Lori J. Wirth, Tito Fojo
Thyroid cancer is the most common endocrine malignancy with an estimated 60,220 cases to be diagnosed in the United States in 2013 (1). In the United States, the incidence of thyroid cancers has risen steadily from the 1970s to the present, with the increasing incidence in part due to the incidental detection of small tumors. There are also data indicating that the incidence of larger tumors is on the rise, suggesting that additional factors, such as environmental exposures, are leading to a true rise in incidence. Thyroid cancer is three times more prevalent in women than men, whereas higher mortality is seen in men.
There are three major types of thyroid cancer, each with its own unique natural history and approach to treatment: differentiated thyroid cancer (DTC), anaplastic thyroid cancer (ATC), and medullary thyroid cancer (MTC). DTC is the most common, accounting for >90% of all cases, with ATC and MTC accounting for approximately 2% and 5% of cases, respectively.
DIFFERENTIATED THYROID CANCER
There are two predominant subtypes of DTC: papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), with PTC comprising approximately 85% of cases. Of the multiple staging systems for DTC, the AJCC/UICC TNM system is used most often. Features that impact prognosis most include age >45 years, gross extrathyroidal extension, nodal metastasis, especially with extranodal extension, distant metastasis, FDG avidity, absence of radioiodine uptake, and more aggressive histologic subtypes, such as tall cell, diffuse sclerosing, hobnail, as well as insular or poorly differentiated variants.
There are a variety of genetic alterations seen in DTC, although little overlap is seen in the genetics of PTC and FTC. Alterations in the mitogen-activated protein kinase (MAPK) signaling pathway are common. Mutations in BRAF are the most commonly encountered mutations, occurring in 40%–50% of PTCs. BRAF mutation is associated with older age, lymph node involvement, distant metastasis, decreased sensitivity to radioiodine, and risk of recurrence. RET/PTC rearrangements are the second most common abnormality seen in PTC. In FTC, RAS mutations and PPARG rearrangements are seen in approximately 50% and 35%, respectively. These molecular changes and others now offer strong rationale for exploring targeted therapies in advanced DTC.
The prognosis of DTC is usually quite good. Most cases can be treated adequately with surgery, frequently followed by radioiodine. Unless there is a contraindication to the procedure, total thyroidectomy is indicated when the primary tumor is >1 cm. Total thyroidectomy addresses the potential for multicentric DTC, facilitates subsequent radioiodine therapy, and allows for subsequent surveillance by serum thyroglobulin levels and radioiodine scanning. Metastasis to cervical nodes is frequent in PTC, while uncommon in FTC. Therefore, prophylactic central compartment neck dissection is usually performed only in PTC. Treatment with radioiodine is indicated for patients with intermediate- and high-risk disease, whereas the role for radioiodine in patients with low-risk disease remains unclear. Beyond surgery and radioiodine, TSH suppression with levothyroxine is employed in most patients to reduce the risk of disease recurrence. The role of external beam radiotherapy (EBRT) in the management of DTC is less clear due to a paucity of prospective data, but in general, patients with unresectable disease in the neck or gross residual disease following surgery may be considered for EBRT.
While long-term overall survival (OS) for DTC is quite good for most patients, approximately 30% will experience disease recurrence. Recurrent disease can involve the thyroid bed or cervical lymph nodes, the trachea, or neck muscles, or can occur distantly. Recurrent disease in the neck is managed with surgery and additional radioiodine, when feasible. In patients with recurrent disease, radioiodine uptake and FDG avidity can be used in risk stratification. Those with FDG-avid disease that does not concentrate radioiodine are at the highest risk for death. Locoregionally recurrent and/or metastatic iodine-refractory DTC not amenable to surgery has traditionally been treated with cytotoxic chemotherapy, although activity is poor and the toxicities are difficult to justify. Studies investigating targeted therapy for iodine-refractory DTC, most notably agents targeting isoforms of the vascular endothelial growth factor receptor (VEGFR), have shown evidence of antitumor activity, while underscoring the difficulties of evaluating anticancer therapies in diseases that are often indolent in nature (Table 65-1). In “differentiated thyroid cancer,” 8 VEGFR tyrosine kinase inhibitors (TKIs) have been evaluated in 605 patients: sorafenib, sunitinib, pazopanib, motesanib, selumetinib, axitinib, levanitinib, and vandetanib (2–8). Only one patient has had a complete response, with partial response rates of 2.6%–50% with a median of 18%. Progression-free survival, a difficult endpoint in patients with variably indolent disease, has ranged from 7.4 to 20 months with a median of 13.4 months. One cannot discern major differences amongst all the agents, and randomized trials will be needed to clearly establish the benefit of these therapies. A high incidence of toxicities is evidenced by drug discontinuation and dose adjustments in a median of 20% and 42% of patients, respectively. These high rates of toxicity underscore that these therapies, if shown to be effective, should be reserved only for those with advanced refractory disease, given that in the advanced thyroid cancer patient population, many patients have slow-growing, asymptomatic disease. Thus, the decision when to treat and when not to treat must be individualized to each patient.
TABLE 65-1 SELECTED TARGETED THERAPY STUDIES IN ADVANCED THYROID CANCER
ANAPLASTIC THYROID CARCINOMA
ATC, constituting approximately 2% of all thyroid cancers, remains one of the most lethal of human cancers, with nearly 100% mortality and a median OS of only 5–6 months. ATC can arise de novo or result from the dedifferentiation of PTC or FTC. ATC most commonly presents in the seventh decade of life and occurs more in women than in men. Because of the clinical implications of misclassifying ATC, a definitive tissue biopsy, rather than FNA alone, should be performed as part of the diagnosis of ATC, particularly as there is some cytologic overlap with other diagnoses, particularly lymphoma, medullary thyroid carcinoma, and the insular variant of follicular thyroid carcinoma.
ATCs typically harbor multiple genetic abnormalities. In addition to frequent chromosomal gains and losses, gene amplifications and deletions, mutations in RAS and BRAF are also seen in ATC, suggesting these mutations are early events in carcinogenesis. Late mutations can involve p53, β-catenin, and PIK3CA.
The management of ATC is particularly challenging because most patients present with both extensive locoregional disease and distant metastasis. Long-term survival is essentially limited to patients who have undergone complete resection, often in incidentally discovered disease. Adjuvant chemoradiotherapy, which should be started as soon as the patient has recovered from surgery, is generally administered with the goal to improve locoregional control and prevent death from airway obstruction. Doxorubicin, platinums, and taxanes are the cytotoxic therapies most often given concurrently with radiation.
Taxanes, anthracyclines, and platinums, either as monotherapy and or in combination, are reasonable choices for systemic therapy in ATC patients with locally advanced disease or distant metastasis, although objective response rates are low. Because no clinical trial has shown improvement in OS or quality of life with any systemic regimen, involvement in clinical trials, when available, is encouraged (9).
More effective therapies for ATC are urgently needed. Potential molecular targets under investigation include the ras/RAF/MEK and PI-3K/AKT/mTOR pathways, PPARγ aurora kinases, and “anti-vascular agents” similar to combretastatin. Any targeted therapy shown to be potentially effective will likely require a development strategy that includes cytotoxic chemotherapy due to the rapidly progressive nature of the disease.
MEDULLARY THYROID CARCINOMA
MTC is a rare tumor arising from the thyroid’s calcitonin-producing parafollicular C cells. MTC is hereditary in 20%–25% of cases, resulting from germline RET mutation in the familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia (MEN) 2A and B syndromes. The identification of individuals with MTC harboring a germline mutation is critical, since other family members affected by the mutation must be identified and treated. Moreover, patients with MEN2A and B are at risk for pheochromocytoma and primary hyperparathyroidism. Patients with hereditary MTC and MEN2 should be referred for genetic counseling, and all patients with newly diagnosed MTC should undergo genetic testing to establish whether they have sporadic or hereditary disease.
The presentation of MTC is variable and may range from a solitary thyroid nodule to metastatic disease. FNA is the initial test most frequently used to diagnose MTC, with subsequent measurement of serum calcitonin if MTC is suspected. Biochemical screening is generally performed preoperatively to rule out pheochromocytoma. Surgery plays a central role in the management of MTC. Preoperative neck and chest CT, and liver CT or MRI, is also generally recommended for suspected MTC patients if there is evidence of cervical nodal metastasis or the serum calcitonin is >400 pg/ml. A total thyroidectomy is recommended for all patients with newly diagnosed MTC. Bilateral prophylactic central compartment dissection is generally performed, due to a high rate of occult nodal metastasis, while surgical management of the lateral neck is variable.
The TNM staging system used for MTC does not take into account several prognostic factors, such as postoperative calcitonin and CEA levels or tumor marker doubling times, which are predictive of OS. Surveillance by calcitonin and CEA are recommended to detect persistent or recurrent disease following surgery. Levels are usually not measured until at least 2 months following surgery because of a long half-life and inflammatory effects on calcitonin synthesis.
MTC is not highly responsive to EBRT, although radiotherapy can be considered in the adjuvant setting or for palliation. Historically, cytotoxic chemotherapy was used in metastatic or locally recurrent unresectable MTC, although there is little evidence to support its use. As with well-differentiated thyroid cancers, TKIs targeting the VEGFR isoforms have also been investigated in MTC, including axitinib, sorafenib, sunitinib, and motesanib (Table 65-1) (3,10–12). Generally they have shown much lower response rates than those observed in well-differentiated cancers with similar toxicity profiles. However, there has been greater interest in drugs with putative anti-RET kinase activity (13, 14). Both vandetanib and cabozantinib have received FDA approval for patients with “late-stage (metastatic) medullary thyroid cancer who are ineligible for surgery and who have disease that is growing or causing symptoms.” Vandetanib, with demonstrated preclinical activity against RET, as well as VEGFR and EGFR, has been evaluated in an international placebo-controlled phase III study in which 331 patients with sporadic or hereditary locally advanced or metastatic MTC were enrolled (13). PFS was improved from 19 to approximately 31 months. Adverse events including diarrhea, rash, nausea, hypertension, asthenia, and QTc prolongation have been reported and should be managed with dose reductions to 200 and 100 mg, since in many patients these lower doses retain antitumor activity. As with advanced DTC, the side effect profile of TKI treatment that may impact a patient’s quality of life needs to be taken into account when treatment decisions are made in these patients who are often minimally symptomatic and have a life measured in years. A second large randomized phase III study investigating another TKI, cabozantinib, in MTC has been successfully completed (14). In the 330 patients enrolled, PFS was significantly improved by cabozantinib, from 4 to 11 months. As with vandetanib and all VEGFR inhibitors, dose adjustments and discontinuations were frequent. Caution should be used when considering cabozantinib since the starting dose of 140 mg used in the MTC trial is no longer being investigated, in large part due to the side effects encountered at this dose. Consequently a lower starting dose might be considered. For both vandetanib and cabozantinib, treatment should be limited to MTC patients with unresectable, locoregionally recurrent, and/or metastatic disease that is progressive or symptomatic, while watchful waiting should continue to be the preferred approach in those patients who are asymptomatic and have indolent, slow-growing disease.
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