For patients with confirmed Medullary Thyroid Cancer (MTC) diagnosed using fine needle aspiration (FNA), surgical treatment is the only curative option. A preoperative work-up is required for disease staging and will determine the surgical procedure of choice, need for additional imaging, and choice of medical management if necessary. Preoperative evaluation involves a neck ultrasound (US), measurement of calcitonin (Ctn) and carcinoembryonic antigen (CEA) levels, and DNA analysis for RET germline mutations.
For RET-negative tumors with preoperative Ctn levels < 500 pg/mL, the treatment is total thyroidectomy (TTX) with cervical lymph node dissection depending on preoperative and intraoperative US findings. If no evidence of lymph node metastasis is detected, a prophylactic central compartment lymph node dissection is recommended. The American Thyroid Association taskforce was unable to achieve a consensus for dissection of the lymph nodes in the lateral compartment, and they state that it may be considered based on serum calcitonin levels. If extensive nodal disease is detected during TTX or if there is extension of the cancer beyond the thyroid, external beam radiation may also be considered.1
RET-Positive or RET Unknown Tumors
In 25% of cases, MTC is inherited as part of multiple endocrine neoplasia type 2 (MEN2) syndrome. The majority (75%) of cases occur sporadically.2 RET germline mutations may be seen in either case, and it is recommended that physicians evaluate for pheochromocytomas and hyperparathyroidism. Some patients with sporadic disease have unsuspected germline mutations, therefore routine testing is recommended as these de novo mutations can be inherited in future generations.1 If there is no evidence of metastatic disease and serum Ctn is < 500 pg/mL, surgical management for RET-positive tumors is identical to that of RET-negative tumors.
Preoperative Calcitonin Levels
For both RET-positive and RET-negative tumors, measurement of Ctn is recommended to establish baseline levels and determine the need for additional imaging procedures. If preoperative levels of serum Ctn are > 500 pg/mL, additional preoperative imaging to detect the presence of metastatic disease and staging using the American Joint Committee on Cancer TNM Classification for thyroid cancer is required. Imaging studies of choice are contrast-enhanced computed tomography (CT) scans of the neck and chest, three-phase contrast-enhanced multi-detector liver CT or contrast-enhanced magnetic resonance imaging (MRI) of the liver, and axial MRI and bone scintigraphy. These studies are also recommended for patients with extensive nodal disease and signs or symptoms of regional or distant metastases.1
Results of TNM Staging
The most important determinant of TNM staging is the presence of distant metastasis. Surgical management of tumors without distant metastasis is identical to those described above. Patients that have regionally advanced or metastatic disease will require TTX and central compartment node dissection; however, the treatment goals in this group are mostly palliative. Less aggressive surgical procedures may be considered to spare the parathyroid glands, and lateral compartment node dissection is generally not performed to preserve speech, shoulder movement, and swallowing. External beam radiotherapy (EBRT), systemic medical therapy, and other nonsurgical therapies should be considered to achieve local tumor control.
After a TTX, serum TSH should be measured within 4–6 weeks postoperatively. Patients will require replacement therapy with levothyroxine to maintain a euthyroid state, not for TSH suppression since C-cells are not TSH-responsive. Treatment may be initiated immediately after surgery. Serum Ctn and CEA should be measured 3 months after surgery to detect the presence of residual disease.1 Patients are considered biochemically cured if CEA and Ctn values are undetectable at follow-up, and these cases have the best prognosis with a 5-year recurrence rate of 5%.3
If levels are undetectable or within the normal range, they should be repeated every 6 months for 1 year and then yearly. Persistently elevated Ctn levels post-TTX are associated with persistent locoregional disease. Levels exceeding 150 pg/mL on follow-up may indicate recurrence. The ATA recommends that if the postoperative serum Ctn levels exceed 150 pg/mL, patients should be evaluated with imaging procedures, including neck US, chest CT, contrast-enhanced MRI or three-phase contrast-enhanced CT of the liver, and bone scintigraphy and MRI of the pelvis and axial skeleton. Other useful imaging procedures include 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) scan, fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) PET scan, and gallium-68 (68Ga) radiolabeled somatostatin analogue peptides (DOTATATE, DOTATOC, and DOTANOC) PET scan.
MTC has a poor response rate to cytotoxic chemotherapeutic regimens, and they are therefore not considered a first-line treatment option. They are generally reserved for patients who are unable to tolerate tyrosine kinase inhibitors (TKIs). TKIs are the preferred treatment for RET-positive patients with advanced disease, and they are preferably administered in the setting of a clinical trial. At the time when the ATA guidelines were published, only 2 orally administered TKIs were US Food and Drug Administration (FDA)-approved: vandetanib and cabozantinib.1 Several novel TKIs have been introduced since then and are discussed below.
Selpercatinib is FDA-approved for the treatment of advanced or metastatic MTC.4 In patients with MTC that have not received either vandetanib and cabozantinib, response to treatment is 73% (95% confidence interval [CI], 62-82), and 1-year progression-free survival is 92% (95% CI, 82-97).5 Clinical trials with selpercatinib plus either vandetanib and cabozantinib are ongoing.6
Pralsetinib is FDA-approved for the treatment of advanced or metastatic MTC with RET alterations.7 Preliminary results show that the overall response rate is 66% (partial response 55%, and complete response 10%). Clinical trials are ongoing.8
Vandetanib is a multitargeted TKI available in the United States through the Risk Evaluation Mitigation Strategy (REMS) program.9 It is also available in Europe, where it is regulated by the Commission on Human Medicines and the Medicines and Healthcare Products Regulatory Agency.10 An international, randomized phase III trial showed that progression-free survival was significantly prolonged for patients in the vandetanib group after a median follow-up of 24 months (hazard ratio [HR], 0.46; 95% CI, 0.31-0.69).11
Cabozantinib is FDA-approved for the treatment of progressive, metastatic MTC.12 Cabozantinib seems to have a greater therapeutic effect in patients with RET M918T mutation-positive tumors. In a phase III randomized trial, patients with RET M918T-positive disease had a median overall survival of 44.3 months versus 18.9 months for those receiving placebo (HR, 0.60; 95% CI, 0.38-0.94; P = 0.03 [not adjusted for multiple subgroup analyses]), with corresponding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70-1.82; P = 0.63) in the RET M918T-negative subgroup.13
Sorafenib is approved in the United States for treatment of advanced renal cell carcinoma and unresectable hepatocellular carcinoma.14 Data on the use of sorafenib for MTC are limited.
Sunitinib is FDA-approved for the treatment of advanced renal cell carcinoma and refractory gastrointestinal stromal tumors.15 Small studies have reported varying response rates when used for MTC.
Lenvatinib is FDA-approved to treat progressive, metastatic, radioiodine-refractory differentiated thyroid cancer. Lenvatinib may be considered as a second- or third-line therapy for patients with progressive, metastatic MTC who have failed other therapies.16
1. Wells SA Jr, Asa SL, Dralle H, 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;25(6):567-610. doi:10.1089/thy.2014.0335
2. Moline J, Eng C. Multiple endocrine neoplasia type 2: an overview. Genet Med. 2011;13(9):755-764. doi:10.1097/GIM.0b013e318216cc6d
3. Modigliani E, Cohen R, Campos JM, et al. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d’étude des tumeurs à calcitonine. Clin Endocrinol (Oxf). 1998;48(3):265-273. doi:10.1046/j.1365-2265.1998.00392.x
4. RETEVMOTM (selpercatinib) capsules, for oral use. Lilly USA, LLC. Updated May 2020. Accessed July 8, 2021.
5. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020;383(9):825-835. doi:10.1056/NEJMoa2005651
6. A study of selpercatinib (LY3527723) in participants with RET-mutant medullary thyroid cancer (LIBRETTO-531). ClinicalTrials.gov. December 26, 2019. Updated July 7, 2021. Accessed July 8, 2021.
7. GAVRETOTM (pralsetinib) capsules, for oral use. Blueprint Medicines Corporation. Updated December 2020. Accessed July 8, 2021.
8. Phase 1/2 study of the highly-selective RET inhibitor, pralsetinib (BLU-667), in patients with thyroid cancer, non-small cell lung cancer, and other advanced solid tumors (ARROW). ClinicalTrials.gov. January 31, 2017. Updated July 1, 2021. Accessed July 8, 2021.
9. Vandetanib (vandetanib) tablets for oral use. AstraZeneca Pharmaceuticals LP. March 23, 2011. Accessed July 8, 2021.
10. Caprelsa (vandetanib). European Medicines Agency. Updated November 2016. Accessed July 8, 2021.
11. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30(2):134-141. doi:10.1200/JCO.2011.35.5040
12. COMETRIQTM (cabozantinib) capsules, for oral use. Exelixis, Inc. Updated November 2012. Accessed July 8, 2021.
13. Schlumberger M, Elisei R, Müller S, et al. Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Ann Oncol. 2017;28(11):2813-2819. doi:10.1093/annonc/mdx479
14. NEXAVAR (sorafenib) tablets, for oral use. Bayer HealthCare Pharmaceuticals Inc. Updated April 2020. Accessed July 8, 2021.
15. SUTENT® (sunitinib malate) capsules, oral. Pfizer Labs. Updated December 2014. Accessed July 8, 2021.
16. LENVIMA® (lenvatinib) capsules, for oral use. Eisai Inc. Updated August 2018. Accessed July 8, 2021.
Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.