11 Medical Management of Aggressive Differentiated Thyroid Cancer
11.1 Introduction
Although patients with thyroid cancer present with either intermediate- or low-risk disease that is very effectively treated with thyroid surgery (with or without the addition of radioactive iodine [RAI]), as many as 10 to 15% of patients have advanced disease that is manifest either by distant metastases or locally aggressive disease. Distant metastases can occur during follow-up in 6 to 20% of patients with thyroid cancer and can be seen in 3 to 15% of patients at their presentation. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 In locally advanced disease, the primary clinical management issues relate to invasion of major cervical structures (vessels, esophagus, trachea, larynx, recurrent laryngeal nerves). In distant metastases, the management issues are often related to local compressive symptoms if metastatic foci are located near (or in) major neurovascular structures or the aerodigestive tract, or as an impending (or actual) pathological bone fracture.
Although advanced disease can manifest either at the time of initial presentation or during follow-up, the basic management principles remain the same. Management of advanced disease is ideally undertaken in the context of a functional, integrated team, because the care of these patients usually requires complex decision making and a wide array of potential therapies.
Treatment options for advanced disease can be divided into localized therapies directed toward one or more individual tumor foci or systemic therapies designed to treat more widespread disease. A wide variety of localized therapies are currently available and include options such as extensive surgery or focused surgical metastasectomy, external beam radiation therapy (EBRT), embolization, and radiofrequency ablation. 10 In most clinical situations, a biopsy of the suspected metastatic foci is needed to confirm the diagnosis prior to proceeding with localized therapies. Although thyroid-stimulating hormone (TSH) suppression and RAI therapy have been the mainstays of systemic therapy for more than 50 years, recent studies have demonstrated clinical efficacy of several oral kinase inhibitors in the treatment of RAI refractory thyroid cancer.
11.2 Localized Therapies in Advanced Thyroid Cancer
In patients with advanced thyroid cancer, localized therapies are valuable tools to address malignant foci that arise in critical locations and are at high risk of causing significant morbidity or mortality secondary to tumor infiltration or compression of vital structures if not treated expeditiously. 11 In fact, treatment of disease at these critical locations takes precedence over thyroidectomy and RAI therapy. Examples of critical locations include the brain, neurovascular structures (e.g., spine metastases; major disease in the neck, upper mediastinum, or base of the skull; or metastases causing superior vena cava syndrome), major airways (e.g., trachea, larynx, major bronchi), or bone with impending (or previous) pathological fracture. In addition to averting local symptoms that could develop from tumor progression, directly treating these lesions before using RAI therapy may prevent morbidity related to swelling that can occur in some of these metastatic foci with an increase in TSH (either endogenous or exogenous TSH). The choice of a specific localized therapy is dependent on tumor size, tumor location, and preferences of the patient and disease management team.
11.2.1 Localized Therapy for Distant Metastases
Localized therapies are very frequently used in the management of bone metastases from thyroid cancer. Bone metastases occur in 2 to 13% of all patients with differentiated thyroid cancer and are associated with poor clinical outcome and significant morbidities, including pathological fracture, severe pain, and immobility. 12 Surgical metastasectomy is the preferred treatment option for bone metastases that are associated with structural instability or are in critical locations that may cause neurovascular compromise.
A retrospective study of 109 patients with bone metastases from thyroid cancer reported that complete resection of bone metastases in young patients is associated with a significant improvement in survival. 13 EBRT is the preferred treatment option for bone metastases that are structurally stable but are causing pain, increasing in size, or located where progressive growth could cause local compressive symptoms or structural instability. Although embolization of tumor vasculature can be used for pain control, it is more often used prior to surgical resection of bone lesions because these metastatic foci tend to be very vascular and prone to intraoperative bleeding. Radiofrequency ablation has been predominantly used to treat liver metastasis from thyroid cancer, but it has also been reported to reduce the pain from thyroid cancer skeletal metastases. 14 , 15 , 16
Brain metastases originating from differentiated thyroid carcinoma are uncommon. They are usually found in the setting of widespread distant metastases and associated with a very poor prognosis. 17 , 18 , 19 Once identified, high-dose glucocorticoids are usually recommended to decrease the surrounding edema. Then the preferred treatment option is surgical resection of the metastatic lesion unless the lesions are very small and/or multifocal. 20 , 21 Stereotactic radiation can be an effective treatment if fewer than 3 to 5 small lesions are present, whereas whole brain radiation is required for more numerous lesions. 17
Localized therapies can also be effective treatment options for disease involving the airways. Bronchoscopy with laser therapy can be effectively used to treat intraluminal disease. Endobronchial stents are occasionally used to maintain patent airways. Because postobstructive pneumonia is a common cause of death in advanced thyroid cancer, localized therapies to prevent or alleviate compression of major bronchi can decrease morbidity. Depending on the size of the lesion, location of lesions, and clinical condition of the patient, additional options include surgical resection of metastatic lesions or focused EBRT.
Although not commonly performed, resection of individual dominant metastatic lesions in the lung or liver can be considered in patients in whom the remainder of the disease is relatively stable. Even though metastasectomy is not curative, resection of a dominant progressive metastatic lesion may obviate the need for systemic therapies for months to years.
11.2.2 Localized Therapy for Advanced Disease in the Neck
In patients presenting with locally advanced thyroid cancer, the treatment options may extend beyond total thyroidectomy and RAI ablation. Consideration should be given to EBRT in all patients with clinically evident gross extrathyroidal extension. 22 , 23 , 24 It is important to balance the potential for locoregional control with the well-described long-term complications of EBRT (particularly when used in conjunction with RAI) of dental decay, tracheal stenosis, esophageal stricture, osteonecrosis, fibrosis, and xerostomia. 2
There is consensus that EBRT can provide effective locoregional control for gross residual disease that cannot be surgically removed. Current available radiotherapy techniques such as intensity-modulated radiation therapy (IMRT) has made it possible to give a higher dose of EBRT safely without exceeding the tolerance of surrounding critical structures. 25 , 26 , 27
However, the role of EBRT as adjuvant therapy in patients that had all clinical evidence of locally invasive disease surgically removed is much more controversial. 26 , 27 , 28 , 29 , 30 In the absence of gross residual disease, we usually reserve EBRT for use in older patients (> 50 y) with tumors that are likely to be RAI refractory (e.g., Hürthle cell carcinoma, poorly differentiated thyroid cancer, tall cell variants) who we feel are at high risk of early locoregional disease recurrence that may not be amenable to additional surgery in the future. In younger patients, especially those with tumors that are likely to be RAI responsive (classic papillary thyroid cancer, follicular thyroid cancer), we seldom use EBRT as adjuvant therapy but rather follow with close cross-sectional imaging, reserving EBRT for the very few younger patients that develop rapid structural disease recurrence that cannot be adequately treated with additional surgery or RAI.
EBRT is also considered in the recurrent disease setting if the gross recurrent disease cannot be surgically resected or if the extent of resection required would result in removal of structures that is unacceptable to the patient (e.g., laryngectomy). However, surgical resection remains the primary treatment modality for recurrent thyroid cancer in the neck and is associated with the best locoregional control in most settings.
11.3 Systemic Therapies in Advanced Thyroid Cancer
Although localized therapies are frequently effective at managing individual metastatic lesions, systemic therapies are often required in patients with more widespread disease. Over time, these systemic therapy options have become more diverse and more effective.
11.3.1 TSH Suppressive Therapy with Levothyroxine
Differentiated thyroid cancer cells express the TSH receptor and respond to TSH stimulation by increasing the expression of several thyroid-specific proteins and the rates of cell growth. TSH suppression by using supraphysiological doses of levothyroxine is usually used in patients with thyroid cancer to decrease the risk of recurrence. 11
Both the 2009 and the 2015 American Thyroid Association (ATA) management guidelines recommended initial TSH suppression to < 0.1 mIU/L in high- and intermediate-risk thyroid cancer patients and a TSH between 0.1 and 0.5 mIU/L in low-risk patients. In long-term follow-up, the TSH goals are based on an integration of the patient’s response to therapy classification with the patient’s comorbid conditions that could be associated with an increased risk of prolonged aggressive TSH suppression. In the absence of comorbid conditions, a TSH goal of 0.5 to 2 mIU/L is recommended in patients without evidence of disease (excellent response). However, in patients with structurally or biochemically incomplete responses to therapy, a TSH goal of < 0.1 mIU/L is recommended unless comorbidities that increase the risk of complications from TSH suppression (e.g., postmenopausal women, underlying heart disease, osteopenia/osteoporosis, atrial fibrillation) are present, in which cases TSH levels as high as 0.1 to 0.5 mIU/L are considered appropriate. 11 , 31
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