Lack of therapeutic effect of the histone deacetylase inhibitor vorinostat in patients with metastatic radioiodine-refractory thyroid carcinoma.
BACKGROUND
Aberrant histone deacetylase activity is seen in a variety of malignancies, and histone deacetylase inhibitors such as vorinostat have been shown to induce cell death and sensitize cells to cytotoxic chemotherapy in thyroid cancer cell lines. This phase II study was undertaken to assess objective response to vorinostat in patients with advanced thyroid cancer.


METHODS
A total of 19 patients with differentiated thyroid cancer (n = 16) and medullary thyroid cancer (n = 3) were enrolled in the study. Patients received oral vorinostat at a starting dose of 200 mg twice daily, with dose adjustments allowed as necessary for toxicity. Patients were treated for 2 wk, followed by 1 wk off therapy (3-wk cycle) until disease progression or study withdrawal. Responses were measured by Response Evaluation Criteria in Solid Tumors criteria and correlated with tumor markers.


RESULTS
No patient achieved a partial or complete response. Median duration of therapy in patients with differentiated thyroid cancer was 17 wk, whereas in medullary thyroid cancer patients it was 25 wk. Reasons for termination included progression of disease by RECIST criteria (n = 7), clinical progression (n = 3), and adverse events (AEs) (n = 9). AEs were primarily grade 1-3; no clinical grade 4 or grade 5 events were observed. Clinical grade 3 AEs consisted of fatigue, dehydration, ataxia, pneumonia, bruises, and deep vein thrombosis. Severe thrombocytopenia was seen in seven patients (grade 3, n = 5; grade 4, n = 2) and was associated with minor bleeding or bruises.


CONCLUSIONS
Vorinostat at this dose and schedule is not an effective treatment for advanced thyroid cancer.
Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
Jennifer A
JA
Woyach
Richard T
RT
Kloos
Matthew D
MD
Ringel
Daria
D
Arbogast
Minden
M
Collamore
James A
JA
Zwiebel
Michael
M
Grever
Miguel
M
Villalona-Calero
Manisha H
MH
Shah
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002116:Calcitonin / Q000097:blood; D002272:Carcinoembryonic Antigen / Q000032:analysis; D018276:Carcinoma, Medullary / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D013954:Thyroglobulin / Q000097:blood; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D000077337:Vorinostat
D000970:Antineoplastic Agents; D002272:Carcinoembryonic Antigen; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007457:Iodine Radioisotopes; D000077337:Vorinostat; D002116:Calcitonin; D013954:Thyroglobulin