<div class="post-content"><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div><div class="small"><span class="label">Bookshelf ID: NBK65719</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/26389164" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">26389164</a></span></div></div></div>
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ref="log$=inpage&link_id=inpage">General Information About Thyroid Cancer</a></li><li><a href="#CDR0000062913__6" ref="log$=inpage&link_id=inpage">Cellular Classification of Thyroid Cancer</a></li><li><a href="#CDR0000062913__14" ref="log$=inpage&link_id=inpage">Stage Information for Thyroid Cancer</a></li><li><a href="#CDR0000062913__555" ref="log$=inpage&link_id=inpage">Treatment Option Overview for Thyroid Cancer</a></li><li><a href="#CDR0000062913__435" ref="log$=inpage&link_id=inpage">Papillary and Follicular Thyroid Cancer</a></li><li><a href="#CDR0000062913__132" ref="log$=inpage&link_id=inpage">Medullary Thyroid Cancer (MTC)</a></li><li><a href="#CDR0000062913__139" ref="log$=inpage&link_id=inpage">Anaplastic Thyroid Cancer</a></li><li><a href="#CDR0000062913__203" ref="log$=inpage&link_id=inpage">Changes to This Summary (02/18/2022)</a></li><li><a href="#CDR0000062913__AboutThis_1" ref="log$=inpage&link_id=inpage">About This PDQ Summary</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related publications</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK65857/">Patient Version</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=2825634" 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class="invert">Review</span> Thyroid Cancer Screening (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Thyroid Cancer Screening (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Screening and Prevention Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389244" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" 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