Background: The magnitude of risk conferred by the interaction between tobacco and alcohol use on the risk of head and neck cancers is not clear because studies have used various methods to quantify the excess head and neck cancer burden.

Methods: We analyzed individual-level pooled data from 17 European and American case-control studies (11,221 cases and 16,168 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We estimated the multiplicative interaction parameter (ψ) and population attributable risks (PAR).

Results: A greater than multiplicative joint effect between ever tobacco and alcohol use was observed for head and neck cancer risk (ψ = 2.15; 95% confidence interval, 1.53-3.04). The PAR for tobacco or alcohol was 72% (95% confidence interval, 61-79%) for head and neck cancer, of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to tobacco and alcohol combined. The total PAR differed by subsite (64% for oral cavity cancer, 72% for pharyngeal cancer, 89% for laryngeal cancer), by sex (74% for men, 57% for women), by age (33% for cases <45 years, 73% for cases >60 years), and by region (84% in Europe, 51% in North America, 83% in Latin America).

Conclusions: Our results confirm that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk. However, a substantial proportion of head and neck cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head and neck cancer among women and among young-onset cases. (Cancer Epidemiol Biomarkers Prev 2009;18(2):541–50)

Over half a million head and neck cancer cases occur each year and is a significant cause of morbidity and mortality (1). The interaction between tobacco and alcohol use is important for head and neck cancer risk (2). Numerous epidemiologic studies have examined the interaction between tobacco and alcohol and the risk of head and neck cancers, but many reports assessed interactions only descriptively, without applying formal statistical testing (2). Some studies tested for the presence of interactions on the additive scale, whereas others tested on the multiplicative scale, and different categories were used for tobacco use and alcohol use. These results are therefore difficult to compare across studies. Due to these limitations, the magnitude of head and neck cancer risk conferred by the interaction between tobacco and alcohol is not clear. Furthermore, it is unknown whether interactions differ by subsite, sex, age, or geographic region. Finally, the proportion of cases that can be attributed to tobacco alone, alcohol alone, and tobacco and alcohol combined has not been estimated precisely. Better estimation of attributable risks for tobacco and alcohol may clarify the importance of other known or potential risk factors, such as human papillomavirus (HPV), high body mass index (BMI), or family history of head and neck cancer.

To evaluate the interaction between tobacco and alcohol and the risk of head and neck cancer, we conducted a pooled analysis within the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Our aim was (a) to formally test the multiplicative model of interaction between alcohol and tobacco use with a very large sample size; (b) to assess the population attributable risk (PAR) due to the effects of alcohol alone, tobacco alone, and tobacco and alcohol combined; and (c) to examine whether there is heterogeneity in the estimates for interactions by head and neck cancer subsite, as well as due to potential effect modifiers such as sex, age, and geographic region.

The INHANCE Consortium31

was established in 2004 based on the collaboration of research groups leading large epidemiology studies of head and neck cancer that are ongoing or have been recently completed. We pooled the data from 18 individual case-control studies (version 1.1), including 12,282 cases and 17,189 controls (3-19). Compared with our previous publication (20), the current data set added a Rome study (5), New York multicenter study (14), and Boston study (16). In this current analysis, we excluded from the analyses a French study (323 cases and 234 controls) that was restricted to regular smokers (4) and the Sudan (106 cases and 151 controls) and India (576 cases and 582 controls) centers of the International Multicenter study (12) because of the small number of subjects to represent these regions for estimation of PARs. Additionally in India, contrary to other countries, betel quid and areca nut chewing are major contributors to attributable fractions (AF) of oral cavity cancer.

Characteristics of the individual studies are presented in Table 1 in the Appendix. Most were hospital-based case-control studies and frequency matched their controls to the cases on age, sex, and additional factors (study center, hospital, race/ethnicity). The Los Angeles study individually matched the control subjects to case subjects on age decade, gender, and neighborhood, although in the analysis the matching was broken. Face-to-face interviews were conducted in all studies except for the Iowa study, in which subjects completed self-administered questionnaires.

Table 1.

Selected characteristics of head and neck cancer cases and controls

Cases, n (%)Controls, n (%)
Total 11,221 16,168
Study
Milan 416 (3.7) 1,531 (9.5)
Aviano 482 (4.3) 855 (5.3)
Italy Multicenter 1,058 (9.4) 2,579 (16.0)
Switzerland 516 (4.6) 883 (5.5)
Central Europe Multicenter 762 (6.8) 907 (5.6)
Rome 275 (2.5) 294 (1.8)
New York Multicenter 1,118 (10.0) 906 (5.6)
Seattle 407 (3.6) 607 (3.8)
Iowa 546 (4.9) 759 (4.7)
North Carolina 180 (1.6) 202 (1.2)
Tampa 207 (1.8) 897 (5.5)
Los Angeles 417 (3.7) 1,005 (6.2)
Texas 829 (7.4) 865 (5.4)
Boston 584 (5.2) 659 (4.1)
Puerto Rico 350 (3.1) 521 (3.2)
Latin America Multicenter 2,191 (19.5) 1,706 (10.6)
IARC Multicenter* 883 (7.9) 992 (6.1)
Age (y)
<40 415 (3.7) 1,023 (6.3)
40-44 629 (5.6) 1,151 (7.1)
45-49 1,223 (10.9) 1,800 (11.1)
50-54 1,714 (15.3) 2,487 (15.4)
55-59 2,096 (18.7) 2,801 (17.3)
60-64 1,901 (16.9) 2,531 (15.7)
65-69 1,555 (13.9) 2,064 (12.8)
70-74 1,024 (9.1) 1,517 (9.4)
≥75 664 (5.9) 794 (4.9)
Sex
Women 2,256 (20.1) 4,557 (28.2)
Men 8,965 (79.9) 11,611 (71.8)
Race/ethnicity
White 8,272 (73.7) 13,358 (82.6)
Black 403 (3.6) 485 (3.0)
Hispanic 164 (1.5) 350 (2.2)
Asian/Pacific Islanders 53 (0.5) 86 (0.5)
Other 138 (1.2) 183 (1.1)
Latin American 2,191 (19.5) 1,706 (10.6)
Education
None 93 (0.8) 106 (0.7)
<Junior high school 4,347 (38.7) 6,169 (38.2)
Some high school 1,576 (14.0) 1,784 (11.0)
High school graduate 1,765 (15.7) 2,163 (13.4)
Vocational, some college 1,368 (12.2) 2,514 (15.5)
≥College 1,417 (12.6) 2,888 (17.9)
Missing 655 (5.8) 544 (3.4)
Subtype
Oral 2,993 (26.7)
Pharynx 4,040 (36.0)
Oral/pharynx NOS 917 (8.2)
Larynx 2,965 (26.4)
Head and neck NOS 306 (2.7)
Cases, n (%)Controls, n (%)
Total 11,221 16,168
Study
Milan 416 (3.7) 1,531 (9.5)
Aviano 482 (4.3) 855 (5.3)
Italy Multicenter 1,058 (9.4) 2,579 (16.0)
Switzerland 516 (4.6) 883 (5.5)
Central Europe Multicenter 762 (6.8) 907 (5.6)
Rome 275 (2.5) 294 (1.8)
New York Multicenter 1,118 (10.0) 906 (5.6)
Seattle 407 (3.6) 607 (3.8)
Iowa 546 (4.9) 759 (4.7)
North Carolina 180 (1.6) 202 (1.2)
Tampa 207 (1.8) 897 (5.5)
Los Angeles 417 (3.7) 1,005 (6.2)
Texas 829 (7.4) 865 (5.4)
Boston 584 (5.2) 659 (4.1)
Puerto Rico 350 (3.1) 521 (3.2)
Latin America Multicenter 2,191 (19.5) 1,706 (10.6)
IARC Multicenter* 883 (7.9) 992 (6.1)
Age (y)
<40 415 (3.7) 1,023 (6.3)
40-44 629 (5.6) 1,151 (7.1)
45-49 1,223 (10.9) 1,800 (11.1)
50-54 1,714 (15.3) 2,487 (15.4)
55-59 2,096 (18.7) 2,801 (17.3)
60-64 1,901 (16.9) 2,531 (15.7)
65-69 1,555 (13.9) 2,064 (12.8)
70-74 1,024 (9.1) 1,517 (9.4)
≥75 664 (5.9) 794 (4.9)
Sex
Women 2,256 (20.1) 4,557 (28.2)
Men 8,965 (79.9) 11,611 (71.8)
Race/ethnicity
White 8,272 (73.7) 13,358 (82.6)
Black 403 (3.6) 485 (3.0)
Hispanic 164 (1.5) 350 (2.2)
Asian/Pacific Islanders 53 (0.5) 86 (0.5)
Other 138 (1.2) 183 (1.1)
Latin American 2,191 (19.5) 1,706 (10.6)
Education
None 93 (0.8) 106 (0.7)
<Junior high school 4,347 (38.7) 6,169 (38.2)
Some high school 1,576 (14.0) 1,784 (11.0)
High school graduate 1,765 (15.7) 2,163 (13.4)
Vocational, some college 1,368 (12.2) 2,514 (15.5)
≥College 1,417 (12.6) 2,888 (17.9)
Missing 655 (5.8) 544 (3.4)
Subtype
Oral 2,993 (26.7)
Pharynx 4,040 (36.0)
Oral/pharynx NOS 917 (8.2)
Larynx 2,965 (26.4)
Head and neck NOS 306 (2.7)

NOTE: Information on ethnicity was not collected in the Central Europe and Latin America studies. In the Central Europe study, all subjects were classified as non-Hispanic White because the large majority of these populations are expected to be White. In the Latin American study, we categorized subjects as Latin American.

Abbreviation: NOS, not otherwise specified.

*

We excluded the Sudan (100 cases and 102 controls) and India (576 cases and 582 controls) centers of the International Multicenter study because the Asia and Africa regions are not well represented for estimation of PARs.

Written informed consent was obtained from all study subjects and the investigations were approved by institutional review boards at each of the institutes involved. Questionnaires were collected from all the individual studies to assess the comparability of the collected data and of the wording of interview questions among the studies. Data from individual studies were received at the IARC with personal identifiers removed. Each data item was checked for illogical or missing values and inconsistencies were resolved as necessary.

Cases and controls with missing data on age, sex, or race/ethnicity and cases with missing information on the site of origin of their cancer were excluded (56 cases and 54 controls). Cases were included in this study if their tumor had been classified by the original study as an invasive tumor of oral cavity, oropharynx, hypopharynx, oral cavity or pharynx not otherwise specified, larynx, or head and neck cancer unspecified. Subjects with cancers of the major salivary glands [parotid, submandibular, or sublingual glands; International Classification of Diseases for Oncology, 2nd edition (ICD-O-2) codes C07-C08] or of the nasal cavity/ear/paranasal sinuses (ICD-O-2 codes C30-C31) were excluded from the analysis. The ICD coding used for the classification into subsites was specified in detail previously (20). Thus, the data for this analysis included 11,221 head and neck cancer cases and 16,168 controls from 17 studies. There were a total of 2,993 oral cavity cancer cases, 4,040 oropharyngeal and hypopharyngeal cancer cases (pharyngeal), 917 unspecified oral cavity/pharynx cases, 2,965 laryngeal cancer cases, and 306 unspecified head and neck cancer cases. We focused our site-specific analyses on oral cavity, pharyngeal, and laryngeal cancers. Three of the studies did not collect information on tumor histology. Of the studies that collected histology, 86.7% (8,034 of 9,265) of head and neck cancer cases were squamous cell carcinoma.

The questions about tobacco smoking and alcohol drinking in the study questionnaires were conceptually similar across studies, although the exact wording differed. The questions about tobacco and alcohol use were examined carefully for comparability before variables were created for this analysis (definitions for being a cigarette, cigar, or pipe smoker for each study are provided in the Appendix). Variables on the frequency (i.e., number of cigarettes, cigars, or pipes smoked per day), duration (in years), and pack-years (i.e., cumulative smoking) of tobacco smoking were available in all studies.

Information about snuff use and chewing habits was collected by the Puerto Rico study, the International multicenter studies, and all studies in North America. Snuff use and chewing are not common behaviors in Europe or Latin America, except in specific populations (e.g., Norway and Sweden) that were not included in the pooled data set (definitions of ever chewing and ever use of snuff are provided in the Appendix). Frequency and duration variables for chewing and snuff use habits were pooled across relevant studies. For this study, never users of tobacco were defined as individuals who had not used cigarettes, cigars, pipes, snuff, or chewing products during their lifetimes. A combined tobacco frequency variable was created, where ever tobacco users were categorized as having used 1 to 20 cigarettes, 1 to 20 cigars, 1 to 20 pipes, 1 to 2 chewing products, or 1 to 2 snuff units per day, or >20 cigarettes, >20 cigars, >20 pipes, >2 chewing products, or >2 snuff units per day.

In the alcohol section of the study questionnaires, subjects were asked if they were alcohol drinkers (definitions by study in the Appendix); for those who responded that they were, subsequent questions were asked about the frequency of drinking, the duration of drinking, and the different types of alcoholic beverages consumed (i.e., beer, wine, hard liquors, and/or aperitif). Details on the pooling of frequency and duration variables on alcohol are provided in the Appendix.

### Statistical Methods

The interactions between tobacco and alcohol on the risk of head and neck cancer were assessed by estimating odds ratios (OR) and 95% confidence intervals (95% CI) using unconditional logistic regression models for each study. To assess interactions on the multiplicative scale, we estimated ORs for joint effects (OR11 = OR for ever tobacco/ever alcohol use, OR01 = OR for never tobacco/ever alcohol use, OR10 = OR for ever tobacco/never alcohol use). The multiplicative interaction parameters and 95% CIs [ψ = OR11 / (OR01 * OR10)] were also estimated by including variables for ever alcohol use, ever tobacco use, and a product term (equivalent to the multiplicative interaction parameter) of those two variables in the logistic regression model. ψ > 1 is suggestive of a joint effect that is greater than expected under the multiplicative model. When a joint effect greater than multiplicative was not observed, interactions on the additive scale were assessed with relative excess risk due to interaction (RERI), attributable proportion (AP; proportion of disease among those with both exposures that is attributable to their interaction), and synergy index (SI; ref. 21). We estimated 95% CIs for each of these measures. The null values of RERI and AP are 0, whereas the null value for SI is 1.

The logistic regression models included age (<40, 40-44, 45-49, 50-54, 55-59, 60-64, 65-69, 70-74, or ≥75 y), sex, education level (no formal education, less than junior high school, some high school, high school graduate, vocational/some college, or college graduate/postgraduate), race/ethnicity (non-Hispanic White, Black, Hispanic/Latino, Asian/Pacific Islander, other, Latin American), and study center to adjust for potential confounders. We tested for heterogeneity among the study ORs by conducting a likelihood ratio test comparing a model including the product terms between each study (other than the reference study) with the variable of interest and a model without the product terms (degrees of freedom = number of studies − 1), for the risk of head and neck cancer combined, and for the risk of each of these head and neck cancer subsites. Heterogeneity was detected consistently; therefore, to calculate the summary estimates of association, the study-specific estimates were included in a two-stage random effects logistic regression model with between-study variability and the common OR being estimated using maximum likelihood estimation.

Information on ethnicity was not collected in the Central Europe and Latin America studies. In the Central Europe study, all subjects were classified as non-Hispanic White because the large majority of these populations are expected to be White. In the Latin American study, we categorized subjects as Latin American. For the Latin America study only, study center was used as a proxy variable for race/ethnicity in all logistic regression models because each center had an expected predominant ethnic group distribution.

For subjects with missing data on education level (655 cases and 544 controls), we applied multiple imputation with the PROC MI procedure in SAS statistical software 9.1. We assumed that the education data were missing at random with respect to unmeasured covariates; whether education level was missing did not depend on any other unobserved or missing values (22). We used a logistic regression model (23) to predict education level for each of the geographic regions separately (North America, Europe, Latin America) using age, sex, race/ethnicity, study, and case/control status as the covariates. The logistic regression results to assess summary estimates for cigarettes and alcohol drinking for five imputations were combined by using the PROC MIANALYZE procedure in SAS statistical software.

Stratified analyses were conducted by cancer site (oral, pharynx, larynx), sex, age (<45 y, 45-60 y, ≥60 y), education (<high school, ≥high school), geographic region (Europe, North America, Latin America), type of controls (hospital based, population based), study size (<500 cases, ≥500 cases), BMI 2 to 5 y before diagnosis (<18.5 kg/m2, 18.5 to <25 kg/m2, 25 to <30 kg/m2, ≥30 kg/m2), and BMI at age 20 or 30 and after restriction to squamous cell carcinoma cases.

The PARs were estimated based on the formula AF = p(ec) × (OR − 1) / OR, where p(ec) is the proportion exposed among the cases (24). ORs adjusted for potential confounding factors were used in these equations. The CIs for the AFs were calculated from the lower and upper limit ORs. The PAR for tobacco and/or alcohol exposures (PARtotal) was estimated with the equation below where a00 = never tobacco/never alcohol users, a01 = never tobacco/ever alcohol users, a10 = ever tobacco/never alcohol users, and a11 = ever tobacco/ever alcohol users, m = total number of cases.

$\mathrm{PAR}_{\mathrm{total}}=1{-}[((a_{11}/m)/\mathrm{OR}_{11})+((a_{10}/m)/\mathrm{OR}_{10})+((a_{01}/m)/\mathrm{OR}_{01})+((a_{00}/m)/\mathrm{OR}_{00})]$

ORs from multivariate analysis were used. The PARs for the tobacco and alcohol were estimated as follows (25):

$\mathrm{PAR}_{\mathrm{tobacco\ and\ alcohol\ combined}}\mathrm{=PAR}_{\mathrm{tobacco}}\mathrm{+PAR}_{\mathrm{alcohol}}\mathrm{{-}PAR}_{\mathrm{total}}$
$\mathrm{PAR}_{\mathrm{tobacco\ alone}}\mathrm{=PAR}_{\mathrm{tobacco}}\mathrm{{-}PAR}_{\mathrm{tobacco\ and\ alcohol\ combined}}$
$\mathrm{PAR}_{\mathrm{alcohol\ alone}}\mathrm{=PAR}_{\mathrm{alcohol}}\mathrm{{-}PAR}_{\mathrm{tobacco\ and\ alcohol\ combined}}$

.

Characteristics of cases and controls are shown in Table 1. The Latin America and New York multicenter studies contributed the largest proportion of cases. There were a higher proportion of men among cases compared with the controls. The majority of cases and controls were European in ethnic origin. Cases had completed lower levels of education than the controls.

The ORs were 2.37 (95% CI, 1.66-3.39) for ever tobacco use among never alcohol drinkers, 1.06 (95% CI, 0.88-1.28) for ever alcohol use among never tobacco users, and 5.73 (95% CI, 3.62-9.06) for the joint effect according to the random effects model (results not shown). Thus, the joint effect between tobacco and alcohol was greater than expected under the multiplicative model for all head and neck cancers (ψ = 2.15; 95% CI, 1.53-3.04; Table 2). The ψ from the random effects model was not exactly equal to that calculated from the joint effects estimates [5.73 / (2.37 * 1.06) = 2.28 ≠ 2.15], possibly due to the coefficient allowing for unknown sources of heterogeneity in the random effects models. For the fixed effects model, the ORs were 2.17 for ever tobacco use among never alcohol drinkers, 0.98 for ever alcohol use among never tobacco users, 5.04 for the joint effect, and 2.38 for the ψ. Thus, the ψ calculated from the joint effects was similar to that of the ψ from the model [5.04 / (2.17 * 0.98) = 2.37 ≈ 2.38].

Table 2.

Tobacco and alcohol multiplicative interaction parameters and attributable risks for head and neck cancer and subsites

Cases, n (%)Controls, n (%)OR* (95% CI)PAR (95% CI)
Alcohol alone 831 (7.4) 1,587 (9.8) 1.06 (0.88-1.28) 4.0 (1.5-5.3)
Tobacco alone 673 (6.0) 3,653 (22.6) 2.37 (1.66-3.39) 33.0 (42.6-25.9)
Tobacco and alcohol 9,146 (81.6) 8,574 (53.1) 5.73 (3.62-9.06) 34.9 (17.2-48.0)
Total 11,211 16,152 ψ = 2.15 (1.53-3.04) 72.0 (61.2-79.1)
By subsite
Oral cavity
Alcohol alone 221 (7.4) 1,587 (9.8) 0.79 (0.60-1.04) −1.1 (−11.4 to 3.7)
Tobacco alone 191 (6.4) 3,653 (22.6) 1.74 (1.10-2.76) 24.8 (19.6-31.1)
Tobacco and alcohol 2,354 (78.7) 8,574 (53.1) 4.78 (2.59-8.81) 39.9 (24.9-51.4)
Total 2,992 16,152 ψ = 3.09 (1.82-5.23) 63.7 (44.7-74.7)
Pharynx
Alcohol alone 247 (6.1) 1,587 (9.8) 1.28 (0.91-1.80) 5.6 (1.9-7.3)
Tobacco alone 289 (7.2) 3,653 (22.6) 1.91 (1.39-2.62) 24.3 (30.7-19.2)
Tobacco and alcohol 3,321 (82.2) 8,574 (53.1) 5.42 (3.21-9.16) 41.6 (25.0-53.7)
Total 4,038 16,152 ψ = 1.90 (1.41-2.56) 71.5 (57.6-80.2)
Larynx
Alcohol alone 284 (9.6) 1,308 (10.0) 1.21 (0.77-1.92) 2.9 (−0.3 to 4.4)
Tobacco alone 89 (3.0) 3,041 (23.2) 6.76 (4.58-9.96) 52.2 (77.8-36.0)
Tobacco and alcohol 2,541 (85.9) 6,850 (52.2) 14.22 (8.26-24.46) 33.4 (4.5-52.1)
Total 2,959 13,130 ψ = 1.62 (0.85-3.09) 88.5 (82.1-92.4)
By sex
Alcohol alone 389 (17.3) 608 (13.4) 0.93 (0.73-1.19) 1.6 (−4.4 to 5.1)
Tobacco alone 247 (11.0) 1,348 (29.6) 2.83 (1.97-4.06) 31.5 (29.0-33.6)
Tobacco and alcohol 1,247 (55.4) 1,181 (25.9) 6.66 (3.89-11.41) 24.3 (16.4-31.2)
Total 2,252 4,553 ψ = 2.05 (1.35-3.11) 57.4 (45.6-65.3)
Alcohol alone 442 (4.9) 979 (8.4) 1.07 (0.80-1.44) 0.9 (−3.7 to 3.2)
Tobacco alone 426 (4.8) 2,305 (19.9) 2.06 (1.34-3.18) 29.5 (21.2-41.9)
Tobacco and alcohol 7,899 (88.2) 7,393 (63.7) 5.19 (3.11-8.65) 43.6 (21.6-58.4)
Total 8,959 11,599 ψ = 2.36 (1.66-3.36) 74.0 (59.9-82.8)
By age
Head and neck cancer, <45 y
Alcohol alone 65 (6.2) 213 (9.8) 0.71 (0.46-1.09) −10.8 (−34.8 to 1.8)
Tobacco alone 130 (12.5) 547 (25.2) 1.01 (0.56-1.82) 15.2 (−0.2 to 20.8)
Tobacco and alcohol 745 (71.4) 1,036 (47.7) 2.17 (1.22-3.86) 29.1 (28.4-34.4)
Total 1,043 2,172 ψ = 2.93 (1.42-6.02) 33.5 (−6.7 to 56.8)
Head and neck cancer, 45-60 y
Alcohol alone 330 (6.6) 687 (9.7) 1.22 (0.88-1.69) 2.5 (−2.2 to 4.6)
Tobacco alone 286 (5.7) 1,650 (23.3) 2.7 (1.71-4.25) 31.3 (23.8-41.0)
Tobacco and alcohol 4,241 (84.3) 3,818 (53.9) 6.65 (3.63-12.16) 43.0 (24.1-56.4)
Total 5,028 7,079 ψ = 1.93 (1.40-2.66) 76.8 (63.1-84.8)
Head and neck cancer, >60 y
Alcohol alone 436 (8.5) 687 (10.0) 0.98 (0.75-1.30) 3.2 (0.0-5.0)
Tobacco alone 257 (5.0) 1,456 (21.1) 2.68 (1.94-3.70) 35.1 (26.1-48.5)
Tobacco and alcohol 4,160 (80.9) 3,720 (53.9) 6.02 (3.94-9.22) 34.4 (14.3-48.4)
Total 5,140 6,901 ψ = 2.19 (1.46-3.29) 72.7 (62.8-79.5)
By geographic region
Alcohol alone 208 (5.0) 542 (7.0) 1.21 (0.75-1.96) 4.6 (−2.7 to 7.4)
Tobacco alone 216 (5.2) 2,101 (27.2) 3.72 (2.24-6.18) 33.2 (17.2-68.3)
Tobacco and alcohol 3,641 (87.2) 4,225 (54.6) 11.72 (5.58-24.59) 46.5 (7.1-65.8)
Total 4,177 7,736 ψ = 2.41 (1.35-4.30) 84.3 (72.6-90.3)
Head and neck cancer, North America
Alcohol alone 403 (9.3) 741 (12.4) 0.98 (0.74-1.30) 4.3 (−3.5 to 9.2)
Tobacco alone 380 (8.7) 1,162 (19.4) 1.48 (0.95-2.30) 22.6 (15.6-34.9)
Tobacco and alcohol 3,205 (73.6) 3,026 (50.5) 2.84 (2.05-3.94) 23.5 (2.7-37.4)
Total 4,352 5,991 ψ = 1.98 (1.12-3.49) 50.5 (34.2-62.2)
Head and neck cancer, Latin America
Alcohol alone 220 (8.2) 304 (12.5) 1.07 (0.49-2.36) 4.3 (−0.2 to 5.6)
Tobacco alone 77 (2.9) 390 (16.1) 3.35 (1.69-6.65) 32.9 (26.3-40.2)
Tobacco and alcohol 2,300 (85.8) 1,323 (54.6) 9.78 (5.36-17.85) 45.7 (30.1-57.7)
Total 2,682 2,425 ψ = 2.87 (1.16-7.06) 82.9 (70.1-89.6)
Cases, n (%)Controls, n (%)OR* (95% CI)PAR (95% CI)
Alcohol alone 831 (7.4) 1,587 (9.8) 1.06 (0.88-1.28) 4.0 (1.5-5.3)
Tobacco alone 673 (6.0) 3,653 (22.6) 2.37 (1.66-3.39) 33.0 (42.6-25.9)
Tobacco and alcohol 9,146 (81.6) 8,574 (53.1) 5.73 (3.62-9.06) 34.9 (17.2-48.0)
Total 11,211 16,152 ψ = 2.15 (1.53-3.04) 72.0 (61.2-79.1)
By subsite
Oral cavity
Alcohol alone 221 (7.4) 1,587 (9.8) 0.79 (0.60-1.04) −1.1 (−11.4 to 3.7)
Tobacco alone 191 (6.4) 3,653 (22.6) 1.74 (1.10-2.76) 24.8 (19.6-31.1)
Tobacco and alcohol 2,354 (78.7) 8,574 (53.1) 4.78 (2.59-8.81) 39.9 (24.9-51.4)
Total 2,992 16,152 ψ = 3.09 (1.82-5.23) 63.7 (44.7-74.7)
Pharynx
Alcohol alone 247 (6.1) 1,587 (9.8) 1.28 (0.91-1.80) 5.6 (1.9-7.3)
Tobacco alone 289 (7.2) 3,653 (22.6) 1.91 (1.39-2.62) 24.3 (30.7-19.2)
Tobacco and alcohol 3,321 (82.2) 8,574 (53.1) 5.42 (3.21-9.16) 41.6 (25.0-53.7)
Total 4,038 16,152 ψ = 1.90 (1.41-2.56) 71.5 (57.6-80.2)
Larynx
Alcohol alone 284 (9.6) 1,308 (10.0) 1.21 (0.77-1.92) 2.9 (−0.3 to 4.4)
Tobacco alone 89 (3.0) 3,041 (23.2) 6.76 (4.58-9.96) 52.2 (77.8-36.0)
Tobacco and alcohol 2,541 (85.9) 6,850 (52.2) 14.22 (8.26-24.46) 33.4 (4.5-52.1)
Total 2,959 13,130 ψ = 1.62 (0.85-3.09) 88.5 (82.1-92.4)
By sex
Alcohol alone 389 (17.3) 608 (13.4) 0.93 (0.73-1.19) 1.6 (−4.4 to 5.1)
Tobacco alone 247 (11.0) 1,348 (29.6) 2.83 (1.97-4.06) 31.5 (29.0-33.6)
Tobacco and alcohol 1,247 (55.4) 1,181 (25.9) 6.66 (3.89-11.41) 24.3 (16.4-31.2)
Total 2,252 4,553 ψ = 2.05 (1.35-3.11) 57.4 (45.6-65.3)
Alcohol alone 442 (4.9) 979 (8.4) 1.07 (0.80-1.44) 0.9 (−3.7 to 3.2)
Tobacco alone 426 (4.8) 2,305 (19.9) 2.06 (1.34-3.18) 29.5 (21.2-41.9)
Tobacco and alcohol 7,899 (88.2) 7,393 (63.7) 5.19 (3.11-8.65) 43.6 (21.6-58.4)
Total 8,959 11,599 ψ = 2.36 (1.66-3.36) 74.0 (59.9-82.8)
By age
Head and neck cancer, <45 y
Alcohol alone 65 (6.2) 213 (9.8) 0.71 (0.46-1.09) −10.8 (−34.8 to 1.8)
Tobacco alone 130 (12.5) 547 (25.2) 1.01 (0.56-1.82) 15.2 (−0.2 to 20.8)
Tobacco and alcohol 745 (71.4) 1,036 (47.7) 2.17 (1.22-3.86) 29.1 (28.4-34.4)
Total 1,043 2,172 ψ = 2.93 (1.42-6.02) 33.5 (−6.7 to 56.8)
Head and neck cancer, 45-60 y
Alcohol alone 330 (6.6) 687 (9.7) 1.22 (0.88-1.69) 2.5 (−2.2 to 4.6)
Tobacco alone 286 (5.7) 1,650 (23.3) 2.7 (1.71-4.25) 31.3 (23.8-41.0)
Tobacco and alcohol 4,241 (84.3) 3,818 (53.9) 6.65 (3.63-12.16) 43.0 (24.1-56.4)
Total 5,028 7,079 ψ = 1.93 (1.40-2.66) 76.8 (63.1-84.8)
Head and neck cancer, >60 y
Alcohol alone 436 (8.5) 687 (10.0) 0.98 (0.75-1.30) 3.2 (0.0-5.0)
Tobacco alone 257 (5.0) 1,456 (21.1) 2.68 (1.94-3.70) 35.1 (26.1-48.5)
Tobacco and alcohol 4,160 (80.9) 3,720 (53.9) 6.02 (3.94-9.22) 34.4 (14.3-48.4)
Total 5,140 6,901 ψ = 2.19 (1.46-3.29) 72.7 (62.8-79.5)
By geographic region
Alcohol alone 208 (5.0) 542 (7.0) 1.21 (0.75-1.96) 4.6 (−2.7 to 7.4)
Tobacco alone 216 (5.2) 2,101 (27.2) 3.72 (2.24-6.18) 33.2 (17.2-68.3)
Tobacco and alcohol 3,641 (87.2) 4,225 (54.6) 11.72 (5.58-24.59) 46.5 (7.1-65.8)
Total 4,177 7,736 ψ = 2.41 (1.35-4.30) 84.3 (72.6-90.3)
Head and neck cancer, North America
Alcohol alone 403 (9.3) 741 (12.4) 0.98 (0.74-1.30) 4.3 (−3.5 to 9.2)
Tobacco alone 380 (8.7) 1,162 (19.4) 1.48 (0.95-2.30) 22.6 (15.6-34.9)
Tobacco and alcohol 3,205 (73.6) 3,026 (50.5) 2.84 (2.05-3.94) 23.5 (2.7-37.4)
Total 4,352 5,991 ψ = 1.98 (1.12-3.49) 50.5 (34.2-62.2)
Head and neck cancer, Latin America
Alcohol alone 220 (8.2) 304 (12.5) 1.07 (0.49-2.36) 4.3 (−0.2 to 5.6)
Tobacco alone 77 (2.9) 390 (16.1) 3.35 (1.69-6.65) 32.9 (26.3-40.2)
Tobacco and alcohol 2,300 (85.8) 1,323 (54.6) 9.78 (5.36-17.85) 45.7 (30.1-57.7)
Total 2,682 2,425 ψ = 2.87 (1.16-7.06) 82.9 (70.1-89.6)

NOTE: ψ = multiplicative interaction parameter. Note that where PAR is negative, PARalcohol < PARtobacco and alcohol, suggesting that the effect of alcohol was mainly with tobacco. The negative PAR does not suggest that alcohol prevented any cancers; the main effects for alcohol overall and among never tobacco users were not protective.

*

ORs were adjusted for age, sex, education, race/ethnicity, and study center.

PARalcohol alone = PARalcohol − PARtobacco and alcohol; PARtobacco alone = PARtobacco − PARtobacco and alcohol; PARtobacco and alcohol = PARtobacco + PARalcohol − PARtotal; PARtotal = 1 − [((a11/m)/OR11) + ((a10/m)/OR10) + ((a01/m)/OR01) + ((a00/m)/OR00)] (25). Where a = number of exposed cases, m = total number of cases. First subscript refers to tobacco use (0 = never tobacco user, 1 = ever tobacco user), and second subscript refers to alcohol use (0 = never alcohol drinker, 1 = ever alcohol drinker).

By subsite, joint effects greater than multiplicative were observed for oral cavity cancer (ψ = 3.09; 95% CI, 1.82-5.23) and pharyngeal cancer (ψ = 1.90; 95% CI, 1.41-2.56; Table 2). For laryngeal cancer, the ψ was consistent with an interaction that is greater than multiplicative but the CI included the null value (ψ = 1.62; 95% CI, 0.85-3.09). A more than additive interaction was detected between tobacco and alcohol for laryngeal cancer risk (RERI = 4.97; 95% CI, 3.16-6.78; AP = 0.42; 95% CI, 0.32-0.52; SI = 1.85; 95% CI, 1.50-2.26; data not shown). The study-specific ψs are shown for head and neck cancer in Fig. 1 and for the subsites in Supplementary Figs. S1 to S3. Statistically significant differences were not observed in the ψs for head and neck cancer, oral cavity cancer, pharyngeal cancer, or laryngeal cancer, in the different strata of education, study size, source of controls, or BMI (results not shown). The analysis restricted to squamous cell carcinomas (8,034 cases) resulted in a ψ similar to the overall analysis (ψ = 2.27; 95% CI, 1.52-3.38). Adjustment for family history of head and neck cancer or ever passive smoking did not alter the magnitude of the ORs.

Figure 1.

Multiplicative interaction parameters (ψ) for tobacco (cigarette, cigar, pipe, snuff, chewing tobacco) and alcohol by study and combined using INHANCE pooled data version 1.1. ORs used to calculate ψ were adjusted for age, sex, race/ethnicity, and education level.

Figure 1.

Multiplicative interaction parameters (ψ) for tobacco (cigarette, cigar, pipe, snuff, chewing tobacco) and alcohol by study and combined using INHANCE pooled data version 1.1. ORs used to calculate ψ were adjusted for age, sex, race/ethnicity, and education level.

Close modal

The PAR for tobacco and alcohol, alone and overlapped, was 72% (95% CI, 61-79) for head and neck cancer, of which 4% was for alcohol alone, 33% was for tobacco alone, and 35% was for overlap between tobacco and alcohol (Table 2). Comparing across cancer subsites, the PAR for oral cavity cancer was lower (64%; 95% CI, 45-75) than for laryngeal cancer (89%; 95% CI, 82-92), whereas the PAR for pharyngeal cancer was intermediate to those of oral cavity and laryngeal cancer. For women, the PAR for head and neck cancer seemed to be lower than for men. The overall PAR is probably closer to the PAR for men because the majority of cases and controls are men. The PARs due to the overlap of tobacco and alcohol were greater than the PARs due to the effects of tobacco alone on the risk of head and neck cancer among men, but not for women. The estimated PAR due to the effect of alcohol alone was negative for oral cavity, although as indicated by the CIs this is consistent with either no effect of alcohol alone (PAR = 0%) or a very small effect.

When stratified by age and by geographic region, the ψs were fairly similar across age strata, but the PARs were substantially lower among subjects <45 years of age compared with subjects who were 45 or older. The PARs were also lower in North America, relative to the PARs in Europe and Latin America.

In Table 3, the ORs and PARs for head and neck cancer by tobacco and alcohol frequency categories are shown. The cancer risk was greatest for individuals in the high frequency categories for tobacco and alcohol use. An interaction was suggested between the frequency of tobacco and alcohol use on the risk of head and neck cancer (P < 0.01), oral cavity cancer (P < 0.01), pharyngeal cancer (P < 0.01), but not on the risk of laryngeal cancer (P = 0.63). The PARs indicate that the greatest proportion of the head and neck cancers was attributable to heavy drinking (≥3 drinks/day) among smokers.

Table 3.

ORs and population AFs for tobacco and alcohol frequency categories, for head and neck cancer and subsites

TobaccoAlcoholCases (%)Controls (%)OR* (95% CI)PAR (95% CI)
Never Never 5.2 14.8 1.00
1-20 cigs/day Never 5.1 7.7 2.20 (1.57-3.09) 2.9 (1.9-3.6)
>20 cigs/day Never 2.5 2.4 4.15 (2.44-7.07) 2.0 (1.5-2.2)
Never 1-2 drinks/day 4.4 16.1 1.03 (0.84-1.25) 0.1 (−0.9 to 0.9)
1-20 cigs/day 1-2 drinks/day 18.4 21.5 3.09 (2.13-4.50) 12.8 (10.0-14.7)
>20 cigs/day 1-2 drinks/day 10.6 8.2 4.81 (3.21-7.20) 8.7 (7.5-9.4)
Never ≥3 drinks/day 1.5 6.2 1.91 (1.27-2.87) 0.7 (0.3-1.0)
1-20 cigs/day ≥3 drinks/day 27.3 15.2 9.92 (6.36-15.46) 25.2 (23.6-26.2)
>20 cigs/day ≥3 drinks/day 25.1 7.8 14.23 (8.30-24.40) 24.0 (22.7-24.8)
Total  10,851 15,751  76.3 (66.8-82.8)
P for interaction   <0.01
Oral cavity cancer
Never Never 7.9 14.8 1.00
1-20 cigs/day Never 5.7 7.7 1.72 (1.17-2.53) 2.4% (0.8-3.4)
>20 cigs/day Never 2.4 3.13 (1.14-8.59) 1.4% (0.2-1.8)
Never 1-2 drinks/day 5.1 16.1 0.88 (0.65-1.20) −0.7% (−2.8 to 0.9)
1-20 cigs/day 1-2 drinks/day 19.2 21.5 2.72 (1.47-5.04) 12.2% (6.1-15.4)
>20 cigs/day 1-2 drinks/day 10.1 8.2 3.23 (1.84-5.67) 7.0% (4.6-8.3)
Never ≥3 drinks/day 0.9 6.2 1.05 (0.62-1.77) 0.0% (−0.6 to 0.4)
1-20 cigs/day ≥3 drinks/day 23.9 15.2 9.60 (5.04-18.28) 21.4% (19.2-22.6)
>20 cigs/day ≥3 drinks/day 25.1 7.8 15.49 (7.24-33.14) 23.5% (21.6-24.4)
Total  2,875 15,751  67.1% (49.3-77.2)
P for interaction   <0.01
Pharyngeal cancer
Never Never 4.6 14.8 1.00
1-20 cigs/day Never 4.3 7.7 1.90 (1.34-2.68) 2.0 (1.1-2.7)
>20 cigs/day Never 2.1 2.4 2.83 (1.66-4.82) 1.3 (0.8-1.6)
Never 1-2 drinks/day 5.2 16.1 1.26 (0.92-1.73) 1.1 (−0.5 to 2.2)
1-20 cigs/day 1-2 drinks/day 16.3 21.5 2.57 (1.72-3.83) 10.0 (6.8-12.1)
>20 cigs/day 1-2 drinks/day 10.2 8.2 4.10 (2.66-6.32) 7.7 (6.4-8.6)
Never ≥3 drinks/day 1.9 6.2 2.94 (1.73-5.02) 1.3 (0.8-1.5)
1-20 cigs/day ≥3 drinks/day 28.9 15.2 11.37 (6.50-19.89) 26.4 (24.5-27.5)
>20 cigs/day ≥3 drinks/day 26.5 7.8 14.29 (7.26-28.15) 24.6 (22.8-25.5)
Total  3,899 15,751  74.3 (62.7-81.7)
P for interaction   <0.01
Laryngeal cancer
Never Never 1.6 14.9 1.00
1-20 cigs/day Never 5.9 7.9 6.06 (4.03-9.11) 4.9 (4.4-5.2)
>20 cigs/day Never 3.9 2.2 12.83 (7.95-20.71) 3.6 (3.4-3.7)
Never 1-2 drinks/day 1.8 16.3 1.20 (0.72-2.02) 0.3 (−0.7 to 0.9)
1-20 cigs/day 1-2 drinks/day 20.8 21.3 8.33 (5.07-13.69) 18.3 (16.7-19.3)
>20 cigs/day 1-2 drinks/day 12.7 7.3 16.91 (9.66-29.61) 11.9 (11.4-12.3)
Never ≥3 drinks/day 1.2 6.6 3.16 (1.23-8.16) 0.8 (0.2-1.0)
1-20 cigs/day ≥3 drinks/day 28.8 16.5 18.94 (10.64-33.71) 27.3 (26.1-27.9)
>20 cigs/day ≥3 drinks/day 23.4 7.1 36.87 (16.60-81.90) 22.8 (22.0-23.2)
Total  2,901 12,935  89.9 (83.5-93.5)
P for interaction   0.63
TobaccoAlcoholCases (%)Controls (%)OR* (95% CI)PAR (95% CI)
Never Never 5.2 14.8 1.00
1-20 cigs/day Never 5.1 7.7 2.20 (1.57-3.09) 2.9 (1.9-3.6)
>20 cigs/day Never 2.5 2.4 4.15 (2.44-7.07) 2.0 (1.5-2.2)
Never 1-2 drinks/day 4.4 16.1 1.03 (0.84-1.25) 0.1 (−0.9 to 0.9)
1-20 cigs/day 1-2 drinks/day 18.4 21.5 3.09 (2.13-4.50) 12.8 (10.0-14.7)
>20 cigs/day 1-2 drinks/day 10.6 8.2 4.81 (3.21-7.20) 8.7 (7.5-9.4)
Never ≥3 drinks/day 1.5 6.2 1.91 (1.27-2.87) 0.7 (0.3-1.0)
1-20 cigs/day ≥3 drinks/day 27.3 15.2 9.92 (6.36-15.46) 25.2 (23.6-26.2)
>20 cigs/day ≥3 drinks/day 25.1 7.8 14.23 (8.30-24.40) 24.0 (22.7-24.8)
Total  10,851 15,751  76.3 (66.8-82.8)
P for interaction   <0.01
Oral cavity cancer
Never Never 7.9 14.8 1.00
1-20 cigs/day Never 5.7 7.7 1.72 (1.17-2.53) 2.4% (0.8-3.4)
>20 cigs/day Never 2.4 3.13 (1.14-8.59) 1.4% (0.2-1.8)
Never 1-2 drinks/day 5.1 16.1 0.88 (0.65-1.20) −0.7% (−2.8 to 0.9)
1-20 cigs/day 1-2 drinks/day 19.2 21.5 2.72 (1.47-5.04) 12.2% (6.1-15.4)
>20 cigs/day 1-2 drinks/day 10.1 8.2 3.23 (1.84-5.67) 7.0% (4.6-8.3)
Never ≥3 drinks/day 0.9 6.2 1.05 (0.62-1.77) 0.0% (−0.6 to 0.4)
1-20 cigs/day ≥3 drinks/day 23.9 15.2 9.60 (5.04-18.28) 21.4% (19.2-22.6)
>20 cigs/day ≥3 drinks/day 25.1 7.8 15.49 (7.24-33.14) 23.5% (21.6-24.4)
Total  2,875 15,751  67.1% (49.3-77.2)
P for interaction   <0.01
Pharyngeal cancer
Never Never 4.6 14.8 1.00
1-20 cigs/day Never 4.3 7.7 1.90 (1.34-2.68) 2.0 (1.1-2.7)
>20 cigs/day Never 2.1 2.4 2.83 (1.66-4.82) 1.3 (0.8-1.6)
Never 1-2 drinks/day 5.2 16.1 1.26 (0.92-1.73) 1.1 (−0.5 to 2.2)
1-20 cigs/day 1-2 drinks/day 16.3 21.5 2.57 (1.72-3.83) 10.0 (6.8-12.1)
>20 cigs/day 1-2 drinks/day 10.2 8.2 4.10 (2.66-6.32) 7.7 (6.4-8.6)
Never ≥3 drinks/day 1.9 6.2 2.94 (1.73-5.02) 1.3 (0.8-1.5)
1-20 cigs/day ≥3 drinks/day 28.9 15.2 11.37 (6.50-19.89) 26.4 (24.5-27.5)
>20 cigs/day ≥3 drinks/day 26.5 7.8 14.29 (7.26-28.15) 24.6 (22.8-25.5)
Total  3,899 15,751  74.3 (62.7-81.7)
P for interaction   <0.01
Laryngeal cancer
Never Never 1.6 14.9 1.00
1-20 cigs/day Never 5.9 7.9 6.06 (4.03-9.11) 4.9 (4.4-5.2)
>20 cigs/day Never 3.9 2.2 12.83 (7.95-20.71) 3.6 (3.4-3.7)
Never 1-2 drinks/day 1.8 16.3 1.20 (0.72-2.02) 0.3 (−0.7 to 0.9)
1-20 cigs/day 1-2 drinks/day 20.8 21.3 8.33 (5.07-13.69) 18.3 (16.7-19.3)
>20 cigs/day 1-2 drinks/day 12.7 7.3 16.91 (9.66-29.61) 11.9 (11.4-12.3)
Never ≥3 drinks/day 1.2 6.6 3.16 (1.23-8.16) 0.8 (0.2-1.0)
1-20 cigs/day ≥3 drinks/day 28.8 16.5 18.94 (10.64-33.71) 27.3 (26.1-27.9)
>20 cigs/day ≥3 drinks/day 23.4 7.1 36.87 (16.60-81.90) 22.8 (22.0-23.2)
Total  2,901 12,935  89.9 (83.5-93.5)
P for interaction   0.63
*

ORs were adjusted on age, sex, education, race/ethnicity, and study center.

The total number of cases and controls is different from Table 2 due to missing values for the tobacco and alcohol frequency categories.

Our results confirm a greater than multiplicative joint effect between tobacco and alcohol on head and neck cancer risk, particularly for oral and pharyngeal cancers. Heterogeneity in the multiplicative interaction parameters was not detected in the analysis stratified by anatomic subsite, sex, education level, geographic region, or BMI. Tobacco smoking and alcohol drinking are responsible for a large proportion of oral and pharyngeal cancers, and an even greater proportion of laryngeal cancers. Additionally, tobacco smoking and alcohol drinking account for a higher proportion of head and neck cancers among men than among women. Generally for men, tobacco and alcohol combined accounted for a larger proportion of cases than smoking or drinking alone, whereas for women the effect of tobacco alone accounted for a larger proportion of cases than the overlap between tobacco and alcohol, or alcohol alone. Our estimates for PARs are consistent with previous estimates from a large-scale case-control study on oral and pharyngeal cancers (not included in current INHANCE data set), which reported PARs of 80% for men, 61% for women, and 74% overall (26). It will be important to determine the risk factors for at least 28% of head and neck cancer patients (42% for women, 26% for men) and specifically for at least 36% of oral cavity cancer patients, whose cancer cannot be attributed to tobacco or alcohol.

The differences observed for the multiplicative interaction parameter did not necessarily translate to differences in the PARs, or vice versa. The ψ seemed to be greater for oral cavity cancer than for laryngeal cancer, but the PAR for oral cavity cancer was lower than that of laryngeal cancer. The difference stemmed from the greater ORs observed for laryngeal cancer for subjects who smoked tobacco (regardless of whether they drank alcohol or not), relative to oral cavity and pharyngeal cancers. Similarly, although differences in the ψs were not observed by geographic region, we observed a statistically significant lower PAR for tobacco and alcohol in North America relative to Latin America and Europe. The source of this difference may be the larger proportion of cases that drank alcohol and smoked tobacco in Latin America and Europe in comparison with North America and the higher ORs observed for tobacco and tobacco and alcohol combined. The difference in risk for tobacco may reflect the differences in the types of cigarettes and tobacco used. This may point to a more important role for other risk factors in North America. Studies of HPV in North America provide some preliminary evidence that this may be true (27, 28), in contrast to a study including cases mostly from Europe (12).

Tobacco and alcohol seemed to be responsible for a smaller proportion of the head and neck cancer cases in individuals who were younger (<45 years) compared with the older age groups. The number of cases and controls in subjects <45 years was limited (although larger than any previous study), as reflected in the OR estimate for smoking tobacco. The younger subjects also had a lower proportion of cases that drank alcohol and smoked tobacco. It is possible that other head and neck cancer risk factors, such as genetic susceptibility, HPV infection, or some nutritional factors, are more important risk factors in these groups, although further work is required to clarify this.

Although the PAR for the effect of alcohol alone was negative for oral cavity cancer and among young subjects, this should not be interpreted as evidence that alcohol prevented any cancers. The main-effect OR for alcohol drinking overall and among never tobacco users was not <1 for head and neck cancer or any of the subsites. In our previous analysis, we showed that alcohol is an independent risk factor among never tobacco users (20). The CIs of the PAR for the effect of alcohol alone generally included the null value of 0%. These results suggest that either alcohol is acting only through its interaction effect with tobacco or that the PAR of alcohol alone is minimal and difficult to detect without greater statistical power. Significant PARs for the effect of alcohol alone were detected for the larger case groups of head and neck cancer and pharyngeal cancer, favoring the latter explanation.

There are several limitations in our pooled analysis. One potential source of bias is that regional differences in social acceptance of tobacco and alcohol habits may have influenced how a subject responded to questions in a face-to-face interview. Our adjustment for study center may have partially addressed this limitation. Recall bias was also a potential limitation because in all of the studies, the subjects knew their disease status when they were interviewed. We explored whether there were differences in the ψ by the type of control subjects (hospital based or population based) because hospital-based controls but not population-based controls could also have a recall similar to that of cases depending on the type of disease. The estimates by type of control were not different, suggesting a minimal role for recall bias.

Another limitation is that we are unable to adjust for unmeasured potential confounders such as HPV infection and nutritional factors. Low fruit and vegetable intake is a suspected risk factor of head and neck cancer (29). However, low fruit intake and low vegetable intake may increase risk by ∼2-fold (30), which could not explain the magnitude of the ORs observed in some of the higher combination categories of tobacco and alcohol intake. It would be of interest to examine the three-way interaction for tobacco use, alcohol use, and low fruit and vegetable intake on head and neck cancer risk. HPV infection is thought to be a stronger risk factor for oropharyngeal cancers (31), but the multiplicative interaction parameters were not particularly stronger for pharyngeal cancer. However, our pharyngeal group included hypopharyngeal cases in addition to oropharyngeal cases. Because hypopharyngeal cancer has very strong associations with tobacco and alcohol, this may have resulted in higher PARs than may have been seen for a pharyngeal group restricted to oropharyngeal cancers. In any case, we believe it is unlikely that our results are due to confounding by HPV. We hope to explore this area in the future when HPV data may be available with a standardized measure across the INHANCE studies.

The major strength of our pooled analyses was the assembling of a very large series of head and neck cancer patients and control subjects, which allowed us to examine in detail the interaction between tobacco smoking and alcohol drinking, and explore differences in the interaction by cancer subsite, geographic region, and sex. Our results confirm that the joint effect between tobacco and alcohol is more than expected under the multiplicative model for head and neck cancer and the oral and pharyngeal subsites. Tobacco and alcohol are responsible for a large proportion of laryngeal cancers and head and neck cancer among men. However, a substantial proportion of head and neck cancers cannot be attributed to either tobacco or alcohol, particularly for oral cavity cancer, among women and below age 45.

No potential conflicts of interest were disclosed.

For cigarettes, ever smoking was defined as smoked ≥100 cigarette in a lifetime (Central Europe, Los Angeles, North Carolina, Puerto Rico, Seattle, Houston, and Boston studies); smoked 1 cigarette/day for ≥1 year (International Multicenter, Tampa, Latin America, Milan, Aviano, Italy multicenter, and Switzerland studies); smoked 0.5 pack/week for ≥1 year (Iowa study), once a day for 1 year of time (New York); and ever smoked (Rome study).

For cigars and pipes, ever smoking was defined as smoked cigars or pipes for ≥6 months (Seattle, North Carolina, and Puerto Rico studies); smoked 1 cigar or 1 pipeful of tobacco/month for ≥6 months (Los Angeles study); smoked 1 cigar or pipe/day for ≥1 year (Milan, Aviano, Italy, Switzerland, Latin America); smoked cigars or pipes “regularly” (Central Europe studies); once a day for 1 year of time (New York study); ever used cigars or pipes (Houston study); 1 cigar or 1 pipefuls of tobacco a week for ≥1 year (Iowa); smoked daily for >1 year (International Multicenter study); smoked a cigar or pipe once a day for ≥1 year (Tampa study); ever smoked 12 ounces of pipe tobacco or smoked 1 cigar/week for 1 year (Boston study); and ever smoked cigars or pipes (Rome study).

The definitions of ever chewing and ever use of snuff differed across studies: ever use of snuff or chew for ≥6 months (Seattle, North Carolina, and Puerto Rico studies); 1 small can of snuff or 1 pouch of chewing tobacco per week for ≥1 year (Iowa study); use chew or snuff once per day for ≥1 year (Tampa study); chewed daily tobacco, betel quid, areca nut, and pan masala or snuffed tobacco daily for ≥1 year (International Multicenter studies); 1 plug of tobacco or 1 pinch of snuff of tobacco/month for ≥6 months (Los Angeles study); at least once a week for at least one year (New York); ever use of snuff or chew (Houston and Rome studies); and ever chewed smokeless tobacco (Boston study).

The definitions of ever alcohol drinking were as follows: “ever” consumed alcohol (Central Europe, Aviano, Milan, Italy Multicenter, Switzerland, New York, Boston, and Rome studies); >4 drinks in a year (Seattle study); ≥1 drink/month for ≥6 months in a lifetime (Los Angeles study); ≥12 drinks of any kind of alcohol in a lifetime (Puerto Rico study); ≥once/month (Multicenter, Latin America studies); average ≥1 drink/week for ≥1 year (Iowa study); ≥once/week for ≥1 year (Tampa and Houston study); and ≥4 times/month of beer, wine, or liquor (North Carolina study).

The volume specification for alcoholic beverages by type differed across studies. For example, a glass of wine was defined as 100 to 150 mL in the European studies, whereas the North American studies defined a wine glass as 3.6 to 5 ounces. To estimate cumulative alcohol consumption (mL of beverage over a lifetime) for each beverage type, we converted into milliliters the beverage volume specified in the questionnaire for the alcoholic beverage type and multiplied this value by the number of beverage type consumed per week and the duration of beverage type consumption reported. We then applied the volume percentage of pure ethanol by beverage type [5% for beer, 12% for wine, 40% for liquor, and 40% for aperitifs to the beverage volume (32)] to estimate the cumulative consumption of pure ethanol for each subject in mL. We then divided the cumulative consumption of pure ethanol by 15.6 mL, the mean volume of pure ethanol per drink across all alcoholic beverage types for the 15 studies, to calculate the lifetime number of standardized drinks consumed for each subject (i.e., one standardized drink contains 15.6 mL of pure ethanol). For the overall frequency of alcohol drinking (i.e., the number of drinks/day), the frequency of consumption of each alcoholic beverage type was weighted by the corresponding duration. For the Iowa and Tampa studies, data on duration by type of alcoholic beverage were not available; thus, the average of the frequency of all alcoholic beverage types within those studies was used as the overall frequency.

Grant support: NIH, National Cancer Institute grant R03CA113157. S. Chuang was supported by a Special Training Award from the IARC.

Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The individual studies were funded by the following grants:

1. Milan study: Italian Association for Research on Cancer.

2. Aviano and Italy Multicenter studies: Italian Association for Research on Cancer, Italian League Against Cancer, and Italian Ministry of Research.

3. Swiss study: Swiss League against Cancer and the Swiss Research against Cancer/Oncosuisse (KFS-700 and OCS-1633).

4. Central Europe study: World Cancer Research Fund and the European Commission's INCO-COPERNICUS Program (Contract No. IC15-CT98-0332).

5. New York study: NIH grants P01CA068384 and K07CA104231.

6. Seattle study: NIH grants R01CA048896 and R01DE012609.

7. Boston study: NIH grants R01CA078609 and R01CA100679.

8. Iowa study: NIH grants R01DE11979 and R01DE13110, NIH Fogarty International Research Collaboration Award TW01500, and Veterans Affairs Merit Review Funds.

9. North Carolina study: NIH grants R01CA61188 and P30ES010126.

10. Tampa study: NIH grants P01CA068384 and K07CA104231.

11. Los Angeles study: NIH grants P50CA90388, R01DA11386, R03CA77954, T32CA09142, U01CA96134, and R21ES011667, as well as the Alper Research Program for Environmental Genomics of the University of California at Los Angeles Jonsson Comprehensive Cancer Center.

12. Houston study: NIH grants R01ES11740 and R01CA100264.

13. Puerto Rico study: jointly funded by National Cancer Institute and National Institute of Dental and Craniofacial Research intramural programs.

14. Latin America study: Fondo para la Investigacion Cientifica y Tecnologica Argentina, IMIM (Barcelona), Fundação de Amparo à Pesquisa no Estado de São Paulo No 01/01768-2, and European Commission (IC18-CT97-0222).

15. IARC Multicenter study: Fondo de Investigaciones Sanitarias of the Spanish Government (FIS 97/0024, FIS 97/0662, and BAE 01/5013), International Union Against Cancer, and Yamagiwa-Yoshida Memorial International Cancer Study Grant.

1
Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: cancer incidence, mortality and prevalence worldwide, version 2.0. IARC Cancer Base No. 5. Lyon (France): IARC Press; 2004.
2
Tobacco smoke and involuntary smoking.
IARC Monogr Eval Carcinog Risks Hum
2004
;
83
:
1
–1438.
3
Baron AE, Franceschi S, Barra S, Talamini R, La Vecchia C. A comparison of the joint effects of alcohol and smoking on the risk of cancer across sites in the upper aerodigestive tract.
Cancer Epidemiol Biomarkers Prev
1993
;
2
:
519
–23.
4
Benhamou S, Tuimala J, Bouchardy C, Dayer P, Sarasin A, Hirvonen A. DNA repair gene XRCC2 and XRCC3 polymorphisms and susceptibility to cancers of the upper aerodigestive tract.
Int J Cancer
2004
;
112
:
901
–4.
5
Boccia S, Cadoni G, Sayed-Tabatabaei FA, et al. CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms, smoking, consumption of alcohol and fruit and vegetables and risk of head and neck cancer.
J Cancer Res Clin Oncol
2007
;
134
:
93
–100.
6
Bosetti C, Gallus S, Trichopoulou A, et al. Influence of the Mediterranean diet on the risk of cancers of the upper aerodigestive tract.
Cancer Epidemiol Biomarkers Prev
2003
;
12
:
1091
–4.
7
Cui Y, Morgenstern H, Greenland S, et al. Polymorphism of xeroderma pigmentosum group G and the risk of lung cancer and squamous cell carcinomas of the oropharynx, larynx and esophagus.
Int J Cancer
2006
;
118
:
714
–20.
8
Elahi A, Zheng Z, Park J, Eyring K, McCaffrey T, Lazarus P. The human OGG1 DNA repair enzyme and its association with orolaryngeal cancer risk.
Carcinogenesis
2002
;
23
:
1229
–34.
9
Franceschi S, Talamini R, Barra S, et al. Smoking and drinking in relation to cancers of the oral cavity, pharynx, larynx, and esophagus in northern Italy.
Cancer Res
1990
;
50
:
6502
–7.
10
Hashibe M, Boffetta P, Zaridze D, et al. Evidence for an important role of alcohol and aldehyde metabolizing genes in head and neck cancer susceptibility.
Cancer Epidemiol Biomarkers Prev
2006
;
15
:
696
–703.
11
Hayes RB, Bravo-Otero E, Kleinman DV, et al. Tobacco and alcohol use and oral cancer in Puerto Rico.
Cancer Causes Control
1999
;
10
:
27
–33.
12
Herrero R, Castellsague X, Pawlita M, et al. Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study.
J Natl Cancer Inst
2003
;
95
:
1772
–83.
13
Levi F, Pasche C, La Vecchia C, Lucchini F, Franceschi S, Monnier P. Food groups and risk of oral and pharyngeal cancer.
Int J Cancer
1998
;
77
:
705
–9.
14
Muscat JE, Richie JP, Jr., Thompson S, Wynder EL. Gender differences in smoking and risk for oral cancer.
Cancer Res
1996
;
56
:
5192
–7.
15
Olshan AF, Weissler MC, Watson MA, Bell DA. GSTM1, GSTT1, GSTP1, CYP1A1, and NAT1 polymorphisms, tobacco use, and the risk of head and neck cancer.
Cancer Epidemiol Biomarkers Prev
2000
;
9
:
185
–91.
16
Peters ES, McClean MD, Liu M, Eisen EA, Mueller N, Kelsey KT. The ADH1C polymorphism modifies the risk of squamous cell carcinoma of the head and neck associated with alcohol and tobacco use.
Cancer Epidemiol Biomarkers Prev
2005
;
14
:
476
–82.
17
Rosenblatt KA, Daling JR, Chen C, Sherman KJ, Schwartz SM. Marijuana use and risk of oral squamous cell carcinoma.
Cancer Res
2004
;
64
:
4049
–54.
18
Wang D, Ritchie JM, Smith EM, Zhang Z, Turek LP, Haugen TH. Alcohol dehydrogenase 3 and risk of squamous cell carcinomas of the head and neck.
Cancer Epidemiol Biomarkers Prev
2005
;
14
:
626
–32.
19
Zhang Z, Shi Q, Liu Z, Sturgis EM, Spitz MR, Wei Q. Polymorphisms of methionine synthase and methionine synthase reductase and risk of squamous cell carcinoma of the head and neck: a case-control analysis.
Cancer Epidemiol Biomarkers Prev
2005
;
14
:
1188
–93.
20
Hashibe M, Brennan P, Benhamou S, et al. Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.
J Natl Cancer Inst
2007
;
99
:
777
–89.
21
Lundberg M, Fredlund P, Hallqvist J, Diderichsen F. A SAS program calculating three measures of interaction with confidence intervals.
Epidemiology
1996
;
7
:
655
–6.
22
Greenland S, Finkle WD. A critical look at methods for handling missing covariates in epidemiologic regression analyses.
Am J Epidemiol
1995
;
142
:
1255
–64.
23
Rubin DB. Multiple imputation for nonresponse in surveys. New York: John Wiley and Sons, Inc; 1987.
24
Rothman KJ, Greenland S, Lash TL. Modern epidemiology. 3rd ed. Philadelphia: Wolters Kluwer, Lippincott Williams & Wilkins; 2008.
25
Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic research: principles and quantitative methods. New York: Van Nostrand Reinhold; 1982.
26
Blot WJ, McLaughlin JK, Winn DM, et al. Smoking and drinking in relation to oral and pharyngeal cancer.
Cancer Res
1988
;
48
:
3282
–7.
27
D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer.
N Engl J Med
2007
;
356
:
1944
–56.
28
Smith EM, Ritchie JM, Pawlita M, et al. Human papillomavirus seropositivity and risks of head and neck cancer.
Int J Cancer
2007
;
120
:
825
–32.
29
IARC handbooks of cancer prevention. Volume 8: fruits and vegetables. Lyon: IARC Publications; 2003.
30
Pavia M, Pileggi C, Nobile CG, Angelillo IF. Association between fruit and vegetable consumption and oral cancer: a meta-analysis of observational studies.
Am J Clin Nutr
2006
;
83
:
1126
–34.
31
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Human papillomaviruses.
IARC Monogr Eval Carcinog Risks Hum
2007
;
90
:
1
–636.
32
Alcohol drinking. IARC Working Group, Lyon, 13-20 October 1987.
IARC Monogr Eval Carcinog Risks Hum
1988
;
44
:
1
–378.