Thyroid Cancer: Pharmacologic Management

Thyroid cancer — a malignancy affecting the thyroid gland, which is located in the front of the throat — occurs more frequently in women than men. Patients are often diagnosed with thyroid cancer at a younger age compared with most other cancers.^1,2 The American Cancer Society estimates that approximately 44,000 new cases of thyroid cancer will be diagnosed in 2023.² However, mortality from thyroid cancer is generally low at 5%.²

Although most thyroid nodules are benign, detecting certain types of thyroid cancer can be difficult. The American Thyroid Association (ATA) has released guidelines to assist clinicians in properly assessing a thyroid nodule for malignancy.³ 

For most patients with thyroid cancer, the first-line treatment is surgery, followed by thyroid hormone suppression therapy and, in cases in which recurrence is likely, radioiodine therapy. Second-line treatments consisting of immunotherapy or chemotherapy are also recommended if the thyroid cancer recurs or progresses.⁴ 

Unlike many other types of cancers, treatment for thyroid cancer is not typically determined using tumor, node, and metastasis (TNM) staging. Instead, the exact management, including specific medications, depends on numerous factors, including the cancer type, genetic molecular markers, and risk of recurrence.⁴ 

Thyroid Cancer Types

Thyroid cancer is commonly divided into differentiated, medullary, and anaplastic thyroid cancer. Each cancer type has a different survival rate and management plan, as described below.

Differentiated Thyroid Cancer

Differentiated thyroid cancer is the most common type of thyroid cancer and generally consists of papillary and follicular thyroid cancers, among other rarer cancer types.⁵ Papillary and follicular thyroid cancers are typically nonaggressive, with a 5-year survival rate of more than 90%, and treated using surgical resection and thyroid hormone therapy followed by radiation, if risk of recurrence is high.^4,6 Only in cases of locally recurrent or progressive disease is further treatment, such as the kinase inhibitor therapies lenvatinib or sorafenib, considered.⁴

Medullary Thyroid Cancer

Medullary thyroid cancer develops from the neuroendocrine C, or parafollicular, cells of the thyroid.¹⁶ The 5-year survival rate for patients diagnosed with medullary thyroid cancer is 91%.⁶

Unlike papillary and follicular thyroid cancers, medullary thyroid cancer does not take up radioiodine and is not controlled using thyroid hormone therapies. Typically, kinase inhibitor therapies, namely vandetanib or cabozantinib, are prescribed to slow the progression of advancing medullary thyroid cancer.⁴

Molecular testing is also very important, as other kinase inhibitors that specifically act against tumors with RET mutations also can slow the progression of medullary thyroid cancer.⁴

Anaplastic Thyroid Cancer

Anaplastic thyroid carcinoma is an undifferentiated and aggressive type of thyroid cancer that generally develops from a differentiated thyroid carcinoma that has undergone additional mutations.⁷ Anaplastic thyroid carcinoma is rare compared with the other types of thyroid cancer. The 5-year survival rate for patients diagnosed with anaplastic thyroid cancer is approximately 8% for all stages combined.⁶ 

Anaplastic thyroid cancer is metastatic, so treatments typically include more pharmaceutical intervention compared with differentiated or medullary thyroid cancers, which can often be managed using standalone treatment or a combination of surgery, radiation, and hormone replacement therapy. Regardless of the medication used, the prognosis for patients with anaplastic thyroid cancer is poor.⁴ Patients should be advised about supportive and end-of-life care and may avoid surgery, especially given its comorbidities and the low likelihood of successful recovery.⁸

Genetic Markers

Thyroid tumors are typically tested for individual mutations, such as BRAF V600E, RET, RAS, and PAX8/PPAR, among others. These molecular markers often predict the likelihood of recurrence and serve as targets for selecting medications in the case of metastasis or disease progression.⁴

Although molecular testing is difficult to perform on some rare thyroid cancer variants, molecular diagnostic testing of papillary carcinoma can be very helpful.⁴ The most common mutation in papillary thyroid cancer is a BRAF V600E mutation, which is often linked to a poorer prognosis.⁹ 

Likewise, mutations in RET are very common in medullary thyroid cancer. In fact, if a RET mutation is found in the germline, genetic counselors will often advise family members to also undergo testing for a likely familial variant of medullary thyroid cancer.⁴

As anaplastic thyroid cancer has particularly poor outcomes, molecular testing of actionable mutations — including BRAF, NTRK, ALK, MET, MSI, and others — is recommended. Guidelines created by the National Comprehensive Cancer Network (NCCN) recommend several different kinase inhibitors based on the existence of specific mutations when treating anaplastic thyroid cancer or metastases derived from other types of thyroid cancer.⁴

Risk of Recurrence of Thyroid Cancer

According to NCCN guidelines, the risk of recurrence of thyroid cancer is determined to be low, medium, or high based on different clinicopathologic features.⁴ Tumor histology and size, along with the presence of any metastases following surgery, influence a patient’s risk level. Imaging modalities and measurement of serum thyroglobulin levels, both before and after treatment, may also dynamically factor into and change risk assessment.^4,10

Patient background strongly influences final treatment outcomes. For example, the sex and age of a patient when they are first being treated affects the likelihood of recovery from thyroid cancer. Although thyroid cancer occurs more frequently in women, it is typically more aggressive in men for unclear reasons.¹¹ Moreover, thyroid cancer becomes more lethal with each extra decade of life.¹²

However, thyroid cancer recurs most frequently among patients who are younger than 20 years or older than 60 years.¹³ The difference in mortality and likelihood of thyroid cancer recurrence often lead physicians to disagree about appropriate treatments, especially when treating younger patients for differentiated thyroid cancer.⁴

The degree of risk may influence if a patient with differentiated thyroid cancer is given radiation-based treatment and how aggressive thyroid hormone therapy should be.¹⁰

Surgical and Radiation-Based Management for Thyroid Cancer

In almost all cases of thyroid cancer, the initial treatment approach is resection, although the extent of surgical removal of the thyroid depends on the cancer type and risk for recurrence.⁴

Following surgery, patients undergo imaging to evaluate if any malignancy remains. If cancer remains or there is a high risk that cancer will recur, patients with differentiated thyroid cancer are treated with postoperative radioactive iodine (RAI).^3,4 Certain thyroid gland cells are sensitive to iodine; following oral administration of RAI, thyroid cells will selectively concentrate iodine and die.¹⁴ One exception is parafollicular cells — or C cells — from which medullary thyroid cancer is derived. As medullary thyroid tumors do not take up iodine, RAI should be avoided in this setting.⁴ In addition, RAI is ineffective in patients with anaplastic thyroid cancer.¹⁵

Patients about to undergo RAI treatment will be asked to start on a low iodine diet by avoiding salts and grains to increase the efficacy of treatment. Patients are also often advised to limit dairy products and avoid seafood, restaurant food, and high-sugar desserts. Additionally, patients may need to discontinue thyroid hormone medication.¹⁶

External beam radiation may also be considered to treat metastases located outside the thyroid.⁴

Pharmacotherapeutic Management of Thyroid Cancer

Pharmacotherapeutic agents are often given concurrently or after surgery and RAI to prevent tumor recurrence, slow cancer progression, and replace thyroid hormones following the loss of thyroid cells.¹⁴ This section will primarily focus on agents currently approved by the US Food and Drug Administration (FDA) to treat specific types of thyroid cancer, although other recommended treatments also exist.¹⁷ 

Thyroid Hormone Therapy

Thyroid hormone therapy is often recommended to either prevent the growth of tumors or to produce more thyroid hormone after the death of thyroid gland cells following surgery or RAI. Patients with differentiated thyroid cancer are typically given levothyroxine to replace thyroid hormone and decrease production of thyroid-stimulating hormone (TSH), a hormone that stimulates the growth of cells that are derived from the epithelium of thyroid follicles. The NCCN guidelines recommend targeting the level of TSH suppression according to the patient’s recurrence risk to avoid adverse effects related with overdosing levothyroxine, including arrhythmias and bone demineralization.^4,18 According to ATA guidelines, recommended target levels of TSH in patients with differentiated thyroid cancer are³:

• <0.1 mU/L for high-risk patients;
• 0.1 to 0.5 mU/L for medium-risk patients; and
• 0.5 to 2 mU/L for low-risk patients.

Patients with medullary thyroid cancer should avoid TSH suppression. Although levothyroxine is still recommended following thyroid gland removal to maintain appropriate thyroid hormone levels, the C cells that medullary thyroid tumors are derived from lack receptors for TSH. Thus, suppressing TSH will not change the likelihood of medullary thyroid cancer recurrence.⁴

Table 1. Guidelines for Levothyroxine for Thyroid Cancer Management

Drug	Dosage	Administration	Recommended Use
Levothyroxine	>2 µg/kg of body weight daily, if suppressing TSH to <0.1 U/L; dose may need to be adjusted depending on target TSH levels	Orally, without food	Adjuvant therapy following surgery and RAI for differentiated thyroid cancer

TSH =  thyroid-stimulating hormone; RAI = radioactive iodine.

From FDA-approved prescribing information.¹⁸

From NCCN and ATA thyroid cancer management guidelines.^3,4

Patients should take calcium and vitamin D supplements while undergoing TSH suppression.⁴

In addition, patients undergoing concurrent RAI need high TSH levels to help thyroid cells concentrate iodine. As a result, patients should be asked to temporarily stop taking levothyroxine. Alternatively, they may be given an injection of recombinant TSH.¹⁶

Targeted Therapy

Targeted therapy is generally recommended for thyroid cancer when the carcinoma is recurrent, advanced, or metastatic and does not respond well to RAI therapy.⁴ 

Kinase Inhibitor Therapy

Several kinase inhibitor therapies, or treatments blocking proteins responsible for sending growth signals to cells, are currently approved by the FDA for specific types of metastatic thyroid cancer. These agents slow the progression of thyroid cancer in slightly less than half of subjects for 1 year or less, but they are not curative.⁴

The choice of kinase inhibitor therapy is determined by molecular testing, as some medications are more effective against certain mutations. For example, combined dabrafenib/trametinib treatment is only approved as a treatment against tumors containing the BRAF V600E mutation, and pralsetinib and selpercatinib work on tumors with a RET fusion-positive gene.⁴

Table 2. Guidelines for Kinase Inhibitor Therapies for Thyroid Cancer Management

Drug or Drug Combination	Dosage	Administration	Recommended Use	Duration of Treatment
Cabozantinib	60 mg once daily (for differentiated thyroid cancer)  OR  140 mg once daily (for medullary thyroid cancer)	Orally, without food	Systemic treatment for metastatic differentiated thyroid cancer in patients who cannot receive RAI and whose cancer worsened following VEGF receptor-targeted therapy (ie, lenvatinib and/or sorafenib) Systemic treatment for progressive, metastatic medullary thyroid cancer	Until patient no longer receives clinical benefit or experiences unacceptable toxicity
Dabrafenib plus trametinib	Dabrafenib 150 mg (taken in two 75-mg doses) and trametinib 2 mg once daily	Orally	Systemic treatment in patients with metastatic anaplastic thyroid cancer containing the BRAF V600E mutation who cannot be treated using alternative modalities	Until patient no longer receives clinical benefit or experiences unacceptable toxicity
Entrectinib	600 mg once daily	Orally	Systemic treatment in patients with metastatic cancer with an NTRK fusion gene that is refractory to other therapies	Until patient no longer receives clinical benefit or experiences unacceptable toxicity
Larotrectinib	100 mg twice daily	Orally	Systemic treatment in patients with metastatic cancer with an NTRK fusion gene that is refractory to other therapies	Until patient no longer receives clinical benefit or experiences unacceptable toxicity
Lenvatinib	24 mg once daily	Orally	Systemic treatment in patients with differentiated thyroid cancer that is progressive, recurrent, or metastatic and that does not respond to RAI	Until patient no longer receives clinical benefit or experiences unacceptable toxicity
Pralsetinib	400 mg once daily	Orally, without food	Systemic treatment in patients with advanced or metastatic thyroid cancer with a RET fusion gene and in whom RAI treatment does not work	Until patient no longer receives clinical benefit or experiences unacceptable toxicity
Selpercatinib	120 mg (<50 kg body weight) twice daily OR 160 mg (≥50 kg body weight) twice daily	Orally	Systemic treatment in patients with advanced or metastatic thyroid cancer with a RET fusion gene and in whom RAI treatment does not work	Until patient no longer receives clinical benefit or experiences unacceptable toxicity
Sorafenib	400 mg twice daily	Orally, without food	Systemic treatment in patients with differentiated thyroid cancer that is progressive, recurrent, or metastatic and does not respond to RAI	Until patient no longer receives clinical benefit or experiences unacceptable toxicity
Vandetanib	300 mg once daily	Orally	Systemic treatment in patients with locally advanced or metastatic medullary thyroid cancer that cannot be surgically removed	Until patient no longer receives clinical benefit or experiences unacceptable toxicity

RAI = radioactive iodine; VEGF = vascular endothelial growth factor.

From FDA-approved prescribing information.^19-29

From NCCN and ATA thyroid cancer management guidelines.^3,4,15

NCCN guidelines recommend that patients with RAI-refractory papillary or follicular thyroid cancer first be given lenvatinib or sorafenib. If neither drug is effective, treatment with cabozantinib or, depending on the genetic molecular markers present, other kinase inhibitors may be considered.⁴

Patients with medullary thyroid cancer are advised to undergo treatment with vandetanib or cabozantinib. If the tumor contains a RET mutation, treatment with pralsetinib or selpercatinib may also be considered.⁴

For patients with anaplastic thyroid cancer, treatment with either dabrafenib/trametinib, larotrectinib, entrectinib, pralsetinib, or selpercatinib may be considered if the correct actionable mutation exists.⁴

Although kinase inhibitors can prolong progression-free survival, they have significant side effects that can negatively affect quality of life. As a result, NCCN guidelines suggest that patients whose disease is asymptomatic or slowly progressing may prefer to avoid using these treatments. However, the side effects may need to be tolerated for patients with thyroid cancer that would otherwise progress rapidly.⁴

Immunotherapy

The immune checkpoint inhibitor pembrolizumab has also been approved by the FDA to treat solid thyroid tumors that have high microsatellite instability, assuming no other suitable alternatives exist. Pembrolizumab works by blocking the programmed cell death receptor-1 (PD-1), which helps restore the immune response against tumors.³⁰

Table 3. Guidelines for Pembrolizumab for Thyroid Cancer Management

Drug	Dosage	Administration	Recommended Use
Pembrolizumab	200 mg every 3 wk  OR 400 mg every 6 wk	Intravenously	Systemic treatment in patients with metastatic thyroid cancer with a high mutational burden, assuming alternative treatments do not work

From FDA-approved prescribing information.³⁰

From NCCN thyroid cancer management guidelines.⁴

Other more commonly used therapies against thyroid cancer — such as surgery, RAI, or kinase inhibitors — should be considered prior to prescribing pembrolizumab.⁴

Chemotherapy

Traditional cytotoxic chemotherapy agents have not been found to improve outcomes for patients with metastatic differentiated thyroid cancer, although the clinical studies evaluating these agents in this setting have been underpowered.³¹ However, doxorubicin is approved by the FDA for the treatment of metastatic thyroid cancer.¹⁷ Additionally, both doxorubicin and paclitaxel are currently recommended by ATA guidelines for the treatment of anaplastic thyroid cancer, assuming no actionable mutations exist for kinase inhibitor therapies.¹⁵

Table 4. Guidelines for Chemotherapy for Thyroid Cancer Management

Drug	Dosage	Administration	Recommended Use
Doxorubicin	20 mg/m2 weekly OR 60-75 mg/m2 every 3 wk	Intravenously	Systemic treatment in patients with anaplastic thyroid cancer
Paclitaxel	60-90 mg/m2 weekly  OR 135-200 mg/m2 every 3-4 wk	Intravenously	Systemic treatment in patients with anaplastic thyroid cancer

From FDA-approved prescribing information.^32,33

From ATA anaplastic thyroid cancer management guidelines.¹⁵

Generally, ATA guidelines recommend using weekly chemotherapy regimens.¹⁵ 

Other chemotherapy regimens such as combined paclitaxel/carboplatin or docetaxel/doxorubicin have also been tested on patients with anaplastic thyroid cancer, but the NCCN and other panels disagree on their efficacy and use.⁴

Monitoring Side Effects, Adverse Events, and Drug-Drug Interactions for Thyroid Cancer Treatment

Thyroid cancer treatments are often associated with numerous side effects and potential adverse events that clinicians should be aware of prior to prescribing. Thyroid hormone therapy, which strongly influences metabolism, has several known interactions with drugs and should be administered with caution.¹⁸ Additionally, kinase inhibitors and chemotherapy are known to be very toxic; patients should be carefully monitored during treatment with these agents.

The charts below describe common side effects, drug-drug interactions, and considerations for special populations for levothyroxine, targeted therapy, and chemotherapy currently recommended to treat thyroid cancer.

Table 5. Side Effect Profile for Levothyroxine

Drug	Adverse Events	Drug-Drug Interactions	Special Population Considerations
Levothyroxine	Arrhythmias, myocardial infarction, dyspnea, muscle spasm, headache, mood changes (ie, nervousness and irritability), insomnia, tremors, increased appetite, weight loss, diarrhea, heat intolerance, menstrual irregularities, skin rash, decrease in bone mineral density	Antacids, bile acid sequestrants (ie, colesevelam), calcium carbonate, ferrous sulfate, ion exchange resins (ie, kayexalate), orlistat, proton pump inhibitors, and sucralfate reduce levothyroxine absorption Clofibrate, estrogen-containing oral contraceptives, heroin/methadone, 5-fluorouracil, mitotane, tamoxifen, androgens, asparaginase, glucocorticoids, slow-release nicotinic acid, salicylates, carbamazepine, furosemide, heparin, hydantoins, NSAIDs, and fenamates alter levothyroxine transport Phenobarbital and rifampin degrade levothyroxine β-adrenergic antagonists, glucocorticoids, and amiodarone may also decrease the conversion of levothyroxine to thyroid hormone Other drug-drug interactions may occur with oral anticoagulants, digitalis glycosides, antidepressants, ketamine, sympathomimetics, and tyrosine kinase inhibitors	Dosage should be decreased for elderly patients and those with cardiovascular disease to reduce the risk of cardiac adverse reactions Patients with adrenal insufficiency should be treated with glucocorticoids prior to levothyroxine treatment to avoid acute adrenal crisis Additional monitoring for diabetic patients is necessary as levothyroxine may alter glycemic control

NSAIDS = nonsteroidal anti-inflammatory drugs.

From FDA-approved prescribing information.¹⁸

Table 6. Side Effect Profile for Kinase Inhibitor Therapies

Drug	Adverse Events	Drug-Drug Interactions	Special Population Considerations
Cabozantinib	Hemorrhage, perforations, thrombotic events, hypertension, diarrhea, fatigue, decreased appetite, stomatitis, nausea, vomiting, palmar-palmar erythrodysesthesia, proteinuria, osteonecrosis of the jaw, reversible posterior leukoencephalopathy syndrome, decreased weight, oral pain, hair color changes, dysgeusia, abdominal pain, constipation	Avoid use, or otherwise change dosing, with CYP3A4 inducers and inhibitors	Additional monitoring and potential dose reduction are necessary for patients with hepatic impairment. Cabozantinib should not be used in pregnant patients.
Dabrafenib	New or growth of BRAF wild-type tumors, hemorrhage, cardiomyopathy, uveitis, pyrexia, serious skin toxicities, hyperglycemia, glucose-6-phosphate dehydrogenase deficiency	Avoid use with CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 substrates or inhibitors Should be used in combination with trametinib to treat anaplastic thyroid cancer	Use of dabrafenib impairs fertility in patients of reproductive age. Dabrafenib should not be used in pregnant patients.
Entrectinib	Congestive heart failure, central nervous system effects (ie, cognitive impairment, mood disorders, dizziness, and sleep disturbances), skeletal fractures, hepatotoxicity, hyperuricemia, QT-interval prolongation, vision disorders, fatigue, constipation, dysgeusia, edema, diarrhea, nausea, dysesthesia, dyspnea, myalgia, increased weight, cough, vomiting, pyrexia, arthralgia	Avoid use, or otherwise alter dosing, with CYP3A inhibitors or inducers	Entrectinib should not be used in pregnant patients.
Larotrectinib	Neurotoxicity, hepatotoxicity, fatigue, nausea, dizziness, vomiting, cough, constipation, diarrhea	Avoid use, or otherwise alter dosing, with CYP3A4 inhibitors, inducers, or substrates	Dose reduction is necessary for patients with hepatic impairment. Larotrectinib should not be used in pregnant patients.
Lenvatinib	Hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure, proteinuria, diarrhea, fistula formation, QT-interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhage, thyroid dysfunction, impaired wound healing, osteonecrosis of the jaw, fatigue, diarrhea, arthralgia, decreased appetite, decreased weight, nausea, vomiting, stomatitis, headache, plantar-plantar erythrodysesthesia syndrome, abdominal pain, dysphonia	Avoid use with products that may prolong the QT interval	Use of lenvatinib impairs fertility in patients of reproductive age. Lenvatinib should not be used in pregnant patients.
Pralsetinib	Interstitial lung disease, hypertension, hepatotoxicity, hemorrhage, tumor lysis syndrome, impaired wound healing, constipation, fatigue, musculoskeletal pain, diarrhea	Avoid use with CYP3A and P-gp inhibitors and inducers	Monitoring of open growth plates is necessary for adolescents. Pralsetinib should not be used in pregnant patients.
Selpercatanib	Hepatotoxicity, hypertension, QT-interval prolongation, hemorrhage,  hypersensitivity, impaired wound healing, dry mouth, diarrhea, fatigue, edema, rash, constipation	Avoid use with acid-reducing agents and inhibitors, inducers, or substrates of CYP3A or CYP2C8	Use of selpercatinib impairs fertility in patients of reproductive age. Selpercatanib should not be used in pregnant patients.
Sorafenib	Cardiovascular events, bleeding, hypertension, dermatologic toxicities, gastrointestinal perforation, QT-interval prolongation, drug-induced liver injury, TSH suppression impairment, diarrhea, fatigue, infection, alopecia, rash, weight loss, decreased appetite, nausea, abdominal pain, hemorrhage	Avoid use with CYP3A4 inducers	Use of sorafenib may impair fertility in male patients of reproductive age. Sorafenib should not be used in pregnant patients.
Trametinib	New or growth of BRAF wild-type tumors, hemorrhage, colitis, venous thromboembolism, cardiomyopathy, ocular toxicities, interstitial lung disease, serious febrile reactions, serious skin toxicities, hyperglycemia	Should be used in combination with dabrafenib to treat anaplastic thyroid cancer	Use of trametinib impairs fertility in patients of reproductive age. Trametinib should not be used in pregnant patients.
Vandetanib	QT-interval prolongation, severe skin toxicities, interstitial lung disease, ischemic cerebrovascular events, hemorrhage, heart failure, diarrhea, hypertension, reversible posterior leukoencephalopathy syndrome, nausea, headache, upper respiratory tract infections, decreased appetite, abdominal pain	Avoid use with products that may prolong the QT interval Avoid use with CYP3A4 inducers, as they may reduce vandetanib efficacy	Dose reduction to 200 mg is necessary for patients with renal impairment. Vandetanib should not be used in pregnant patients.

P-gp = P-glycoprotein; TSH = thyroid-stimulating hormone.

From FDA-approved prescribing information.^19-29

Table 7. Side Effect Profile for Pembrolizumab

Drug	Adverse Events	Drug-Drug Interactions	Special Population Considerations
Pembrolizumab	Immune-related adverse reactions (ie, pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, and solid organ transplant rejection), infusion-related reactions, fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain	None indicated	Pembrolizumab should not be used in pregnant patients.

From FDA-approved prescribing information.³⁰

Table 8. Side Effect Profile for Chemotherapy Agents

Drug	Adverse Events	Drug-Drug Interactions	Special Population Considerations
Doxorubicin	Alopecia, nausea, vomiting	Avoid use with CYP3A4, CYP2D6, and P-gp inhibitors and inducers Administration of trastuzumab and doxorubicin increase the risk of cardiac dysfunction	Use of doxorubicin impairs fertility in patients of reproductive age
Paclitaxel	Nausea, vomiting, diarrhea, infections, hypersensitivity reactions, myelosuppression, alopecia	Avoid use with CYP2C8 or CPY3A4 substrates, inducers, or inhibitors	Additional monitoring and potential dose reduction are necessary for patients with hepatic impairment Caution should be used in geriatric populations.

P-gp = P-glycoprotein.

From FDA-approved prescribing information.^32,33

Considerations for Specific Populations

Pregnant Patients

Many treatments for thyroid cancer — including chemotherapy, kinase inhibitor therapies, and RAI — should not be used in pregnant patients because they can cause fetal harm.^{4,19-29,32,33} Although levothyroxine as a thyroid hormone therapy is safe in pregnant patients, its dose will need to be increased.¹⁸

For patients who are pregnant or considering becoming pregnant, treatment should be delayed or conception only considered after treatment is finished.

Pediatric and Young Adult Patients

Although children and adolescents are less likely to die from thyroid cancer, their risk of recurrence from differentiated thyroid cancer is much higher compared with patients who are first treated when they are older than 20 years.¹³ As a result, patients will need lifelong follow-up evaluations to check for any possible recurrence. Such follow-up visits may need to include physical examination, laboratory testing, and imaging such as ultrasound evaluation of the neck or computed tomographic (CT) imaging of the chest.⁴

Geriatric Patients

One difficulty of treating geriatric patients is properly diagnosing thyroid cancer. Thyroid nodules, including those that are benign, are more common in geriatric patients and will need to be evaluated for malignancy as more aggressive types of thyroid cancer, such as anaplastic thyroid cancer, are more likely to occur.³⁴

Although the risk of cancer recurrence is higher in geriatric populations, overall rates of morality from differentiated and medullary thyroid cancers are low. As a result, clinicians will need to balance more aggressive treatments with an awareness of the morbidities associated with cancer treatments.³⁴

Suppressing TSH using levothyroxine may be especially dangerous in the elderly population due to the increased risk of cardiac tachyarrhythmias. Additional monitoring and decreased dosing should therefore be considered.⁴

Thyroid Cancer Treatment Guidelines

Appropriate treatment of thyroid cancer is nuanced and depends on multiple factors. As a result, numerous guidelines for thyroid cancer are available from well-respected medical societies and organizations, including:

• The 2023 NCCN Guideline for Thyroid carcinoma, found here⁴;
• The 2021 American Thyroid Association Guidelines for Management of Patients With Anaplastic Thyroid Cancer, found here¹⁵;
• The 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer, found here³;
• The 2019 Thyroid Cancer: European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for Diagnosis, Treatment, and Follow-Up, found here³⁵; and
• The 2016 American Association of Clinical Endocrinology (AACE)/American College of Endocrinology (ACE)/Associazione Medici Endocrinologi (AME) Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules, found here.³⁶

References

1. What is thyroid cancer? American Cancer Society. Updated March 14, 2019. Accessed June 9, 2023. https://www.cancer.org/cancer/types/thyroid-cancer/about/what-is-thyroid-cancer.html
2. Key statistics for thyroid cancer. American Cancer Society. Updated January 18, 2023. Accessed June 9, 2023. https://www.cancer.org/cancer/types/thyroid-cancer/about/key-statistics.html
3. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-133 doi:10.1089/thy.2015.0020
4. Haddad RI, Bischoff L, Ball D, et al. Thyroid carcinoma. National Comprehensive Cancer Network. Updated May 18, 2023. Accessed June 9, 2023. https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf
5. Differentiated thyroid cancer. Children’s Hospital of Philadelphia. Published February 9, 2014. Accessed June 12, 2023. https://www.chop.edu/conditions-diseases/differentiated-thyroid-cancer
6. Thyroid cancer survival rates, by type and stage. American Cancer Society. Updated March 1, 2023. Accessed June 11, 2023. https://www.cancer.org/cancer/types/thyroid-cancer/detection-diagnosis-staging/survival-rates.html
7. Maatouk J, Barklow TA, Zakaria W, Al-Abbadi MA. Anaplastic thyroid carcinoma arising in long-standing multinodular goiter following radioactive iodine therapy: report of a case diagnosed by fine needle aspiration. Acta Cytol. 2009;53(5):581-583. doi:10.1159/000325388
8. Shaha AR. Airway management in anaplastic thyroid carcinoma. Laryngoscope. 2008;118(7):1195-1198. doi:10.1097/MLG.0b013e3181726d36
9. Li C, Lee KC, Schneider EB, Zeiger MA. BRAF V600E mutation and its association with clinicopathological features of papillary thyroid cancer: a meta-analysis. J Clin Endocrinol Metab. 2012;97(12):4559-4570. doi:10.1210/jc.2012-2104
10. Tuttle RM, Tala H, Shah J, et al. Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system. Thyroid. 2010;20(12):1341-1349. doi:10.1089/thy.2010.0178
11. Rahbari R, Zhang L, Kebebew E. Thyroid cancer gender disparity. Future Oncol. 2010;6(11):1771-1779. doi:10.2217/fon.10.127
12. Thyroid cancer mortality statistics. Cancer Research UK. Published May 15, 2015. Accessed June 13, 2023. https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/thyroid-cancer/mortality
13. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med. 1994;97(5):418-428. doi:10.1016/0002-9343(94)90321-2
14. Thyroid Cancer Treatment (PDQ)-Patient Version. National Cancer Institute. Updated March 16, 2023. Accessed June 11, 2023. https://www.cancer.gov/types/thyroid/patient/thyroid-treatment-pdq
15. Bible KC, Kebebew E, Brierley J, et al. 2021 American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2021;31(3):337-386. doi:10.1089/thy.2020.0944
16. Preparing for radioactive iodine treatment for thyroid cancer. Cancer Research UK. Updated May 20, 2021. Accessed June 13, 2023. https://www.cancerresearchuk.org/about-cancer/thyroid-cancer/treatment/radiotherapy/radioactive-iodine-treatment/preparing-radioactive-iodine-treatment
17. Drugs approved for thyroid cancer. National Cancer Institute. Updated January 19, 2021. Accessed June 11, 2023. https://www.cancer.gov/about-cancer/treatment/drugs/thyroid
18. Levo-T®. Prescribing Information. Neolpharma, Inc.; 2017. Accessed June 11, 2023. 
19. Cabometyx®. Prescribing Information. Exelixis, Inc.; 2019. Accessed June 11, 2023. 
20. Cometriq. Prescribing Information. Exelixis, Inc.; 2012. Accessed June 11, 2023. 
21. Tafinlar®. Prescribing Information. Novartis Pharmaceuticals Corporation; 2022. Accessed June 11, 2023.
22. Rozlytrek. Prescribing Information. Genentech, Inc.; 2019. Accessed June 11, 2023. 
23. Mekinist®. Prescribing Information. Novartis Pharmaceuticals Corporation; 2022. Accessed June 11, 2023.
24. Vitrakvi®. Prescribing Information. Bayer HealthCare Pharmaceuticals Inc.; 2018. Accessed June 11, 2023.
25. Lenvima®. Prescribing Information. Eisai Inc.; 2021. Accessed June 11, 2023. 
26. Gavreto. Prescribing Information. Blueprint Medicines Corporation; 2020. Accessed June 11, 2023.
27. Retevmo. Prescribing Information. Eli Lilly and Company; 2020. Accessed June 11, 2023.
28. Nexavar. Prescribing Information. Bayer HealthCare Pharmaceuticals Inc.; 2018. Accessed June 11, 2023.
29. Caprelsa®. Prescribing Information. AstraZeneca; 2014. Accessed June 11, 2023. 
30. Keytruda®. Prescribing Information. Merck & Co., Inc; 2021. Accessed June 11, 2023. 
31. Sherman SI. Cytotoxic chemotherapy for differentiated thyroid carcinoma. Clin Oncol. 2010;22(6):464-468. doi:10.1016/j.clon.2010.03.014
32. Doxorubicin hydrochloride. Prescribing Information. Pfizer, Inc.; 2020. Accessed June 11, 2023. 
33. Taxol®. Prescribing Information. Bristol-Myer Squibb Company; 2011. Accessed June 11, 2023.
34. Lechner MG, Hershman JM. Thyroid nodules and cancer in the elderly. In: Feingold KR, Anawalt B, Blackman MR, et al, eds. Endotext. MDText.com, Inc.; 2000. Accessed June 13, 2023. http://www.ncbi.nlm.nih.gov/books/NBK278969/
35. Filetti S, Durante C, Hartl D, et al. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30(12):1856-1883. doi:10.1093/annonc/mdz400
36. Gharib H, Papini E, Garber JR, et al. American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules – 2016 update appendix. Endocr Pract. 2016;22 (suppl 1):1-60. doi:10.4158/EP161208.GL

Author Bio

Sierra Lear, PhD, earned a Bachelor of Science degree in chemical engineering and neuroscience from Tulane University and will graduate with a PhD in bioengineering from the University of California, Berkeley and the University of California, San Francisco in September 2023. She has spent a decade in the lab developing gene editing and other molecular tools to understand and treat different diseases.