The results from this meta-analysis of eight prospective studies suggest that red and processed meat consumption is not associated with risk of ovarian cancer. These results are partly in contrast to the conclusions from the previous meta-analysis, including both case–control studies and a smaller number of cohort studies, which reported a positive association with processed meat (Kolahdooz et al, 2010
A strength of this study, in addition to the use of a dose-response approach, is that the assessment was based on data from prospective cohort studies only, which are less susceptible to recall and selection bias than retrospective case–control studies. Our findings also have limitations. First, a meta-analysis of observational studies cannot solve inherent problems with confounding in the included studies, which may introduce bias. Although most studies controlled for parity, BMI or waist-to-hip ratio, and total energy intake, other factors suspected to influence the risk of ovarian cancer were less consistently included in the multivariate models. Residual confounding by inadequately measured covariates could also be of concern. Second, our findings are likely to have been affected by misclassification of meat consumption because of imprecise measurement of diet in the included studies. In cohort studies, misclassification is generally non-differential, which most likely attenuates the association. Finally, because studies with null results or small sample sizes tend not to be published, publication bias, which may overestimate the summary RR, could be of concern. However, we found no evidence of publication bias in this meta-analysis.
Although the dose-response approach to meta-analysis offers advantages over the conventional methodology, it also requires a number of assumptions to be made. In terms of associations between absolute intake levels and disease risk, a meta-analysis can only be as good as the individual study instruments have been. All included studies used FFQs to assess meat consumption, which are generally more valuable to rank study participants according to their consumption than to measure exact levels. In addition, combining results from different studies requires comparing different instruments. Assumptions also had to be made regarding the median level of consumption for each category when this information was missing in the individual studies. However, sensitivity analysis around the assignment of the dose of open-ended top categories did not change the results. Finally, since some studies expressed consumption levels in servings rather than in grams, we had to make assumptions about average serving sizes.
Suggested mechanisms for a potential association between red and processed meat and ovarian cancer include high fat intake, which has been shown to be associated with elevated levels of circulating oestrogens (Hill et al, 1971
; Aubertin-Leheudre et al, 2008
). Although the role of oestrogen in ovarian cancer aetiology is not yet clear, the current evidence suggests that high levels may promote ovarian carcinogenesis (Lukanova and Kaaks, 2005
). In a pooled analysis of 12 cohort studies, a weak positive association was observed for saturated fat intake, whereas other types of fat did not affect the risk of ovarian cancer (Genkinger et al, 2006
). An earlier meta-analysis of primarily case–control studies found significant associations for total fat, saturated fat and animal fat (Huncharek and Kupelnick, 2001
). Another possible mechanism is that preservation, cooking and/or processing methods can introduce mutagens and carcinogens to meat. These include N-nitroso compounds (NOC), heterocyclic amines and polycyclic aromatic hydrocarbons, many of which have been shown to induce tumours in several animal species and at several sites (Cross and Sinha, 2004
). Haeme iron, which is more abundant in red meat than in white meat, has also been shown to stimulate endogenous NOC production (Cross et al, 2003
). However, epidemiological studies have linked these compounds primarily to cancers of the gastrointestinal tract (De Stefani et al, 1998
; Cross et al, 2010
), whereas their potential role in ovarian cancer aetiology has not yet been investigated.
When investigating meat consumption, it has to be considered that any association with a diet high in meat may in part be attributable to a low intake of fruit and vegetables or other plant foods. Only two of the studies included in this meta-analysis controlled for fruit and vegetable consumption. Fruits and vegetables are high in antioxidants that have been shown to protect cells against oxidative damage and are hypothesised to reduce the risk of cancer (Thompson et al, 1999
). In addition, plant foods contain phytoestrogens and fibre that may lower levels of circulating oestrogens (Adlercreutz, 1995
; Aubertin-Leheudre et al, 2008
). However, few prospective studies have shown significant associations between intake of fruit, vegetables or antioxidants and risk of ovarian cancer, although the overall evidence concerning vegetable consumption indicates a possible inverse association (Koushik et al, 2005
). Another possibility is that a potential association between high meat consumption and risk of ovarian cancer may be mediated through obesity, as a result of high energy intake. Obesity influences endogenous hormones by increasing adrenal secretion of androgens, enhancing conversion of androgens to oestrogens and reducing plasma levels of sex hormone-binding globulin, which results in higher levels of biologically active oestrogen (Siiteri, 1987
). In a meta-analysis of 28 studies, a moderate positive association between obesity and risk of ovarian cancer was suggested (Olsen et al, 2007
). On the other hand, most of the studies included in our meta-analysis adjusted for BMI or waist-to-hip ratio and for total energy intake.
In conclusion, results from this dose-response meta-analysis suggest that red and processed meat consumption is not associated with risk of ovarian cancer. Considering the borderline significant results, a possible weak association cannot be excluded. However, ovarian cancer risk was only elevated by 2 and 5% for every 100
g increment in consumption of red and processed meat, respectively. Although a lower consumption of red and processed meat may offer protection against other types of cancer (Ferguson, 2010
), other interventions are needed to reduce the risk of ovarian cancer.