Medullary Thyroid Carcinoma Treatment & Management

The primary treatment for medullary thyroid carcinoma (MTC) is extensive and meticulous surgical resection. Indirect or fiberoptic laryngoscopy may be performed prior to surgery to evaluate airway and vocal cord mobility and to provide preoperative documentation of any unrelated abnormalities.

Thyroid hormone therapy is not as effective as surgical treatment for MTCs, which are neuroendocrine tumors of thyroid parafollicular cells that do not concentrate iodine. Radiation therapy is also less effective; however, positive surgical margins or mediastinal extension may be an indication for adjuvant radiotherapy, and external beam radiotherapy (EBRT) may provide a palliative benefit in controlling symptoms from bony metastases.

In cases of metastasis, the approach depends on the severity and rate of progression of disease. Metastatic MTC can be treated with limited surgical resection, EBRT in certain situations, or medical management with tyrosine kinase inhibitors (TKIs) or other agents. 

Metastatic disease

Asymptomatic metastatic tumors (generally less than 1 to 2 cm in diameter) growing in diameter less than 20% per year should be monitored for progression with imaging every 6 to 12 months.

For other patients, first-line treatment is surgery or palliative EBRT. If they are not candidates for surgery or radiotherapy, systemic treatment as part of a clinical trial may be the best option.

Other options include tyrosine kinase inhibitor (TKI) therapy, such as with cabozantinib, vandetanib, sorafenib, or sunitinib. Selpercatinib, a RET-specific TKI, received accelerated approval by the US Food and Drug Administration (FDA) in 2020 for adults and children aged 12 years or older for advanced or metastatic RET-mutant MTC who require systemic therapy. ^[17]

Cytotoxic agents are used for metastatic MTC only if the patient is unable to participate in clinical trials or experiences intolerance or failure of TKIs. Most regimens combine dacarbazine with other agents, including vincristine, 5-fluorouracil, cyclophosphamide,  streptozocin, or doxorubicin. No one combination has demonstrated a significant advantage over others. ^[18]  

Radioimmunotherapy using anti-carcinoembryonic antigen/anti-diethylenetriamine pentaacetic acid (DTPA)-indium recombinant bispecific antibody (BsMAb), followed 4 days later by a ¹³¹I-labeled bivalent hapten, resulted in a median overall survival of 110 months compared with 60 months in a contemporaneous untreated cohort. ^[19]

Peptide receptor radionuclide therapy produces a cytotoxic effect through the binding of a radiolabeled ligand to its respective receptor expressed on a tumor’s surface. Phase 2 trials in patients with metastatic MTC whose tumors expressed somatostatin or cholecystokinin (CCK) receptors have demonstrated some benefit. ^[18]

In 2009, the M.D. Anderson Cancer Center provided a paradigm for targeted therapy in MTC, demonstrating that activating mutations of the RET (rearranged during transfection) tyrosine kinase receptor in MTC made this disease a good model for the use of TKIs for treatment of metastatic cases. ^[20] Several TKIs have since entered clinical practice. Vandetanib (Caprelsa) and cabozantinib (Cometriq), which target various tyrosine kinases, including MET, RET, and VEGFR-2, are approved for progressive, metastatic MTC. Selpercatinib (Retevmo) and pralsetinib (Gavreto) are approved for MTC that has RET mutations.

FDA approval of vandetanib was based on the results of the phase III ZETA study, in which participants randomized to vandetanib (n=231) showed a statistically significant improvement in progression-free survival (PFS) compared with those randomized to placebo (n=100): median PFS was at least 22.6 months in the vandetanib arm, versus 16.4 months in the placebo arm (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.24-0.53; P <  0.0001). This difference reflects a 65% reduction in risk for disease progression. At the primary PFS analysis, no significant difference in overall survival (OS) was noted. ^{[21, 22, 23]}

Approval for cabozantinib was based on the EXAM clinical trial, an international, multicenter, randomized study that included 330 patients with progressive, metastatic MTC. A statistically significant prolongation in PFS was seen with cabozantinib compared with placebo (11.2 vs 4.0 months; P <  0.0001). Partial responses were observed only among patients in the active treatment arm (27% vs 0%; P < 0.0001), and more patients in the cabozantinib group than in the placebo group were alive and free of disease progression at 1 year (47.3% vs 7.2%). Median duration of response was 14.7 months. ^[24]

Selpercatinib is the first RET targeted therapy to be approved by the FDA for MTC. It is indicated for advanced or metastatic RET-mutant MTC in adults and children aged 12 years or older who require systemic therapy. Accelerated approval for MTC was based on the open-label LIBRETTO-001 phase I/II clinical trial (n = 143). The objective response rate (ORR) was 69% in cabozantinib/vandetanib treatment–experienced patients (n = 55) and 73% in treatment-naïve patients (n = 88). The phase III confirmatory trial (LIBRETTO-531) is in progress. ^[17]

Pralsetinib was approved by the FDA for adult and pediatric patients aged 12 years and older with advanced or metastatic RET-mutant MTC who require systemic therapy. Efficacy was evaluated in the ARROW trial, a multicenter, open label, multicohort clinical trial. In the 55 patients with advanced or metastatic RET-mutant MTC who were previously treated with cabozantinib or vandetanib, the ORR was 60% (95% CI: 46%, 73%); the rate of duration of response (DOR) of 6 months or longer was 79%. Efficacy was also evaluated in 29 treatment-naïve patients with RET-mutant MTC: in this arm, the ORR was 66% (95% CI: 46%, 82%); DOR lasting 6 months or longer was 84%. ^[25]

See Thyroid Cancer Treatment Protocols for summarized information.

Surgical treatment goals of medullary thyroid carcinoma (MTC) are as follows:

• Provide local control of the cancer
• Maintain laryngoesophageal function (speech and swallowing)
• Tailor surgical treatment according to the type of MTC presentation (ie, sporadic, familial)

Sporadic MTC

Sporadic MTC occurring in patients presenting with a palpable thyroid nodule verified by fine-needle aspiration is treated as follows:

• Perform a total thyroidectomy and central neck dissection for cases of symptomatic (clinically detected) MTC.

• For patients with microscopic involvement of regional lymph nodes, advocate a central neck dissection, which involves complete dissection of structures and removal of node-bearing tissue between the hyoid bone and innominate vessels, sternothyroid resection, removal of paratracheal lymph nodes, and possible thymectomy.

• Autograft an inferior parathyroid gland that is histologically confirmed as cancer-free into the sternocleidomastoid or forearm muscle.

• In palpable lymph node disease, perform a modified radical neck dissection. For increasing calcitonin levels, a reoperative neck dissection may be indicated.

• In a 2009 retrospective review of elective superior mediastinal neck dissections for thyroid carcinomas, the authors concluded that "elective transcervical superior mediastinal dissection was commonly positive in patients with papillary, medullary, and anaplastic thyroid carcinomas. A transcervical approach may be safely performed without sternotomy to the level of the brachiocephalic vein." They pointed out that further studies are needed to determine the impact of elective superior mediastinal lymph node dissections on survival. ^[26]

Familial MTC

Prophylactic thyroidectomy is indicated for carriers of RET mutations who have no apparent disease but are at risk for aggressive MTC. Guidelines from the American Thyroid Association classify RET carriers into four risk levels, on the basis of the particular mutation involved. The age at which thyroidectomy is recommended corresponds to the level of risk and varies from as soon as possible within the first year of life (for those at highest risk) to beyond 5 years of age, provided that stringent criteria are met. ^[2]

Perform a total thyroidectomy with a central neck dissection or modified radial neck dissection for patients with clinically detectable disease evidenced by increased calcitonin levels, thyroid nodule on ultrasonography, or findings on physical examination. MTC is diagnosed after thyroidectomy in approximately 10-15% of cases.

Patients with persistently elevated serum calcitonin levels, positive RET findings, or nodal disease are good candidates for completion thyroidectomy and lymph node dissection. ^[27] However, patients with undetectable calcitonin levels, negative RET test findings, and no ultrasonography abnormalities may be conservatively monitored.

Consultations may include the following:

• General physician
• Head and neck surgeon
• Endocrinologist
• Geneticist, for cases of inherited MTC such as in patients with MEN2 syndromes
• Oncologist

Management guidelines from the American Thyroid Association (ATA) recommend prophylactic thyroidectomy for individuals with documented RET mutation who are at risk for aggressive medullary thyroid carcinoma. ^[2]  The ATA has proposed schedules for the recommended age of RET testing, first ultrasound, serum calcitonin level, and prophylactic surgery, depending on the level of risk; in those at highest risk, surgery is recommended within the first year of life.

Measure calcitonin and carcinoembryonic antigen (CEA) levels after thyroidectomy. Patients with undetectable calcitonin—or, in patients with sporadic MTC who have undergone hemithyroidectomy, calcitonin levels within the normal reference range—should have follow-up testing every 6-12 months.

Detectable CEA levels after total thyroidectomy, or above-normal levels after hemithyroidectomy, mandate further assessment with imaging studies, as per American Thyroid Association guidelines. If calcitonin becomes detectable after total thyroidectomy but imaging studies do not identify disease or if calcitonin levels rise after hemithyroidectomy, doubling time of calcitonin and CEA levels may be used to assess tumor progression. ^[28]  In one study, 94% of patients with doubling times shorter than 25 months had progressive disease and 86% of patients with doubling times longer than 24 months had stable disease. ^[29]

Further intervention may include the following:

• Perform reoperative cervical exploration for isolated recurrent cervical disease (without distant metastases) identified by ultrasonography or CT scanning
• Identification of distant metastatic disease may require laparoscopy with probe ultrasonography to detect liver surface lesions and bone scanning to detect osseous disease
• Selective hepatic venous sampling for liver metastases is an experimental procedure that is used to detect intrahepatic lesions with greater sensitivity
• If metastatic workup findings are negative in a patient with elevated plasma calcitonin levels, elective cervical lymph node dissection or modified radial neck dissection may be performed.

For patients with undetectable calcitonin and normal CEA levels, post-surgical followup may include the following:

• Physical examination twice yearly for 2 years and then yearly thereafter
• Measurement of serum calcitonin and CEA levels twice yearly for 2 years and then yearly thereafter
• Neck ultrasound 3 to 12 months postoperatively (depending on the extent of lymph node involvement prior to surgery) to establish a baseline; additional imaging is not required unless the calcitonin or CEA values rise during follow-up

Calcitonin values that remain ≥150 pg/mL 2 to 6 months after surgery increase the likelihood that the patient may have distant metastases. These patients should undergo neck ultrasound and additional imaging (eg, CT or MRI of neck, chest, and abdomen; bone scan or bone MRI in patients suspected of having skeletal metastases) to identify possible distant metastases. However, adjuvant radiation has not been shown to influence 10-year survival rates.