Medullary Thyroid Carcinoma Treatment & Management

Updated: May 13, 2020
  • Author: Anastasios K Konstantakos, MD; Chief Editor: Neetu Radhakrishnan, MD  more...
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Treatment

Approach Considerations

The primary treatment for medullary thyroid carcinoma (MTC) is extensive and meticulous surgical resection. 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 or vandetanib or sorafenib or sunitinibSelpercatinib, a RET-specific TKI, received accelerated approval by the FDA in May 2020 for adults and children aged 12 years or older for advanced or metastatic RET-mutant MTC who require systemic therapy. [16]

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, cyclophosphamidestreptozocin, or doxorubicin. No one combination has demonstrated a significant advantage over others. 

 Clinical trials involving injection of autologous dendritic cells are ongoing, with mixed responses. [17]

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. [18]

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. [17]

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Medical Care

In 2009, the M.D. Anderson Cancer Center provided a paradigm for targeted therapy in medullary thyroid cancer.  Activating mutations of the RET tyrosine kinase receptor in medullary thyroid carcinoma makes MTC a good model for the use of small organic molecule tyrosine kinase inhibitors for treatment of metastatic disease. Clinical trials have shown promising results and tolerable toxicity. [19]

Vandetanib (Caprelsa) and cabozantinib (Cometriq) are tyrosine kinase inhibitors approved  for progressive, metastatic medullary thyroid cancer. These agents target various tyrosine kinases including MET, RET, and VEGFR-2.

The FDA approval of vandetanib was based on the results of the ZETA study, a phase III, double-blind trial that randomized 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer to vandetanib 300 mg (n=231) or placebo (n=100). Participants randomized to vandetanib showed a statistically significant improvement in progression-free survival (PFS) when compared to those randomized to placebo (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. Median progression-free survival was 16.4 months in the placebo arm and at least 22.6 months in the vandetanib arm. At the primary PFS analysis, no significant overall survival difference was noted. [20, 21, 22]

Approval for cabozantinib was based on the EXAM clinical trial, an international, multicenter, randomized study that included 330 patients with progressive, metastatic medullary thyroid carcinoma. A statistically significant prolongation in progression-free survival 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. [23]

Selpercatinib is the first targeted therapy to be approved by the FDA for tumors that have rearranged during transfection (RET) mutations. It is indicated for advanced or metastatic RET-mutant MTC in adults and children aged 12 years or older who required systemic therapy. 

Accelerated approval in May 2020 for MTC was based on the open-label LIBRETTO-001 phase I/II clinical trial (n = 143). 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 underway. [16]

See Thyroid Cancer Treatment Protocols for summarized information.

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Surgical Care

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. [24]

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. [25] However, patients with undetectable calcitonin levels, negative RET test findings, and no ultrasonography abnormalities may be conservatively monitored.

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Consultations

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
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Prevention

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.

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Long-Term Monitoring

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. [26]  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. [27]

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. Adjuvant radiation has not been shown to influence 10 yr survival rates, however.

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