title: Thyroid Dysfunction in Patients with Metastatic Carcinoma Treated with Sunitinib: Is Thyroid Autoimmunity Involved?
abstract: BACKGROUND
  Sunitinib is a tyrosine kinase inhibitor (TKI) inducing thyroid dysfunction, but the precise mechanism(s) involved remains to be explained, including the role of thyroid autoimmunity. The objective of this study was to evaluate thyroid function, parameters of autoimmunity, and thyroid ultrasound findings in patients with metastatic cancer and normal thyroid function/autoimmunity before the initiation of sunitinib therapy. This was a prospective, observational cohort study.
  
  
  METHODS
  Twenty-seven patients with metastatic carcinomas at comparable tumor stages were evaluated over 12-18 months after initiating therapy with sunitinib given at a daily oral dose of 50 mg for four weeks (ON), followed by one to two weeks off therapy (OFF). Serum thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3), and antithyroglobulin (TgAb), and antithyroid peroxidase (TPOAb) autoantibodies were measured in all cases. Thyroid morphology and volume were evaluated by echo-color Doppler ultrasound.
  
  
  RESULTS
  A total of 16/27 patients (60%) became hypothyroid (TSH range 7-114 mIU/L) within 30-120 days of therapy. The thyroid volume decreased in 24/27 (89%) patients (from M = 14.6 mL, SD = 6.4 mL to M = 3.8 mL, SD = 2.6 mL after 12 months; p < 0.001), together with the appearance of mild to severe hypoechogenicity. TPOAb (40-3000 IU/mL) became detectable in 7/27 (25%) patients, and TPOAb-positive patients displayed a higher degree of hypothyroidism and volume reduction. The progression-free survival (PFS) was significantly longer in patients developing TPOAb (10.8 months) than in the other group of patients (5.8 months).
  
  
  CONCLUSIONS
  These data confirm the thyroid inhibitory effect of sunitinib, in keeping with the key role of kinases in controlling thyroid function and growth. However, the novel appearance of TPOAb in a subgroup of patients with more severe hypothyroidism and longer survival indicates that sunitinib may also trigger/exacerbate thyroid autoimmunity contributing to thyroid failure. The development of TPOAb was associated with a longer PFS.
authors.affiliation: 1 Endocrinology Unit, University of Cagliari , Cagliari, Italy .
authors.forename: Fabiana
authors.initials: F
authors.lastname: Pani
authors.affiliation: 2 Medical Oncology Unit, Department of Medical Sciences, University of Cagliari , Cagliari, Italy .
authors.forename: Francesco
authors.initials: F
authors.lastname: Atzori
authors.affiliation: 1 Endocrinology Unit, University of Cagliari , Cagliari, Italy .
authors.forename: Germana
authors.initials: G
authors.lastname: Baghino
authors.affiliation: 1 Endocrinology Unit, University of Cagliari , Cagliari, Italy .
authors.forename: Francesco
authors.initials: F
authors.lastname: Boi
authors.affiliation: 3 Medical Oncology, Businco Hospital , Cagliari, Italy .
authors.forename: Luciana
authors.initials: L
authors.lastname: Tanca
authors.affiliation: 2 Medical Oncology Unit, Department of Medical Sciences, University of Cagliari , Cagliari, Italy .
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ionta
authors.affiliation: 1 Endocrinology Unit, University of Cagliari , Cagliari, Italy .
authors.forename: Stefano
authors.initials: S
authors.lastname: Mariotti
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011758:Pyrroles / Q000009:adverse effects* / Q000627:therapeutic use; D000077210:Sunitinib; D013954:Thyroglobulin / Q000276:immunology; D013959:Thyroid Diseases / Q000097:blood / Q000139:chemically induced* / Q000276:immunology; D013960:Thyroid Function Tests; D013961:Thyroid Gland / Q000276:immunology* / Q000473:pathology; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D001323:Autoantibodies; D007211:Indoles; D011758:Pyrroles; C006606:anti-thyroglobulin; D014284:Triiodothyronine; D013972:Thyrotropin; D013954:Thyroglobulin; D013974:Thyroxine; D000077210:Sunitinib