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Ovarian cancer remains the most lethal of the gynaecological cancers . Although relatively uncommon, afflicting ∼ 1 in 60 women in the USA, the high mortality rate makes this disease a major health concern. The high mortality rate arises from the lack of an effective screening approach  combined with inadequate therapeutic approaches for advanced disease . Indeed, fewer than 25% of ovarian cancers are identified at an early curable stage. Strategies that focus on prevention may therefore provide the most rational approach for meaningful reductions in deaths attributable to ovarian carcinoma .
Two dominant hypotheses – the ovulation hypothesis [5, 6], which relates ovarian cancer risk to incessant ovulation, and the pituitary gonadotropin hypothesis , which implicates elevations in gonadotropin/oestrogen levels—have sought to explain the genesis of this disease, but epidemiological and biological observations do not fit entirely with either theory. Epidemiological evidence suggests that ovarian cancer may be related to chronic inflammatory processes. Ness and Cottreau proposed that inflammation of the ovarian epithelium is a pathophysiological contributor to the development of ovarian cancer . Therefore, nonsteroidal anti-inflammatory drugs (NSAIDs) are potential agents for the chemoprevention of ovarian cancer.
Several observational epidemiological studies have examined the relation between NSAIDs and ovarian cancer. The findings from these studies are inconsistent. Some reported that the use of these drugs is inversely related to the risk of ovarian cancer, while others found no or positive associations. Thus, the effect of NSAID use on the risk of ovarian cancer remains to be determined.
Some recent review articles [9–11] have summarized the association between NSAID use and ovarian cancer risk. However, none of these articles has made a quantitative meta-analytic approach, and certainly none focused specifically on ovarian cancer. Therefore, we systematically identified case–control and cohort studies of the association between NSAID ingestion and ovarian cancer risk. We then performed a meta-analysis of these studies to evaluate the association, to compare the magnitude of any associations between aspirin and ovarian cancer with that between non-aspirin NSAIDs and ovarian cancer, and to examine associations with dose and with duration of NSAID use.
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- Materials and methods
- Competing interests
The current interest in aspirin and other NSAIDs as potential agents for the chemoprevention of ovarian cancer stems from the fact that many animal experiments and human epidemiological studies link aspirin and other NSAIDs with beneficial effects in various cancers, including breast, oesophageal, colorectal and prostate cancer. Recent meta-analyses have supported the idea that the overall relative risk of breast , gastric , oesophageal  and prostate cancer  is reduced in people taking aspirin and other NSAIDs.
To the best of our knowledge, this is the first meta-analysis of published studies to evaluate specifically the association between NSAID use and ovarian cancer risk. According to the findings of our meta-analysis, NSAID use does not appear to affect the risk of developing ovarian cancer. Furthermore, our results did not show decreasing risks with increasing frequency or duration of use, features often associated with causal relationships.
Our results are in agreement with cohort studies of women with rheumatoid arthritis, who chronically use NSAIDs. In a Swedish cohort  of nearly 8000 women, the standardized incidence ratio was 0.96, based on 30 cases of ovarian cancer. In a Danish cohort  of nearly 14 000 women, there were 50 incident cases, corresponding to a relative risk of 1.0. In a Canadian cohort  of women with rheumatoid arthritis, the standardized incidence ratio was 0.89, based on five cases. Similarly, in the Rochester rheumatoid arthritis cohort , there was one case of ovarian cancer on two expected.
When meta-analysis of observational data is performed, consideration of study bias is critical . Existence of a bias in favour of publication of statistically significant results is well documented in the literature [45–47]. The publication bias detected in the meta-analysis of exposure to aspirin implies that the statistically nonsignificant 8% reduction of risk shown (RR = 0.92) is overestimated. It was also shown that the right corner of the pyramidal part of the funnel for aspirin, which should contain studies reporting positive or null results, was missing (Figure 1). It indicates that studies for which the direction of estimate was against expectations (i.e. more than 1.0) may have been less likely to be published than those which showed a trend in the direction expected. This fact is compatible with the overall conclusion that aspirin use is not correlated to ovarian cancer risk.
Nevertheless, several limitations should be considered in interpreting the results of this meta-analysis. First, our search was restricted to studies published in indexed journals. We did not search for unpublished studies or for original data. However, we did not impose any exclusion criteria with regard to language, place of publication or quality.
Second, the included studies were different in terms of study design and definitions of drug exposure. We tried to explore sources of heterogeneity conducting several subgroup analyses. However, the summary effect estimates are based on sparse and heterogeneous data. Similarly, for the non-aspirin NSAIDs, all drugs have been regarded as being the same. Pharmacologically, this is not correct in that the drugs are different in terms of kinetics and dynamics, and may therefore have different effects on risk.
Third, the method used to elicit the exposure differs among the individual studies. Most studies [31, 34, 36–40] used personal interviews or self-administered questionnaires that rely on the subject's ability to recall, which was repeatedly shown to be relatively poor for nonrepetitive NSAID use . Fewer studies [32, 33, 35] used automated databases that provide detailed information on dates of use and types of drugs used. This information is equally good for cases and controls irrespective of the event of interest, since it was recorded prospectively. However, studies that used prescription databases lacked information on over-the-counter use, and were based on the assumption that the amount of NSAIDs dispensed is a good approximation of actual consumption. This may not be true, especially for non-aspirin NSAIDs that are frequently prescribed to be taken only when needed.
Fourth, observational studies lack the experimental random allocation of the intervention necessary to test exposure-outcome hypotheses optimally. Thus, results may have been confounded by several factors, given that each one of the studies included in our meta-analysis controlled for somewhat different confounding factors (Table 1). None of the individual studies adjusted for some factors that may affect the use of these drugs, such as the motivation for NSAID use [49, 50]. For example, aspirin is also used in the primary and secondary prevention of coronary heart disease. We cannot totally exclude the possibility that earlier mortality among aspirin users (e.g. from heart disease) may preclude diagnosis of ovarian cancer and therefore produce a beneficial effect.
Fifth, dose relationship was evaluated on the basis of regular and irregular intake, which are not very precise and may not by themselves indicate the lack of dose dependency. Therefore, our results should be interpreted with caution.
Several laboratory studies have tried to investigate the link between NSAIDs and ovarian cancer and explore the potential underlying mechanisms. At present, investigation relies on ovarian cancer cell lines and cultures of normal ovarian epithelium . The studies by Rodriguez-Burford et al. demonstrated that acetylsalicylic acid and a COX-2 inhibitor (NS-398) can decrease the growth of fully transformed epithelial ovarian cancer cells. The COX-2 agent both decreased cell proliferation in established cell lines and induced apoptosis in freshly isolated ovarian cancer cells. However, concentrations far above the therapeutic range and well above the maximal tolerated dose were required to demonstrate antiproliferative effects in vitro. This is compatible with the observation that human epithelial ovarian cancer cells appear to express COX-1 and COX-2 at very low levels [52, 53]. In contrast, bowel cancer cells are very sensitive to the effects of NSAIDs, probably as a consequence of overexpression of COX-2, and dependent on COX-2 function for growth and survival [54–57].
Thus, the observations that very high concentrations of NSAIDs are required to decrease the proliferation of ovarian cancer cell lines and that ovarian cancer cells express very low levels of COX-1 and COX-2 [52, 53] are compatible with the findings of our meta-analysis of observational studies.
In conclusion, the findings of our meta-analysis do not support that NSAID use plays a role in the chemoprevention of ovarian neoplasia. However, whilst the data provide no evidence for a beneficial effect, reductions in risk, which would be clinically important, cannot be excluded. Therefore, future research should examine potential relationships between specific NSAIDs and ovarian cancer risk, over extended periods of time, with examination of subgroups that may benefit most from anti-inflammatory effects. Because long-term NSAID use may occasionally result in serious gastrointestinal bleeding and haemorrhagic stroke, the risk–benefit balance of long-term NSAID use should also be assessed.