title: Clinical, safety, and economic evidence in radioactive iodine-refractory differentiated thyroid cancer: a systematic literature review.
abstract: BACKGROUND
  Thyroid cancer is the most common endocrine malignancy, with differentiated thyroid cancer (DTC) comprising ~93% of all thyroid cancers. While most cases of DTC are curable with the use of surgery and radioactive iodine (RAI) ablation of the remaining thyroid remnant, prognosis is dire and treatment options limited when DTC becomes RAI-refractory (RAI-R). Standard cytotoxic chemotherapy has limited efficacy, making enrollment in clinical trials of novel targeted therapies the preferred treatment approach. Thus, we conducted a comprehensive systematic review of the clinical trial scientific literature with a focus on efficacy, safety, and economics to identify all potential treatment options that have been or are currently being evaluated for the treatment of RAI-R DTC.
  
  
  METHODS
  Embase.com (including Medline), Medline In-Process and other nonindexed citations, the Cochrane Libraries, ClinicalTrials.gov, and relevant recent conference proceedings were searched using predefined search criteria. Important inclusion criteria included English language, randomized controlled studies or interventional single-arm studies only, and studies of drug therapies only. Search results were screened utilizing the discretion of multiple researchers, and key data were abstracted.
  
  
  RESULTS
  Forty-five unique trials (16 full-text, 4 conference abstracts, and 25 ClinicalTrials.gov entries) were included in the clinical review. No studies that met criteria for inclusion in the economic review were identified. Among 20 trials with results available, all were Phase II and only one was randomized. The most commonly studied drugs were tyrosine kinase inhibitors (TKIs); other drugs included celecoxib, doxorubicin with interferon alpha-2b, rosiglitazone, selumetinib (AZD6244), thalidomide, VEGF trap, and vorinostat. Overall, efficacy and safety profiles were specific to treatment regimen, with objective response rates (ORR) ranging from 0% on gefitinib, rosiglitazone, VEGF trap, and vorinostat to 50% on lenvatinib, a TKI.
  
  
  CONCLUSIONS
  Limited clinical research and no economic research has been conducted in RAI-R DTC. Certain treatments, notably TKIs, have shown promise in Phase II trials, and two Phase III randomized placebo-controlled trials are ongoing. New research on the economic and humanistic burden of RAI-R DTC must be paired with the clinical evidence currently in development to examine the existing burden and future promise in treating patients with RAI-R DTC.
authors.affiliation: Department of Public Health Sciences, Penn State College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, USA.
authors.forename: Roger T
authors.initials: RT
authors.lastname: Anderson
authors.forename: John E
authors.initials: JE
authors.lastname: Linnehan
authors.forename: Vanita
authors.initials: V
authors.lastname: Tongbram
authors.forename: Karen
authors.initials: K
authors.lastname: Keating
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Wirth
mesh_terms: D002986:Clinical Trials as Topic / Q000191:economics; D003362:Cost-Benefit Analysis; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D013964:Thyroid Neoplasms / Q000191:economics / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors