title: Critical role of sorafenib exposure over time for its antitumor activity in thyroid cancer.
abstract: Sorafenib, a multi-kinase inhibitor that targets the VEGF, PDGF and BRAF pathways, has demonstrated significant clinical activity in metastatic differentiated thyroid cancer. However, all patients eventually experience disease progression with a median progression-free survival close to 10 months. Since sorafenib exposure is known to decrease over time, we hypothesized that dose adjustments aiming to restore adequate exposure could lead to further clinical activity. We report, as a proof of concept on a patient with radio-iodine resistant metastatic thyroid cancer, who experienced disease progression after an initial response to sorafenib (400 mg twice daily). Whereas the thyroglobulin-progression-free survival at standard doses was 6 months, iterative dose optimization led to a prolonged progression-free survival up to 41 months. Sorafenib doses were increased up to 1600 mg bid, in order to maintain clinical activity, and to restore active plasma concentration, since sorafenib exposure had decreased over the time. Toxicity was mild and manageable for more than 2 years. However, the patient eventually experienced grade 3 proteinuria leading to treatment discontinuation. This observation opens up new horizons for daily management of radioactive iodine-refractory differentiated thyroid cancer patients progressing under standard doses of sorafenib, and stress the need to monitor its plasma concentration.
authors.affiliation: CERIA, Centre for Research on Angiogenesis Inhibitors, Department of Medical Oncology, Cochin Teaching Hospital, AP-HP, Université Paris Descartes, 27, rue du faubourg Saint Jacques, 75014, Paris, France, audreybellesoeur@gmail.com.
authors.forename: Audrey
authors.initials: A
authors.lastname: Bellesoeur
authors.forename: Edith
authors.initials: E
authors.lastname: Carton
authors.forename: Olivier
authors.initials: O
authors.lastname: Mir
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
authors.forename: Benoit
authors.initials: B
authors.lastname: Blanchet
authors.forename: Bertrand
authors.initials: B
authors.lastname: Billemont
authors.forename: Jérôme
authors.initials: J
authors.lastname: Clerc
authors.forename: François
authors.initials: F
authors.lastname: Goldwasser
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D000077157:Sorafenib; D013954:Thyroglobulin / Q000097:blood; D013964:Thyroid Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D013954:Thyroglobulin; D000077157:Sorafenib