Department of Pharmacology and Toxicology School of Medicine University of Louisville Louisville, KY 40292
Division of Epidemiology and Biostatistics School of Public Health University of Illinois at Chicago Chicago, IL 606127260
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INTRODUCTION |
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Any conclusion from epidemiologic data alone that alcohol is a carcinogen must therefore examine the effect in never smokers. Of the 784 patients in the report by Schlecht et al., there were only 17 never smokers who were drinkers. Furthermore, only the group of seven patients who drank "more than" the equivalent of one beer per day had a statistically significant increase in cancer above controls (calculated at 18 g/day x 365 days x 37 years = 243 kg, average age of patients, 58 years, assuming that drinking started at age 21 years). The authors give no indication of how much more than the equivalent of one beer per day the individual patients consumed or of whether they had other risk factors associated with cancer of the UADT. Excessive consumption of alcohol (the alcoholic lifestyle) and other specific factors, such as poor dentition and diet, have been associated with cancer of the UADT. Consequently, potential confounding in the never smokers in the study by Schlecht et al. leaves serious doubts about the validity of their conclusion.
We are puzzled by the "crude" odds ratios shown for never smokers only in their table 6. These odds ratios are apparently based on the discordant data only, since the controls were matched individually two to one to the cases on 5-year age group, sex, and location. Examining the raw data on number of cases and controls at each level of drinking, we obtain odds ratios of 1.59, 0.68, and 1.78 for increasing classes of drinking (based on ordinal values of one, two, and three given to the classes). This visually and statistically (p = 0.48) indicates no evidence of trend and contrasts sharply with their odds ratios of 2.5, 2.0, and 7.7 (trend p = 0.022) apparently obtained from the discordant data only. Assuming that their computations are valid, we find it highly unusual that the matching design would change the point estimates so dramatically (e.g., from 1.78 to 7.7 for the highest drink class) and suspect the existence of some kind of artifact or interaction that was not explored in their analysis and may threaten the external validity of their findings.
Authors of studies of a potential association of smoking and drinking with cancer of the UADT complain of the "problem" of too few cases of drinkers who do not smoke. Different reports have dealt with this problem in different ways; some combine light drinkers or light smokers or select groups with "convenient" doses for comparison, etc., in order to be able to apply statistics. The fact speaks for itselfthere are very few drinkers who do not smoke who develop cancer of the UADT. Even among those nonsmoking drinkers who do develop cancer, other potential confounders have not been eliminated. There are many moderate drinkers who do not smoke. It is a disservice to these individuals to conclude that alcohol is an independent risk factor when the evidence does not support this conclusion.
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Departments of Epidemiology and Oncology McGill University Montreal, Quebec, Canada H2W 1S6
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INTRODUCTION |
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They point out that we included few cases of nonsmokers who drank and conclude that there was lack of evidence because statistical significance was shown only for the highest category of consumption (>243 kg alcohol). However, this ignores the significant dose-response trend with alcohol consumption and the elevated odds ratios across all consumption categories. They also suggest that our point estimates were affected by residual confounding due to omission of covariates in our models. We argue that this is highly unlikely, since we adjusted all analyses for confounders that were selected empirically on the basis of a 5 percent change in the estimates for alcohol, arguably a very conservative threshold. Using this low cutpoint to select covariates, we screened more than 100 candidate exposures, including tens of dietary and dental health variables (the latter reported earlier (4)). We are not aware of any study of this kind that has controlled for confounding with such zeal. Furthermore, with a mean consumption of 7.4 drinks per week in the highest category, it is unlikely that the contribution of nonsmoking subjects with an "alcoholic lifestyle" is important.
Waddell and Levy mistakenly ignored the conditional assumptions in the matched design of our study and calculated unconditional odds ratios for alcohol consumption using our frequency data. They then used the resulting underestimated odds ratios to buttress their claim of no effect for alcohol. In a multicenter study involving populations from diverse geographic areas, there are differentials in UADT cancer risk for many exposures that vary markedly according to the matching factors that we used (city, gender, age, and period). To avoid bias, one must consider the net influence of these relations via conditional logistic regression. To illustrate this point, we calculated the odds ratios of UADT cancer for tobacco and alcohol based on tertiles (tobacco: 010, 1145, and >45 pack-years; alcohol: 010, 11530, and >530 kg). Without taking matching into account, we obtained estimates of 1.0 (reference), 2.9, and 4.5 for tobacco and 1.0 (reference), 0.9, and 2.0 for alcohol. However, when matching is preserved by conditional analysis, the odds ratios are 1.0, 4.2, and 10.9 for tobacco and 1.0, 1.7, and 7.3 for alcohol. Even with adjustment for the matching factors while ignoring matching, the odd ratios remain severely underestimated, stressing the importance of conserving the matching introduced in the study.
Although not mentioned in the letter by Waddell and Levy (1), differential misclassification of smoking could be a concern. However, this is unlikely to have happened to an appreciable extent because our hospital-based controls were recruited and interviewed under conditions similar to those of cases (2
). Compared with North American and Western European populations, our subjects were not as aware of the hazards of smoking and excessive drinking.
In conclusion, we stand by our original findings (2), since the arguments in the letter by Waddell and Levy either are incorrect or are based on untenable assumptions. Admittedly, our study did not distinguish between types of alcohol, which prevents us from reaching firm conclusions about the role of specific alcoholic beverages. We refer to other studies that have attempted to address this problem (5
7
). Detailed investigations are needed to elucidate the role of alcohol in UADT cancers, particularly comparing populations with respect to the impact of changes in consumption and cancer incidence.
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