In this pooled analysis of case-control studies, caffeinated coffee was inversely related with the risk of OP cancer. The protection was similar across the oral cavity and pharyngeal sites, with a substantial amount of heterogeneity between studies. No association of caffeinated coffee drinking was found with cancer of the larynx. Data on decaffeinated coffee and tea indicated a lack of material association. However, for decaffeinated coffee data were limited, as both the prevalence of consumption and the amount consumed by drinkers were low.
Risk estimates of OP cancer for caffeinated coffee drinking were heterogeneous between studies. Chemical composition of coffee beverages varies according to variety of the plant (Arabica or Robusta) and preparation, but most studies had inadequate information on these issues. Another source of heterogeneity is that some subjects with low or irregular consumption of coffee may have been included among non drinkers because of the way the unexposed group was defined in some studies. In fact, results were heterogeneous among intermediate levels of consumption, but not among subjects with high consumption. This possible misclassification, however, if anything, could have attenuated the inverse association.
Other sources of heterogeneity are the different patterns of alcohol drinking and tobacco smoking in various populations, positively correlated with both coffee intake and HN cancer risk (42
). However, the inverse association was similar in strata of tobacco smoking and alcohol drinking. When we stratified for geographic region, no heterogeneity was detected within European studies and within American studies, separately, indicating that it could be at least partly explained by different modalities of consumption among European and US populations (e.g., variety of coffee, type of processing and/or preparation, patterns of consumption, etc.). In a sensitivity analysis, exclusion of each study from the pooled-analysis did not materially change the summary estimates, showing that results were not driven by any single study. Recall of coffee drinking has been shown satisfactorily reproducible and valid (45
), and should not be different on the basis of the disease status or among various types of controls, as coffee is not commonly known to affect OP cancer risk.
The presence of pre-neoplastic changes in the oral cavity or symptoms of the disease may cause changes in coffee or tea drinking among the cases, notably a decrease among cases due to high temperature of coffee or tea (reverse causation). However, the difference in results between caffeinated coffee and tea intake would suggest that reverse causality due to disease-related change in drinking patterns is not the main reason for the observed associations for caffeinated coffee intake. Additionally, limited findings from cohort studies – where information on coffee drinking is collected several years before diagnosis – weigh against a relevant role of reverse causation. There are, in fact, two Norwegian cohorts: one cohort (22
) included 38 cases of OP cancer and found a relative risk (RR) of 0.73 for drinkers of 7 or more cups per day of coffee compared to 2 or less; the other cohort included 33 cases of cancers and found a RR of 0.5 for drinkers of 7 or more cups per day, with a significant inverse trend in risk (6
). A third cohort study was based on the Miyagi Cohort in Japan, included 48 cases and found a RR of 0.35 (95% CI: 0.16–0.77) for drinkers of one or more cups per day (7
). Thus, overall the limited evidence from cohort studies suggests a decreased risk for high coffee intake, although publication bias cannot be excluded.
In this analysis, the risk estimates did not materially change after adjustment for body weight and for vegetable and fruit consumption, which have been inversely associated with oral cancer in several studies (49
). More important, caffeinated coffee drinking was moderately correlated with tobacco (r=0.24, p<0.001) and alcohol (r=0.14, p<0.001) consumption. However, careful allowance for alcohol drinking and tobacco smoking did not materially modify any of the risk estimates, indicating that residual confounding is not a plausible explanation of the inverse relation between caffeinated coffee and OP cancer. Additionally, assuming that coffee drinkers also smoke and drink more, any residual confounding would result in a positive bias away from the null, which we did not observe in our study. Information was not available on human papillomavirus (HPV) infection, which has been causally associated with oropharyngeal cancer (50
), but there is no reason to think that coffee intake is associated with HPV infection. Another limitation of this study is the lack of good quality data on duration of coffee drinking or other time-related factors of the exposure in several studies, which did not allow investigation of these issues in the pooled analysis.
With reference to other studies investigating the relation of coffee drinking and HN cancer risk, of the at least eleven case-control studies not included in the INHANCE consortium (8
), one study from the USA (13
), one from Brazil (14
) and one from Montenegro (20
) considering OP cancer, and six studies considering oral or hypopharyngeal cancer (9
) found no significant association with coffee drinking, but the point estimates were below unity in several of them. Each study, however, was not large enough to have adequate statistical power to detect a relatively weak association and often did not focus on coffee or had no adjustment for tobacco smoking and alcohol drinking. When we conducted a summary meta-analysis of the six most informative studies not included in the INHANCE consortium, i.e., those with a quantification of the amount of coffee (one cohort and five case-control, for a total of 1628 cases) (7
), the summary RR for the highest category of coffee consumption as compared to the lowest one (as categorized in each study) was 0.72 (95% CI 0.55–0.95).
As for laryngeal cancer risk, results of studies not included in this pooled-analysis were inconsistent, and overall compatible with no relation. One Norwegian cohort study (22
) found an inverse relation of laryngeal cancer with coffee intake, two case-control studies (8
) found an increased risk and one prospective (6
) and two case-control studies (14
) found no relation.
For both OP and laryngeal cancers, the few other published data on decaffeinated coffee consumption are inadequate for any meaningful inference (52
With reference to tea intake, one Japanese prospective study (29
) on oral cancer, four case-control studies on OP/oral cancers (9
) and two case-control studies on laryngeal cancer (14
) found no significant relation, similarly to the results of our pooled-analysis. The World Cancer Research Fund Expert Report concluded that the evidence for a relation between tea consumption and HN cancers is too limited to draw any conclusion (49
Support for a real inverse association between caffeinated coffee intake and OP cancer comes from the significant inverse dose-relation in a subset of studies, the consistent relation across strata of potential confounders and effect modifiers, and the consistent association in European and American populations. Furthermore, the absence of a relation observed in the same studies between caffeinated coffee intake and the risk of laryngeal cancer, which shares similar risk factors of OP cancer (4
), support a real association between caffeinated coffee intake and the risk of OP cancer. The lack of association with tea drinking argues against reverse causality and report bias too, though tea is generally less consumed than caffeinated coffee in these populations and it is likely to be more misclassified.
The inverse relationship between caffeinated coffee drinking and OP cancer can be related to various components of coffee. Besides caffeine, coffee contains more than a thousand chemicals (5
), some of which have antioxidant and antimutagenic activities in animal models and cell culture systems (53
). These include several phenolic compounds (such as chlorogenic, caffeic, ferulic and cumaric acids), melanoidins and diterpenes (such as cafestol and kahweol) (54
) whose concentration in the beverage varies depending on type of raw coffee (Arabica or Robusta), roasting and preparation, as unfiltered coffee contains less amounts of lipid component, such as diterpenes (56
). In particular, cafestol and kahweol may reduce the genotoxicity of some carcinogens (53
), and may activate enzymes involved in cancerogenic detoxification (57
), such as glutathione-S-transferase and inhibiting N-acetyltransferase (59
). Still, no definite biological mechanism of the potential healthy role of coffee on HN cancers is available (52
). Coffee drinking has also been inversely related to colorectal cancer (60
), liver cirrhosis and cancer (52
), and endometrial cancer (61
), again in the absence of a clear interpretation.
In conclusion, the results of this pooled-analysis of case-control studies support the hypothesis of an inverse association between caffeinated coffee drinking and OP cancer risk, and provide a more precise estimate of the magnitude of the effect. Bias, confounding and reverse causality, however, cannot be excluded. Given widespread use of coffee and the high incidence and low survival of HN cancers (62
), it is important to conclusively establish whether the observed association between caffeinated coffee drinking and HN cancer risk is causal as this would have appreciable public health relevance, though alcohol and tobacco remain the key risk factors for OP cancer in most population (1