Medullary Thyroid Carcinoma (MTC)


The primary treatment method of medullary thyroid carcinoma (MTC) is surgical. MTC is a malignant neoplasia of parafollicular cells which do not concentrate iodine and are not influenced by thyroid stimulating hormone (TSH). Therefore, TSH suppression and radioiodine therapy, while useful in other thyroid malignancies, are not viable options for MTC. Surgical resection is insufficient in patients with metastatic disease and has an unfavorable prognosis. Such patients, however, are candidates for systemic treatment, usually in the setting of a clinical trial.1 

Cytotoxic Chemotherapy 

Single-agent or combined cytotoxic chemotherapy is not considered first-line due to low response rates (15% to 20%), although it may be considered in patients who do not qualify for clinical trial enrollment or have failed to respond to other systemic treatments.1 Regimens that may be utilized are combination therapies with dacarbazine along with other

agents such as cyclophosphamide, vincristine, or 5-fluorouracil or doxorubicin with or without another agent.1,2 Results are usually disappointing, however, promising novel therapies that are currently being developed. 

Tyrosine Kinase Inhibitors

Activating mutations to the RET proto-oncogene are found in most cases of MTC, both sporadic and MEN 2-related. The development of novel RETtargeting therapies and multitargeted kinase inhibitors are changing the way metastatic MTC is being treated.3 The American Thyroid Association recommends that patients with metastatic or progressive disease be enrolled in a clinical trial to receive one of these novel agents, which provide superior results to traditional chemotherapy.1 Kinase inhibitors may be selective, targeting RET mutations specifically, or multitargeted, inhibiting multiple ligands and are sometimes referred to as antiangiogenic multikinase inhibitors (aaMKIs). 

RET-Selective Kinase Inhibitors

Two RET mutation-selective oral kinase inhibitors have been approved by the FDA for the treatment of advanced or metastatic MTC. 

Selpercatinib appears to be most effective against “gatekeeper” mutations in RET codon 804. Treatment with selpercatinib can rapidly palliate disease-related symptoms, such as diarrhea and Cushing’s syndrome. In an open-label trial of selpercatinib patients with advanced or metastatic RET-mutant MTC, previously treated or not treated with cabozantinib and/or vandetanib, the overall response rate (ORR) was 69% and 73%, respectively.4 Common side effects are dry mouth, diarrhea, constipation, nausea, abdominal pain, rash, hypertension, headache, fatigue, and edema. 

Pralsetinib has an ORR of 60% in patients previously treated with cabozantinib and/or vandetanib and 66% in treatment-naïve subjects. Common adverse events are constipation, hypertension, fatigue, musculoskeletal pain, and diarrhea 5 

Multi-Targeted Kinase Inhibitors

Vandetanib targets the vascular endothelial growth factor receptor (VEGFR), RET, and the epidermal growth factor receptor (EGFR) used to treat symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic disease.6 It is available in the US through a Risk Evaluation Mitigation Strategy program and in Europe, through the Commission on Human Medicines and the Medicines and Healthcare products Regulatory Agency.6,7

Cabozantinib targets VEGFRs 1 and 2, c-MET (a receptor tyrosine kinase), and RET and is FDA-approved for the treatment of progressive, metastatic MTC.8 It is most effective in patients harboring RET M918T mutations.9 

Other aaMKIs that are being used to treat MTC include sorafenib, sunitinib, and lenvatinib. Adverse events that are common among all aaMKIs include hypertension, renal toxicity, bleeding, myelosuppression, arterial thromboembolism, cardiotoxicity, thyroid dysfunction (typically hypothyroidism), cutaneous toxicity including hand-foot skin reaction, delayed wound healing, hepatotoxicity, and muscle wasting.

Investigational Therapies

Immunotherapy using tumor vaccines and radioimmunotherapy are being investigated as potential treatment options for MTC but are still in their infancy. 

Tumor vaccines hope to harness the body’s own cytotoxic T-cell response as a weapon for fighting cancer by training the immune system to attack malignant cells. Specialized antigen-presenting cells derived from bone marrow have been developed to present tumor-associated antigens with the intention of generating an immune response to tumor cells that possess that antigen.  So far, results have been promising but this technique is still under investigation.10,11  

Radiotherapy involves administration of radiolabeled monoclonal antibodies against CAE. Major limitations are severe adverse events such as neutropenia and thrombocytopenia.12

Treatment with Radiolabeled octreotide has also been investigated and was associated with longer survival from time of diagnosis in one study.13

References

1. Wells SA, Asa SL, Dralle H, et al. Revised american thyroid association guidelines for the management of medullary thyroid carcinoma. Thyroid Off J Am Thyroid Assoc. 2015;25(6):567-610. doi:10.1089/thy.2014.0335

2. Ernani V, Kumar M, Chen AY, Owonikoko TK. Systemic treatment and management approaches for medullary thyroid cancer. Cancer Treat Rev. 2016;50:89-98. doi:10.1016/j.ctrv.2016.09.006

3. Subbiah V, Yang D, Velcheti V, Drilon A, Meric-Bernstam F. State-of-the-Art strategies for targeting RET-dependent cancers. J Clin Oncol. 2020;38(11):1209-1221. doi:10.1200/JCO.19.02551

4. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid ancers. N Engl J Med. 2020;383(9):825-835. doi:10.1056/NEJMoa2005651

5. Blueprint medicines corporation. GAVRETO (pralsetinib) capsules, for oral use. Published online December 2020. Accessed July 6, 2021.

6. Pharmaceuticals LP. Vandetanib (vandetanib) tablets for oral AstraZeneca se. Published online March 23, 2021. accessed July 8, 2021.

 7. European Medicines Agency. Caprelsa (vandetanib). Published online 2016. Accessed July 6, 2021.www.ema.europa.eu/en/documents/overview/caprelsa-epar-summary-public_en

8. Exelixis, Inc. COMETRIQTM (cabozantinib) capsules, for oral use. Published online November 2012.https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203756lbl.pdf

9. Meeting Library | Final overall survival analysis of EXAM, an international, double-blind, randomized, placebo-controlled phase III trial of cabozantinib (Cabo) in medullary thyroid carcinoma (MTC) patients with documented RECIST progression at baseline. Accessed July 9, 2021. https://meetinglibrary.asco.org/record/111956/abstract

10. Schott M, Seissler J, Lettmann M, Fouxon V, Scherbaum WA, Feldkamp J. Immunotherapy for medullary thyroid carcinoma by dendritic cell vaccination. J Clin Endocrinol Metab. 2001;86(10):4965-4969. doi:10.1210/jcem.86.10.7949

11. Stift A, Sachet M, Yagubian R, et al. Dendritic cell vaccination in medullary thyroid carcinoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2004;10(9):2944-2953. doi:10.1158/1078-0432.ccr-03-0698

12. Chatal J-F, Campion L, Kraeber-Bodéré F, et al. Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anti-carcinoembryonic-antigen radioimmunotherapy: a collaborative study with the french endocrine tumor group. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(11):1705-1711. doi:10.1200/JCO.2005.04.4917

13. Iten F, Müller B, Schindler C, et al. Response to [90Yttrium-DOTA]-TOC treatment is associated with long-term survival benefit in metastasized medullary thyroid cancer: a phase II clinical trial. Clin Cancer Res Off J Am Assoc Cancer Res. 2007;13(22 Pt 1):6696-6702. doi:10.1158/1078-0432.CCR-07-0935

Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.

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