Thyroid Cancer Treatment Protocols 

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Treatment protocols for thyroid cancer are provided below. These include a general treatment approach, ^{[1, 2, 3]} as well as treatment recommendations for the three categories of thyroid cancer: differentiated (Hürthle cell, papillary, and follicular), anaplastic (undifferentiated), and medullary thyroid cancer. ^[1]

The treatment of choice for patients diagnosed with thyroid cancer is surgery, when possible. Usually, surgery is followed by treatment with radioiodine and thyroxine therapy. Generally, radiation therapy and chemotherapy do not have a prominent role in the treatment of 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 radioactive iodine (RAI) may be considered. Ablation of residual normal thyroid tissue facilitates early detection of recurrence based on serum thyroglobulin measurement and/or RAI whole-body scan.

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

Large (>4 cm) tumors

Known distant metastasis

Gross extrathyroid extension

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

Moderate-size (1-4 cm) and node positive

Grossly multifocal

Aggressive, based on histology

High risk, based on patient factors (age >45 y, history of head and neck radiation, family history of thyroid cancer)

RAI ablation is not recommended for the following:

Small (<1 cm), solitary tumors

Multifocal tumors when all foci are < 1 cm

Early 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 (TSH) suppression therapy (levothyroxine)

TSH suppression to < 0.1 mU/L is indicated in intermediate and high-risk disease. TSH maintenance at or slightly below the lower-normal limit (0.3-2 mU/L) may be considered for low-risk disease

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 in the context of a clinical trial for persistent metastatic disease despite radioiodine, TSH suppression, and radiotherapy

Consider tyrosine kinase inhibitors (TKIs) such as sorafenib 400 mg PO BID ^[5] or sunitinib 50 mg PO daily for 4wk of a 6-wk cycle ^[6] for patients who cannot participate in a clinical trial, as well as for those who are not likely to tolerate systemic therapy; since these drugs are usually tumorostatic rather than tumoricidal, they are considered second-line therapy compared with systemic treatments in clinical trials

Pazopanib 800 mg PO daily may be considered for progressive or symptomatic metastatic differentiated (Hürthle cell, papillary, and follicular) thyroid carcinoma

Randomized phase III clinical trials supporting a TKI benefit in thyroid cancer are currently unavailable; thus, there are no specific regimens

Doxorubicin 60 mg/m² as monotherapy or in combination with cisplatin 40 mg/m² may be considered for patients who cannot tolerate TKIs or in whom TKIs have failed; however, the efficacy of these, and other cytotoxic drugs, is very limited ^{[7, 8]}

Follicular neoplasm (indeterminate cytology) treatment options are as follows:

Consider scintigraphy if not already done, especially in the setting of thyroid-stimulating hormone (TSH) in the low-normal range

Hyperfunctioning nodules may be observed; however, if a concordant hyperfunctioning nodule is not identified, lobectomy or total thyroidectomy should be considered

Hürthle cell neoplasm or suspected papillary thyroid cancer (indeterminate cytology) treatment options are as follows:

Surgery is ultimately based on patient factors and surgeon expertise (scintigraphy not required)

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

If papillary thyroid cancer (PTC) diagnosis is made following hemithyroidectomy, completion thyroidectomy is recommended

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

Papillary and follicular thyroid cancer stages I-IV (confirmed by cytology) treatment options are as follows ^{[1, 9, 10, 11]} :

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)—formerlyclassified 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 RAI therapy or to enhance follow-up, based upon disease features and/or patient preference.

Total thyroidectomy is recommended for tumors >4 cm in diameter

Therapeutic central neck dissection 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 clinically N0 disease, especially for advanced primary tumors (T3 or T4)

Locally recurrent or metastatic, progressive DTC treatment options are as follows:

Sorafenib and lenvatinib are VEGF inhibitors approved for DTC refractory to RAI treatment ^{[12, 13]}

Sorafenib: 400 mg PO q12h at least 1 h ac or 2 h pc

Lenvatinib: 24 mg PO once daily with or without food

Continue treatment until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs

Therapeutic options in anaplastic thyroid cancer (ATC) are as follows:

Surgery ^{[14, 15, 16]}

Combined-modality therapy ^{[14, 15, 16, 17]}

Palliative care ^{[14, 15, 16]}

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, lobectomy with wide margins of ipsilateral soft tissues is recommended, often in conjunction with postoperative adjuvant radiotherapy or combined-modality therapy

As long as the tumor is small and entirely confined to the thyroid, total thyroidectomy does not appear to improve survival, as compared with lobectomy, and is associated with a higher risk for complications

Surgical debulking may provide symptomatic relief for patients with very large tumors and significant airway compression

Combined-modality therapy

Combined-modality options are as follows:

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

Since there are no randomized, controlled trials available to definitively prove the therapeutic efficacy of combined-modality therapy, most management strategies are based on single-institution phase II trials and retrospective reviews; thus, there are no standard regimens.

Doxorubicin is the only cytotoxic chemotherapy specifically approved by the US Food and Drug Administration for use in ATC ^[14] ; a typical doxorubicin-based regimen includes doxorubicin 20 mg once weekly given prior to the first radiotherapy session ^[8]  Other agents with the greatest established clinical activity in metastatic ATC are the taxanes paclitaxel or docetaxel and perhaps also platins. ^[14]

Chemotherapy is followed by hyperfractionated radiation and often by an additional round of chemotherapy after radiotherapy completion

Doxorubicin has also been given concurrently with radiation therapy as a radiosensitizer

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

Palliative care

Even with aggressive treatment, anaplastic thyroid cancer is almost always fatal, and there is no effective therapy for metastatic disease. End-of-life issues, comfort, and care options are essential considerations during initial treatment planning.

Surgical options in medullary thyroid cancer are as follows ^[18] :

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 its high risk of surgery and anesthesia complications

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 ^[18] (standard dosing with thyroxine replacement) should be initiated postoperatively with the goal of maintaining euthyroidism. In contrast to epithelial cell–derived thyroid cancers, TSH suppression to lower-than-normal levels is not indicated, since C-cells are not TSH responsive. Similarly, radioactive iodine [RAI] 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 ^[18] :

Radiotherapy may be considered for patients with gross residual disease after surgery and for those with distant metastasis

The role of external beam radiation therapy (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 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 by the FDA for progressive, metastatic medullary thyroid cancer

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

Vandetanib: 300 mg PO daily

Cabozantinib: 140 mg PO daily

Dosage adjustment for these TKIs may be required depending on toxicity and coadministered drugs

Nondiagnostic fine-needle aspiration (FNA) can be managed as follows ^[19] :

Repeat ultrasonographically guided FNA; if repeat FNA is nondiagnostic, may consider close follow-up or surgery

Surgery should be more strongly considered if the nodule is solid

Nodules <1 cm can be managed as follows ^[19] :

Routine FNA is not recommended unless there are 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

Multiple nodules >1 cm can be managed as follows ^[19] :

Aspirate any that are suspicious on ultrasonography

If 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 the presence of low or low-normal TSH, scintigraphy should be compared to ultrasonographic images

Isofunctioning or hypofunctioning nodules >1-1.5 cm should be aspirated

[Guideline] NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Available at http://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. Version 2.2017 — May 17, 2017; Accessed: December 28, 2017.

Hegedüs L. Clinical practice. The thyroid nodule. N Engl J Med. 2004 Oct 21. 351(17):1764-71. [Medline].

Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009 Jun. 19(6):565-612. [Medline].

Tala H, Robbins R, Fagin JA, Larson SM, Tuttle RM. Five-year survival is similar in thyroid cancer patients with distant metastases prepared for radioactive iodine therapy with either thyroid hormone withdrawal or recombinant human TSH. J Clin Endocrinol Metab. 2011 Jul. 96(7):2105-11. [Medline].

Gupta-Abramson V, Troxel AB, Nellore A, Puttaswamy K, Redlinger M, Ransone K. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008 Oct 10. 26(29):4714-9. [Medline].

Cohen EE, Needles BM, Cullen KJ, et al. Phase 2 study of sunitinib in refractory thyroid cancer. J Clin Oncol. 2008 May 20. 26 (suppl):Abstract 6025.

Shimaoka K, Schoenfeld DA, DeWys WD, Creech RH, DeConti R. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer. 1985 Nov 1. 56(9):2155-60. [Medline].

Tennvall J, Lundell G, Wahlberg P, Bergenfelz A, Grimelius L, Akerman M, et al. Anaplastic thyroid carcinoma: three protocols combining doxorubicin, hyperfractionated radiotherapy and surgery. Br J Cancer. 2002 Jun 17. 86(12):1848-53. [Medline]. [Full Text].

Brown AP, Chen J, Hitchcock YJ, Szabo A, Shrieve DC, Tward JD. The risk of second primary malignancies up to three decades after the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab. 2008 Feb. 93(2):504-15. [Medline].

[Guideline] Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, 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 Jan. 26 (1):1-133. [Medline]. [Full Text].

Ito Y, Hirokawa M, Uruno T, Kihara M, Higashiyama T, Takamura Y, et al. Prevalence and biological behaviour of variants of papillary thyroid carcinoma: experience at a single institute. Pathology. 2008 Oct. 40(6):617-22. [Medline].

Brose MS, Nutting C, Jarzab B, et al. Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: the Phase 3 DECISION trial. June 2013.

Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015 Feb 12. 372(7):621-30. [Medline].

[Guideline] Smallridge RC, Ain KB, Asa SL, Bible KC, Brierley JD, Burman KD, et al. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2012 Nov. 22 (11):1104-39. [Medline]. [Full Text].

Nel CJ, van Heerden JA, Goellner JR, et al. Anaplastic carcinoma of the thyroid: a clinicopathologic study of 82 cases. Mayo Clin Proc. 1985 Jan. 60(1):51-8. [Medline].

Venkatesh YS, Ordonez NG, Schultz PN, Hickey RC, Goepfert H, Samaan NA. Anaplastic carcinoma of the thyroid. A clinicopathologic study of 121 cases. Cancer. 1990 Jul 15. 66(2):321-30. [Medline].

Pudney D, Lau H, Ruether JD, Falck V. Clinical experience of the multimodality management of anaplastic thyroid cancer and literature review. Thyroid. 2007 Dec. 17(12):1243-50. [Medline].

Wu LS, Roman SA, Sosa JA. Medullary thyroid cancer: an update of new guidelines and recent developments. Curr Opin Oncol. 2011 Jan. 23(1):22-7. [Medline].

Mackenzie EJ, Mortimer RH. Thyroid nodules and thyroid cancer. Med J Aust. 2004 Mar 1. 180(5):242-7. [Medline].

Bible KC, Suman VJ, Molina JR, Smallridge RC, Maples WJ, Menefee ME, et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 2010 Oct. 11(10):962-72. [Medline]. [Full Text].

[Guideline] Wells SA Jr, et al; American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun. 25 (6):567-610. [Medline]. [Full Text].

Eric J Lentsch, MD Assistant Professor of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Christopher D Braden, DO Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital; Medical Director, Deaconess Hospital Outpatient Infusion Centers; Chairman, Deaconess Hospital Cancer Committee

Christopher D Braden, DO is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Neetu Radhakrishnan, MD Associate Professor (Adjunct) of Medicine, Division of Hematology/Oncology, University of Cincinnati Medical Center; Hematology/Oncology Medical Director, West Chester Outpatient Clinics

Neetu Radhakrishnan, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Thyroid Cancer Treatment Protocols 

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