Clinical and Diagnostic Features and Treatment Outcomes of Locally Advanced Medullary Thyroid Carcinoma in the Tyumen Region, Russia

Introduction. Medullary thyroid carcinoma (MTC) is a rare and aggressive malignancy, accounting for 2–5% of all thyroid cancers. Aim. This study examined the epidemiological profile of MTC in the Tyumen Region (Russia) and evaluated the effectiveness and tolerability of multikinase inhibitors (MKIs) in MTC therapy.

Materials and methods. The analysis included 69 patients with MTC treated between 2017 and 2025. Patient age ranged from 39 to 78 years (median 57). Sonographic characteristics of thyroid nodules were classified according to the EU-TIRADS. Cytological evaluation of fine-needle aspiration samples followed the Bethesda Thyroid Classification (2009, 2017, 2023). Survival outcomes were calculated using the Kaplan–Meier method. Serum calcitonin (CT) and carcinoembryonic antigen (CEA) levels were measured by electrochemiluminescence. RET mutation testing was performed on blood samples and, in one case, on surgical tissue.

Results. Between 2017 and 2025, peak MTC incidence in the Tyumen Region occurred in 2021 and 2024, reaching 0.65 and 0.74 per 100,000 population, respectively. During cabozantinib therapy, mean survival was 19.30 months (95% CI 14.45–21.39), with a median of 17.01 months. For vandetanib in first-line therapy, mean survival was 18 months (95% CI 12.57–23.59), with a median of 14.00 months (95% CI 12.46–20.55). The objective response rate was 29.4% with vandetanib and 36.8% with cabozantinib. The most frequent adverse events were arterial hypertension with vandetanib, palmar-plantar erythrodysesthesia with cabozantinib, and toxic hepatitis with selpercatinib. Discussion. This retrospective analysis demonstrates the effectiveness and safety of MKIs in routine clinical practice. Cabozantinib showed superior survival outcomes and objective response rates compared to vandetanib. The observed adverse events were expected and manageable. The findings are consistent with published clinical evidence.

Conclusion. Given the aggressive nature of MTC, continuous monitoring of disease progression is essential. In cases of progression, MKI therapy should be considered, with careful evaluation of potential toxicity in relation to individual treatment goals.

1. International Agency for Research on Cancer, World Health Organization. Globocan fact sheet: Thyroid cancer (2020). Available from: https://gco.iarc.fr/today/data/factsheets/cancers/32-Thyroid-fact-sheet.pdf [cited 19 April 2022].

2. Kaprin A.D., Starinsky V.V., Shakhzadova A.O. (ed.) State of cancer care for population in Russia in 2024 (morbidity and mortality). Moscow: P.A. Gertsen Moscow Research Oncology Institute, 2024.

3. National Comprehensive Cancer Network. Thyroid carcinoma v.3.2024: NCCN clinical practice guidelines in oncology (NCCN Guidelines®): National Comprehensive Cancer Network, 2024. Available from: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1470 [cited June 16, 2024].

4. Wells S.A. Jr, Asa S.L., Dralle H., Elisei R., Evans D.B., Gagel R.F., et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567–610. DOI: 10.1089/thy.2014.0335

5. Hazard J., Hawk W., Crile G. Medullary (solid) carcinoma of the thyroid — a clinicopathologic entity. J Clin Endocrinol Metab. 1959;19(1):152–61. DOI: 10.1210/jcem-19-1-152

6. Jaquet J. Ein Fall von metastasierenden Amyloid- tumoren (Lymphosarkom). Virchows Arch Path Anat. 1906;185:251–68. DOI: 10.1007/BF01948712

7. Stoffel E. Lokales amyloid der schilddrüse. Virchows Arch Path Anat. 1910;201(2):245–52. DOI: 10.1007/BF0199550

8. Hadoux J., Elisei R., Brose M.S., Hoff A.O., Robinson B.G., Gao M., et al. Phase 3 trial of selpercatinib in advanced RET-mutant medullary thyroid cancer. N Engl J Med. 2023;389(20):1851–61. DOI: 10.1056/NEJMoa2309719

9. Ciampi R., Romei C., Ramone T., Prete A., Tacito A., Cappagli V., et al. Genetic landscape of somatic mutations in a large cohort of sporadic medullary thyroid carcinomas studied by next-generation targeted sequencing. iScience. 2019;20:324–36. DOI: 10.1016/j.isci.2019.09.030

10. Romei C., Casella F., Tacito A., Bottici V., Valerio L., Viola D., et al. New insights in the molecular signature of advanced medullary thyroid cancer: evidence of a bad outcome of cases with double RET mutations. J Med Genet. 2016;53(11):729–34. DOI: 10.1136/jmedgenet-2016-103833

11. Severskaya N.V., Choinzonov E.L., Reshetov I.V., Ivanov S.А., Polyakov A.P., Kropotov M.A., et al. Draft of clinical guidelines for the diagnosis and treatment of medullary thyroid cancer in adult patients. Endocrine Surgery. 2022;16(3):5–23 (In Russ.). DOI: 10.14341/serg12794

12. Wirth L.J., Sherman E., Robinson B., Solomon B., Kang H., Lorch J., et al. Efficacy of selpercatinib in RET-altered thyroid tumors. New Engl J Med. 2020;383(9):825–35. DOI: 10.1056/nejmoa2005651

13. Brose A., Mansfield М., Results of the phase I/II registration study ARROW on the use of pralsetinib (BLU-667) in patients (Pts) with advanced RET-mutated medullary thyroid cancer (RET+ MTC). Ann Oncol. 2020;31:1084. DOI: 10.1016/j.annonc.2020.08.1401

14. Ramos H.E., Hecht F., Berdelou A., Borget I., Leboulleux S., Baudin E., et al. Long-term follow-up and safety of vandetanib for advanced medullary thyroid cancer. Endocrinology. 2020;71:434–42. DOI: 10.1007/s12020-020-02426-x

15. Subbiah V., Velcheti V., Tuch B.B., Ebata K., Busaidy N.L., Cabanillas M.E., et al. Selective RET kinase inhibition for patients with RET-altered cancers. Ann Oncol. 2018;29(8):1869–76. DOI: 10.1093/annonc/mdy137

16. Zhang X., Shao Y., Wang K. Incidence and risk of hypertension associated with cabozantinib in cancer patients: a systematic review and meta-analysis. Expert Rev Clin Pharmacol. 2016;9(8):1109–15. DOI: 10.1080/17512433.2016.1190269

17. Cabanillas M.E., Habra M.A. Lenvatinib: role in thyroid cancer and other solid tumors. Cancer Treat Rev. 2016;42:47–55. DOI: 10.1016/j.ctrv.2015.11.003

18. Vanden Borre P., Schrock A.B., Anderson P.M., Morris J.C. 3rd, Heilmann A.M., Holmes O., et al. Pediatric, adolescent, and young adult thyroid carcinoma harbors frequent and diverse targetable genomic alterations, including kinase fusions. Oncologist. 2017;22(3):255–63. DOI: 10.1634/theoncologist.2016-0279

19. Landa I., Ibrahimpasic T., Boucai L., Sinha R., Knauf J.A., Shah R.H., et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest. 2016;126(3):1052–66. DOI: 10.1172/JCI85271

20. Pozdeyev N., Gay L.M., Sokol E.S., Hartmaier R., Deaver K.E., Davis S., et al. Genetic analysis of 779 advanced differentiated and anaplastic thyroid cancers. Clin Cancer Res. 2018;24(13):3059–68. DOI: 10.1158/1078-0432.CCR-18-0373

21. Ciampi R., Romei C., Ramone T., Prete A., Tacito A., Cappagli V., et al. Genetic landscape of somatic mutations in a large cohort of sporadic medullary thyroid carcinomas studied by next-generation targeted sequencing. iScience. 2019;20:324–36. DOI: 10.1016/j.isci.2019.09.030

22. Su X., Li Z., He C., Chen W., Fu X., Yang A. Radiation exposure, young age, and female gender are associated with high prevalence of RET/PTC1 and RET/PTC3 in papillary thyroid cancer: a meta-analysis. Oncotarget. 2016;7(13):16716–30. DOI: 10.18632/oncotarget.7574

23. Schlumberger M., Tahara M., Wirth L.J., Robinson B., Brose M.S., Elisei R., et al. Lenvatinib versus placebo in radio iodine-refractory thyroid cancer. New Engl J Med. 2015;372:621–30. DOI: 10.1056/NEJMoa1406470

24. Duan H., Li Y., Hu P., Gao J., Ying J., Xu W., et al. Mutational profiling of poorly differentiated and anaplastic thyroid carcinoma by the use of targeted next-generation sequencing. Histopathology. 2019;75(6):890–9. DOI: 10.1111/his.13942

25. Ciampi R., Giordano T.J., Wikenheiser-Brokamp K., Koenig R.J., Nikiforov Y.E. HOOK3-RET: a novel type of RET/PTC rearrangement in papillary thyroid carcinoma. Endocr Relat Cancer. 2007;14(2):445–52. DOI: 10.1677/ERC-07-0039

26. Ito Y., Onoda N., Ito K.I., Sugitani I., Takahashi S., Yamaguchi I., et al. Sorafenib in japanese patients with locally advanced or metastatic medullary thyroid carcinoma and anaplastic thyroid carcinoma. Thyroid. 2017;27(9):1142–8. DOI: 10.1089/thy.2016.0621

27. Ravaud A., de la Fouchardière C., Caron P., Doussau A., Do Cao C., Asselineau J., et al. A multicenter phase II study of sunitinib in patients with locally advanced or metastatic differentiated, anaplastic or medullary thyroid carcinomas: mature data from the THYSU study. Eur J Cancer. 2017;76:110–7. DOI: 10.1016/j.ejca.2017.01.029

28. Chen J., Ji Q., Cao J., Ji D., Bai C., Lin Y., et al. A phase II multicenter trial of the multitargeted kinase inhibitor sulfatinib in advanced medullary thyroid cancer and radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). J Clin Oncol. 2017;35(15_suppl):6037. DOI: 10.1200/JCO.2017.35.15_suppl.6037

29. Lin S.F., Lin J.D., Hsueh C., Chou T.C., Wong R.J. A cyclin-dependent kinase inhibitor, dinaciclib in preclinical treatment models of thyroid cancer. PLoS One. 2017;12(2):e0172315. DOI: 10.1371/journal.pone.0172315

30. Ho A., Chau N., Wong D., Cabanillas M., Bauman J.R., Bible K.Ch., et al. An open-label, phase II study of tipifarnib for the treatment of HRAS mutant solid tumors, including squamous cell carcinomas of the head and neck. J Clin Oncol. 2017;35(15_suppl):TPS2618. DOI: 10.1200/JCO.2017.35.15_suppl.TPS2618

31. Rey S., Schito L., Wouters B.G., Eliasof S., Kerbel R.S. Targeting hypoxia-inducible factors for antiangiogenic cancer therapy. Trends Cancer. 2017;3(7):529–41. DOI: 10.1016/j.trecan.2017.05.002

32. Dicitore A., Grassi E.S., Caraglia M., Borghi M.O., Gaudenzi G., Hofland L.J., et al. The cAMP analogs have potent anti-proliferative effects on medullary thyroid cancer cell lines. Endocrine. 2016;51(1):101–12. DOI: 10.1007/s12020-015-0597-7