Study V did not show any clear association between menopausal hormone therapy and biliary tract cancer and there was no clear difference between hormone regimens. Yet, a non-
significant, protective effect against gallbladder cancer was suggested. In addition, the study could confirm the previously reported increased risk of gallstone disease in women exposed to menopausal hormone therapy.
Some previous studies have reported a positive association between menopausal hormone therapy and biliary tract cancer, whereas others have found opposite results. However, the studies that indicated an increased risk did not adjust for gallstone disease and it is unclear how cholecystectomy was handled in the studies. (149, 150) It is possible that gallstone disease influenced the results in those studies. One study, where adjustment for gallstone disease was performed, indicated a borderline reduced risk of gallbladder cancer specifically, similar to what was seen in this study.(145) Some of the older studies did not differentiate between biliary tract and liver cancer, making comparison to the present study
inappropriate.(151, 153)
Study V adjusted for some potentially important confounding factors such as age, diabetes, and prior hysterectomy. Furthermore, the study was analyzed using two different approaches and the results were similar, strengthening the reliability of the observations. The matched cohort was constructed in an effort to account for unmeasured factors, such as dietary patterns and other lifestyle factors, that may be similar in women with other similarities. The
unmatched approach using survival analyses was employed in parallel to verify the observed associations.
Gallstone disease was accounted for to assess any influence of menopausal hormone therapy on the risk of biliary tract cancer without the gallstone mediated pathway. The increased risk of gallstone disease in women exposed to hormone therapy is well documented.(135)
Furthermore, obesity is also associated with gallstone disease.(188) However, obesity may also be more prevalent in women using menopausal hormones compared to women who do not.(189) Even though the matched cohort design was employed to address an influence of unmeasured potentially confounding factors, the study may not reliably account for life style factors such as obesity, dietary pattern etc. and residual confounding cannot, therefore, be completely ruled out. Based on the results of the present study and the results of the previous
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literature, there is insufficient data to support the hypothesis that menopausal hormone therapy increases the risk of biliary tract cancer.
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CONCLUSIONS
• A substantial proportion of biliary tract cancers are not reported to the Swedish Cancer Register. The under-reporting increases with increasing patient age and later time period.
• The decreasing incidence trend of biliary tract cancer in Sweden is likely over- estimated.
• Reproductive factors are associated with biliary tract cancer in both women and men and a hormonal mechanism in biliary tract cancer is thus not supported. A role of sex hormone exposure in gallbladder cancer etiology specifically cannot be ruled out.
• Men with prostate cancer might have a generally decreased risk of biliary tract cancer, but any potential risk increase in indivuduals with prolonged estrogen exposure seems to be small. Further reserach is needed to investigate a protective effect of estrogen exposure on the development of biliary tract cancer in men.
• Menopasusal hormone therapy does not seem to increase the risk of biliary tract cancer in women.
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FUTURE RESEARCH
The incidence and time trends of any cancer are important to correctly understand the disease and to help guide future research. Furthermore, the robustness of academic research based on a register will always depend on the quality of the data. There is a great need to evaluate the Swedish health-care registers from a disease-specific point of view. This thesis shows that the elderly are less likely to be included in the Cancer Register. This raises the question as to whether this applies to other cancers as well and to what extent? One other interesting research question would be if there are differences in the rate of reporting depending on geography or type of health-care provider diagnosing the cancer. In biliary tract cancer specifically, an investigation into the correctness of diagnoses in the Patient Register would be of interest to understand to what extent the reported incidence rates are under-estimated. Concerning sex hormones and the risk of developing biliary tract cancer, there is a need for further investigations. The need to adequately distinguish between gallbladder cancer and other extra-hepatic lesions is clear, however. One general difficulty in studying endogenous sex hormones as an exposure is to assess the exposure over time. Future research should focus on how to better measure cumulative estrogen exposure over time and then use that information to investigate the risk of biliary tract cancer further. Additionally, to approach the problem from another angle, investigations of biliary tract cancer risk in hormone deficient subjects such as women subjected to oophorectomy/hysterectomy (removal of the
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