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

Maya Lodish, Alexandra Gkourogianni, Ethan Bornstein, Ninet Sinaii, Elizabeth Fox, Meredith Chuk, Leigh Marcus, Srivandana Akshintala, Frank Balis, Brigitte Widemann, Constantine A Stratakis, Maya Lodish, Alexandra Gkourogianni, Ethan Bornstein, Ninet Sinaii, Elizabeth Fox, Meredith Chuk, Leigh Marcus, Srivandana Akshintala, Frank Balis, Brigitte Widemann, Constantine A Stratakis

Abstract

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/m(2)/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/m(2)/day (±24) to 116 mcg/m(2)/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.

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

Figures

Figure 1
Figure 1
TSH levels prior to initiation of vandetanib in thyroidectomized patients compared to first peak TSH concentration on study p = 0.0010.
Figure 2
Figure 2
Free T4 levels prior to initiation of vandetanib in thyroidectomized patients compared to levels at first peak TSH concentration, p = 0.039.
Figure 3
Figure 3
Dose of LT (mcg/m2/day at baseline vs. dose required in order to resume normative TSH in thyroidectomized patients, p = (p = 0.00005).

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