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thesis
Ovarian
cancer has a poor prognosis because the disease in the majority of
patients is diagnosed at an advanced stage as a result of nonspecific
symptoms and lack of efficient screening methods. Because of the poor
prognosis of ovarian cancer and the challenge of early detection of the
disease, identification of protective factors is important. It has been
suggested that some commonly used drugs may have a protective effect
against cancer, including ovarian cancer; however, the literature on
chemopreventive measures for ovarian cancer is sparse and the results
are inconclusive. Most previous studies have substantial methodological
constraints, including limited study size and self-reporting of drug
use, which introduces potential recall bias and misclassification. This
PhD thesis includes a nationwide case-control study to evaluate
associations between use of drugs with potential chemopreventive
properties and risk of epithelial ovarian cancer. The study is nested in
the entire Danish female population using data from the following
nationwide registries: the Danish Cancer Registry, the Danish Civil
Registration System, the Danish Prescription Registry, the Danish
National Patient Register, and registries in Statistics Denmark on
fertility, education, and income. Information from the included
registries is linked by use of the unique personal identification number
assigned to all Danish citizens. The cases were all women in Denmark
with epithelial ovarian cancer diagnosed during 2000-2009 (Paper 1) and
2000-2011 (Papers 2 and 3), identified in the Cancer Registry.
Age-matched female population controls were randomly selected from the
Civil Registration System by risk-set sampling. We required that cases
and controls have no history of cancer (except non-melanoma skin cancer)
and that controls not previously have undergone bilateral oophorectomy
or salpingo-oophorectomy. The total study population comprised 3741
epithelial ovarian cancer cases and 50,576 controls in Paper 1, and 4103
epithelial ovarian cancer cases and 58,706 controls in Papers 2 and 3.
We used the Danish Prescription Registry to assess use (≥2 prescriptions
on separate dates) of paracetamol, non-aspirin non-steroidal
anti-inflammatory drugs (NSAIDs), low-dose aspirin, and statins.
Conditional logistic regression was used to estimate odds ratios (ORs)
and 95% confidence intervals (CIs) for epithelial ovarian cancer
associated with use of the study drugs, with adjustment for potential
confounding factors selected a priori. We performed detailed analyses
according to duration, intensity, and continuity of study drug use, and
the analyses were stratified according to specific histologic types of
epithelial ovarian cancer. In all studies, non-use (< 2
prescriptions) of the individual study drugs was defined as the
reference group. A striking result of the PhD thesis was a strong
inverse association between prescription use of paracetamol and risk of
epithelial ovarian cancer. The risk estimates decreased with increasing
duration and intensity of paracetamol use, reaching a more than 50%
reduction for the longest duration (>10 years) and the highest doses
(OR: 0.45; 95% CI: 0.24-0.86). In contrast, we did not observe an
inverse association between use of non-aspirin NSAIDs and risk of
epithelial ovarian cancer. Moreover, this thesis provides further
evidence that use of low-dose aspirin is associated with a reduced risk
of epithelial ovarian cancer. In particular, long-term (≥5 years)
continuous use of low-dose aspirin, defined as overlapping prescription
coverage periods, was associated with a large reduction in risk (OR:
0.56; 95% CI: 0.32-0.97). Finally, we found no apparent association
between statin use and epithelial ovarian cancer risk, although the
analysis by histologic type suggested an inverse association with the
risk of mucinous tumors. The results of this PhD thesis add important
knowledge to the area of chemoprevention in relation to epithelial
ovarian cancer. As for any observational study, we cannot exclude
potential con-founding and exposure misclassification; however,
methodological limitations appear unlikely to fully explain the observed
reductions in epithelial ovarian cancer risk associated with
paracetamol and low-dose aspirin use. Additional research, ideally from
clinical trials, is needed before our observations may lead to
recommendations for chemopreventive measures against ovarian cancer. In
case consensus points to a true protective effect of paracetamol or
low-dose aspirin, comprehensive risk-benefit evaluations will also have
to be performed. We hope that our results will encourage researchers to
look more deeply into the potential chemo-preventive effects of the
study drugs against epithelial ovarian cancer risk.
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