Confounding by alcohol use: benzodiazepines and risk of liver cancer.

In their case–control study of benzodiazepines and risk of cancer, Pottegard et al. 1 found an association with cancer of the liver (adjusted odds ratio 1.81 (95% confidence interval (CI) 1.18, 2.80), which they attributed to likely uncontrolled confounding by lifestyle factors, particularly alcohol use. Heavy alcohol use can lead to cirrhosis of the liver which is a known strong risk factor for liver cancer 2. In our case–control screening of pharmaceuticals and cancer risk in the Kaiser Permanente Medical Care Program in northern California (KPNC) 3 with follow-up extended further, through February 2008, we found associations of some benzodiazepines with liver cancer of similar magnitude, two statistically significant and one of borderline significance. For three or more prescriptions dispensed vs. none odds ratios (95% CIs) were diazepam 1.43 (1.08, 1.90), temazepam 1.55 (1.16, 2.07) and oxazepam 1.60 (0.95, 2.68). We attempted to control for alcohol use but the stored medical record data proved to be inadequate for this purpose. We did find evidence, however, to support the view that alcohol use could be an important confounder in the benzodiazepine/liver cancer association. Member Health Surveys 4 are conducted among random samples of the KPNC membership approximately every 3 years starting in 1993, the latest in 2012. Respondents have been asked whether they had a ‘problem with alcohol or drugs’ ‘during the past 12 months’ and ‘ever’. Of the 85 321 respondents to any survey, age 50 years and above, free of pre-existing cancer, 2097 (2.46%) reported the alcohol/drug problem in either period and 125 (0.15%) developed liver cancer. In Cox proportional hazards analysis, with follow-up through 2013 in the KPNC Cancer Registry and excluding persons under age 50 years or with pre-existing cancer the hazard ratio for developing liver cancer in persons who reported the alcohol/drug problem in either period compared with persons who did not was 5.67 (95% CI 3.02, 10.66). Approximately half of persons who have attended the Program's chemical dependency clinic were diagnosed with either alcohol dependence or alcohol abuse, but it is not clear whether clinic attenders are representative of survey responders or how much drug use, especially if intravenous, was responsible for the increased risk of liver cancer through infection with hepatitis B or C. If alcohol was responsible for more than half of the increased risk, its hazard ratio would be higher than 5.67. Searching records of pharmacy prescription dispensing also revealed an association of the alcohol/drug problem with use of benzodiazepines. Of the 13 438 survey respondents age 40 years and above in 2008, 41.74% of the 690 persons with the alcohol/drug problem received diazepam, oxazepam or temazepam vs. 22.96% of those not reporting the ‘problem’ (P = 0.0003). Since heavy alcohol use is associated with both benzodiazepine use and liver cancer, it is a likely confounder of the benzodiazepine/liver cancer association. Our data are not sufficiently precise and specific to allow us to determine the extent of the confounding. Ths work was supported by Grant R01 098838 from The National Cancer Institute.