Oral contraceptives and liver cancer. Results of the Multicentre International Liver Tumor Study (MILTS).
Many, but not all, previous epidemiological studies indicated a greater risk of hepatocellular cancer (HCC) in women who have used combined oral contraceptives for a long period of time, but no one has analyzed this risk based upon use of different formulations. It was decided to analyze specifically the risk of OC containing cyproterone acetate (CPA) after toxicological experiments in animals found hints for a potential genotoxicity. This report describes the risk associated with ever having used combined oral contraceptives (OC) among 317 cases of primary hepatocellular cancer (HCC) in women under age 65, compared with 1060 age-matched hospital and 719 population controls in a case-control study, which was conducted in six European countries. The adjusted odds ratio (unconditional logistic regression) for ever having used any OC was found to be 0.75 (0.54 to 1.03) when all cases were compared with all controls, and compared to hospital and population controls separately: 1.13 (0.86 to 1.48) and 0.78 (0.59 to 1.03), respectively. The adjusted odds ratios for OC containing all progestins of the CPA group were 0.89 (0.49 to 1.61); and 0.89 (0.37 to 2.18) for OC containing only CPA. There was no increase in risk for HCC with increasing duration of OC use among the different groups of OCs in the total group of cases with pooled controls. The risk estimates were not related to time since first or last use of any of the types of OCs considered. The most important risk factors for HCC were confirmed as a prior history of hepatitis B and C (adjusted odds ratio 3.1 (2.2; 4.3) and 37.9 (20.2; 70.9) for HBV and HCV, respectively). In the small subgroup of HCC cases without liver cirrhosis and with negative serology for HBV and HCV, there was evidence of an association with duration of OC use. No such trend was observed for the CPA group of OCs. Altogether, there is no evidence for an increased risk of HCC associated with CPA or CPA-like OCs. Oral contraceptives in the aggregate may enhance the risk of liver carcinomas not associated with HBV or HCV infection, but if so, this is an extremely rare adverse effect of their use.