Long-term use of valproic acid in US veterans is associated with a reduced risk of smoking-related cases of head and neck cancer

Abstract

Background: Epigenetic events play a major role in the carcinogenesis of tobacco-related cancers. The authors conducted a retrospective cohort study to evaluate the effects of exposure to the anticonvulsant agent valproic acid (VPA), a histone deacetylase inhibitor, on the risk of developing cancers of the lung, head and neck, prostate, bladder, and colon.

Methods: The study was based on the 2002 through 2008 National Veterans Affairs (VA) medical SAS data set linked to the VA Central Cancer Registry. The cohort was defined as subjects aged>40 years who were followed in the VA system for at least 1 year for 1 of 4 diagnoses for which a VPA indication exists (bipolar disorder, posttraumatic stress disorder, migraines, and seizures). Multivariable Cox proportional hazards models were used to estimate hazards ratios (HR) and 95% confidence intervals (95% CI) reflecting the association between use of VPA and cancer incidence.

Results: VPA use was associated with a significant reduction in the risk of cancers of the head and neck (HR, 0.66; 95% CI, 0.48-0.92). Additional associations were noted with the duration of treatment and median VPA drug levels. No significant differences in cancer incidence were observed for cancers of the lung (HR, 1.00; 95% CI, 0.84-1.19), bladder (HR, 0.86; 95% CI, 0.64-1.15), colon (HR, 0.95; 95% CI, 0.74-1.22), and prostate (HR, 0.96; 95% CI, 0.88-1.12).

Conclusions: Use of VPA is associated with a lower risk of developing head and neck cancers.

Keywords: DNA methylation; head and neck cancer; histone deacetylase (HDAC) inhibition; squamous cell carcinoma; valproic acid.

Conflict of interest statement

Conflicts of interest

None

© 2013 American Cancer Society.

Figures

Figure 1

Forrest Plot showing hazard ratio and 95% confidence intervals for the associations between VPA use and clinical scenarios. All analyses were conducted as Cox Proportional Hazard models and controlled for age, gender, race, smoking status, psychiatric disease (bipolar disorder, PTSD, schizophrenia, depression, anxiety), neurologic disease (seizures and migraines), and evidence of alcohol and substance abuse, COPD