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Alcohol consumption, cigarette smoking and the risk of subtypes of head-neck cancer: results from the Netherlands Cohort Study

  • Denise HE Maasland1Email author,
  • Piet A van den Brandt1,
  • Bernd Kremer2,
  • R Alexandra (Sandra) Goldbohm3 and
  • Leo J Schouten1
BMC Cancer201414:187

DOI: 10.1186/1471-2407-14-187

Received: 11 October 2013

Accepted: 27 February 2014

Published: 14 March 2014

Abstract

Background

Prospective data on alcohol consumption, cigarette smoking and risk of head-neck cancer (HNC) subtypes, i.e. oral cavity cancer (OCC), oro-/hypopharyngeal cancer (OHPC), and laryngeal cancer (LC), are limited. We investigated these associations within the second largest prospective study on this topic so far, the Netherlands Cohort Study.

Methods

120,852 participants completed a questionnaire on diet and other cancer risk factors in 1986. After 17.3 years of follow-up, 395 HNC (110 OCC, 83 OHPC, and 199 LC) cases and 4288 subcohort members were available for case-cohort analysis using Cox proportional hazards models.

Results

For total HNC, the multivariable adjusted incidence rate ratio (RR) was 2.74 (95% confidence interval (CI) 1.85-4.06) for those drinking ≥30 g ethanol/day compared with abstainers; in subtypes, RRs were 6.39 for OCC, 3.52 for OHPC, and 1.54 for LC. Compared with never cigarette smokers, current cigarette smokers had a RR of 4.49 (95%CI 3.11-6.48) for HNC overall, and 2.11 for OCC, 8.53 for OHPC, and 8.07 for LC. A significant, positive, multiplicative interaction between categories of alcohol consumption and cigarette smoking was found for HNC overall (P interaction 0.03).

Conclusions

Alcohol consumption and cigarette smoking were independently associated with risk of HNC overall, with a positive, multiplicative interaction. The strength of these associations differed among HNC-subtypes: OCC was most strongly associated with alcohol consumption but most weakly with cigarette smoking, whereas LC was not statistically significantly associated with alcohol consumption.

Keywords

Alcohol consumption Cigarette smoking Cohort studies Etiology Head-neck cancer Head-neck cancer subtypes

Background

Head and neck cancer (HNC) includes several malignancies that originate in the paranasal sinuses, nasal cavity, salivary glands, oral cavity, pharynx, and larynx [1]. HNC is the seventh most common type of cancer in the world and in the European Union; in Europe, HNC accounts for an estimated 130,000 new cases every year [2].

Alcohol consumption and cigarette smoking are established risk factors for HNC originating from the oral cavity, pharynx, and larynx, and are likely to be differentially associated with risk of those HNC-subtypes [38]. However, the majority of conducted studies are case-control studies, a study design susceptible to misclassification with regard to exposure. Prospective cohort studies are less sensitive to this bias, but only six population-based cohort studies have reported on alcohol consumption, cigarette smoking and HNC-risk [915]. Of these studies, most had a small number of cases and were thereby hardly able to examine subtypes; HNC was often combined with other cancers into upper aerodigestive tract cancer [9, 1215]. In addition, the largest prospective study so far lacked information on smoking duration [10]. Finally, a greater than multiplicative joint effect between alcohol and tobacco consumption has been shown, but most evidence comes from case-control studies as well [9, 1214, 1618].

Therefore, we wanted to investigate these associations in HNC-subtypes within the large prospective Netherlands Cohort Study (NLCS). We focused on the most frequent HNC-subtypes: those located in the oral cavity, pharynx, and larynx, and hypothesized that 1) alcohol consumption and cigarette smoking are strongly, positively associated with HNC-risk, with multiplicative interaction, and that 2) these risks are different for oral cavity cancer (OCC), oro-/hypopharyngeal cancer (OHPC), and laryngeal cancer (LC).

Methods

Design and study population

The present study was conducted within the NLCS, which started in September 1986 with the inclusion of 120,852 participants, aged 55-69 years from 204 Dutch municipal population registries [19].

For data processing and analysis, the case-cohort design was used for reasons of efficiency [20]. Cases were derived from the total cohort, whereas the number of person-years at risk for the total cohort was estimated from a subcohort of 5000 persons, randomly sampled from the entire cohort at baseline.

Follow-up for cancer incidence was done by annual record linkage to the Netherlands Cancer Registry and the nationwide network and pathology registry [21]. The completeness of cancer follow-up is estimated to be ≥96% [22], and follow-up for vital status of the subcohort was nearly 100% complete after 17.3 years.

We excluded cohort members who reported to have prevalent cancer other than skin cancer at baseline, and cases and subcohort members with missing data on exposure or confounding variables. Only microscopically confirmed, first occurrences of squamous cell carcinomas – which include nearly all malignancies of the mouth, pharynx, and larynx [1, 3] – of the head and neck were included.

In total, 395 incident HNC cases and 4288 subcohort members were available for analysis (Figure 1). Of these cases, 110 were oral cavity cancer (ICD-O-3 C003-009, C020-C023, C030-C031, C039-C041, C048-C050, C060-C062, C068-C069), 83 oro-/hypopharyngeal cancer (C019, C024, C051-C052, C090-C091, C098-C104, C108-C109, C129-C132, C138-C139); 3 oral cavity, pharynx unspecified, or overlapping (C028-C029, C058-C059, C140-C142, C148), and 199 laryngeal cancer (C320-C329) cases, classified as proposed by Hashibe et al. [23], according to the International Classification of Diseases for Oncology (ICD-O-3) [24].
https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-14-187/MediaObjects/12885_2013_Article_5229_Fig1_HTML.jpg
Figure 1

Flow diagram of the number of subcohort members and cases on whom the analyses were based. *PALGA: nationwide network and registry of histopathology and cytopathology in the Netherlands. aOral cavity cancer; oro-/hypopharyngeal cancer; oral cavity, pharynx unspecified or overlapping cancer; laryngeal cancer.

The NLCS has been approved by the Medical Ethics Committee of Maastricht University (Maastricht, The Netherlands).

Exposure information

At baseline, all cohort members completed a self-administered questionnaire, which included a 150-item food frequency questionnaire (FFQ) with detailed questions on alcohol consumption, smoking habits, and other cancer risk factors.

We asked about the habitual intake of alcohol during the year preceding the start of the study, measured by six items: (1) beer; (2) red wine; (3) white wine; (4) sherry and other fortified wines; (5) liquor types containing on average 16% alcohol; and (6) (Dutch) gin, brandy, and whisky. In addition, questions were asked about the frequency of consumption and the number of glasses consumed on each drinking occasion. For analysis, we combined (2), (3), and (4) into “wine”, and (5) and (6) into “liquor”. Total mean daily ethanol intake was calculated using the Dutch food-composition table [25]. On the basis of pilot study data, standard glass sizes were defined as 200 mL for beer, 105 mL for wine, and 45 mL for liquor, corresponding to 8g, 10g, and 13g of ethanol, respectively [26]. We also asked questions about the consumption of “beer” and “other alcoholic beverages” 5 years before baseline and selected participants with stable alcohol consumption to perform a sensitivity analysis [27]. Participants who indicated that they used alcoholic beverages never or less than once a month were considered abstainers.

We asked detailed information regarding cigarette smoking. Among others, questions were asked about whether the subject was a smoker at baseline; age at which they started and stopped smoking; the number of cigarettes smoked daily and the number of smoking years (excluding stopping periods). Based on these questions, the following variables were constructed for analysis: smoking status (never/former/current); current smoking (yes/no); frequency (cigarettes/day); duration (years); the number of pack-years; and time since smoking cessation (years). We also asked about cigar and pipe smoking and the use of smokeless tobacco. Participants who indicated they had never smoked cigarettes were considered never smokers.

The FFQ was validated against a 9-day diet record, and the Spearman correlation coefficient between the alcohol intake assessed by the questionnaire and that estimated by the diet record was 0.89 for all subjects and 0.85 for users of alcoholic beverages [28]. The reproducibility of the FFQ was assessed through annually repeated measurements in a subgroup of the subcohort and the test-retest correlation was 0.90 for alcohol intake; this correlation declined only 0.01-0.02 per year [29].

Data were key-entered and processed in a standardized manner, blinded with regard to case/subcohort status in order to minimize observer bias in coding and data interpretation.

Data analysis

Person-years at risk were calculated from baseline until diagnosis of HNC, death, emigration, loss to follow-up or end of follow-up (i.e. 31 December 2003), whichever occurred first.

Age (years) and sex were considered predefined confounders. The potential confounders considered were [3, 30, 31]: level of education, non-occupational physical activity, energy intake, coffee and tea consumption, intake of fruit, vegetables, fish, fat, red meat, meat products, and family history of head-neck cancer. Alcohol consumption and cigarette smoking were mutually adjusted in statistical models. A variable was considered a confounder if including it in the model changed the rate ratio (RR) for any of the cancer (sub-) types by >10%; according to this, none of the potential confounders was included in the final model.

The Cox proportional hazards model was used to estimate incidence RRs and corresponding 95% confidence intervals (CI) for alcohol consumption and cigarette smoking in multivariable adjusted case-cohort analyses. Analyses were done using the Stata 11.2 statistical software package (StataCorp, College Station, Texas, USA). Standard errors were calculated using the robust Huber-White sandwich estimator to account for additional variance introduced by sampling from the cohort; this method is equivalent to the variance-covariance estimator by Barlow [32]. The proportional hazards (PH) assumption was assessed using the scaled Schoenfeld residuals [33]. If there was an indication for violation of the assumption for a variable, we further investigated this by adding a time-varying covariate for that variable to the model.

We also analyzed beer, wine, and liquor consumption, adjusted for ethanol intake, to examine whether substances in alcoholic beverages, other than ethanol, have an effect on HNC-risk. In smoking analyses, different aspects of cigarette smoking were investigated and mutually adjusted for, in order to obtain a complete exposure model. The total number of cases that exclusively smoked cigar and/or pipe or used smokeless tobacco was too low (N < 10) to further analyze associations with HNC-risk.

When adjusting for smoking frequency, duration, or pack-years, we centered these continuous variables as proposed by Leffondré et al. [34]

Tests for linear dose-response trends were assessed by fitting ordinal exposure variables as continuous terms. To evaluate possible multiplicative interaction between categories of alcohol consumption and cigarette smoking, we estimated RRs of HNC overall and all HNC-subtypes for combinations of these exposures. The interaction was investigated by including cross-product terms in the model and performing a Wald test. Two-sided P values are reported throughout the article.

Tests for heterogeneity among HNC-subtypes were performed to investigate differences between HNC subtypes by a bootstrapping method developed for the case-cohort design [35]. For each bootstrap sample, X subcohort members were randomly drawn from the subcohort of X subjects and Y cases from the total of Y cases outside the subcohort, both with replacement, out of the dataset of X + Y observations. The logHRs were obtained from this sample using Stata’s competing risks procedure and recalculated for each bootstrap-replication. The confidence interval and P value of the differences in hazard ratio of the subtypes were then calculated from the replicated statistics. Each bootstrap analysis was based on at least 1,000 replications [36].

Results

Compared to the subcohort, cases were more frequently men than women, and less often alcohol abstainers (Table 1). Among alcohol consumers, cases had a substantially higher alcohol intake and generally drank more beer, wine, and liquor than subcohort members. In both cases and subcohort members, men mostly consumed beer and liquor, whereas women drank more wine. With respect to cigarette smoking, cases were far more often current smokers and also smoked a substantially higher number of pack-years than subcohort members. Women were more often never smokers than men; among ever smokers, men generally smoked more pack-years than women, in cases and subcohort members.
Table 1

Characteristics of cases and subcohort members in the Netherlands Cohort Study (NLCS), 1986 - 2003

 

Subcohort

Head-neck cancer cases

  

Overall

Subtypes

   

OCCa

OHPCa

LCa

Exposure variables and potential confounders

( N = 4288)b

( N = 395)b

(N = 110)b

(N = 83)b

(N = 199)b

Age at baseline (years)

61.3 (4.2)c

61.8 (4.1)

61.8 (4.3)

61.5 (4.2)

61.8 (4.0)

Sex: men (%)

49.2

79.5

59.1

73.5

94.0

Abstainer from alcohol (%)

23.9

12.4

10.9

13.3

13.1

 Men (%)

14.8

9.2

4.6

9.8

10.7

 Women (%)

32.6

24.7

20.0

22.7d

50.0e

Alcohol consumers:

     

Ethanol intake (grams/day)

13.4 (15.0)

27.3 (25.6)

28.7 (25.4)

35.0 (31.6)

23.2 (22.1)

 Men

17.5

29.1

34.3

40.2

23.5

 Women

8.5

18.6

19.1

18.0

14.7

Beer intake (glasses/week)

2.2 (5.8)

6.3 (12.5)

4.4 (10.2)

10.3 (18.3)

5.8 (10.4)

 Men

3.7

6.9

6.1

11.1

5.8

 Women

0.3

3.5

1.4

7.9

4.5

Wine intake (glasses/week)

3.7 (5.6)

4.4 (9.1)

5.5 (8.1)

6.0 (11.5)

3.1 (8.4)

 Men

3.1

4.0

4.2

6.7

3.1

 Women

4.4

6.0

7.7

3.5

4.1

Liquor intake (glasses/week)

2.9 (5.7)

7.3 (10.0)

8.4 (11.2)

7.7 (11.7)

6.4 (8.3)

 Men

4.6

8.2

11.5

9.4

6.6

 Women

0.9

3.0

3.1

1.9

1.9

Cigarette smoking status

     

Total

     

 Never smokers (%)

36.9

11.1

26.4

7.2

4.5

 Former smokers (%)

35.5

27.9

21.8

26.5

32.2

 Current smokers (%)

27.6

61.0

51.8

66.3

63.3

Men

     

 Never smokers (%)

13.8

6.7

16.9

4.9

3.7

 Former smokers (%)

51.4

31.5

27.7

29.5

33.7

 Current smokers (%)

34.8

61.8

55.4

65.6

62.6

Women

     

 Never smokers (%)

59.4

28.4

40.0

13.6d

16.7e

 Former smokers (%)

20.0

13.6

13.3

18.2

8.3

 Current smokers (%)

20.6

58.0

46.7

68.2

75.0

Ever cigarette smokers:

     

Frequency of cigarette smoking (N/day)

15.3 (10.2)

19.5 (10.9)

19.9 (11.9)

21.4 (12.7)

18.6 (9.6)

 Men

17.1

19.9

21.6

22.9

18.4

 Women

11.6

17.4

16.5

16.7

22

Duration of cigarette smoking (years)

31.7 (12.1)

39.1 (9.5)

37.8 (9.2)

38.5 (9.8)

39.9 (9.4)

 Men

33.6

39.8

38.9

39.8

40.0

 Women

27.8

35.8

35.4

34.5

38.2

Pack-years of cigarette smoking (N)

22.8 (17.7)

34.4 (20.9)

34.5 (23.5)

37.0 (23.2)

33.5 (18.9)

 Men

26.2

35.7

38.5

40.5

33.2

 Women

16.0

28.3

26.4

26.3

38.5

Level of education (%)

     

 Primary

29.5

27.6

20.9

25.6

31.5

 Lower vocational

22.0

18.9

17.3

17.1

20.8

 Secondary and medium vocational

34.8

35.7

41.8

36.6

32.5

 University and higher vocational

13.8

17.9

20.0

20.7

15.2

aOCC: oral cavity cancer; OHPC: oro-/hypopharyngeal cancer; LC: laryngeal cancer.

bThe number of subcohort members or cases used in age- and sex-adjusted, multivariate analyses of alcohol consumption and cigarette smoking.

cValues are given as mean (SD); for categorical variables, N (%) is presented.

dBased on only 22 female OHPC cases.

eBased on only 12 female LC cases.

Alcohol consumption

Alcohol consumption of ≥30 grams (g) per day compared with abstinence was associated with a statistically significantly increased risk of HNC overall (multivariate RR = 2.74, 95% CI 1.85-4.06), OCC (RR = 6.39, 95% CI 3.13-13.03), and OHPC (RR = 3.52, 95% CI 1.69-7.36), but not LC (RR = 1.54, 95% CI 0.91-2.60) (Table 2). A strong dose-response relationship (P trend < 0.001) was found between categories of increasing alcohol consumption and HNC overall, OCC, and OHPC risk. A significant interaction was found between sex and continuous alcohol consumption in HNC overall (P = 0.02) and OCC (P = 0.004), with women having higher RRs than men.
Table 2

Associations (multivariable a adjusted incidence RRs) between alcohol consumption and risk of subtypes of head-neck cancer; Netherlands Cohort Study (NLCS), 19862003

  

Subcohort

Head-neck cancer cases

   

Overall

Subtypes

  
     

OCCb

 

OHPCb

 

LCb

  
 

Categorical median

Person time at risk (years)

No. of cases

RR (95% CI)

No. of cases

RR (95% CI)

No. of cases

RR (95% CI)

No. of cases

RR (95% CI)

Pfor heterogeneity

Alcohol consumption (grams ethanol/day)

Abstainers

0

15 255

49

1 (reference)

12

1 (reference)

11

1 (reference)

26

1 (reference)

0.86

>0 to <5

2

19 008

67

1.11 (0.75-1.65)

17

1.25 (0.59-2.65)

14

1.06 (0.47-2.40)

36

1.03 (0.60-1.77)

 

5 to <15

9

14 468

72

1.15 (0.77-1.71)

19

1.91 (0.91-4.03)

12

0.90 (0.38-2.13)

40

0.94 (0.56-1.58)

 

15 to <30

22

9 961

92

1.52 (1.02-2.27)

30

3.88 (1.86-8.12)

13

0.99 (0.41-2.38)

49

1.10 (0.66-1.83)

 

≥30

40

5 659

115

2.74 (1.85-4.06)

32

6.39 (3.13-13.03)

33

3.52 (1.69-7.36)

48

1.54 (0.91-2.60)

 

P for trendc

   

<0.001

 

<0.001

 

<0.001

 

0.05

 

Continuous, 10 gram

           

ethanol/day increments

           

Overall

 

64 352

395

1.20 (1.12-1.27)

110

1.28 (1.18-1.39)

83

1.27 (1.16-1.38)

199

1.10 (1.02-1.18)

0.18

Men

 

30 169

314

1.19 (1.12-1.27)

65

1.27 (1.17-1.38)

61

1.27 (1.16-1.39)

187

1.10 (1.03-1.19)

 

Women

 

34 183

81

1.40 (1.18-1.65)

45

1.58 (1.33-1.87)

22

1.31 (0.91-1.87)

12

0.85 (0.46-1.59)

 

P for interactiond

   

0.02

 

0.004

 

0.68

 

0.67

 

Alcohol consumption (grams ethanol/day) stable users e

Abstainers

0

11 810

38

1 (reference)

9

1 (reference)

9

1 (reference)

20

1 (reference)

1.00

>0 to <5

2

11 813

36

0.98 (0.60-1.61)

12

1.65 (0.68-4.01)

7

0.86 (0.30-2.41)

17

0.72 (0.35-1.46)

 

5 to <15

9

8 749

38

0.96 (0.58-1.59)

9

1.68 (0.63-4.47)

8

0.89 (0.32-2.47)

21

0.72 (0.37-1.40)

 

15 to <30

22

5 293

45

1.27 (0.76-2.11)

12

3.20 (1.25-8.19)

6

0.72 (0.23-2.26)

27

0.96 (0.50-1.83)

 

≥30

42

3 047

69

2.90 (1.78-4.73)

17

7.50 (3.15-17.88)

20

3.46 (1.46-8.20)

31

1.57 (0.82-3.02)

 

P for trend

   

<0.001

 

<0.001

 

0.001

 

0.03

 

Continuous, 10 grams

 

39712

226

1.26 (1.16-1.36)

59

1.37 (1.24-1.52)

50

1.35 (1.20-1.52)

116

1.16 (1.04-1.28)

0.72

ethanol/day increments

           

Alcoholic beverages (glasses/day) f

Beer

           

No beer

0

43 519

183

1 (reference)

59

1 (reference)

36

1 (reference)

87

1 (reference)

0.84

>0- < 1

0.2

16 408

129

0.94 (0.71-1.24)

34

1.10 (0.65-1.86)

24

0.98 (0.54-1.76)

69

0.85 (0.60-1.22)

 

1- < 2

1.4

2 853

37

1.12 (0.72-1.74)

8

1.17 (0.49-2.77)

6

1.04 (0.41-2.66)

23

1.19 (0.71-2.01)

 

≥2

3.4

1 554

46

1.39 (0.83-2.34)

9

0.99 (0.34-2.82)

17

2.48 (1.03-5.98)

20

1.30 (0.69-2.46)

 

P for trend

   

0.14

 

0.95

 

0.03

 

0.20

 

Continuous, 1

 

64 335

395

1.07 (0.97-1.19)

110

0.97 (0.80-1.16)g

83

1.19 (1.01-1.40)

199

1.08 (0.96-1.23)

0.07

glass/day increments

           

Wine

           

No wine

0

30 263

197

1 (reference)

44

1 (reference)

38

1 (reference)

114

1 (reference)

0.93

>0- < 1

0.2

25 975

132

0.88 (0.67-1.14)

40

1.07 (0.67-1.71)

33

1.01 (0.59-1.75)

57

0.74 (0.52-1.05)

 

1- < 2

1.4

5 277

39

0.95 (0.63-1.44)

14

1.31 (0.67-2.55)

5

0.52 (0.19-1.39)

20

1.07 (0.63-1.83)

 

≥2

2.6

2 751

24

0.56 (0.29-1.07)

11

0.93 (0.34-2.57)

7

0.52 (0.15-1.81)g

6

0.39 (0.15-0.99)

 

P for trend

   

0.15

 

0.93

 

0.16

 

0.21

 

Continuous, 1

 

64 265

392

0.88 (0.74-1.05)

109

0.89 (0.69-1.16)

83

0.86 (0.64-1.17)

197

0.88 (0.68-1.14)

0.26

glass/day increments

           

Liquor

           

No liquor

0

33 299

137

1 (reference)

40

1 (reference)

34

1 (reference)

63

1 (reference)

0.44

>0- < 1

0.2

23 492

133

1.09 (0.84-1.43)

31

1.10 (0.67-1.80)

23

0.86 (0.48-1.53)

78

1.17 (0.81-1.67)

 

1- < 2

1.9

5 370

67

1.09 (0.76-1.57)

18

1.65 (0.87-3.15)

12

0.79 (0.39-1.62)

37

1.08 (0.67-1.74)

 

≥2

2.8

2 115

56

1.18 (0.71-1.95)

20

2.26 (1.02-4.99)

14

0.83 (0.33-2.13)

20

0.95 (0.47-1.93)

 

P for trend

   

0.61

 

0.03

 

0.64

 

0.83

 

Continuous, 1

 

64 275

393

1.01 (0.86-1.18)

109

1.18 (0.89-1.56)

83

0.89 (0.68-1.15)

198

0.98 (0.80-1.21)

0.25

glass/day increments

           

aAdjusted for age (years), sex, cigarette smoking (status (never/former/current), frequency (continuous; centered), and duration (continuous; centered)).

bOCC: oral cavity cancer; OHPC: oro-/hypopharyngeal cancer; LC: laryngeal cancer.

cTests for dose-response trends were assessed by fitting ordinal variables as continuous terms in the Cox proportional hazards model.

d P Value for interaction between sex and alcohol consumption, based on cross-product terms in the Cox proportional hazards model and Wald test.

eSubjects who had not changed their continuous alcohol consumption habits in the 5 years before baseline: for “beer” and “other alcoholic beverages”, participants could indicate whether 5 years before baseline they drunk (1) more than, (2) equal amounts of or (3) less than at baseline; the fourth answer option was (4) “I never use this”.

fAdditionally adjusted for continuous ethanol intake (g ethanol/day).

gProportional hazards assumption was possibly violated for the exposure variable, and there was a statistically significant interaction with time.

After adjustment for total alcohol intake, consumption of beer, wine, and liquor was generally not significantly associated with HNC-risk. Beer consumption was, however, statistically significantly, positively associated with OHPC-risk (P trend = 0.03); liquor consumption was significantly associated with an increased risk of OCC (P trend = 0.03). Wine consumption was largely inversely associated – although not statistically significantly – with risk of HNC overall and HNC-subtypes.

Although risk rates clearly varied among HNC-subtypes, tests for heterogeneity did not show any significant risk differences, possibly due to low power.

Cigarette smoking

Current cigarette smoking was statistically significantly associated with risk of HNC overall (multivariate RR = 4.49, 95% CI 3.11-6.48) and all subtypes, with strongest associations in OHPC (RR = 8.53, 95% CI 3.38-21.55) and LC (RR = 8.07, 95% CI 3.94-16.54), compared with never smoking (Table 3). Compared with never smoking, former cigarette smoking was also associated with risk of HNC overall, although not statistically significantly (RR = 1.44, 95% CI 0.97-2.14), OHPC (RR = 2.68, 95% CI 1.00-7.14), and LC (RR = 2.63, 95% CI 1.26-5.47), but not OCC (RR = 0.70, 95% CI 0.37-1.33). Frequency and duration of cigarette smoking were also strongly, statistically significantly associated with an increased risk of HNC overall, OHPC, and LC (Table 3).
Table 3

Associations (multivariable a adjusted incidence RRs) between cigarette smoking and risk of subtypes of head-neck cancer; Netherlands Cohort Study (NLCS), 1986 - 2003

  

Subcohort

Head-neck cancer cases

   

Overall

Subtypes

    

OCCb

OHPCb

LCb

 
 

Categorical median

Person time at risk (years)

No. of cases

RR (95% CI)

No. of cases

RR (95% CI)

No. of cases

RR (95% CI)

No. of cases

RR (95% CI)

Pfor heterogeneity

Cigarette smoking status

           

Never smokers

 

25051

44

1 (reference)

29

1 (reference)

6

1 (reference)

9

1 (reference)

0.97

Former smokers

 

22644

110

1.44 (0.97-2.14)

24

0.70 (0.37-1.33)

22

2.68 (1.00-7.14)i

64

2.63 (1.26-5.47)

 

Current smokers

 

16657

241

4.49 (3.11-6.48)

57

2.11 (1.23-3.62)

55

8.53 (3.38-21.55)

126

8.07 (3.94-16.54)

 

P for trendc

   

<0.001

 

0.001

 

<0.001

 

<0.001

 

P for interaction with sexd

   

0.25

 

0.08

 

0.44

 

0.46

 

Cigarette smoking status, additionally adjusted for frequency and duration of cigarette smoking e

Never smokers

 

25051

44

1 (reference)

29

1 (reference)

6

1 (reference)

9

1 (reference)

0.97

Former smokers

 

22644

110

1.64 (1.08-2.49)

24

0.79 (0.40-1.58)

22

3.03 (1.09-8.45)

64

2.87 (1.34-6.13)

 

Current smokers

 

16657

241

3.51 (2.36-5.23)

57

1.91 (1.06-3.42)

55

7.49 (2.87-19.54)

126

5.26 (2.45-11.28)

 

P for trend

   

<0.001

 

0.03

 

<0.001

 

<0.001

 

Frequency of cigarette smoking ( N /day) f

Never smokers

0

25051

44

1 (reference)

29

1 (reference)

6

1 (reference)

9

1 (reference)

0.99

>0 to <20

10

24787

155

1.30 (0.84-2.01)

38

0.63 (0.30-1.32)

30

2.08 (0.73-5.94)

85

2.32 (1.07-5.04)

 

≥20

20

14514

196

2.23 (1.45-3.44)

43

1.06 (0.52-2.16)

47

4.67 (1.64-13.34)

105

3.75 (1.73-8.14)

 

P for trend

   

<0.001

 

0.33

 

<0.001

 

<0.001

 

Continuous, 10 cigarettes/day increments

 

64352

395

1.25 (1.13-1.38)

110

1.20 (1.00-1.44)j

83

1.42 (1.20-1.69)

199

1.21 (1.08-1.36)

0.71

Duration of cigarette smoking (years) g

Never smokers

0

25051

44

1 (reference)

29

1 (reference)

6

1 (reference)

9

1 (reference)

<0.001

>0 to <20

13

7433

20

1.00 (0.56-1.77)

4

0.38 (0.13-1.17)

5

2.11 (0.59-7.51)

11

1.88 (0.75-4.69)

 

20 to <40

30

18999

105

1.44 (0.95-2.21)

30

0.80 (0.41-1.59)

25

2.74 (0.98-7.68)

50

2.35 (1.09-5.06)

 

≥40

43

12868

226

2.45 (1.49-4.02)

47

0.98 (0.39-2.46)

47

3.89 (1.22-12.40)

129

4.81 (2.11-11.00)

 

P for trend

   

<0.001

 

0.87

 

0.02

 

<0.001

 

Continuous, 10 years increments

 

64352

395

1.28 (1.14-1.42)

110

1.03 (0.85-1.24)

83

1.36 (1.09-1.70)

199

1.49 (1.25-1.78)

0.25

Pack-years of cigarette smoking h

Never smokers

0

25051

44

1 (reference)

29

1 (reference)

6

1 (reference)

9

1 (reference)

1.00

>0 to <20

9

20832

96

1.16 (0.77-1.76)

24

0.58 (0.30-1.14)

20

2.12 (0.77-5.80)

51

2.07 (0.97-4.41)

 

20 to <40

28

12732

132

1.65 (1.04- 2.60)

32

0.84 (0.39-1.83)

26

2.87 (0.94-8.79)

73

2.93 (1.33-6.48)

 

≥40

48

5736

123

2.82 (1.76-4.50)

25

1.28 (0.58-2.82)

31

6.49 (2.11-19.95)

66

4.79 (2.15-10.64)

 

P for trend

   

<0.001

 

0.07

 

<0.001

 

<0.001

 

Continuous, 10 pack-years increments

 

64352

395

1.18 (1.11-1.25)

110

1.16 (1.04-1.28)

83

1.24 (1.12-1.36)

199

1.16 (1.09-1.24)

0.77

Cigarette smoking cessation i

Never smokers

25

25051

44

1 (reference)

29

1 (reference)

6

1 (reference)

9

1 (reference)

<0.001

Stopped ≥20 years

14

6953

24

1.25 (0.72-2.19)

5

0.63 (0.22-1.81)

6

3.35 (0.97-11.55)

13

1.92 (0.79-4.70)

 

Stopped 10 to <20 years

5

7717

36

1.49 (0.91-2.43)

8

0.78 (0.32-1.86)

8

3.29 (1.04-10.39)

20

2.45 (1.07-5.61)k

 

Stopped >0 to <10 years

0

7918

50

1.73 (1.09-2.76)

11

0.84 (0.39-1.83)

8

2.48 (0.77-7.93)

31

3.45 (1.56-7.62)

 

Current smokers

 

16657

241

4.26 (2.93-6.20)

57

2.03 (1.16-3.56)

55

8.10 (3.14-20.87)

126

7.53 (3.65-15.51)

 

P for trend

   

<0.001

 

0.004

 

<0.001

 

<0.001

 

aAll analyses were adjusted for age (years), sex, and alcohol consumption (g ethanol/day; continuous).

bOCC: oral cavity cancer; OHPC: oro-/hypopharyngeal cancer; LC: laryngeal cancer.

cTests for dose-response trends were assessed by fitting ordinal variables as continuous terms in the Cox proportional hazards model.

d P Value for interaction between sex and cigarette smoking status, based on cross-product terms in the Cox proportional hazards model and Wald test.

eAdditionally adjusted for frequency (N/day; continuous; centered) and duration of cigarette smoking (years; continuous; centered).

fAnalyses of cigarette smoking frequency were additionally adjusted for current cigarette smoking and duration of cigarette smoking (years; continuous; centered).

gAnalyses of cigarette smoking duration were additionally adjusted for current cigarette smoking and frequency of cigarette smoking (N/day; continuous; centered).

hAnalyses of cigarette smoking pack-years were additionally adjusted for current cigarette smoking.

iCigarette smoking cessation was additionally adjusted for the no. of cigarette pack-years (continuous; centered).

j P < 0.05.

kProportional hazards assumption was possibly violated for the exposure variable, and there was a statistically significant interaction with time.

Regarding different aspects of cigarette smoking, after mutual adjustment, cigarette smoking status, frequency, and duration all remained statistically significantly associated with risk of HNC overall, OHPC, and LC (see Additional file 1). After additional adjustment for alcohol consumption (Table 3), most RRs between cigarette smoking status, frequency, duration and risk of HNC(-subtypes) slightly attenuated, but remained statistically significantly associated with increased risks.

Results regarding smoking cessation show that the risk of HNC overall and all subtypes diminished for smokers who stopped smoking since <10, 10 to <20, or ≥20 years, compared with current smokers (all P trend < 0.01) (Table 3). Nevertheless, compared with never smokers, RRs 20 years after smoking cessation were still elevated for HNC overall, OHPC, and LC, although not statistically significantly.

Despite considerable differences in risk rates among HNC-subtypes, tests for heterogeneity only showed statistically significant risk rates for duration of cigarette smoking (P < 0.001) and time since smoking cessation (P < 0.001).

Interaction between alcohol consumption and cigarette smoking

For HNC overall, increased risks were found for every exposure combination of alcohol consumption and cigarette smoking, mostly statistically significantly, compared to never smokers and abstainers as reference group (Table 4). In addition, a statistically significant, positive, multiplicative interaction was found (P interaction 0.03) between categories of alcohol consumption and cigarette smoking, with a RR of 8.28 (95% CI 3.98-17.22), comparing participants smoking ≥ 20 cigarettes and drinking ≥30 g alcohol per day with never smokers abstaining from alcohol.
Table 4

Combinations of categories of alcohol consumption and cigarette smoking and risk (multivariable a adjusted incidence RRs) of subtypes of head-neck cancer; Netherlands Cohort Study (NLCS), 1986 - 2003

 

Head-neck cancer cases

 

Overall

Subtypes

     
      

OCCb

OHPCb

LCb

 

Alcohol consumption (grams ethanol/day)

Alcohol consumptionc

Alcohol consumptionc

Alcohol consumptionc

 

0

>0 to <5

5 to <15

15 to <30

≥30

0-15

>15

0-15

>15

0-15

>15

Frequency of cigarette smoking ( N /day)

Never smokers

           

Cases/person time at riskd

10/8959

13/9729

7/4245

11/1499

3/619

21/22933

8/2118

3/22933

3/2118

6/22933

3/2118

RR

1 (ref)

1.20

1.23

5.53

2.97

1 (ref)

4.16

1 (ref)

10.18

1 (ref)

3.05

95% CI

 

0.52 – 2.75

0.46 – 3.29

2.27 – 13.49

0.78 – 11.40

 

1.82 – 9.52

 

2.03 – 51.06

 

0.72 – 12.92

>0 to <20

           

Cases/person time at risk

21/4194

25/6534

37/7061

40/4814

32/2184

20/17789

18/6998

18/17789

12/6998

44/17789

41/6998

RR

1.89

1.56

2.04

2.63

3.81

0.76

1.55

4.02

5.63

2.66

4.19

95% CI

0.83 – 4.34

0.71 – 3.41

0.95 – 4.40

1.22 – 5.67

1.71 – 8.51

0.34 – 1.71

0.66 – 3.62

1.07 – 15.14

1.44 – 22.00

1.03 – 6.86

1.60 – 11.02

≥20

           

Cases/person time at risk

18/2102

29/2745

28/3162

41/3648

80/2856

7/8010

36/6504

16/8010

31/6504

52/8010

53/6504

RR

2.78

3.88

2.85

3.32

8.28

0.58

3.54

7.26

16.12

5.42

5.54

95% CI

1.18 – 6.54

1.77 – 8.49

1.28 – 6.34

1.52 – 7.25

3.98 – 17.22

0.21 – 1.58

1.66 – 7.52

1.86 – 28.44

4.31 – 60.27

2.10 – 13.98

2.15 – 14.27

P for interactione

    

0.03

 

0.10

 

0.09

 

0.19

aAdjusted for age, sex, current cigarette smoking, and duration of cigarette smoking (years; continuous; centered).

bOCC: oral cavity cancer; OHPC: oro-/hypopharyngeal cancer; LC: laryngeal cancer.

cFor the categorical interaction analyses in HNC-subtypes, it was necessary to aggregate categories of alcohol consumption (grams ethanol/day) in order to obtain sufficient numbers in strata.

dPerson time at risk in years.

e P Value for interaction between categories of alcohol consumption and cigarette smoking, based on cross-product terms in the Cox proportional hazards model and Wald test.

In HNC-subtypes, RRs were mostly increased as well when comparing participants smoking ≥ 20 cigarettes and drinking >15 g alcohol per day with never smokers consuming 0 to 15g alcohol per day, with the highest RR for OHPC (RR = 16.12, 95% CI 4.31-60.27), but no significant interaction was found, possibly due to low numbers in strata.

Discussion

In this large prospective study on alcohol consumption, cigarette smoking, and risk of HNC(-subtypes), alcohol consumption and cigarette smoking were strongly, independently associated with an increased risk of HNC overall. The strength of these associations however differed between HNC-subtypes; OCC was most strongly associated with alcohol consumption but most weakly with cigarette smoking, whereas LC was not statistically significantly associated with alcohol consumption. For HNC overall, a multiplicative interaction between categories of alcohol consumption and cigarette smoking was found.

Alcohol consumption

Our results are in agreement with those of previous studies, showing alcohol consumption to be an independent risk factor for the development of HNC, with a strong, dose-response relationship [4, 9, 1114, 17, 23, 37, 38]. Alcoholic beverages and acetaldehyde, the main metabolite of ethanol, are classified as a class I carcinogen [18]. It is plausible that alcohol – after being metabolized – acts both directly and indirectly in HNC carcinogenesis, the latter for example by acting as a solvent for other possible carcinogens, such as tobacco carcinogens [3, 39].

The differential risk among HNC-subtypes is consistent with other studies, in which LC was also least associated with alcohol consumption [8, 40, 41]. However, several other studies found OHPC being most associated with alcohol consumption, although sometimes in specific subgroups, as opposed to OCC in our study [11, 23, 41]. Nevertheless, the differential risk among HNC-subtypes is likely to be explained by the larynx having the least direct exposure to alcohol compared with the oral cavity and pharynx [39, 42]. The slightly increased RRs for alcohol consumption and LC may be due to inhalation of alcohol containing aerosols, silent aspiration, systemic effects, and possibly residual confounding.

After adjustment for total alcohol intake, we generally found similar risks between intake of beer, wine, liquor and HNC. These findings imply that ethanol itself probably is the most important factor in determining HNC-risk, rather than other substances in alcoholic beverages, which is in line with the results from other studies [3, 11, 42]. Consumption of wine was, however, generally inversely associated with HNC-risk, as was also shown in a pooled analysis [42], which could be due to residual confounding by a general healthier lifestyle of wine-consumers in our study population [3, 42, 43].

The significantly higher RRs between alcohol consumption and HNC risk in women as compared with men were seen earlier and could possibly be explained by women having stronger carcinogenic effects of alcohol at the same exposure level, suggesting possible gender-specific risk or protective factors [11].

Cigarette smoking

This study confirms the strong associations of cigarette smoking with increased risk of HNC overall and all subtypes [3, 5, 7, 10, 14, 23, 37, 41]. Among subtypes, however, OCC was least associated with cigarette smoking, and strongest associations were found with OHPC and LC. In addition, smoking status, frequency, and duration all appear to be of importance in the association between cigarette smoking and risk of HNC overall, OHPC, and LC. These results are generally consistent with previous reviews showing that cigarette smoking has a stronger effect on the larynx and/or pharynx than on the oral cavity [7, 8, 10, 23, 41]; in two meta-analyses, the larynx seemed to be clearly most susceptible to the effects of cigarette smoking [23, 41]. A possible explanation for this could be the aerodynamics of respiratory flow in the upper airway: this flow changes from laminar in the oral cavity to turbulent in the larynx, which may result in the larynx and pharynx having a higher exposure to inhaled air - and thus to cigarette smoke - than the oral cavity.

Finally, our study shows smoking cessation leads to decreased HNC-risks, which is in line with results from a recent pooled analysis as well [44].

Interaction between alcohol consumption and cigarette smoking

Our study confirms a multiplicative interaction between categories of alcohol consumption and cigarette smoking in HNC overall [9, 14, 1618, 37, 38, 41]. The interaction effect between alcohol consumption and cigarette smoking is biologically plausible, since alcohol can act as a solvent for carcinogens in cigarette smoke and make the mucosa more permeable for these carcinogens; as a result, the carcinogenic properties of both factors are likely to be enhanced in the presence of one another [3, 39]. Still, in HNC-subtypes, we had low numbers of cases in strata, which probably resulted in limited power to detect a significant deviation from the multiplicative model.

Strengths and limitations

Important strengths of our study are the prospective character and completeness of follow-up. Our study is the second largest prospective cohort study investigating alcohol consumption and cigarette smoking on the risk of HNC overall and subtypes so far [915]. Furthermore, we were able to take into account data on smoking duration, and to investigate as well as adjust for several aspects of smoking behavior.

A possible limitation of our study is the single measurement of exposure data. Alcohol consumption and cigarette smoking were however extensively addressed in the questionnaire, with questions about lifetime exposure history of smoking and alcohol intake 5 years before baseline. It is however possible that participants who smoked at baseline in 1986 stopped smoking at some point during follow-up or changed their alcohol intake, and this may have led to bias due to misclassification. Furthermore, although our study includes a large number of cases, a lack of power is a possible explanation for finding non-significant results for some associations and the tests for heterogeneity.

We lack information on human papillomavirus (HPV) infection. HPV-infection is associated with HNC-risk [45, 46], but mainly with OHPC, in particular tonsil cancer and cancer of the base of the tongue. According to rates in our university medical center, only 25% of the diagnosed and treated oropharyngeal cancers between 1997 and 2003 were HPV-positive (all oropharyngeal cancer cases have been analyzed by p16-immunostaining and HPV16-specific fluorescence in situ hybridization (FISH), and – if FISH was negative – HPV-specific polymerase chain reaction). Moreover, the role of HPV in HNC-carcinogenesis is mainly of importance in young HNC-patients, and has increased since 1990 [4749]. Since our participants were aged 55-69 years at baseline in 1986, we assume that the number of HPV-associated HNC cases in our cohort is low, and we expect potential bias due to possible misclassification to be very limited.

Other factors we did not take into account in our analyses are the use of drugs and oral hygiene. Although we investigated several potential confounders, residual confounding is still possible, but we presume this to be limited as well.

It might also be interesting to examine the RRs of HNC for smokers among non-drinkers and for drinkers among non-smokers. However, as the case numbers for these subgroups would be too small to analyze, we decided not to investigate this.

Finally, though we wanted to examine the role of alcohol consumption and cigarette smoking in HNC-subtypes, we did not investigate HNC located in the major salivary glands, nasal cavity, paranasal sinuses, and nasopharynx, because of low numbers of these cases as well as a presumably different etiology [50].

Conclusions

In conclusion, the present study, which is the second largest prospective cohort study regarding this topic so far, confirms the principal role of alcohol consumption and cigarette smoking in HNC-carcinogenesis, as well as the differential associations with HNC-subtypes, and a significant, positive, multiplicative interaction between both factors. As the existing evidence is largely based on case-control studies, this cohort study contributes to establish in which extent alcohol consumption and cigarette smoking are associated with risk of HNC overall and, more specifically, HNC-subtypes.

Abbreviations

CI: 

Confidence interval

FFQ: 

Food frequency questionnaire

FISH: 

Fluorescence in situ hybridization

HNC: 

Head and neck cancer

HPV: 

Human papillomavirus

LC: 

Laryngeal cancer

NLCS: 

Netherlands Cohort Study

OCC: 

Oral cavity cancer

OHPC: 

Oro-/hypopharyngeal cancer

PH: 

Proportional hazards

RR: 

Rate ratio

Declarations

Grants

This work was supported by World Cancer Research Fund International (WCRF) and Wereld Kanker Onderzoek Fonds (WCRF NL) [grant number 2010/253]. The funding body was not involved in design, collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.

Acknowledgements

The authors wish to thank the participants of this study, The Netherlands Cancer Registry (IKNL and IKZ), and the nationwide network and registry of histopathology and cytopathology in the Netherlands (PALGA). They also thank Dr. A. Kester, Dr. A. Volovics, and Dr. A. Keszei for statistical advice; S. van de Crommert, J. Nelissen, A. Pisters, and C. de Zwart from Maastricht University, and H. Brants from the Dutch National Institute for Public Health, for assistance; and Ellen Dutman from TNO and J. Berben, H. van Montfort, and R. Schmeitz from Maastricht University for programming assistance.

Authors’ Affiliations

(1)
Department of Epidemiology, GROW - School for Oncology & Developmental Biology, Maastricht University
(2)
Department of Otorhinolaryngology, Head & Neck Surgery, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Center
(3)
TNO

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