Patterns of Thyroid Hormone Levels in Athyrotic Pediatric Medullary Thyroid Carcinoma Patients on Vandetanib Therapy

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 471-496-Thyroid Neoplasia & Case Reports
Clinical
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-496
Maya Beth Lodish*1, Ethan Bornstein1, Ninet Sinaii2, Elizabeth Fox3, Meredith Chuk4, Leigh Marcus5, Akshintala Srivandana5, Patricia Whitcomb6, Alberta Aikin6, Frank Balis3, Brigitte Widemann5 and Constantine A Stratakis7
1National Institutes of Health (NIH), 2National Institutes of Health, Bethesda, MD, 3The Children’s Hospital of Philadelphia, 4The Children’s Hospital of Pittsburgh, 5National Cancer Institute, 6NCI, 7NIH
Objective: Tyrosine kinase inhibitors (TKIs) have been associated with elevated TSH as a drug class effect (1). Prior studies of vandetanib (VD) in adults with medullary thyroid carcinoma (MTC) described an increase in levothyroxine (LT) requirement (2,3). We studied TSH, free T4, and LT dosing in children and adolescents enrolled in the phase I/II trial of VD for Multiple Endocrine Neoplasia Type 2B (MEN 2B) and MTC., NCT00514046.  

Methods: Data from 11 patients with MEN 2B and MTC were analyzed (5 M, 6 F, median age 12.8 y (9.1-17.3). Patients had undergone thyroidectomy and received single-drug therapy with VD for >6 months. Confirmed compliance with VD (67 -150 mg/m2/day) and LT was a necessary inclusion criterion. 1 patient was excluded due to LT non-compliance. Data were analyzed using paired t-tests for normally distributed data and the Wilcoxon signed rank test for non-parametric data and are reported as mean (±SD) or median (range).

Results: While on VD treatment, all 11 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 VD was 15.70 mclU/ml (12.50 - 137.00, p = 0.0010). The median time it took to reach the first peak of elevated TSH was 1.8 months (0.3 - 9.3). Free T4 levels remained within the normal reference range, yet significantly decreased from baseline levels of 1.47 ng/dL (±0.21) to 1.27 ng/dL (±0.30) when measured at the time of maximum TSH (p = 0.039). TSH levels normalized after subsequent increases in LT doses. An increase from a baseline LT dose of 3.21 mcg/kg/day (±0.77) to 3.99 mcg/kg/day (±0.66) was required in order to resume normative TSH levels (p = 0.0003), equal to an increase of 36.6% (±16.56) in the dosage of LT in mcg/day.

Conclusions: In our cohort of pediatric MTC patients, athyrotic patients with preexisting hypothyroidism developed increased TSH and reduced T4 during the first few months of treatment with VD, necessitating an increase in LT dosage. The 2 patients with normal pretreatment thyroid functions and intact glands showed minimal change in TFTs. Elevated TSH in athyrotic patients may be due to an indirect effect of VD on the metabolism of thyroid hormone, or with thyroid hormone action at the pituitary level. Proper recognition and management of abnormal thyroid hormone levels is critical in growing children on TKIs.

(1)Brown RL 2011 Tyrosine kinase inhibitor-induced hypothyroidism: incidence, etiology, and management. Target Oncol. 6:217-26.    (2) Wells SA, Jr., Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei R, Jarzab B, Vasselli JR, Read J, Langmuir P, Ryan AJ, Schlumberger MJ 2012 Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 30:134-141 (3) Brassard, M., Neraud, B., Trabado, S., Salenave, S., Brailly-Tabard, S., Borget, I., Baudin, E., Leboulleux, S., Chanson, P., Schlumberger, M., et al. 2011. Endocrine effects of the tyrosine kinase inhibitor vandetanib in patients treated for thyroid cancer. The Journal of clinical endocrinology and metabolism 96:2741-2749.

Nothing to Disclose: MBL, EB, NS, EF, MC, LM, AS, PW, AA, FB, BW, CAS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This research was conducted with support from the Intramural Research Division of Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Cancer Institute, and the Investigator-Sponsored Study Program of AstraZeneca, Wilmington, DE
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