Cancer Risk in Long-term Users of Valproate: A Population-Based Case-Control Study

Hallas, Jesper; Friis, Søren; Bjerrum, Lars; Støvring, Henrik; Narverud, Sverre Flatabø; Heyerdahl, Thomas; Grønbæk, Kirsten; Andersen, Morten

doi:10.1158/1055-9965.epi-08-0646

Cited by 31 publications

(34 citation statements)

References 27 publications

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“…Even persons who had filled a large number of prescriptions (≥20), and therefore could be assumed to have had considerable exposure to anti‐epileptic medication, had at most moderately increased cancer risks. By way of contrast, recent studies have continued to find large increases (>400%) in the risk of a number of cancers (CNS, lung, colon, prostate) associated with use of anti‐epileptic medications . However, in these studies, medication users also had epilepsy, such that the observed increases in risk cannot necessarily be attributed directly to the use of the medications in question.…”

Section: Discussionmentioning

confidence: 94%

Epilepsy, anti‐epileptic medication use and risk of cancer

Kaae

Carstensen

Wohlfahrt

et al. 2013

Intl Journal of Cancer

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Whether the powerful medications used to treat epilepsy increase the risk of cancer has been debated for decades, but until now no study could disentangle the contributions of anti-epileptic medications and epilepsy itself to cancer risk. Using a cohort comprising all Danish residents 16 years old at some point during the period 1996-2010 (>56 million person-years of follow-up) and information from national health registers, we examined associations between anti-epileptic medication use and cancer rates in persons with and without epilepsy, and between epilepsy and cancer rates in treated and untreated individuals. Associations were expressed as incidence rate ratios (IRRs) estimated using Poisson regression. Among persons without epilepsy, use of anti-epileptic medication increased the rates of most cancers little or not at all, although we observed moderately increased rates of liver, mouth and throat, and respiratory tract cancers (IRRs 1.40-1.59). In contrast, we observed strong associations between epilepsy and the rates of central nervous system and mouth and throat cancers (IRRs 2.00-3.91), and a modest association between epilepsy and the rate of respiratory tract cancers (IRRs 1.30-1.35), independent of anti-epileptic medication use. Our finding of only modest increases in cancer risk directly attributable to anti-epileptic medication use suggests that these medications may not be as strongly carcinogenic as has been feared, and that it is not primarily anti-epileptic medications that are responsible for the increased cancer risk among epileptics but another aspect of epilepsy diagnosis or treatment or an etiologic factor common to the two conditions.

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Section: Discussionmentioning

confidence: 94%

Epilepsy, anti‐epileptic medication use and risk of cancer

Kaae

Carstensen

Wohlfahrt

et al. 2013

Intl Journal of Cancer

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“…Risk reduction was only observed in patients with median VPA levels in the therapeutic range (>40uM) for seizure prevention and HDAC inhibition and only after at least 3years of use, reducing the likelihood that the conclusions were build on spurious results. The lack of effect on lung-, colon- and prostate-cancer risk is confirmed in a study from Denmark, which did not find a significant correlation between VPA use and cancer risk between VPA users and non-users, but did not specifically investigate head-and neck cancer risk 21 . A third study based on the UK General Practice Research database found no impact of VPA on total cancer incidence, but did detect an increase in colorectal cancers (HR: 3.95, 95% CI: 1.97–7.92, P = 0.001) and trends towards increased prostate cancer risks (HR: 2.15, 95% CI: 0.92–5.02, P = 0.08) and decreased breast cancer risks (HR: 0.40, 95% CI: 0.14–1.30, P = 0.08) 22 .…”

Section: Vpa In Cancer Preventionmentioning

confidence: 95%

Could valproic acid be an effective anticancer agent? The evidence so far

Brodie

Brandes

2014

Expert Review of Anticancer Therapy

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Valproic acid is an inhibitor of class I histone deacetylases. Epigenetic therapies in cancer have been focus of a keen interest and HDAC inhibitors in particular have been approved for certain types of hematologic malignancies. Valproic acid is an attractive candidate for cancer therapy due to its mechanism of action, its low cost and generally good clinical tolerability. In the following editorial we will review its role as monotherapy for cancer, its place in combination epigenetic therapy, and its role as chemosensitizer, immunomodulator and cancer preventative agent.

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“…There has been one previous epidemiologic study of VPA use and incident cancers in the Danish Cancer Registry [15] . This study showed a suggestion that breast cancer incidence may be reduced in women with VPA use, although the result was not statistically significant (0.62; 95%CI 0.21-1.76).…”

Section: Discussionmentioning

confidence: 99%

The Association of Valproic Acid and Incident Breast Cancer in a Managed Care Cohort

Hwang¹,

Shims²

2011

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information were in women without history of VPA use. Mean age at diagnosis of the cohort was 61 .8 years; mean years of prescription drug coverage was 7.4 years. Among cases, 73% of the cohort was non-hispanic white, 7.6% were African American, and 10.5% were Asian/Pacific Islander. When compared to never users, patients with at least 2 years of VPA use had an increased odds of a breast cancer diagnosis (OR 1.37; 95% Cl 1.06-1.76). This effect was only significant for HR-positive incident tumors, although the numbers of HR-negative cases was small (n=12) . These findings support that VPA use is not associated with reduction of breast cancer incidence. Moreover, we cannot exclude the possibility that VPA may be associated with a small but increased risk of HR-positive breast cancer. HDAC inhibition does not appear to be an effective or tractable strategy for breast cancer prevention .4

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Cancer Risk in Long-term Users of Valproate: A Population-Based Case-Control Study

Cited by 31 publications

References 27 publications

Epilepsy, anti‐epileptic medication use and risk of cancer

Epilepsy, anti‐epileptic medication use and risk of cancer

Could valproic acid be an effective anticancer agent? The evidence so far

The Association of Valproic Acid and Incident Breast Cancer in a Managed Care Cohort

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