Estimating dose‐response relationship between ethanol and risk of cancer using regression spline models

Abstract

Cancers of the upper aero-digestive tract (i.e., oral cavity, pharynx, larynx and oesophagus) are largely attributable to smoking and drinking habits, but the correct estimation of the dose-response relationship between alcohol and cancer risk is challenging.Step functions are widely used to estimate risks and to evaluate trends of continuous exposure. However, results are influenced by the selection of the reference category and cutpoints. More flexible models, like spline regression and fractional polynomial models, may be an attractive alternative for avoiding strict assumptions about the dose-response relationship. Data from a large series of hospital-based case-control studies conducted in Italy and the Swiss Canton of Vaud in the last 2 decades were reassessed to compare findings from logistic regression spline models and standard step function analysis. For all examined cancers, the risk increased to the consumption of 150 grams of ethanol per day (1.5 litre/day of wine), with a possible threshold effect emerging for cancer of the pharynx and larynx (<50 grams of ethanol per day) only. For higher consumptions, the risks flattened. Our study suggests that regression spline models can be useful to estimate the pattern of risk of a continuous exposure variable, such as alcohol consumption, and provide more accurate estimates than categorical analysis when ORs within each interval, especially in the reference category, are not homogeneous.Key words: spline models; upper aero-digestive tract cancer; dose-response Alcohol consumption, together with tobacco smoking, is an established risk factor for cancer of the upper aero-digestive tract (UADT, i.e., oral cavity, pharynx, larynx and oesophagus). [1][2][3] These neoplasms account for nearly 10% of all male cancers diagnosed in some Italian regions (e.g., the Northeast of Italy) where alcohol consumption is heavy. 4 The risk of UADT cancers is strongly related to the amount of ethanol drunk 1,2 and persists several years after drinking cessation. 5 A strong dose-response relationship between alcohol and the risk of UADT tumours emerged by means of categorical analysis, 1,2,6 but some aspects of the relationship (e.g., the presence of any threshold effect) remain unclear. 7 Step function analysis in the risk estimation for continuous variables has been supported by a number of authors. However, concerns were raised about the potential bias introduced by categorization, 8 -10 as step function analysis is based on the assumption that risks are constant within each interval. Therefore, results and their statistical significance are influenced by the choice of reference category and cutpoints. 11 More flexible approaches for the estimation of the dose-response relationship, such as regression splines and fractional polynomial regression, have long been proposed. [12][13][14][15] However, these methods are still rarely used in epidemiologic research, despite their simple algebraic form that makes them easy to apply by the most common matrix programming languages.A la...

Alcohol and head and neck cancer risk in a prospective study

“…Consistent with previous studies (Blot et al, 1988;Boffetta and Garfinkel, 1990;Adami et al, 1992;Franceschi et al, 1994;Gronbaek et al, 1998;Kjaerheim et al, 1998;Hayes et al, 1999;Boffetta et al, 2001;Boeing, 2002;Castellsague et al, 2004;Sturgis et al, 2004;Polesel et al, 2005;Boffetta and Hashibe, 2006), predominantly of men, we observed a significant dose -response association between increasing alcohol consumption and head and neck cancer in both male and female alcohol drinkers. Results were generally similar for beer, liquor, and wine, although only 0.3% (1528) of the cohort (1064 men and 464 women) drank 43 glasses of wine per day limiting power.…”

“…Although some previous epidemiological studies have observed a protective association between moderate alcohol consumption and cancers of the head and neck and the aesophagus, results overall have been inconsistent (Franceschi et al, 1994;Gronbaek et al, 1998;Hayes et al, 1999;Castellsague et al, 2004;Polesel et al, 2005). Most previous studies were conducted in populations that drink larger amounts of alcohol (Altieri et al, 2005) than that of the current study.…”

“…Most of these studies have not adjusted for tobacco use, an important potential confounder of the relation between alcohol and head and neck cancer (Boffetta and Garfinkel, 1990). Also, few studies (Franceschi et al, 1994;Gronbaek et al, 1998;Hayes et al, 1999;Castellsague et al, 2004;Polesel et al, 2005) have examined non-drinkers and those that drink less than two drinks per day separately, an important comparison as consumption of less than two drinks per day may reduce cardiovascular disease risk (Maclure, 1993).Although men are 2 -7 times more likely to develop these cancers than women (depending on sub-site) (Parkin et al, 2005), few epidemiological studies have compared the association of alcohol and head and neck cancer in men to that in women (Blot et al, 1988;Franceschi et al, 1994;Hayes et al, 1999;Boffetta et al, 2001). These studies generally indicate higher relative risks in women than in men, although many had small case numbers and all but one were case -control studies precluding the examination of incidence rates.…”

“…Most of these studies have not adjusted for tobacco use, an important potential confounder of the relation between alcohol and head and neck cancer (Boffetta and Garfinkel, 1990). Also, few studies (Franceschi et al, 1994;Gronbaek et al, 1998;Hayes et al, 1999;Castellsague et al, 2004;Polesel et al, 2005) have examined non-drinkers and those that drink less than two drinks per day separately, an important comparison as consumption of less than two drinks per day may reduce cardiovascular disease risk (Maclure, 1993).…”

Incidence and Mortality Rates of Oral Cancer in California from 1995-2004

“…California law requires cancer case information to be reported to the California Cancer Registry [4]. The recruitment method was by regular oral cancer screening and by obtaining patient consent.…”