Thyroid Health Blog: Expanding Medical Therapies for Medullary Thyroid Cancer

By February 18, 2021 March 3rd, 2024 Past News Releases, Thyroid Cancer, Thyroid Health Blog
Sarika Rao, DO, FACE

Expanding Medical Therapies for Medullary Thyroid Cancer

Sarika Rao, DO, FACE
Mayo Clinic, FL
February 17, 2021


Medullary thyroid cancer (MTC) is a neuroendocrine tumor involving the parafollicular c-cells, and accounts for 1-2% of all thyroid cancers in the United States (1). Many patients are diagnosed incidentally, without ever having symptoms, though some may experience diarrhea and flushing. About 25% of these cases are driven by germline, or inherited, mutations, and may be part of genetic syndromes such as multiple endocrine neoplasia Types 2A and B. The remaining 75% of cases are acquired and are driven by somatic, or acquired, mutations. The most common gene involved in MTC is the RET proto-oncogene, though the location, or type, of mutation within this gene is highly variable. Hence all patients newly diagnosed with MTC need to be screened for RET or other mutations to help guide management. A RAS mutation may be seen in about 15% of the somatic forms, and the remainder do not have identifiable mutations.


Complete surgical resection of the thyroid plus central and possibly lateral lymph nodes is the mainstay of treatment. For persistent locoregional and/or distant metastases, repeat surgery, external beam radiation, or other focal therapies can be implemented. When these therapies are no longer options for progressive or symptomatic disease, systemic therapy should be considered. Vandetanib and cabozantanib are antiangiogenic multikinase inhibitors and have been approved for nearly a decade by the US Food and Drug Administration (FDA) as viable systemic options in the treatment of metastatic MTC, based on data from randomized phase 3 studies that demonstrated significant difference in progression free-survival (PFS) but not overall survival (2, 3). These drugs have a broader inhibitory landscape (which includes RET) though at the consequence of being less potent and associated with greater toxicities (including diarrhea, hypertension, QT prolongation, mouth or skin sores, weight loss). Hence many patients on these therapies require dose reductions or discontinuation of the drug due to poor tolerance.


In 2020, two selectively targeted RET kinase inhibitors emerged as FDA approved therapies for RET-mutated cancers: selpercatanib and pralsetinib. In their respective phase 1-2 open label trials, most patients saw tumor shrinkage. Although head to head comparison against cabozantanib or vandetinib is not available due to differences in study design, it appeared that these RET inhibitors prolonged PFS more (4, 5). In addition, selpercatanib and pralsetinib were well tolerated and most remained on the full dose, which could explain why the response rate was high and durable. These medications do still have side effects, including hypertension and elevated liver enzymes, that need to be closely monitored. While these “new kids on the block” bring promise and hope to patients and providers alike, they are not considered curative, and may just stabilize or delay progression, with no known change to overall survival to date as compared to standard of care. In addition, those MTC patients without a RET mutation who require systemic therapies would not be candidates for this drug.


Newer iterations of RET specific kinase inhibitors are currently under investigation as are pairing these mutation-specific inhibitors with broader antiangiogenic kinase inhibitor or with immunotherapy for a more comprehensive approach; of course, all the while balancing patient side effects and tolerability. Targeted immunotherapy, specifically involving a tumor vaccine, are also under investigation though data on outcomes are limited to date.


Over the past decade, the field of thyroid oncology has grown tremendously, as we continue to better understand the tumor environment, thereby facilitating innovative therapies. As an oncologic endocrinologist, I am very excited and proud to be part of an era where we can finally offer multiple and novel solutions to rare cancers, including medullary thyroid cancer, and remain confident in our trajectory to cure!


1. Wells SA, Jr., Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-610.
2. Wells SA, Jr., Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, 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):134-41.
3. Elisei R, Schlumberger MJ, Muller SP, Schoffski P, Brose MS, Shah MH, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639-46.
4. Wirth LJ, Sherman E, Robinson B, Solomon B, Kang H, Lorch J, et al. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N Engl J Med. 2020;383(9):825-35.
5. GavretoTM Prescribing Information. Dec. 2020.

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