BACKGROUND: Currently, there is no standard treatment for metastatic anaplastic thyroid cancer (ATC). DNA microarray analysis has shown platelet-dervived growth factor receptor (PDGFR) overexpression in ATC relative to well-differentiated thyroid cancer. In p53-mutated/deficient ATC cell lines, cABL is overexpressed, and selective inhibition of cABL results in a cytostatic effect. Imatinib inhibits tyrosine kinase activity of Bcr-ABL and PDGF. We hypothesize that patients with ATC that over-expresses PDGF receptors or cABL will respond to imatinib. METHODS: Patients with histologically confirmed ATC who had measurable disease and whose disease expressed PDGF receptors by immunohistochemistry were eligible for study. Imatinib was administered at 400 mg orally twice daily without drug holiday. Response to treatment was assessed every 8 weeks. Patients with complete response, partial responses, or stable disease were treated until disease progression. The study was terminated early due to poor accrual. RESULTS: From February 2004 to May 2007, 11 patients were enrolled and were started on imatinib. At baseline, 4/11 had locoregional disease, 5/11 had distant metastases, and 2/11 had both. Nine of 11 had prior chemoradiation, and 7/11 had thyroidectomy. Eight of 11 were evaluable for response; 4 were excluded for lack of follow-up with radiologic evaluation. The overall response rates at 8 weeks were complete response 0/8, partial response 2/8, and stable disease 4/8. The median time to follow-up was 26 months (ranges 23-30 months). The rate of 6-month progression-free survival was 36% (95% confidence interval, 9%-65%). The rate of 6-month overall survival was 45% (95% confidence interval, 16%-70%). The most common grade 3 toxicity was edema in 25%; other grade 3 toxicities included fatigue and hyponatremia (12.5% each). There were no grade 4 toxicities or treatment related deaths. CONCLUSIONS: Imatinib appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing patients with a rare malignancy at a single institution, further investigation of imatinib in ATC may be warranted in a multi-institutional setting.
BACKGROUND: Currently, there is no standard treatment for metastatic anaplastic thyroid cancer (ATC). DNA microarray analysis has shown platelet-dervived growth factor receptor (PDGFR) overexpression in ATC relative to well-differentiated thyroid cancer. In p53-mutated/deficient ATC cell lines, cABL is overexpressed, and selective inhibition of cABL results in a cytostatic effect. Imatinib inhibits tyrosine kinase activity of Bcr-ABL and PDGF. We hypothesize that patients with ATC that over-expresses PDGF receptors or cABL will respond to imatinib. METHODS:Patients with histologically confirmed ATC who had measurable disease and whose disease expressed PDGF receptors by immunohistochemistry were eligible for study. Imatinib was administered at 400 mg orally twice daily without drug holiday. Response to treatment was assessed every 8 weeks. Patients with complete response, partial responses, or stable disease were treated until disease progression. The study was terminated early due to poor accrual. RESULTS: From February 2004 to May 2007, 11 patients were enrolled and were started on imatinib. At baseline, 4/11 had locoregional disease, 5/11 had distant metastases, and 2/11 had both. Nine of 11 had prior chemoradiation, and 7/11 had thyroidectomy. Eight of 11 were evaluable for response; 4 were excluded for lack of follow-up with radiologic evaluation. The overall response rates at 8 weeks were complete response 0/8, partial response 2/8, and stable disease 4/8. The median time to follow-up was 26 months (ranges 23-30 months). The rate of 6-month progression-free survival was 36% (95% confidence interval, 9%-65%). The rate of 6-month overall survival was 45% (95% confidence interval, 16%-70%). The most common grade 3 toxicity was edema in 25%; other grade 3 toxicities included fatigue and hyponatremia (12.5% each). There were no grade 4 toxicities or treatment related deaths. CONCLUSIONS:Imatinib appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing patients with a rare malignancy at a single institution, further investigation of imatinib in ATC may be warranted in a multi-institutional setting.
Authors: Keith C Bible; Vera J Suman; Michael E Menefee; Robert C Smallridge; Julian R Molina; William J Maples; Nina J Karlin; Anne M Traynor; Priya Kumar; Boon Cher Goh; Wan-Teck Lim; Ayoko R Bossou; Crescent R Isham; Kevin P Webster; Andrea K Kukla; Carolyn Bieber; Jill K Burton; Pamela Harris; Charles Erlichman Journal: J Clin Endocrinol Metab Date: 2012-07-06 Impact factor: 5.958
Authors: Robert I Haddad; William M Lydiatt; Douglas W Ball; Naifa Lamki Busaidy; David Byrd; Glenda Callender; Paxton Dickson; Quan-Yang Duh; Hormoz Ehya; Megan Haymart; Carl Hoh; Jason P Hunt; Andrei Iagaru; Fouad Kandeel; Peter Kopp; Dominick M Lamonica; Judith C McCaffrey; Jeffrey F Moley; Lee Parks; Christopher D Raeburn; John A Ridge; Matthew D Ringel; Randall P Scheri; Jatin P Shah; Robert C Smallridge; Cord Sturgeon; Thomas N Wang; Lori J Wirth; Karin G Hoffmann; Miranda Hughes Journal: J Natl Compr Canc Netw Date: 2015-09 Impact factor: 11.908
Authors: R C Smallridge; J A Copland; M S Brose; J T Wadsworth; Y Houvras; M E Menefee; K C Bible; M H Shah; A W Gramza; J P Klopper; L A Marlow; M G Heckman; R Von Roemeling Journal: J Clin Endocrinol Metab Date: 2013-04-15 Impact factor: 5.958