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Smoking patterns and cancer of the oral cavity and pharynx: a case–control study in Uruguay
ORAL ONCOLOGY
Oral Oncology 34 (1998) 340±346
Smoking patterns and cancer of the oral cavity and pharynx: a case±control study in Uruguay E. De Stefani a,*, P. Boetta b, F. Oreggia c, M. Mendilaharsu a, H. Deneo-Pellegrini a, d a Registro Nacional de Cancer, Montevideo, Uruguay Unit of Environmental Cancer Epidemiology, International Agency for Research on Cancer, Lyon, France c Academia Nacional de Medicina, Montevideo, Uruguay d Departmento de Patologia, Instituto Nacional de Oncologia, Montevideo, Uruguay
b
Received 27 January 1998
Abstract A case±control study of cancer of the oral cavity and pharynx was conducted in Uruguay, between 1992 and 1996. 425 patients microscopically diagnosed with squamous cell carcinoma of the oral cavity and pharynx were frequently matched on age, residence, and urban/rural status with 427 hospitalised controls. The study was restricted to males. Smokers of black tobacco cigarettes were associated with an increased risk of 12.1 (95% con®dence interval (CI) 7.6±19.4), when compared with non-smokers after ®tting a model which included the matching variables, birthplace, education, and total alcohol consumption. Lifelong smokers of handrolled cigarettes displayed an odds ratio (OR) of 8.7 (95% CI 5.6±13.4), compared with non-smokers. When smokers were excluded from the calculations, the OR for smokers of black tobacco cigarettes was 3.0 (95% CI 2.0±4.6), compared with smokers of blond tobacco cigarettes, after controlling for the same variables mentioned above, plus pack-years, years since stopping, and ®lter use. Hand-rolling appears to be less important than smoking black tobacco in this study (OR 1.6, 95% CI 0.9±2.5). Thus, smoking black tobacco cigarettes appears to be an important habit in oral and pharyngeal carcinogenesis. # 1998 Elsevier Science Ltd. All rights reserved. Keywords: Oral cancer; Black tobacco; Hand-rolling; Bland tobacco
1. Introduction Cancer of the oral cavity and pharynx is a frequent group of malignancies, with an age-adjusted incidence rate of 14.1 per 100 000 in Uruguayan men [1]. Previous studies have shown that tobacco smoking and alcohol drinking are, as usual in Western countries, the main aetiological factors in oral carcinogenesis [2±4]. In particular, smoking intensity and duration, age at start, and years after quitting the habit have been extensively reviewed [5, 6]. The role of black tobacco has been examined in two previous studies [2, 7], and has also been reviewed by one of the authors of the present study [8]. The Uruguayan study reported an increased risk of 3.4 after controlling for hard liquor consumption, wine intake, and `mate' (a local tea which is drunk at very hot temperatures). On the other hand, Merletti et al. [7] found * Corresponding author. 1368-8375/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved. PII: S1368 -8 375(98)00014 -1
no eect for black tobacco smokers, after controlling for socioeconomic status, birthplace, and tobacco variables. As suggested by Boetta [8], more studies are needed to reach a ®nal conclusion. Latin American countries are suitable places to conduct these studies, since they show a roughly similar prevalence of blond and black tobacco smokers. Therefore, it was considered timely to conduct a new case±control study in Uruguay, in order to elucidate the possible role of black tobacco in oral carcinogenesis. 2. Materials and methods This case±control study was conducted in Montevideo, Uruguay, in the period 1992±1996. The study was restricted to men, because of the low prevalence of oral and pharyngeal cancer in Uruguayan women [5]. Potentially eligible case subjects were men aged 25± 84 years, who were admitted to one of the four major
E. De Stefani et al./Oral Oncology 34 (1998) 340±346
hospitals of Montevideo for diagnosis and treatment. The initial number of oral and pharyngeal cancer patients was 453. From this potential number of cases, 10 patients refused the interview, 10 were too ill to be interviewed, and 8 were not histologically veri®ed. Therefore, 425 patients with microscopically con®rmed squamous cell carcinoma of the oral cavity and pharynx were successfully interviewed (response rate 93.8%). Concerning the site of the tumour, 33 cases were located in the mucosal surface of the lip (7.8%), 89 in the tongue (20.9%), 84 in other parts of the mouth (¯oor of the mouth, palate, alveolar ridge, etc.; 19.8%), 111 in the oropharynx (26.1%), 97 in the hypopharynx (22.8%) and 11 were extensive pharyngeal lesions (2.6%) (Table 1). In total, 206 cases had tumours located in the oral cavity (48.5%), whereas 219 patients presented pharyngeal carcinomas (51.5%). Potentially eligible controls were drawn from the same hospitals as the cases, in the same time period. Conditions of eligibility were: (1) to have been diagnosed with diseases not related with tobacco smoking
Site
No.
%
Lip Tongue Other mouth Oropharynx Hypopharynx Pharynx unspeci®ed
33 89 84 111 97 11
7.8 20.9 19.8 26.1 22.8 2.6
425
100.0
and/or alcohol intake; (2) to not have non-neoplastic lesions of the oral cavity and pharynx; (3) to be in the same age range as the cases (25±84 years old). From an initial number of 469, 42 refused to be interviewed, leading to a total of 427 controls (response rate 91.0%). The most frequent conditions were eye disorders (142 patients, 33.3%), abdominal hernia (80 patients, 18.7%), and acute appendicitis (40 patients, 9.4%) (Table 2). They were frequency matched to the cases on age (10 year periods), residence (Montevideo, other counties), and urban/rural status. Both cases and controls were interviewed shortly after admission (mean time since admission 32 days), using a questionnaire which included: (1) sociodemographic variables; (2) a complete tobacco history (including age at start, age at quit, average number of cigarettes per day, type of tobacco, type of cigarette (colour of tobacco, Table 2 Distribution of controls by disease category ICD-9 360±379 550±553 540 800±829 455 680±709 600 122 280±289 710±739 830±959
Table 1 Distribution of cases by anatomic site
341
Category
No.
%
Eye disorders Abdominal hernia Acute appendicitis Fractures Varicose veins Skin diseases Prostate hyperplasia Hydatid cyst Blood disorders Osteoarticular diseases Trauma
142 80 40 38 30 27 17 14 14 13 12
33.3 18.7 9.4 8.9 6.9 6.4 3.9 3.3 3.3 3.1 2.8
427
100.0
Table 3 Distribution of cases and controls by sociodemographic variables and alcohol intake Variable Age (years)
Residence Urban/rural Birthplace
Education (years) Total alcohol (ml/day)
Number of patients
Category 40±49 50±59 60±69 70±79 80±89 Montevideo Other counties Urban Rural Montevideo South North Migrants 0±4 5+ Non-drinkers 1±60 61±120 121±240 241+
Cases (%) 29 138 170 73 15 188 237 344 81 96 194 119 16 266 159 48 71 84 115 107 425
(6.8) (32.5) (40.0) (17.2) (3.5) (44.2) (55.8) (80.9) (19.1) (22.6) (45.6) (28.0) (3.8) (62.6) (37.4) (11.3) (16.7) (19.8) (27.1) (25.2) (100)
Controls (%) 30 (7.0) 138 (32.3) 170 (39.8) 74 (17.4) 15 (3.5) 188 (44.0) 239 (56.0) 345 (80.8) 82 (19.2) 128 (30.0) 158 (37.0) 120 (28.1) 21 (4.9) 216 (50.6) 211 (49.4) 119 (27.9) 122 (28.6) 76 (17.8) 52 (12.2) 58 (13.6) 427 (100)
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E. De Stefani et al./Oral Oncology 34 (1998) 340±346
Table 4 Odds ratios (OR) of cancer of the oral cavity and pharynx for tobacco variables Variable Smoking status
Cigarettes per day Years smoked Pack-years
Years since quit
Type of tobacco Duration of type of tobacco
Hand-rolling Duration of hand rolling
Filter use Smoking pattern
a
Category
Cases/Controls
OR
95% CI
Non-smokers Former smokers Current smokers All smokers 1±14 15±24 25+ 1±39 40±49 50+ 1±28 29±47 48±76 77+ 10+ 5±9 1±4 Current smokers Mainly blond Mainly black Blond 1±39 years Blond 40+ years Black 1±39 years Black 40+ years Manufactured Mixed Hand-rolled Manufactured 1±39 years Manufactured 40+ years Rolled 1±39 years Rolled 40+ years Lifelong filter Mixed Lifelong plain Blond + manufactured Blond + rolled Black + manufactured Black + rolled
38/150 80/105 307/172 387/287 57/91 150/106 180/80 104/99 154/98 129/80 66/100 105/61 97/70 119/46 12/37 27/28 41/40 307/172 196/222 191/55 66/85 130/137 38/13 153/42 94/107 52/69 241/101 33/49 61/58 71/49 222/121 9/25 104/129 274/123 69/96 132/126 30/11 161/44
1.0 2.9 7.2 5.3 2.5 6.0 8.1 4.6 5.8 5.3 2.7 6.8 5.1 8.3 1.2 3.4 4.1 7.3 3.2 12.1 2.9 3.2 10.9 12.4 3.4 2.6 8.7 2.9 3.8 5.7 6.3 1.5 2.9 7.8 2.4 3.6 9.7 12.8
± 1.8±4.6 4.7±11.1 3.5±7.9 1.5±4.1 3.8±9.5 5.1±12.9 2.7±7.8 3.6±9.2 3.3±8.5 1.6±4.4 4.2±11.1 3.2±8.3 5.0±13.8 0.6±2.6 1.8±6.6 2.3±7.3 4.7±11.2 2.1±4.8 7.6±19.4 1.7±5.1 2.1±4.9 5.1±23.4 7.5±20.5 2.1±5.5 1.5±4.4 5.6±13.4 1.5±5.5 2.2±6.4 3.3±10.1 4.1±9.6 0.6±3.7 1.8±4.6 5.1±11.9 1.4±4.0 2.3±5.6 4.4±21.4 7.8±20.9
CI, con®dence interval. a Adjusted for age, residence, urban/rural status, birthplace, education, and total alcohol consumption.
manufacturing, rolled, ®lter, plain); and (3) a complete alcohol consumption history (including type of beverage and daily intake in glasses or other recipes). The amount smoked was calculated after summing and averaging the number of cigarettes per day in different periods of the lifetime of all subjects. Smoking duration was calculated by substracting age at start from age at quit, whereas smoking cessation was calculated by substracting age at quit from age. Former smokers were de®ned as those smokers who had quit the habit more than 1 year before the interview, whereas current smokers were those smokers who had never quit or who had quit the habit less than 1 year before the interview date. The type of tobacco was classi®ed as blond or black, according to the brand of tobacco smoked. Furthermore, cigarettes were classi®ed as manufactured or hand-rolled, according to the brand
used. According to previous estimations, one pack of tobacco for hand-rolled cigarettes yields 60 cigarettes (Association of Tobacconists, personal communication). In Uruguay, packs for hand-rolling cigarettes could be ®lled by blond or black tobacco. Mainly blond (or black) tobacco smokers were de®ned as those patients who smoked this type of tobacco more than 50% of their lifelong smoking history. A more detailed assessment of the type of tobacco was calculated according to the duration of smoking blond (or black) in three categories: 1±39 years, 40±49 years and 50 years or more. Hand-rolling smokers were de®ned as those smokers who ®lled their own cigarettes with tobacco specially prepared for this purpose. In order to calculate the risk associated with smoking hand-rolled cigarettes, two variables were created: the ®rst one had nonsmokers as the reference category, exclusive smokers
E. De Stefani et al./Oral Oncology 34 (1998) 340±346 Table 5 Odds ratios (OR) of oral cancer for tobacco variables compared with pharyngeal cancer Variable
Smoking status Non-smokers Former smokers Current smokers All smokers Cigarettes per day 1±14 15±24 25+ Years smoked 1±39 40±49 50+ Pack-years 1±28 29±47 48±76 77+ Years since quit 10+ 5±9 1±4 Current smokers Type of tobacco Mainly blond Mainly black Duration of type of tobacco Blond 1±39 years Blond 40+ years Black 1±39 years Black 40+ years Hand-rolling Lifelong manufactured Mixed Lifelong rollers Duration of hand-rolling Manufactured 1±39 years Manufactured 40+ years Rolled 1±39 years Rolled 40+ years Filter use Lifelong ®lter Mixed Lifelong plain Smoking pattern Blond +manufactured Blond + rolled Black + manufactured Black + rolled
343
a
Oral cavity
Pharynx
Cases
OR
95% CI
Cases
OR
95% CI
24 36 146 182
1.0 2.2 5.7 4.2
± 1.2±3.9 3.4±9.5 2.6±6.8
14 44 161 205
1.0 4.3 10.2 7.5
± 2.2±8.3 5.5±18.8 4.1±13.6
27 76 79
1.9 5.1 6.1
1.0±3.5 2.9±8.7 3.5±10.8
30 74 101
3.6 7.8 12.2
1.8±7.1 4.1±14.9 6.4±23.3
51 68 63
3.5 4.3 4.5
1.8±6.5 2.5±7.5 2.5±7.9
53 86 66
6.2 8.3 7.5
2.9±12.8 4.3±15.9 3.9±14.4
34 52 47 49
2.2 5.5 4.4 5.7
1.2±4.1 3.1±9.9 2.4±7.9 3.1±10.6
32 53 50 70
3.5 8.9 6.7 13.3
1.7±7.0 4.5±17.6 3.4±13.2 6.7±26.2
4 12 20 146
0.7 2.7 3.2 5.8
0.2±2.1 1.2±6.1 1.6±6.5 3.5±9.6
8 15 21 161
2.1 5.1 5.9 10.3
0.8±5.5 2.2±12.0 2.7±12.8 5.6±19.1
91 91
2.4 9.4
1.5±4.1 5.4±16.3
105 100
4.4 17.8
2.4±8.1 9.2±34.1
32 59 19 72
2.3 2.5 8.3 9.7
1.2±4.5 1.4±4.3 3.5±19.7 5.4±17.3
34 71 19 81
3.8 4.6 15.1 18.4
1.8±8.1 2.4±8.6 5.8±39.1 9.4±36.2
45 31 106
2.9 2.6 6.1
1.6±5.2 1.4±4.9 3.6±10.2
49 21 135
4.3 2.7 13.7
2.2±8.5 1.3±5.8 7.3±25.5
17 28 34 103
2.6 3.2 4.2 4.8
1.2±5.6 1.7±6.1 2.1±8.2 2.9±8.1
16 33 37 119
3.5 4.9 8.0 9.5
1.5±8.2 2.4±10.1 3.7±17.2 5.0±17.1
6 48 128
1.7 2.3 6.0
0.6±4.8 1.3±4.1 3.6±10.0
3 56 146
1.3 4.0 11.3
0.3±5.2 2.1±7.8 6.1±20.8
28 63 17 74
1.9 2.8 10.3 9.2
0.9±3.5 1.6±4.8 4.2±25.1 5.1±16.3
36 69 13 87
3.4 5.1 9.2 20.6
1.7±6.8 2.7±9.6 3.4±25.0 10.5±40.6
CI, con®dence interval. a Adjusted for age, residence, urban/rural status, birthplace, education, and total alcohol consumption.
of manufactured (commercial) cigarettes, exclusive smokers of hand-rolled cigarettes, and mixed smokers; the second variable categorised manufactured and hand-rolled cigarettes into two periods each, according to the duration of use. The time periods were identical to those employed in assessing the duration of use of the
types of tobacco. Finally, the smoking pattern was a composite variable which combined the type of tobacco and the use of commercial or hand-rolled cigarettes. Alcohol drinking was recorded in glasses of 50, 120, and 250 ml for hard liquor, wine, and beer. The content of pure ethanol was calculated according to the following
344
E. De Stefani et al./Oral Oncology 34 (1998) 340±346
concentrations speci®c for Uruguay: 6% for beer, 12% for wine, and 46% for spirits. The resulting values were converted to grams by multiplying 1 ml of pure ethanol per 789 mg [9]. In Uruguay, spirits are made from or from grapes (grappa). Although sugarcane (cana) they were not discriminated in the questionnaire, the ethanol content of both is the same [9]. Relative risks (RR) of cancer of the oral cavity and pharynx, approximated by the odds ratios (OR) were calculated for all study variables. The method employed was unconditional logistic regression [10]. All models included the matching variables (age, residence, and urban/rural status) and potential confounders (birthplace, education, and alcohol drinking). Age was adjusted by introducing a continuous term and a categorical one. Since the results were similar, all models were adjusted for age as a continuous term. The assessment of tobacco eect was performed through a logistic model which included potential confounders (age, residence, urban/rural status, education, total alcohol consumption, as a continuous variable, and other tobacco variables). The eect modi®cation of tobacco smoking and alcohol drinking was evaluated by including interaction terms in the logistic model. Tests for trend for study variables were calculated by including categorical terms as continuous variables to a model with all the potential confounders. All calculations were performed using the GLIM (General Linear Interactive Modelling) software [11].
3. Results The distribution of cases and controls by sociodemographic variables and total alcohol drinking is shown in Table 3. The proportions of cases and controls, according to age, residence, and urban/rural status, were similar, as a result of the frequency matching. More controls reported Montevideo as their birthplace than cases, and, also, they were more educated than the cases. Cases consumed signi®cantly more alcohol beverages than controls. Odds ratios of oral and pharyngeal cancer for tobacco variables are shown in Table 4. Current smokers displayed an OR of 7.2 (95% con®dence interval (CI) 4.7±11.1), whereas a reduction in risk was observed for former smokers (OR 2.9, 95% CI 1.8±4.6). Risk increased steeply with smoking intensity (OR for heavy smokers 8.1, 95% CI 5.1±12.9) and with smoking duration (OR for smokers of more than 50 years 5.3, 95% CI 3.3±8.5). The risk of quitters of more than 10 years was close to that showed by non-smokers (OR 1.21 95% CI 0.6±2.6). Smokers of black cigarettes were associated with a large increase in risk (OR 12.1, 95% CI 7.6±19.4) compared with non-smokers. When the eect of the type of tobacco was analysed according to its duration of use, the greater eect associated with smoking black tobacco was maintained. Exclusive smokers of handrolled cigarettes were associated with an OR of 8.7 (95% CI 5.6±13.4), compared with non-smokers.
Table 6 Odds ratios (OR) of oral and pharyngeal cancer for type of tobacco and hand-rollingÐsmokers only Variable
Type of tobacco Mainly blond Mainly black Duration of type of tobacco Blond 1±39 years Blond 40+ years Black 1±39 years Black 40+ years Hand-rolling Lifelong manufactured Mixed Lifelong rollers Duration of hand-rolling Manufactured 1±39 years Manufactured 40+ years Rolled 1±39 years Rolled 40+ years Smoking pattern Blond + manufactured Blond + rolled Black + manufactured Black + rolled
Oral cavity
a
Pharynx
Both sites
OR
95% CI
OR
95% CI
OR
95% CI
1.0 3.0
± 1.8±4.9
1.0 3.0
± 1.8±4.9
1.0 3.0
± 2.0±4.6
1.0 1.1 2.6 3.3
± 0.6±2.0 1.1±6.3 1.6±6.7
1.0 1.3 2.4 3.8
± 0.7±2.3 0.9±5.8 1.8±7.8
1.0 1.1 2.6 3.4
± 0.7±1.9 1.2±5.5 1.8±6.2
1.0 0.9 1.3
± 0.5±1.7 0.7±2.3
1.0 0.6 1.9
± 0.3±1.1 1.1±3.5
1.0 0.7 1.6
± 0.4±1.2 0.9±2.5
1.0 1.1 1.1 1.3
± 0.5±2.8 0.5±2.4 0.5±2.9
1.0 1.2 1.0 1.5
± 0.5±2.8 0.4±2.3 0.7±3.4
1.0 1.2 1.1 1.3
± 0.6±2.4 0.5±2.1 0.7±2.6
1.0 1.3 4.0 3.5
± 0.7±2.3 1.6±10.3 1.6±7.3
1.0 1.0 1.9 3.4
± 0.6±1.8 0.7±5.2 1.6±7.0
1.0 1.1 2.7 3.2
± 0.7±1.7 1.2±6.1 1.8±5.8
CI, con®dence interval. a Adjusted for age, residence, urban/rural status, birthplace, education, pack-years, total alcohol intake, years since quit, and ®lter use.
E. De Stefani et al./Oral Oncology 34 (1998) 340±346 Table 7 Odds ratios (OR) of dierent sites of the oral cavity and pharynx for black tobacco smokers (reference category: smokers of blond cigarettes) a Site
Lip Tongue Other parts of the mouth Oropharynx Hypopharynx
Black tobacco OR
95% CI
3.5 3.6 2.3 3.7 2.1
1.3±9.8 1.8±7.1 1.2±4.4 2.0±6.7 1.1±3.9
CI, con®dence interval. a Adjusted for age, residence, urban/rural status, birthplace, education, total alcohol consumption, pack-years, years since quit, and ®lter use.
Lifelong smokers of ®lter cigarettes displayed a risk of 1.5 (95% CI 0.6±3.7), which was not signi®cantly greater than the risk of non-smokers. Finally, the combination of black tobacco and hand-rolled smokers was associated with a large increase in risk (OR 12.8, 95% CI 7.8±20.9), compared with non-smokers. Odds ratios of oral cancer, compared with those of pharyngeal cancer, for tobacco variables, are shown in Table 5. Although both cancer sites (or groups of sites) were associated with signi®cantly elevated ORs for each tobacco variable, pharyngeal cancers displayed a 2-fold excess risk, compared with cancer of the oral cavity. For oral cancer, current smokers were associated with an OR of 5.7 (95% CI 3.4±9.5), whereas the risk of pharyngeal cancer for the same category was of 10.2 (95% CI 5.5±18.8). Heavy smokers (25 or more cigarettes per day) displayed an OR of 6.1 (95% CI 3.5±10.8) in oral cancer patients, and an OR of 12.2 (95% CI 6.4±23.3) for those with cancer of the pharynx. Smokers of black tobacco showed an OR of 9.4 (95% CI 5.4±16.3) compared with non-smokers in patients with oral cancer. The OR of pharyngeal cancer for the same category was 17.8 (95% CI 9.2±34.1). Finally, lifelong smokers of hand-rolled cigarettes were associated with an increased risk of 6.1 (95% CI 3.6±10.2) for oral cancer, whereas the risk for pharyngeal cancer was 13.7 (95% CI 7.3±25.5). Odds ratios of oral and pharyngeal cancer for type of tobacco, hand-rolling, and smoking pattern, after excluding non-smokers, are shown in Table 6. When a model including education, birthplace, pack-years, total alcohol intake, years since quit, and ®lter use was ®tted, smokers of black tobacco were associated with a signi®cantly elevated OR of 3.0 (95% CI 2.0±4.6), when compared with smokers of blond tobacco. When type of tobacco was analysed according to the duration of its use, the higher risk was observed for those who smoked black tobacco for more than 40 years (OR 3.4, 95% CI 1.8±6.2). Lifelong smokers of hand-rolled cigarettes
345
were associated with a signi®cantly elevated risk of 1.9 (95% CI 1.1±3.5), compared with lifelong smokers of manufactured cigarettes, for pharyngeal cancers only. The duration of smoking hand-rolled cigarettes was not associated with a signi®cant increased risk of oral and pharyngeal cancer. Finally, smokers of black tobacco who rolled their cigarettes were associated with an increased risk of 3.2 (95% CI 1.8±5.8) (reference category: smokers of manufactured blond tobacco). Odds ratios of dierent sites of the oral cavity and pharynx for black tobacco smoking are shown in Table 7. The highest risks were observed for the lip, tongue, and oropharynx, but in every site, smoking black tobacco was associated with a signi®cantly elevated risk after controlling for major confounders. 4. Discussion This study replicates previous ®ndings, regarding intensity and duration of tobacco smoking in oral cancer [3±8, 12±22]. Also, the reduction in risk associated with cessation and ®lter use were evident. Most, but not all, previous studies which examined the relationship between smoking black tobacco and the risk of oral cancer, showed an increased risk. In particular, in the study conducted by Merletti et al. [7] in Torino, the risk associated with black tobacco smoking disappeared when smoking cessation and ®lter use were included in the logistic model. In fact, the possibility that failure to include such powerful confounders in the model could result in residual confounding is a major one. For this reason, the present study allowed for years since quit and ®lter use in a model which excluded non-smokers. The eect of black tobacco remained signi®cant after this stringent analysis. Moreover, when black tobacco was analysed by its duration of use, a dose±response pattern was evident. The mechanisms underlying this deleterious eect of black tobacco are probably related to its high content of tobacco-speci®c nitrosamines, as previously shown by Hecht et al. [23]. These compounds appear to have a great carcinogenic potential for oral and pharyngeal mucosa, as shown in experimental studies [24]. As far as hand-rolled cigarettes are concerned, a high tar content has been previously reported in a recent follow-up study from Norway [25]. Therefore, it is not surprising that the combination of black and hand-rolled cigarettes is associated with the higher risks of oral cancer, as shown in the present study. Since smokers of black tobacco frequently roll their own cigarettes, both variables (black tobaccco and hand-rolling) are highly correlated and the independent eect of each variable is dicult to disentangle. Nevertheless, the type of tobacco appears to be more risky than hand-rolling.
346
E. De Stefani et al./Oral Oncology 34 (1998) 340±346
This study presents several advantages and drawbacks. The major strength is perhaps related to the large number of cases and controls, that to its power size, which allowed the estimation of stable odds ratios, even for the lip. On the other hand, the use of hospitalised controls has been questioned on the grounds that the resulting relative risks could be biased to the null. This could be a result of the fact that hospitalised controls, and cancer controls, have a larger proportion of heavy smokers, compared with population-based controls [26]. Since the control series was assembled with patients treated in the same hospitals as the cases, in the same time period, and were frequency matched to the cases on age, residence, and urban/rural status, selection bias appears to be unlikely. Recall bias could have occurred, as in any case±control study, but the use of hospitalised controls is against this possibility, due to the fact that forces of recall are usually of the same magnitude, both in cases and in hospital-based controls. In summary, the present study replicates ®ndings from previous case±control studies, concerning the aetiological role of tobacco smoking in oral cancer. Moreover, it emphasizes the fact that the combination of black tobacco and hand-rolling is particularly deleterious for oral carcinogenesis. Acknowledgements This work was supported by a grant from the ComisioÂn Honoraria de Lucha contra el Cancer, Montevideo, Uruguay. References [1] Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J. Cancer Incidence in Five Continents, Vol. VII. IARC Scienti®c Publication No. 143. Lyon: International Agency for Research on Cancer, 1997. [2] De Stefani E, Correa P, Oreggia F, et al. Black tobacco, wine and mate in oropharyngeal cancer. A case±control from Uruguay. Revue Epidemiologie et Sante Publique 1988;36:389±394. [3] Oreggia F, De Stefani E, Correa P, Fierro L. Risk factors for cancer of the tongue in Uruguay. Cancer 1991;67:180±183. [4] De Stefani E, Oreggia F, Rivero S, Fierro L. Hand-rolled cigarette smoking and risk of cancer of the mouth, pharynx, and larynx. Cancer 1992;70:679±682. [5] IARC. Tobacco Smoking. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Vol. 38. Lyon: International Agency for Research on Cancer, 1986. [6] Blot WJ, McLaughlin JK, Devesa SS, Fraumeni JF Jr. Cancers of the oral cavity and pharynx. In: Schottenfeld D, Fraumeni JF Jr., editors. Cancer Epidemiology and Prevention, 2nd Edition. Oxford: Oxford University Press, 1996.
[7] Merletti F, Boetta P, Ciccone G, Mashberg A, Terracini B. Role of tobacco and alcoholic beverages in the etiology of cancer of the oral cavity/oropharynx in Torino, Italy. Cancer Research 1989;49:4919±4924. [8] Boetta P. Black (air-cured) and blond (¯ue-cured) tobacco and cancer risk. V: Oral cavity cancer. European Journal of Cancer 1993;29:1331±1335. [9] IARC. Alcohol Drinking. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Vol. 44. Lyon: International Agency for Research on Cancer, 1988. [10] Breslow NE, Day NE. Statistical Methods in Cancer Research, Vol. I: The Analysis of Case±Control Studies. Lyon: International Agency for Research on Cancer, 1980. [11] Baker RJ, Nelder JA. The GLIM system. Release 3. Oxford: Numerical Algorithm Group, 1985. [12] Boetta P, Mashberg A, Winkelmann R, Gar®nkel L. Carcinogenic eect of tobacco smoking and alcohol drinking on anatomic sites of the oral cavity and oropharynx. International Journal of Cancer 1992;52:530±533. [13] Blot WJ, McLaughlin JK, Winn DM, et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Research 1988;48:3282±3287. [14] Macfarlane GJ, Zheng T, Marshall JR., et alAlcohol, tobacco, diet and the risk of oral cancer: a pooled analysis of three casecontrol studies. Oral Oncology, European Journal of Cancer 1995;31:181±187. [15] La Vecchia C, Tavani A, Franceschi S, Levi F, Corrao G, Negri E. Epidemiology and prevention of oral cancer. Oral Oncology, European Journal of Cancer 1997;33:302±312. [16] Boyle P, Macfarlane GJ, Scully C. Oral cancer: necessity for prevention strategies. Lancet 1994;343:178±179. [17] Franco EL, , Kowalski LP, Oliveira BV, et al. Risk factors for oral cancer in Brazil: a case-control study. International Journal of Cancer 1989;43:992±1000. [18] Zheng T, Holford T, Chen Y, Jiang P, Zhang B, Boyle P. Risk of tongue cancer associated with tobacco smoking and alcohol consumption: a case-control study. Oral Oncology 1997;33: 82±85. [19] Mashberg A, Boetta P, Winkelmann R, Gar®nkel L. Tobacco smoking, alcohol drinking, and cancer of the oral cavity and oropharynx among U.S. veterans. Cancer 1993;72:1369±1375. [20] Sancho-Garnier H, Theobald S. Black (air-cured) and blond (¯ue-cured) tobacco and cancer risk. II: Pharynx and larynx cancer. European Journal of Cancer 1993;29:273±276. [21] Negri E, La Vecchia C, Franceschi S, Tavani A. Attributable risk for oral cancer in Northern Italy. Cancer Epidemiology Biomarkers and Prevention 1993;2:189±193. [22] Wynder EL, Bross JJ, Feldman RM. A study of the etiologic factors in cancer of the mouth. Cancer 1957;10:1300±1323. [23] Hecht SS, Chen CB, Homann D. Tobacco-speci®c nitrosamines: occurrence, formation, carcinogenicity and metabolism. Acc. Chemical Research 1979;12:92±98. [24] Hecht SS, Homann D. Tobacco-speci®c nitrosamines, an important group of carcinogens in tobacco and tobacco smoke. Carcinogenesis 1988;9:875±884. [25] Engeland A, Haldorsen T, Andersen A, Tretli S. The impact of smoking habits on lung cancer risk: 28 years' observation of 26,000 Norwegian men and women. Cancer Causes Control 1996;7:366±376. [26] Olson SH, Kelsey JL, Pearson TA, Levin B. Characteristics of a hypothetical group of hospital controls for a case-control study. American Journal of Epidemiology 1994;139:302±311.
Oral Oncology 34 (1998) 340±346
Smoking patterns and cancer of the oral cavity and pharynx: a case±control study in Uruguay E. De Stefani a,*, P. Boetta b, F. Oreggia c, M. Mendilaharsu a, H. Deneo-Pellegrini a, d a Registro Nacional de Cancer, Montevideo, Uruguay Unit of Environmental Cancer Epidemiology, International Agency for Research on Cancer, Lyon, France c Academia Nacional de Medicina, Montevideo, Uruguay d Departmento de Patologia, Instituto Nacional de Oncologia, Montevideo, Uruguay
b
Received 27 January 1998
Abstract A case±control study of cancer of the oral cavity and pharynx was conducted in Uruguay, between 1992 and 1996. 425 patients microscopically diagnosed with squamous cell carcinoma of the oral cavity and pharynx were frequently matched on age, residence, and urban/rural status with 427 hospitalised controls. The study was restricted to males. Smokers of black tobacco cigarettes were associated with an increased risk of 12.1 (95% con®dence interval (CI) 7.6±19.4), when compared with non-smokers after ®tting a model which included the matching variables, birthplace, education, and total alcohol consumption. Lifelong smokers of handrolled cigarettes displayed an odds ratio (OR) of 8.7 (95% CI 5.6±13.4), compared with non-smokers. When smokers were excluded from the calculations, the OR for smokers of black tobacco cigarettes was 3.0 (95% CI 2.0±4.6), compared with smokers of blond tobacco cigarettes, after controlling for the same variables mentioned above, plus pack-years, years since stopping, and ®lter use. Hand-rolling appears to be less important than smoking black tobacco in this study (OR 1.6, 95% CI 0.9±2.5). Thus, smoking black tobacco cigarettes appears to be an important habit in oral and pharyngeal carcinogenesis. # 1998 Elsevier Science Ltd. All rights reserved. Keywords: Oral cancer; Black tobacco; Hand-rolling; Bland tobacco
1. Introduction Cancer of the oral cavity and pharynx is a frequent group of malignancies, with an age-adjusted incidence rate of 14.1 per 100 000 in Uruguayan men [1]. Previous studies have shown that tobacco smoking and alcohol drinking are, as usual in Western countries, the main aetiological factors in oral carcinogenesis [2±4]. In particular, smoking intensity and duration, age at start, and years after quitting the habit have been extensively reviewed [5, 6]. The role of black tobacco has been examined in two previous studies [2, 7], and has also been reviewed by one of the authors of the present study [8]. The Uruguayan study reported an increased risk of 3.4 after controlling for hard liquor consumption, wine intake, and `mate' (a local tea which is drunk at very hot temperatures). On the other hand, Merletti et al. [7] found * Corresponding author. 1368-8375/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved. PII: S1368 -8 375(98)00014 -1
no eect for black tobacco smokers, after controlling for socioeconomic status, birthplace, and tobacco variables. As suggested by Boetta [8], more studies are needed to reach a ®nal conclusion. Latin American countries are suitable places to conduct these studies, since they show a roughly similar prevalence of blond and black tobacco smokers. Therefore, it was considered timely to conduct a new case±control study in Uruguay, in order to elucidate the possible role of black tobacco in oral carcinogenesis. 2. Materials and methods This case±control study was conducted in Montevideo, Uruguay, in the period 1992±1996. The study was restricted to men, because of the low prevalence of oral and pharyngeal cancer in Uruguayan women [5]. Potentially eligible case subjects were men aged 25± 84 years, who were admitted to one of the four major
E. De Stefani et al./Oral Oncology 34 (1998) 340±346
hospitals of Montevideo for diagnosis and treatment. The initial number of oral and pharyngeal cancer patients was 453. From this potential number of cases, 10 patients refused the interview, 10 were too ill to be interviewed, and 8 were not histologically veri®ed. Therefore, 425 patients with microscopically con®rmed squamous cell carcinoma of the oral cavity and pharynx were successfully interviewed (response rate 93.8%). Concerning the site of the tumour, 33 cases were located in the mucosal surface of the lip (7.8%), 89 in the tongue (20.9%), 84 in other parts of the mouth (¯oor of the mouth, palate, alveolar ridge, etc.; 19.8%), 111 in the oropharynx (26.1%), 97 in the hypopharynx (22.8%) and 11 were extensive pharyngeal lesions (2.6%) (Table 1). In total, 206 cases had tumours located in the oral cavity (48.5%), whereas 219 patients presented pharyngeal carcinomas (51.5%). Potentially eligible controls were drawn from the same hospitals as the cases, in the same time period. Conditions of eligibility were: (1) to have been diagnosed with diseases not related with tobacco smoking
Site
No.
%
Lip Tongue Other mouth Oropharynx Hypopharynx Pharynx unspeci®ed
33 89 84 111 97 11
7.8 20.9 19.8 26.1 22.8 2.6
425
100.0
and/or alcohol intake; (2) to not have non-neoplastic lesions of the oral cavity and pharynx; (3) to be in the same age range as the cases (25±84 years old). From an initial number of 469, 42 refused to be interviewed, leading to a total of 427 controls (response rate 91.0%). The most frequent conditions were eye disorders (142 patients, 33.3%), abdominal hernia (80 patients, 18.7%), and acute appendicitis (40 patients, 9.4%) (Table 2). They were frequency matched to the cases on age (10 year periods), residence (Montevideo, other counties), and urban/rural status. Both cases and controls were interviewed shortly after admission (mean time since admission 32 days), using a questionnaire which included: (1) sociodemographic variables; (2) a complete tobacco history (including age at start, age at quit, average number of cigarettes per day, type of tobacco, type of cigarette (colour of tobacco, Table 2 Distribution of controls by disease category ICD-9 360±379 550±553 540 800±829 455 680±709 600 122 280±289 710±739 830±959
Table 1 Distribution of cases by anatomic site
341
Category
No.
%
Eye disorders Abdominal hernia Acute appendicitis Fractures Varicose veins Skin diseases Prostate hyperplasia Hydatid cyst Blood disorders Osteoarticular diseases Trauma
142 80 40 38 30 27 17 14 14 13 12
33.3 18.7 9.4 8.9 6.9 6.4 3.9 3.3 3.3 3.1 2.8
427
100.0
Table 3 Distribution of cases and controls by sociodemographic variables and alcohol intake Variable Age (years)
Residence Urban/rural Birthplace
Education (years) Total alcohol (ml/day)
Number of patients
Category 40±49 50±59 60±69 70±79 80±89 Montevideo Other counties Urban Rural Montevideo South North Migrants 0±4 5+ Non-drinkers 1±60 61±120 121±240 241+
Cases (%) 29 138 170 73 15 188 237 344 81 96 194 119 16 266 159 48 71 84 115 107 425
(6.8) (32.5) (40.0) (17.2) (3.5) (44.2) (55.8) (80.9) (19.1) (22.6) (45.6) (28.0) (3.8) (62.6) (37.4) (11.3) (16.7) (19.8) (27.1) (25.2) (100)
Controls (%) 30 (7.0) 138 (32.3) 170 (39.8) 74 (17.4) 15 (3.5) 188 (44.0) 239 (56.0) 345 (80.8) 82 (19.2) 128 (30.0) 158 (37.0) 120 (28.1) 21 (4.9) 216 (50.6) 211 (49.4) 119 (27.9) 122 (28.6) 76 (17.8) 52 (12.2) 58 (13.6) 427 (100)
342
E. De Stefani et al./Oral Oncology 34 (1998) 340±346
Table 4 Odds ratios (OR) of cancer of the oral cavity and pharynx for tobacco variables Variable Smoking status
Cigarettes per day Years smoked Pack-years
Years since quit
Type of tobacco Duration of type of tobacco
Hand-rolling Duration of hand rolling
Filter use Smoking pattern
a
Category
Cases/Controls
OR
95% CI
Non-smokers Former smokers Current smokers All smokers 1±14 15±24 25+ 1±39 40±49 50+ 1±28 29±47 48±76 77+ 10+ 5±9 1±4 Current smokers Mainly blond Mainly black Blond 1±39 years Blond 40+ years Black 1±39 years Black 40+ years Manufactured Mixed Hand-rolled Manufactured 1±39 years Manufactured 40+ years Rolled 1±39 years Rolled 40+ years Lifelong filter Mixed Lifelong plain Blond + manufactured Blond + rolled Black + manufactured Black + rolled
38/150 80/105 307/172 387/287 57/91 150/106 180/80 104/99 154/98 129/80 66/100 105/61 97/70 119/46 12/37 27/28 41/40 307/172 196/222 191/55 66/85 130/137 38/13 153/42 94/107 52/69 241/101 33/49 61/58 71/49 222/121 9/25 104/129 274/123 69/96 132/126 30/11 161/44
1.0 2.9 7.2 5.3 2.5 6.0 8.1 4.6 5.8 5.3 2.7 6.8 5.1 8.3 1.2 3.4 4.1 7.3 3.2 12.1 2.9 3.2 10.9 12.4 3.4 2.6 8.7 2.9 3.8 5.7 6.3 1.5 2.9 7.8 2.4 3.6 9.7 12.8
± 1.8±4.6 4.7±11.1 3.5±7.9 1.5±4.1 3.8±9.5 5.1±12.9 2.7±7.8 3.6±9.2 3.3±8.5 1.6±4.4 4.2±11.1 3.2±8.3 5.0±13.8 0.6±2.6 1.8±6.6 2.3±7.3 4.7±11.2 2.1±4.8 7.6±19.4 1.7±5.1 2.1±4.9 5.1±23.4 7.5±20.5 2.1±5.5 1.5±4.4 5.6±13.4 1.5±5.5 2.2±6.4 3.3±10.1 4.1±9.6 0.6±3.7 1.8±4.6 5.1±11.9 1.4±4.0 2.3±5.6 4.4±21.4 7.8±20.9
CI, con®dence interval. a Adjusted for age, residence, urban/rural status, birthplace, education, and total alcohol consumption.
manufacturing, rolled, ®lter, plain); and (3) a complete alcohol consumption history (including type of beverage and daily intake in glasses or other recipes). The amount smoked was calculated after summing and averaging the number of cigarettes per day in different periods of the lifetime of all subjects. Smoking duration was calculated by substracting age at start from age at quit, whereas smoking cessation was calculated by substracting age at quit from age. Former smokers were de®ned as those smokers who had quit the habit more than 1 year before the interview, whereas current smokers were those smokers who had never quit or who had quit the habit less than 1 year before the interview date. The type of tobacco was classi®ed as blond or black, according to the brand of tobacco smoked. Furthermore, cigarettes were classi®ed as manufactured or hand-rolled, according to the brand
used. According to previous estimations, one pack of tobacco for hand-rolled cigarettes yields 60 cigarettes (Association of Tobacconists, personal communication). In Uruguay, packs for hand-rolling cigarettes could be ®lled by blond or black tobacco. Mainly blond (or black) tobacco smokers were de®ned as those patients who smoked this type of tobacco more than 50% of their lifelong smoking history. A more detailed assessment of the type of tobacco was calculated according to the duration of smoking blond (or black) in three categories: 1±39 years, 40±49 years and 50 years or more. Hand-rolling smokers were de®ned as those smokers who ®lled their own cigarettes with tobacco specially prepared for this purpose. In order to calculate the risk associated with smoking hand-rolled cigarettes, two variables were created: the ®rst one had nonsmokers as the reference category, exclusive smokers
E. De Stefani et al./Oral Oncology 34 (1998) 340±346 Table 5 Odds ratios (OR) of oral cancer for tobacco variables compared with pharyngeal cancer Variable
Smoking status Non-smokers Former smokers Current smokers All smokers Cigarettes per day 1±14 15±24 25+ Years smoked 1±39 40±49 50+ Pack-years 1±28 29±47 48±76 77+ Years since quit 10+ 5±9 1±4 Current smokers Type of tobacco Mainly blond Mainly black Duration of type of tobacco Blond 1±39 years Blond 40+ years Black 1±39 years Black 40+ years Hand-rolling Lifelong manufactured Mixed Lifelong rollers Duration of hand-rolling Manufactured 1±39 years Manufactured 40+ years Rolled 1±39 years Rolled 40+ years Filter use Lifelong ®lter Mixed Lifelong plain Smoking pattern Blond +manufactured Blond + rolled Black + manufactured Black + rolled
343
a
Oral cavity
Pharynx
Cases
OR
95% CI
Cases
OR
95% CI
24 36 146 182
1.0 2.2 5.7 4.2
± 1.2±3.9 3.4±9.5 2.6±6.8
14 44 161 205
1.0 4.3 10.2 7.5
± 2.2±8.3 5.5±18.8 4.1±13.6
27 76 79
1.9 5.1 6.1
1.0±3.5 2.9±8.7 3.5±10.8
30 74 101
3.6 7.8 12.2
1.8±7.1 4.1±14.9 6.4±23.3
51 68 63
3.5 4.3 4.5
1.8±6.5 2.5±7.5 2.5±7.9
53 86 66
6.2 8.3 7.5
2.9±12.8 4.3±15.9 3.9±14.4
34 52 47 49
2.2 5.5 4.4 5.7
1.2±4.1 3.1±9.9 2.4±7.9 3.1±10.6
32 53 50 70
3.5 8.9 6.7 13.3
1.7±7.0 4.5±17.6 3.4±13.2 6.7±26.2
4 12 20 146
0.7 2.7 3.2 5.8
0.2±2.1 1.2±6.1 1.6±6.5 3.5±9.6
8 15 21 161
2.1 5.1 5.9 10.3
0.8±5.5 2.2±12.0 2.7±12.8 5.6±19.1
91 91
2.4 9.4
1.5±4.1 5.4±16.3
105 100
4.4 17.8
2.4±8.1 9.2±34.1
32 59 19 72
2.3 2.5 8.3 9.7
1.2±4.5 1.4±4.3 3.5±19.7 5.4±17.3
34 71 19 81
3.8 4.6 15.1 18.4
1.8±8.1 2.4±8.6 5.8±39.1 9.4±36.2
45 31 106
2.9 2.6 6.1
1.6±5.2 1.4±4.9 3.6±10.2
49 21 135
4.3 2.7 13.7
2.2±8.5 1.3±5.8 7.3±25.5
17 28 34 103
2.6 3.2 4.2 4.8
1.2±5.6 1.7±6.1 2.1±8.2 2.9±8.1
16 33 37 119
3.5 4.9 8.0 9.5
1.5±8.2 2.4±10.1 3.7±17.2 5.0±17.1
6 48 128
1.7 2.3 6.0
0.6±4.8 1.3±4.1 3.6±10.0
3 56 146
1.3 4.0 11.3
0.3±5.2 2.1±7.8 6.1±20.8
28 63 17 74
1.9 2.8 10.3 9.2
0.9±3.5 1.6±4.8 4.2±25.1 5.1±16.3
36 69 13 87
3.4 5.1 9.2 20.6
1.7±6.8 2.7±9.6 3.4±25.0 10.5±40.6
CI, con®dence interval. a Adjusted for age, residence, urban/rural status, birthplace, education, and total alcohol consumption.
of manufactured (commercial) cigarettes, exclusive smokers of hand-rolled cigarettes, and mixed smokers; the second variable categorised manufactured and hand-rolled cigarettes into two periods each, according to the duration of use. The time periods were identical to those employed in assessing the duration of use of the
types of tobacco. Finally, the smoking pattern was a composite variable which combined the type of tobacco and the use of commercial or hand-rolled cigarettes. Alcohol drinking was recorded in glasses of 50, 120, and 250 ml for hard liquor, wine, and beer. The content of pure ethanol was calculated according to the following
344
E. De Stefani et al./Oral Oncology 34 (1998) 340±346
concentrations speci®c for Uruguay: 6% for beer, 12% for wine, and 46% for spirits. The resulting values were converted to grams by multiplying 1 ml of pure ethanol per 789 mg [9]. In Uruguay, spirits are made from or from grapes (grappa). Although sugarcane (cana) they were not discriminated in the questionnaire, the ethanol content of both is the same [9]. Relative risks (RR) of cancer of the oral cavity and pharynx, approximated by the odds ratios (OR) were calculated for all study variables. The method employed was unconditional logistic regression [10]. All models included the matching variables (age, residence, and urban/rural status) and potential confounders (birthplace, education, and alcohol drinking). Age was adjusted by introducing a continuous term and a categorical one. Since the results were similar, all models were adjusted for age as a continuous term. The assessment of tobacco eect was performed through a logistic model which included potential confounders (age, residence, urban/rural status, education, total alcohol consumption, as a continuous variable, and other tobacco variables). The eect modi®cation of tobacco smoking and alcohol drinking was evaluated by including interaction terms in the logistic model. Tests for trend for study variables were calculated by including categorical terms as continuous variables to a model with all the potential confounders. All calculations were performed using the GLIM (General Linear Interactive Modelling) software [11].
3. Results The distribution of cases and controls by sociodemographic variables and total alcohol drinking is shown in Table 3. The proportions of cases and controls, according to age, residence, and urban/rural status, were similar, as a result of the frequency matching. More controls reported Montevideo as their birthplace than cases, and, also, they were more educated than the cases. Cases consumed signi®cantly more alcohol beverages than controls. Odds ratios of oral and pharyngeal cancer for tobacco variables are shown in Table 4. Current smokers displayed an OR of 7.2 (95% con®dence interval (CI) 4.7±11.1), whereas a reduction in risk was observed for former smokers (OR 2.9, 95% CI 1.8±4.6). Risk increased steeply with smoking intensity (OR for heavy smokers 8.1, 95% CI 5.1±12.9) and with smoking duration (OR for smokers of more than 50 years 5.3, 95% CI 3.3±8.5). The risk of quitters of more than 10 years was close to that showed by non-smokers (OR 1.21 95% CI 0.6±2.6). Smokers of black cigarettes were associated with a large increase in risk (OR 12.1, 95% CI 7.6±19.4) compared with non-smokers. When the eect of the type of tobacco was analysed according to its duration of use, the greater eect associated with smoking black tobacco was maintained. Exclusive smokers of handrolled cigarettes were associated with an OR of 8.7 (95% CI 5.6±13.4), compared with non-smokers.
Table 6 Odds ratios (OR) of oral and pharyngeal cancer for type of tobacco and hand-rollingÐsmokers only Variable
Type of tobacco Mainly blond Mainly black Duration of type of tobacco Blond 1±39 years Blond 40+ years Black 1±39 years Black 40+ years Hand-rolling Lifelong manufactured Mixed Lifelong rollers Duration of hand-rolling Manufactured 1±39 years Manufactured 40+ years Rolled 1±39 years Rolled 40+ years Smoking pattern Blond + manufactured Blond + rolled Black + manufactured Black + rolled
Oral cavity
a
Pharynx
Both sites
OR
95% CI
OR
95% CI
OR
95% CI
1.0 3.0
± 1.8±4.9
1.0 3.0
± 1.8±4.9
1.0 3.0
± 2.0±4.6
1.0 1.1 2.6 3.3
± 0.6±2.0 1.1±6.3 1.6±6.7
1.0 1.3 2.4 3.8
± 0.7±2.3 0.9±5.8 1.8±7.8
1.0 1.1 2.6 3.4
± 0.7±1.9 1.2±5.5 1.8±6.2
1.0 0.9 1.3
± 0.5±1.7 0.7±2.3
1.0 0.6 1.9
± 0.3±1.1 1.1±3.5
1.0 0.7 1.6
± 0.4±1.2 0.9±2.5
1.0 1.1 1.1 1.3
± 0.5±2.8 0.5±2.4 0.5±2.9
1.0 1.2 1.0 1.5
± 0.5±2.8 0.4±2.3 0.7±3.4
1.0 1.2 1.1 1.3
± 0.6±2.4 0.5±2.1 0.7±2.6
1.0 1.3 4.0 3.5
± 0.7±2.3 1.6±10.3 1.6±7.3
1.0 1.0 1.9 3.4
± 0.6±1.8 0.7±5.2 1.6±7.0
1.0 1.1 2.7 3.2
± 0.7±1.7 1.2±6.1 1.8±5.8
CI, con®dence interval. a Adjusted for age, residence, urban/rural status, birthplace, education, pack-years, total alcohol intake, years since quit, and ®lter use.
E. De Stefani et al./Oral Oncology 34 (1998) 340±346 Table 7 Odds ratios (OR) of dierent sites of the oral cavity and pharynx for black tobacco smokers (reference category: smokers of blond cigarettes) a Site
Lip Tongue Other parts of the mouth Oropharynx Hypopharynx
Black tobacco OR
95% CI
3.5 3.6 2.3 3.7 2.1
1.3±9.8 1.8±7.1 1.2±4.4 2.0±6.7 1.1±3.9
CI, con®dence interval. a Adjusted for age, residence, urban/rural status, birthplace, education, total alcohol consumption, pack-years, years since quit, and ®lter use.
Lifelong smokers of ®lter cigarettes displayed a risk of 1.5 (95% CI 0.6±3.7), which was not signi®cantly greater than the risk of non-smokers. Finally, the combination of black tobacco and hand-rolled smokers was associated with a large increase in risk (OR 12.8, 95% CI 7.8±20.9), compared with non-smokers. Odds ratios of oral cancer, compared with those of pharyngeal cancer, for tobacco variables, are shown in Table 5. Although both cancer sites (or groups of sites) were associated with signi®cantly elevated ORs for each tobacco variable, pharyngeal cancers displayed a 2-fold excess risk, compared with cancer of the oral cavity. For oral cancer, current smokers were associated with an OR of 5.7 (95% CI 3.4±9.5), whereas the risk of pharyngeal cancer for the same category was of 10.2 (95% CI 5.5±18.8). Heavy smokers (25 or more cigarettes per day) displayed an OR of 6.1 (95% CI 3.5±10.8) in oral cancer patients, and an OR of 12.2 (95% CI 6.4±23.3) for those with cancer of the pharynx. Smokers of black tobacco showed an OR of 9.4 (95% CI 5.4±16.3) compared with non-smokers in patients with oral cancer. The OR of pharyngeal cancer for the same category was 17.8 (95% CI 9.2±34.1). Finally, lifelong smokers of hand-rolled cigarettes were associated with an increased risk of 6.1 (95% CI 3.6±10.2) for oral cancer, whereas the risk for pharyngeal cancer was 13.7 (95% CI 7.3±25.5). Odds ratios of oral and pharyngeal cancer for type of tobacco, hand-rolling, and smoking pattern, after excluding non-smokers, are shown in Table 6. When a model including education, birthplace, pack-years, total alcohol intake, years since quit, and ®lter use was ®tted, smokers of black tobacco were associated with a signi®cantly elevated OR of 3.0 (95% CI 2.0±4.6), when compared with smokers of blond tobacco. When type of tobacco was analysed according to the duration of its use, the higher risk was observed for those who smoked black tobacco for more than 40 years (OR 3.4, 95% CI 1.8±6.2). Lifelong smokers of hand-rolled cigarettes
345
were associated with a signi®cantly elevated risk of 1.9 (95% CI 1.1±3.5), compared with lifelong smokers of manufactured cigarettes, for pharyngeal cancers only. The duration of smoking hand-rolled cigarettes was not associated with a signi®cant increased risk of oral and pharyngeal cancer. Finally, smokers of black tobacco who rolled their cigarettes were associated with an increased risk of 3.2 (95% CI 1.8±5.8) (reference category: smokers of manufactured blond tobacco). Odds ratios of dierent sites of the oral cavity and pharynx for black tobacco smoking are shown in Table 7. The highest risks were observed for the lip, tongue, and oropharynx, but in every site, smoking black tobacco was associated with a signi®cantly elevated risk after controlling for major confounders. 4. Discussion This study replicates previous ®ndings, regarding intensity and duration of tobacco smoking in oral cancer [3±8, 12±22]. Also, the reduction in risk associated with cessation and ®lter use were evident. Most, but not all, previous studies which examined the relationship between smoking black tobacco and the risk of oral cancer, showed an increased risk. In particular, in the study conducted by Merletti et al. [7] in Torino, the risk associated with black tobacco smoking disappeared when smoking cessation and ®lter use were included in the logistic model. In fact, the possibility that failure to include such powerful confounders in the model could result in residual confounding is a major one. For this reason, the present study allowed for years since quit and ®lter use in a model which excluded non-smokers. The eect of black tobacco remained signi®cant after this stringent analysis. Moreover, when black tobacco was analysed by its duration of use, a dose±response pattern was evident. The mechanisms underlying this deleterious eect of black tobacco are probably related to its high content of tobacco-speci®c nitrosamines, as previously shown by Hecht et al. [23]. These compounds appear to have a great carcinogenic potential for oral and pharyngeal mucosa, as shown in experimental studies [24]. As far as hand-rolled cigarettes are concerned, a high tar content has been previously reported in a recent follow-up study from Norway [25]. Therefore, it is not surprising that the combination of black and hand-rolled cigarettes is associated with the higher risks of oral cancer, as shown in the present study. Since smokers of black tobacco frequently roll their own cigarettes, both variables (black tobaccco and hand-rolling) are highly correlated and the independent eect of each variable is dicult to disentangle. Nevertheless, the type of tobacco appears to be more risky than hand-rolling.
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This study presents several advantages and drawbacks. The major strength is perhaps related to the large number of cases and controls, that to its power size, which allowed the estimation of stable odds ratios, even for the lip. On the other hand, the use of hospitalised controls has been questioned on the grounds that the resulting relative risks could be biased to the null. This could be a result of the fact that hospitalised controls, and cancer controls, have a larger proportion of heavy smokers, compared with population-based controls [26]. Since the control series was assembled with patients treated in the same hospitals as the cases, in the same time period, and were frequency matched to the cases on age, residence, and urban/rural status, selection bias appears to be unlikely. Recall bias could have occurred, as in any case±control study, but the use of hospitalised controls is against this possibility, due to the fact that forces of recall are usually of the same magnitude, both in cases and in hospital-based controls. In summary, the present study replicates ®ndings from previous case±control studies, concerning the aetiological role of tobacco smoking in oral cancer. Moreover, it emphasizes the fact that the combination of black tobacco and hand-rolling is particularly deleterious for oral carcinogenesis. Acknowledgements This work was supported by a grant from the ComisioÂn Honoraria de Lucha contra el Cancer, Montevideo, Uruguay. References [1] Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J. Cancer Incidence in Five Continents, Vol. VII. IARC Scienti®c Publication No. 143. Lyon: International Agency for Research on Cancer, 1997. [2] De Stefani E, Correa P, Oreggia F, et al. Black tobacco, wine and mate in oropharyngeal cancer. A case±control from Uruguay. Revue Epidemiologie et Sante Publique 1988;36:389±394. [3] Oreggia F, De Stefani E, Correa P, Fierro L. Risk factors for cancer of the tongue in Uruguay. Cancer 1991;67:180±183. [4] De Stefani E, Oreggia F, Rivero S, Fierro L. Hand-rolled cigarette smoking and risk of cancer of the mouth, pharynx, and larynx. Cancer 1992;70:679±682. [5] IARC. Tobacco Smoking. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Vol. 38. Lyon: International Agency for Research on Cancer, 1986. [6] Blot WJ, McLaughlin JK, Devesa SS, Fraumeni JF Jr. Cancers of the oral cavity and pharynx. In: Schottenfeld D, Fraumeni JF Jr., editors. Cancer Epidemiology and Prevention, 2nd Edition. Oxford: Oxford University Press, 1996.
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