Correlation Between Valproic Acid Exposure And Cancer Risk In The Population With Epilepsy

ObjectivesEpilepsy is a chronic brain disease caused by a variety of reasons.It occurs in people of any age,region or ethnicity.However,the incidence of epilepsy in children and adolescents is relatively higher.The incidence of epilepsy in the elderly has increased in recent years.Epilepsy is a global health problem.Long-term frequent seizures have a serious impact on the patient's body,mind,and intelligence,or even threaten the life and health of patients,placing a heavy burden on patients and their families.Antiepileptic drugs(AEDs)are still the most basic and important means in treatment of epilepsy.Epilepsy patients need to take them for a long time,sometimes for life.Valproic acid(VPA),carbamazepine(CBZ),Phenobarbital(PB)and phenytoin(PHT)are the most common AEDs now.As a commonly used broad-spectrum AEDs,VPA has a good effect on the absence seizures,partial seizures and generalized seizures of epilepsy.It has the characteristics of high oral availability,mild side effects and low cost.Also it can be used for the treatment of bipolar disorder,migraine and so on.VPA,as a representative drug of short-chain fatty acid in HDACis,has been reported in a number of literature.Studies in vitro have shown that VPA could exert a function of HD AC inhibition at a concentration range of 0.5-3 mM.Experiments in cells and animals prove that VPA can inhibit the growth of a variety of the malignant tumors,induce the differentiation and apoptosis of tumor cells.Preliminary clinical evidence shows that VPA could be a drug that eventually be used in combination chemotherapies,either with classical cytotoxics,other molecular-targeted drugs or radiation in a number of solid tumors.What' s more,in several studies aimed to explore the correlation between the VPA exposure and cancer risk based on the large population,some results suggest that VPA may have a role in reducing the risk of cancer.This study conducted a retrospective cohort analysis on the data of the residents' medical insurance payment system of the Shandong Multi-Center Healthcare Big-Data Platform to explore the correlation between VPA exposure and cancer risk,and then determines whether VPA has the effect of reducing the risk of cancer.MethodsThe population of epilepsy from 2012 to 2017 was collected from Shandong Multi-Center Healthcare Big-Data Platform.The diagnosis time of epilepsy was based on the time of the first diagnosis of epilepsy in the consultation information table.According to the presence of VPA exposure in the epileptic population,objects were divided into an exposed group and a non-exposed group.The initial exposure time of VPA in the exposed group was based on the earliest prescription record time of VPA in the medical insurance cost detail information table.And the next step was to determine the cancer diagnosis of the two groups of people and the diagnosis time.The cancer diagnosis in this study was set to the occurrence of any type of cancer,and the cancer diagnosis time was based on the time when the cancer diagnosis first appears in the consultation information table.The VPA exposure group screened out the patients whose VPA initial exposure time was earlier than the cancer diagnosis;the non-exposure group screened out the patients whose epilepsy diagnosis time was earlier than the cancer diagnosis.Gender,age,charlson comorbidity index(CCI),chronic obstructive pulmonary disease(COPD),alcohol-related diseases,long-term CBZ exposure,long-term PB exposure,and long-term PHT exposure,a total of 8 covariates that may affect the risk of cancer were included in this study.The age was calculated based on the year of 2017;the diseases and weights included in CCI were defined by the updated content by Quan et.al;the long-term exposure of CBZ,PB and PHT were defined as the duration of drug exposure above 100 days(including 100 days).Total incidence of cancer in VPA exposed and unexposed group were analyzed,the RR was calculated,too;The Cox model was used to analyze the HR after adjusting the 8 covariates between VPA exposed and non-exposed groups;The linear trend test of total incidence of cancer and the duration of VPA exposure was conducted.The duration of VPA exposure was defined as a period between the last record of VPA prescription and the first prescription;and then the linear trend test of total incidence of cancer and VPA prescription dose was conducted,too.VPA prescription dose was expressed by its prescription quantity.On the basis of grouping analysis of exposure time and VPA dose,the population with high exposure dose of VPA exposure D?100 and PD?10 was screened and the linear trend test were conducted,too.Then,correlation between cancer risk and the duration or prescription dose of VPA exposure were analyzed.Results1.Baseline demographics in VPA exposed and unexposed population with epilepsyThere were 3107 people with epilepsy in the big data platform from 2012 to 2017,and 3021 people were obtained after screening,among which 1233 were VPA exposed and 1788 were unexposed.The proportion of VPA exposure was 40.81%.Differences in gender,age,CCI,proportion of patients with COPD,proportion of patients with alcohol-related diseases,and proportion of PB long-term exposure were statistically significant(P<0.05).2.Total incidence of cancer in VPA exposed and unexposed groupsA total of 50 people were diagnosed with cancer in 3021 people with epilepsy.27 and 23 people in relative two groups were diagnosed with cancer during this period.The total incidence of cancer in two groups were 9.68/1000(6.03-13.33/1000)person-years,5.70/1000(3.37-8.03/1000)person-years,respectively.The adjusted RR was 1.46(0.85-2.53),suggesting that there was no statistically significant difference in the total incidence of cancer between VPA exposure and non-exposure groups(P=0.173).3.Cancer risk in VPA exposed and unexposed groups with Cox modelAfter adjusting gender,age,CCI,COPD,alcohol-related diseases,long-term CBZ exposure,long-term PB exposure,and long-term PHT exposure,a total of 50 outcome events occurred in the Cox model,including 27 in the VPA exposed group and 23 in the non-exposed group.The adjusted HR was 1.40(0.80-2.53),suggesting that there was no statistically significant difference in cancer risk between the exposed group and the non-exposed groups(P=0.224).4.Linear trend test between total incidence of cancer and the duration of VPA exposureThe linear trend test between total incidence of cancer and the duration of VPA exposure divided the exposure duration into four groups:D<100(including those who have only one day to take medication),100-399,400-799,and D?800.The results of original group and the results after excluding those who only took medicine for one day did not find that the total incidence of cancer was linearly related to the duration of exposure(P=0.134,P=0.932).5.Linear trend test between total incidence of cancer and the duration of VPA exposure for the population with a higher VPA exposureFor the population with a higher VPA exposure(D?100 and PD?10),the total incidence of cancer decreased with the increase of the duration of VPA exposure after grouping and there was a significant difference(P=0.031).It was suggested that in the population with a higher exposure,total incidence of cancer was significantly negatively correlated with the duration of VPA exposure.6.Correlation between cancer risk and the duration of VPA exposure for the population with a higher VPA exposureFor the population with a higher VPA exposure whose median exposure was 831.50 days,the adjusted HR was 0.52(0.18-1.47),although there was no significant negative correlation between cancer risk and the duration of VPA exposure(P=0.217),the cancer risk in the D?831.50 group had a tendency to decrease,compared with the D<831.50 group.7.Linear trend test between total incidence of cancer and the VPA prescription dose for the population with a higher VPA exposureLinear trend test between total incidence of cancer and the VPA prescription dose for the population with a higher VPA exposure used 10 days as the average interval between two prescriptions,dividing prescription dose groups into 10-39,40-79 and PD?80 group.After examination,the total incidence of cancer was not found to decrease sequentially with the increase of the VPA prescription dose(P=0.198).8.Correlation between cancer risk and the prescription dose of VPA for the population with a higher VPA exposureFor the population with a higher VPA exposure whose median prescription dose was 34,the adjusted HR was 0.97(0.36-2.61),suggesting that there was no statistically significant difference in cancer risk between the two groups(P=0.957).Conclusions1.The results of this study dosen't support that VPA has a role in reducing the cancer risk in people with epilepsy.2.For the population with a higher VPA exposure(D?100 and PD?10),the cancer risk tends to decreased with the increase of the duration of VPA exposure.3.Exploring that VPA can reduce the cancer risk epileptic population requires further studies in a larger population.