We observed distinct delivery rate patterns for the risk of head and neck cancer by cigarette smoking and by alcohol consumption, and we confirmed prior study results showing that smoking was more strongly associated with laryngeal cancer and that alcohol consumption was more strongly associated with pharyngeal and oral cavity cancers (1
). Results suggested that the greater laryngeal cancer risk with smoking derived from the differential effects of cigarettes/day and not pack-years, while the greater pharyngeal and oral cavity cancer risk with alcohol consumption derived from the differential effects of total drink-years and not drinks/day.
Our analysis is the first to characterize the alcohol consumption rate controlling for total alcohol exposure. For subjects consuming 10 drinks/day or less, which included 95% of controls, the strength of the disease association with total exposure (drink-years) increased with the increasing exposure rate (drinks/day), suggesting that alcohol-related causal mechanisms are not exposure-rate limited at or below 10 drinks/day. Above 10 drinks/day, the strength of the association between drink-years and head and neck cancers decreased with increasing drinks/day; however, interpretation was problematic because of the relatively few drinkers of more than 10 drinks/day and few studies contributing information, resulting in increased heterogeneity among studies.
Ethanol may act as a carcinogenic initiator or as a promoter that enhances permeability of cells to other environmental carcinogens, notably tobacco smoke (1
). Ethanol is oxidized to acetaldehyde primarily though the enzymatic activity of alcohol dehydrogenase and, to a lesser extent, cytochrome P450 enzymes, including CYP2E1, especially in chronic drinkers. Acetaldehyde is metabolized by aldehyde dehydrogenase to acetate (17
). The metabolism of ethanol by alcohol dehydrogenase and aldehyde dehydrogenase occurs primarily in the liver and, to a lesser extent, the stomach (15
). Acetaldehyde is classified as a possible human carcinogen (group 2B) (18
). The effects of acetaldehyde may thus explain the increased cancer risk with alcohol consumption, which has been observed for oral cavity, oropharyngeal, laryngeal, esophagus, liver, colon/rectum, and breast cancers (15
). However, the increased risk for oral cavity and pharyngeal cancers compared with laryngeal cancer, which was observed in our analysis and noted by others (3
), suggests that site-specific factors in addition to acetaldehyde must also play a role. These factors may include increased production of acetaldehyde from oral bacterial flora concomitant with increased alcohol intake or poor dentition that may act directly through the release of proinflammatory cytokines (22
) or may enhance the effects of bacterial flora (23
Unlike the smoking analysis of never and current smokers, the drinking analysis did not limit data by drinking status, because information on drinking status was not available for 4 studies (Milan, Aviano, Central Europe, and New York studies). If we omitted these 4 studies and restricted analyses to never and current drinkers, patterns of EOR/drink-year and drinks/day were similar, while the inference in was clearer. For example, model fit degraded significantly when β replaced βs
0.01 for ≤10 drinks/day and P
0.06 for ≤5 drinks/day), but it did not degrade significantly when ϕ1
replaced ϕ1, s
0.37 for ≤10 drinks/day and P
0.53 for ≤5 drinks/day). These results indicated that site-specific differences in risk derived from variation in risk with drink-years, while drinks/day effects were homogeneous, suggesting the same relative impact of drinks/day for laryngeal, pharyngeal, and oral cavity cancers.
Alcohol-dependent recall bias, with heavier drinkers underestimating drinks/day, may have occurred (25
). Such bias could induce overestimation of the association between disease and drink-years that increased with drinks/day. Analyses have reported correlations of 0.6–0.7 for prospectively and retrospectively collected estimates of alcohol intake and for absolute differences in consumption of 1 g of ethanol per day or less or less than one-tenth of a can of beer or glass of wine (26
). In our data, the EOR/drink-year increased smoothly through 10 drinks/day, with a 1.3-fold (oral cavity), 1.5-fold (pharynx), and 2.3-fold (larynx) increase in the fitted EOR/drink-year at 10 drinks/day relative to 5 drinks/day (). This suggests that recall bias would be insufficient to produce the observed magnitude of effects for increasing drinks/day.
For cigarette smoking, there was an inverse delivery rate or “reduced potency” effect above about 15 cigarettes/day, whereby for equal pack-years smoking more cigarettes/day for a shorter duration was less deleterious than smoking fewer cigarettes/day for a longer duration. This pattern has been observed for a variety of smoking-related cancers, including cancers of the esophagus, lung, kidney, bladder, pancreas, and liver (4
), and it suggests a broader smoking-related phenomenon.
The inverse exposure rate pattern for cigarettes/day likely reflects both biologic effects and intensity-dependent inhalation characteristics. The inverse exposure rate pattern is consistent with various biologic processes linked to carcinogens in cigarette smoke, including increased DNA repair (29
), saturation of activation pathways (33
), and increased induction of detoxification enzymes (36
). The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen, which can be characterized by its urinary metabolites. In data from 4 clinical studies, the ratio of NNK metabolites to urinary cotinine declined with increasing cotinine, suggesting reduced NNK uptake per unit of cotinine with increasing cotinine (37
), a pattern consistent with inverse exposure rate effects. The inverse exposure rate pattern may also reflect heavier smokers inhaling less vigorously, leading to lower carcinogenic exposure per cigarette, as suggested by a study of 190 smokers which reported increased cotinine and nicotine levels with increased intensity and a marginally significant (P
0.08) decline in “nicotine boost,” that is, an increase in blood plasma nicotine per cigarette (38
). Nonetheless, evidence suggests that inhalation characteristics do not fully explain the inverse exposure rate pattern. In a lung cancer case-control study, inhalation was unrelated to cigarettes/day within pack-year categories, suggesting that inhalation does not confound pack-years-adjusted cigarettes/day patterns (4
), while a sensitivity analysis, based on the relation between urinary cotinine and cigarettes/day, indicated that inhalation characteristics do not fully account for the exposure rate pattern (39
). Finally, although inhalation characteristics may have contributed to an inverse exposure rate pattern for lung cancer, we would expect depth and frequency of inhalation to have a lesser impact on modifying the delivered dose for risk of head and neck cancers. However, a literature search failed to find any analyses of head and neck cancer risk in relation to cigarette inhalation patterns.
Consistent with several studies, this study found that smoking-related risks were higher for cancer of the larynx compared with cancer of the pharynx and oral cavity (1
). Our modeling suggested that differences in risk resulted from the differential effects of cigarettes/day, while pack-year effects were homogeneous, indicative of a heightened responsiveness of the larynx to changes in cigarettes/day. However, this may be a chance finding because the variation was not statistically significant (P
The risk patterns for smoking were generally consistent across individual studies, which agrees with other smoking-related analyses (5
). Results for drink-years and drinks/day, while broadly consistent, exhibited greater heterogeneity among studies, particularly at higher drinks/day. This agrees with a meta-analysis that reported greater heterogeneity in alcohol-related risks compared with smoking risks (20
). Increased heterogeneity may be due to population differences in the amount, type (beer, wine, liquor, and so on), and formulation (straight or mixed drink for liquor) of the alcohol products consumed. Reports have linked ethanol concentration to increased risk of head and neck cancer (3
), although an analysis of data from the International Head and Neck Cancer Epidemiology Consortium did not find marked differences in risk by type of drink (12
In summary, we observed an inverse exposure rate effect for cigarette smoking above 15 cigarettes/day, whereby the strength of the association between head and neck cancer and pack-years decreased with cigarettes/day, and a direct exposure rate effect for drinks/day ≤10 drinks/day, whereby the strength of the association between head and neck cancer and total drink-years increased with drinks/day. Smoking risks were greater for the larynx than for the pharynx and oral cavity, while alcohol risks were greater for the pharynx and oral cavity. We found suggestive evidence that greater smoking-related risk of laryngeal cancer was derived primarily from the differential effects of cigarettes/day, while the effect of pack-years was similar by site, and that the greater alcohol-related risk for pharyngeal and oral cavity cancers was derived from a greater effect of total drink-years, while the modification of drink-years–related risk by drinks/day was similar for each site.