Valproic Acid, a Histone Deacetylase Inhibitor, in Combination with Paclitaxel for Anaplastic Thyroid Cancer: Results of a Multicenter Randomized Controlled Phase II/III Trial.

Maria Graziella Catalano,Enrico Brignardello,Mariateresa Pugliese,Fabio Orlandi,Marco Gallo,Alessandro Piovesan,Paolo Piero Limone,Emanuela Arvat,Paola Milla,Giuseppe Boccuzzi

doi:10.1155/2016/2930414

Abstract

Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered with EudraCT 2008-005221-11.

Highlights

Anaplastic thyroid cancer (ATC) is one of the most lethal solid tumors and it usually has a rapidly fatal clinical course, its median survival being less than 5 months from diagnosis
Chemotherapy can be harmful in older patients, like those typically affected by ATC [8], and a dose reduction due to hematological and neurological toxicity is often necessary; its use may be cumbersome in the clinical practice
These findings provided the rationale for the present randomized, controlled, phase II/III, multicenter clinical trial with the aim of assessing the efficacy and safety of TAX with or without valproic acid (VPA) for the treatment of patients affected by ATC

Summary

Introduction

Anaplastic thyroid cancer (ATC) is one of the most lethal solid tumors and it usually has a rapidly fatal clinical course, its median survival being less than 5 months from diagnosis. Belinostat (PXD101) represses thyroid cancer proliferation and exerts synergistic effects in combination with doxorubicin and paclitaxel [13] In both in vitro and in vivo models of ATC, panobinostat (LBH589) has shown cytotoxic activity [14], suppressing migration and invasion [15] and inducing radioiodine cytotoxicity [16]. We previously demonstrated that the DCI valproic acid (VPA) efficiently potentiates the effects of doxorubicin [18] and paclitaxel (TAX) in vitro [19] These findings provided the rationale for the present randomized, controlled, phase II/III, multicenter clinical trial with the aim of assessing the efficacy and safety of TAX with (experimental arm) or without VPA (control arm) for the treatment of patients affected by ATC

Methods

Results

Conclusion