Thyroid Cancer Treatment Protocols

Treatment protocols for advanced thyroid cancer have expanded in the past several years due to the increasing availability of targeted systemic therapies. The following protocols include a general treatment approach, ^{[1, 2, 3]} as well as treatment recommendations for the three categories of thyroid cancer ^[1] :

• Differentiated (papillary, follicular, and oncocytic follicular or Hürthle cell)
• Anaplastic (undifferentiated)
• Medullary

Thyroid nodule management

Before thyroid cancer is diagnosed, patients will often be found to have a thyroid nodule, discovered incidentally on imaging or due to symptoms. The nodule may require fine-needle aspiration (FNA) biopsy, depending upon its characteristics on imaging and its size. ^{[12, 25]}  In addition, thyroid-stimulating hormone (TSH) value must be obtained to ensure the patient does not have hyperthyroidism from a toxic nodule, which is much less likely to harbor malignancy.

Nodules with nondiagnostic (Bethesda I ^[27] ) FNA biopsy results can be managed with repeat ultrasonography-guided FNA; if repeat FNA is nondiagnostic, close follow-up or surgery may be considered. ^[21]  Surgery should be more strongly considered if the nodule is solid.

Nodules < 1 cm can be managed as follows ^[21] :

• Routine FNA is not recommended unless the patient has abnormal lymph nodes, suspicious ultrasonographic findings (solid hyperechoic with microcalcifications), or a high-risk history (radiation exposure, personal or family history of thyroid cancer, incidental 18-F-fluorodeoxyglucose [¹⁸FDG]–positron emission tomography [PET]–positive nodules).

• Abnormal lymph nodes should be aspirated under ultrasonographic guidance.

• Follow-up ultrasound in 6-12 months can be considered for high-suspicion nodules under 1 cm. ^[12]

Multiple nodules > 1 cm can be managed as follows ^[21] :

• Aspirate any nodules that are suspicious, using Thyroid Imaging Reporting and Data Systems (TIRADS) or American Thyroid Association (ATA) guidelines for size criteria on ultrasonography. ^{[12, 25]}

• If the nodules are spongiform in appearance (multiple ultrasonographically similar nodules with no intervening normal parenchyma), aspirate the largest nodules and observe the others with serial ultrasonographic exams.

• In patients with low TSH, scintigraphy results should be compared with ultrasonographic images.

• Isofunctioning or hypofunctioning nodules may be aspirated using the TIRADS or ATA guidelines. ^{[12, 25]}

Recommendations for indeterminate results on thyroid fine needle aspiration

Management options for nodules with atypia of undetermined significance/follicular lesion of undetermined significance (Bethesda III, indeterminate cytology) are as follows:

• Consider repeat FNA. A repeat FNA is found to be definitive (actionable results) in up to two-thirds of cases. ^[28]

• Consider diagnostic lobectomy or total thyroidectomy (with history of radiation exposure, nodules in the contralateral thyroid lobe).

• Consider molecular markers. The molecular markers should have a negative predictive value high enough to allow observation if the goal is to avoid surgery.

• Consider nodule surveillance in nodules with low-risk imaging characteristics and negative molecular testing.

Management options for follicular neoplasm or follicular neoplasm–oncocytic (also called Hürthle cell neoplasm)(Bethesda IV, indeterminate cytology) are as follows:

• Consider diagnostic lobectomy. The risk of malignancy in these cases (which should be independently defined at each institution) ranges from 15-40%. Therapeutic total thyroidectomy may be considered if imaging suggests high-risk features and the nodule is large (ie, > 4 cm) or if the patient has a history of radiation exposure or nodules in the contralateral lobe. However, this risks hypothyroidism for a potentially benign nodule, so the patient must be a part of the decision-making process.

• Consider molecular testing. The molecular markers should have a negative predictive value high enough to allow observation if the goal is to avoid surgery.

• Consider nodule surveillance if molecular testing is negative and the ultrasonic appearance indicates low risk for malignancy.

Treatment for suspected cancer (Bethesda V, indeterminate cytology) should follow the recommendations for the type of malignancy for which the results are suspicious:

• For nodules suspicious for papillary thyroid carcinoma (PTC), preoperative lateral neck ultrasound or CT of the neck with contrast is recommended 

• Hemithyroidectomy may be considered for patients with an isolated, indeterminate, solitary nodule.

• If PTC diagnosis is made following hemithyroidectomy, consider completion thyroidectomy for nodules > 4 cm, with gross extrathyroidal extension, or with clinically involved lymph nodes. ^[12]

• The surgical risks of two-stage thyroidectomy and total or near-total thyroidectomy are similar.

Surgical treatment recommendations for differentiated thyroid cancer (DTC)

Papillary and follicular thyroid cancer stages I-IV (confirmed by cytology) treatment options are as follows ^{[1, 11, 12, 13]} :

• Surgery is ultimately based on patient factors and surgeon expertise.

• Thyroid lobectomy alone is sufficient for small (< 1 cm), unifocal, intrathyroidal carcinomas in the absence of prior head and neck radiation, familial thyroid carcinoma, or clinically detectable cervical nodal metastases. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)—formerly classified as encapsulated follicular variant of PTC—requires only lobectomy.

• Lobectomy may be considered for 1-4 cm, low-risk, unifocal, intrathyroid tumors in the absence of prior head and neck radiation, cervical or distant nodal metastasis, and extrathyroidal extension; however, total thyroidectomy may be chosen to enable radioiodine (RAI) therapy or to enhance follow-up, based on disease features and/or patient preference.

• Total thyroidectomy is recommended for tumors > 4 cm in diameter for PTC and for follicular carcinoma with vascular invasion involving more than 4 vessels.

• Therapeutic central neck dissection should be performed when cervical lymph nodes are involved.

• When lateral cervical lymph nodes have biopsy-proven disease, therapeutic central and lateral compartment neck dissection should be performed.

• Prophylactic unilateral or bilateral central neck dissection may be considered in clinical N0 disease, especially for advanced primary tumors (T3 or T4)

General treatment recommendations for thyroid cancer

The treatment of choice for patients diagnosed with thyroid cancer is surgery, when possible. When indicated, surgery may followed by RAI therapy. Thyroxine therapy is mandatory for patients undergoing total thyroidectomy and may be necessary after lobectomy or less-than-total thyroidectomy. Generally, radiation therapy and chemotherapy do not have a prominent role in the treatment of thyroid cancer. However, systemic therapies are indicated for progressive RAI-refractory thyroid cancer.

Radioactive iodine ablation

Postoperative whole-body scintigraphy scan may identify previously unrecognized disease and influence staging. If residual disease is found, adjuvant therapy with RAI may be considered. Ablation of residual normal thyroid tissue may not be necessary in low-risk disease, especially when a lobectomy or less-than-total thyroidectomy has been deemed adequate oncologic surgery. 

RAI ablation is recommended for patients with any of the following:

• Large (> 4 cm) tumors, especially in older patients
• Known distant metastasis, as RIA is found to improve survival in observational studies. ^[12]
• Gross extrathyroid extension as RIA is found to improve survival in observational studies ^[12]
• Large or > 5 positive lymph nodes or with extra-nodal extension
• Unstimulated thyroglobulin > 10 ng/mL after total thyroidectomy

RAI ablation may be considered for tumors with the following characteristics:

• Moderate size (2-4 cm) and node positive
• Aggressive, based on histology (such as poorly differentiated, tall cell, columnar cell, hobnail variants, diffuse sclerosing, and insular)
• High risk, based on patient factors (older age, history of head and neck radiation, family history of thyroid cancer)

RAI ablation is not recommended for the following:

• Classical PTC that is intrathyroidal and completely removed without lymph node involvement
• Small (< 2 cm), solitary tumors
• Multifocal tumors when all foci are < 1 cm
• Intrathyroidal
• Unstimulated thyroglobulin < 1 ng/mL after total thyroidectomy

Data suggest that RAI is equally effective when used with thyroid hormone withdrawal or with recombinant human thyroid-stimulating hormone (rh-TSH) stimulation. ^[4]

Thyroid-stimulating hormone suppression therapy 

Treatment with levothyroxine) to suppress TSH to < 0.1 mU/L is indicated in high-risk disease. Maintenance of TSH at the lower-normal limit (0.3-2 mU/L) may be considered for low-risk disease. For patients with biochemical evidence of disease but low-risk histopathology, maintaining TSH between 0.1-0.4 mU/L is reasonable. Over time, if patients remain disease free, consider decreasing the intensity of suppression, with a goal of 0.5-2.0 mU/L, since TSH suppression can lead to bone loss and cardiac risk.

Therapy for unresectable gross residual or recurrent disease or metastases

Therapeutic options in patients with unresectable gross residual or recurrent disease or metastases are as follows:

• Unresectable gross residual/recurrent disease/metastases may be treated with external beam radiation therapy (EBRT)

• Consider systemic treatment for persistent and progressive or symptomatic metastatic disease despite RAI, TSH suppression, and radiotherapy

• Consider tyrosine kinase inhibitors (TKIs) such as lenvatinib 24 mg daily (preferred) or sorafenib 400 mg PO twice daily. ^[5]  Toxicity management is imperative with these agents; in the SELECT trial, severe hypertension occurred in two-thirds of the patients receiving lenvatinib, and more than two-thirds of those required a dose decrease. ^[15]

• For treatment of RAI-refractory differentiated thyroid cancer that has progressed after TKI therapy with lenvatinib or sorafenib: Cabozantinib 60 mg daily ^[24]

• For NTRK gene fusion–positive advanced solid tumors: Larotrectinib 100 mg twice daily or entrectinib 600 mg once daily ^[1]

• For advanced or metastatic RET fusion–positive thyroid cancer in patients aged 12 years or older who require systemic therapy and who are RAI refractory (if RAI is appropriate): Selpercatinib 120 mg PO BID (if weight < 50 kg) or 160 mg PO BID (if weight 50 kg or greater); continue until disease progression or unacceptable toxicity ^[9]

• For advanced or metastatic RET-mutant medullary thyroid cancer in adult and pediatric patients ≥12 years who require systemic therapy, or with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate): Pralsetinib 400 mg PO daily on an empty stomach; continue until disease progression or unacceptable toxicity ^[10]

• For patients with tumor mutational burden–high (10 or more mutations/megabase): Consider pembrolizumab, 200 mg IV q3Weeks or  400 mg q6Weeks ^[1]

Recommendations for anaplastic (undifferentiated) thyroid cancer

Diagnosis and molecular testing

Anaplastic thyroid cancer (ATC) requires prompt diagnosis to obtain the best opportunity for treatment, since historically, patients with this disease have a median survival of only 5-6 months. ^[26]  In addition, urgent assessment by a multidisciplinary treatment team is highly recommended to obtain evaluation of the airway, vocal cords, esophagus, and vascular supply. Imaging with PET/CT is also recommended to determine extent of disease. 

ATC is staged as stage IV only. Stage IVa disease is confined to the thyroid gland; stage IVb involves tissue outside the thyroid or neck nodes, but not distant metastases; and stage IVc is metastatic disease outside the nodes of the neck. 

FNA can be diagnostic in most cases, but to obtain molecular testing, a core biopsy is often necessary. This must be expedited. Thyroid lymphoma and metastatic disease must be excluded. BRAF V600E testing is indicated if ATC is confirmed and since it should be done quickly, immunohistochemistry is often performed first, with additional molecular testing confirmation done later. Rapid assessment of BRAF V600E status is necessary to determine whether neoadjuvant therapy might allow resection, in cases initially considered unresectable.

Because of the aggressive nature of this disease, guidelines recommend providing supportive care for these patients from the very start of their cancer journey.

Surgery

Because most patients with ATC have advanced disease at the time of diagnosis, surgery is often not indicated; however, if the tumor appears to be localized to the thyroid, oncologic surgery (usually total or near-total thyroidectomy) can be performed with improved survival when compared with those who do not have surgery. ^[26]  Radical resection of additional structures of the neck is not generally rec,ommended. Palliative surgery can be considered for impending local symptoms such as airway compromise.

Neoadjuvant therapy

In ATC patients with BRAF V600E mutations, neoadjuvant treatment with dabrafenib and trametinib has shown promise in small series and so may be considered, with plans to perform surgery when adequate improvement has been shown. Neoadjuvant radiation therapy as well as combined chemoradiation therapy have also been effective at allowing later surgeries.

Combined-modality therapy:

• Consider primary combined radiotherapy and chemotherapy for locally advanced, unresectable disease.

• Along with definitive-intent radiation, chemotherapy should include paclitaxel or docetaxel with or without doxorubicin or a platin (cisplatin or carboplatin) ^[29]  

• Dabrafenib and trametinib are approved in combination for treatment of BRAF V600E–mutated tumors and have produced response rates higher than seen in this disease in the past. ^[29]

• If other driver mutations, such as NTRK, RET, or ALK fusions are noted, targeted therapies against those mutations are certainly reasonable. ^[29]

• Pembrolizumab is considered for those with high programmed death ligand 1 (PD-L1) expression and/or high mutational burden.

• Consider surgical resection for patients who have a good response to treatment.

• Adjuvant radiation therapy with or without chemotherapy is recommended for patients with an R0/R1 resection.

Palliative care

Even with aggressive treatment, ATC is often quickly fatal. End-of-life issues, comfort, and care options are essential considerations during initial treatment planning.

Recommendations for medullary thyroid cancer

Patients with an FNA biopsy suspicious for medullary thyroid carcinoma should undergo measurement of fasting basal calcitonin and CEA, germline RET testing, and central and lateral neck imaging with ultrasound and/or CT with contrast. If the tumor is RET positive, then plasma metanephrine testing for pheochromocytoma and evaluation for primary hyperparathyroidism are necessary preoperatively.

In patients with known RET mutations, timing of screening and total thyroidectomy depend on the specific mutation. ^[23]

Surgical options in medullary thyroid cancer are as follows ^[20] :

• Total thyroidectomy with prophylactic or therapeutic central neck dissection (level VI) is considered the standard of care for all patients with medullary thyroid cancer.

• Assessment for metastatic disease by preoperative imaging of the neck, chest, and liver is recommended for patients with nodal metastasis and for those with serum calcitonin > 400 pg/mL.

• Therapeutic compartmental lateral neck dissection should be attempted for patients with minimal or no distant metastasis.

• In patients with distant metastasis or advanced local disease, less-aggressive neck surgery that preserves speech and swallowing function may be appropriate.

• Palliative debulking surgery may be considered to relieve tracheal compression and local pain.

• Preoperative exclusion or treatment of a concomitant pheochromocytoma is critical, given the high risk of surgery and anesthesia complications in these patients.

• A second surgery, possibly with remedial central neck dissection, may be considered for patients with evidence of recurrent or persistent disease, rising serum calcitonin levels in the setting of an inadequate initial operation, or threatening tracheal invasion or compression; however, reoperation carries a higher risk of complications, including thoracic duct leak, recurrent laryngeal nerve injury, and hypoparathyroidism.

Thyroxine replacement therapy ^[20] (standard dosing with thyroxine replacement) should be initiated postoperatively with the goal of maintaining euthyroidism. In contrast to management of epithelial cell–derived thyroid cancers, TSH suppression to lower-than-normal levels is not indicated, since C-cells are not TSH responsive. Similarly, RAI therapy is not indicated in medullary thyroid cancer, because C-cells do not concentrate iodine.

Therapy for unresectable or recurrent disease or for metastases is as follows ^[20] :

• Radiotherapy may be considered for patients with gross residual disease after surgery and for those with distant metastasis.
• The role of EBRT in M0 or minimal M1 disease is controversial.
• Consider systemic therapy in the context of a clinical trial for patients with progressive metastatic disease who cannot be treated with surgery or radiotherapy.
• The low incidence of medullary thyroid cancer has limited the development of widespread clinical consensus, as well as the ability to conduct large, definitive, randomized, controlled trials; thus, there are no standard regimens.

• The TKIs vandetanib and cabozantinib have been approved for use in progressive, metastatic medullary thyroid cancer.

• The TKI selpercatinib is approved for advanced or metastatic RET-mutated medullary thyroid cancer in patients aged 12 years or older who require systemic therapy. ^[9]

• The TKI pralsetinib is approved for advanced or metastatic RET-mutant medullary thyroid cancer in adults who require systemic therapy. ^[10]

• Pembrolizumab may be helpful in certain circumstances.

Dosages of TKIs for metastatic medullary thyroid cancer are as follows:

• Vandetanib: 300 mg PO daily
• Cabozantinib: 140 mg PO daily
• Selpercatinib: 120 mg PO BID (if weight < 50 kg) or 160 mg PO BID (if weight 50 kg or greater)
• Pralsetinib: 400 mg PO daily on an empty stomach
• Pembrolizumab: 200 mg IV q3Weeks OR 400 mg q6Weeks
• Dosage adjustment for these TKIs may be required. depending on toxicity and coadministered drugs