title: Patterns of thyroid hormone levels in pediatric medullary thyroid carcinoma patients on vandetanib therapy.
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.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT00514046.
authors.affiliation: 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.
authors.forename: Maya
authors.initials: M
authors.lastname: Lodish
authors.affiliation: 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.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gkourogianni
authors.affiliation: 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.
authors.forename: Ethan
authors.initials: E
authors.lastname: Bornstein
authors.affiliation: Epidemiology & Biostatistics, CC, NIH BG 10 RM 2 N228 10 Center Drive, Bethesda, MD 20814 USA.
authors.forename: Ninet
authors.initials: N
authors.lastname: Sinaii
authors.affiliation: The Children's Hospital of Philadelphia, Colket Translational Research Building 4016, 3501 Civic Center Blvd, Philadelphia, PA 19104 USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, NIH BG 10-CRC RM 1-5750 10 Center Dr., Bethesda, MD 20814 USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Chuk
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, NIH BG 10-CRC RM 1-5750 10 Center Dr., Bethesda, MD 20814 USA.
authors.forename: Leigh
authors.initials: L
authors.lastname: Marcus
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, NIH BG 10-CRC RM 1-5750 10 Center Dr., Bethesda, MD 20814 USA.
authors.forename: Srivandana
authors.initials: S
authors.lastname: Akshintala
authors.affiliation: The Children's Hospital of Philadelphia, Colket Translational Research Building 4016, 3501 Civic Center Blvd, Philadelphia, PA 19104 USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Balis
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, NIH BG 10-CRC RM 1-5750 10 Center Dr., Bethesda, MD 20814 USA.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Widemann
authors.affiliation: 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.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
keywords: Medullary thyroid carcinoma (MTC); Multiple Endocrine Neoplasia type 2 B (MEN2B); Tyrosine kinase inhibitor (TKIs); Vandetanib