Patterns of thyroid hormone levels in pediatric medullary thyroid carcinoma patients on vandetanib therapy

International Journal of Pediatric Endocrinology

Constantine A Stratakis⁴  Brigitte Widemann²  Frank Balis¹  Srivandana Akshintala²  Leigh Marcus²  Meredith Chuk²  Elizabeth Fox¹  Ninet Sinaii³  Ethan Bornstein⁴  Alexandra Gkourogianni⁴  Maya Lodish⁴ 

[1] The Children’s Hospital of Philadelphia, Colket Translational Research Building 4016, 3501 Civic Center Blvd, Philadelphia, PA 19104, USA;Pediatric Oncology Branch, National Cancer Institute, NIH BG 10-CRC RM 1-5750 10 Center Dr., Bethesda, MD 20814, USA;Epidemiology & Biostatistics, CC, NIH BG 10 RM 2 N228 10 Center Drive, Bethesda, MD 20814, USA;National Institute of Child Health & Human Development, National Institutes of Health (NIH), Building 10-CRC, room 1-3330 10 Center Drive, Bethesda, MD 20892, USA

关键词: Vandetanib;    Tyrosine kinase inhibitor (TKIs);    Medullary thyroid carcinoma (MTC);    Multiple Endocrine Neoplasia type 2 B (MEN2B);   

Others  :  1145461
DOI  :  10.1186/1687-9856-2015-3

 received in 2014-09-18, accepted in 2014-12-23,  发布年份 2015

【 摘 要 】

Background

Tyrosine kinase inhibitors (TKIs) have been associated with elevated TSH as a drug class effect. Prior studies of vandetanib in adults with medullary thyroid carcinoma (MTC) described an increase in levothyroxine (LT) requirement. We studied TSH, free T4, and LT dosing in children and adolescents enrolled in the phase I/II trial of vandetanib for medullary thyroid cancer (MTC)

Methods

Data from 13 patients with multiple endocrine neoplasia type 2B (MEN 2B) and MTC were analyzed [6 M, 7 F, median age 13.0 y (9.1-17.3)] Eleven patients (85%) had undergone prior thyroidectomy and all received single-drug therapy with vandetanib for > 6 months. Confirmed compliance with vandetanib (67–150 mg/m²/day) and LT was a necessary inclusion criterion.

Results

While on vandetanib treatment, all 11 athyerotic patients exhibited significantly increased TSH levels. The baseline TSH level was 4.37 mclU/ml (0.08 - 23.30); in comparison, the first peak TSH concentration on vandetanib was 15.70 mclU/ml (12.50 - 137.00, p = 0.0010). The median time to reach the initial peak of elevated TSH was 1.8 months (0.3 - 9.3). Free T4 levels remained within the normal reference range. An increase from a baseline LT dose of 91 mcg/m²/day (±24) to 116 mcg/m²/day (±24) was required in order to resume normative TSH levels (p = 0.00005), equal to an increase of 36.6% (±16.56) in the dosage of LT in mcg/day. For the 2 patients with intact thyroid glands, free T4 and TSH remained normal over a combined 6 patient years of follow up.

Conclusions

In our cohort of pediatric MTC patients, athyreotic patients with preexisting hypothyroidism developed increased TSH and reduced free T4 during the first few months of treatment with vandetanib, necessitating an increase in LT dosage. Additional patients with normal thyroid function before treatment and intact glands (n = 2) maintained normal thyroid function tests during treatment. Elevated TSH in athyreotic patients may be due to an indirect effect of vandetanib on the metabolism of thyroid hormone, or to altered TSH sensitivity at the pituitary. Proper recognition and management of abnormal thyroid hormone levels is critical in growing children on TKIs.

Trial registration

ClinicalTrials.gov Identifier: NCT00514046

【 授权许可】

   
2015 Lodish et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Hogan AR, Zhuge Y, Perez EA, Koniaris LG, Lew JI, Sola JE: Pediatric thyroid carcinoma: incidence and outcomes in 1753 patients. J Surg Res 2009, 156:167-72.
• [2]Kaatsch P, Steliarova-Foucher E, Crocetti E, Magnani C, Spix C, Zambon P: Time trends of cancer incidence in European children (1978–1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006, 42:1961-71.
• [3]Hundahl SA, Fleming ID, Fremgen AM, Menck HR: A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995 [see commetns]. Cancer 1998, 83:2638-48.
• [4]Roman S, Lin R, Sosa JA: Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer 2006, 107:2134-42.
• [5]Raval MV, Sturgeon C, Bentrem DJ, Elaraj DM, Stewart AK, Winchester DJ, Ko CY, Reynolds M: Influence of lymph node metastases on survival in pediatric medullary thyroid cancer. J Pediatr Surg 2010, 45:1947-54.
• [6]Rohmer V, Vidal-Trecan G, Bourdelot A, Niccoli P, Murat A, Wemeau JL, Borson-Chazot F, Schvartz C, Tabarin A, Chabre O, et al.: Prognostic factors of disease-free survival after thyroidectomy in 170 young patients with a RET germline mutation: a multicenter study of the Groupe Francais d'Etude des Tumeurs Endocrines. J Clin Endocrinol Metabol 2011, 96:E509-18.
• [7]de Groot JW, Plukker JT, Wolffenbuttel BH, Wiggers T, Sluiter WJ, Links TP: Determinants of life expectancy in medullary thyroid cancer: age does not matter. Clin Endocrinol (Oxf) 2006, 65:729-36.
• [8]Karras S, Anagnostis P, Krassas GE: Vandetanib for the treatment of thyroid cancer: an update. Expert Opin Drug Metab Toxicol 2014, 10:469-81.
• [9]Tolmachev V, Stone-Elander S, Orlova A: Radiolabelled receptor-tyrosine-kinase targeting drugs for patient stratification and monitoring of therapy response: prospects and pitfalls. Lancet Oncol 2010, 11:992-1000.
• [10]Carlomagno F, Guida T, Anaganti S, Vecchio G, Fusco A, Ryan AJ, Billaud M, Santoro M: Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene 2004, 23:6056-63.
• [11]Carlomagno F, Guida T, Anaganti S, Provitera L, Kjaer S, McDonald NQ, Ryan AJ, Santoro M: Identification of tyrosine 806 as a molecular determinant of RET kinase sensitivity to ZD6474. Endocr Relat Cancer 2009, 16:233-41.
• [12]Fox E, Widemann BC, Chuk MK, Marcus L, Aikin A, Whitcomb PO, Merino MJ, Lodish M, Dombi E, Steinberg SM, et al.: Vandetanib in Children and Adolescents with Multiple Endocrine Neoplasia Type 2B Associated Medullary Thyroid Carcinoma. Clin Cancer Res 2013, 19:4239-48.
• [13]Brown RL: Tyrosine kinase inhibitor-induced hypothyroidism: incidence, etiology, and management. Target Oncol 2011, 6:217-26.
• [14]Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei R, Jarzab B, Vasselli JR, et al.: Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 2012, 30:134-41.
• [15]Brassard M, Neraud B, Trabado S, Salenave S, Brailly-Tabard S, Borget I, Baudin E, Leboulleux S, Chanson P, Schlumberger M, Young J: Endocrine effects of the tyrosine kinase inhibitor vandetanib in patients treated for thyroid cancer. J Clin Endocrinol Metab 2011, 96:2741-9.
• [16]Lodish MB: Clinical review: kinase inhibitors: adverse effects related to the endocrine system. J Clin Endocrinol Metab 2013, 98(4):1333-42.
• [17]Torino F, Corsello SM, Longo R, Barnabei A, Gasparini G: Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol 2009, 6:219-28.
• [18]Makita N, Iiri T: Tyrosine kinase inhibitor-induced thyroid disorders: a review and hypothesis. Thyroid 2013, 23:151-9.
• [19]Robinson BG, Paz-Ares L, Krebs A, Vasselli J, Haddad R: Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Endocrinol Metabol 2010, 95:2664-71.
• [20]Brassard M, Rondeau G: Role of vandetanib in the management of medullary thyroid cancer. Biologics 2012, 6:59-66.
• [21]Ohba K, Takayama T, Matsunaga H, Matsushita A, Sasaki S, Oki Y, Ozono S, Nakamura H: Inappropriate elevation of serum thyrotropin levels in patients treated with axitinib. Thyroid 2013, 23:443-8.
• [22]Kappers MH, van Esch JH, Smedts FM, de Krijger RR, Eechoute K, Mathijssen RH, Sleijfer S, Leijten F, Danser AH, van den Meiracker AH, Visser TJ: Sunitinib-induced hypothyroidism is due to induction of type 3 deiodinase activity and thyroidal capillary regression. J Clin Endocrinol Metabol 2011, 96:3087-94.
• [23]Abdulrahman RM, Verloop H, Hoftijzer H, Verburg E, Hovens GC, Corssmit EP, Reiners C, Gelderblom H, Pereira AM, Kapiteijn E, et al.: Sorafenib-induced hypothyroidism is associated with increased type 3 deiodination. J Clin Endocrinol Metabol 2010, 95:3758-62.
• [24]De Groot J, Zonnenberg B, Plukker J, Van Der Graaf W, Links T: Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin Pharmacol Ther 2005, 78:433-8.