Systematic review of the relation between smokeless tobacco and cancer in Europe and North America

All reports had to satisfy the following inclusion criteria: published in a peer reviewed journal or the results publicly available, epidemiological study in humans, of cohort or case-control design, study location specified, any form of cancer as the outcome, and chewing tobacco, oral snuff or unspecified ST as the exposure. They also had to fall outside the exclusion criteria: conducted in an Asian or African population, no control group, or inappropriate design (case report, qualitative study or review/meta-analysis). Relevant papers were sought from a MEDLINE search conducted in May 2008 of "cancer" AND ("smokeless tobacco" OR "chewing tobacco" OR "snuff" OR "snus"), supplemented by citations in recent reviews [1‐6, 10] and in the papers obtained.

Reports were grouped by study, and for each study details were abstracted (see Tables 1 and 2[11‐114]) relating to the design, period, location, controls used and size, the exposure (method of assessment, type of ST, exposure doses and durations considered), the outcome (cancer sites studied) and issues relating to analysis (type of effect measure, analysis methods, extent of adjustment for smoking and other factors, and availability of dose-response data). The extent of adjustment for smoking for a study was categorised into five groups: A. no information – effect estimates are provided but no details are given of any adjustments made; B. no adjustment – effect estimates are available for the whole population, but smoking is not taken into account; C. never smokers – the only effect estimates available are for never smokers; D. some adjustment – effect estimates adjusted for smoking are available, but the adjustment is relatively simple, using two or three level broad groupings (for example, ever/never smoked, current/non-current smoker, current/former/never smoker), and takes no account of daily amount smoked or duration of smoking; and E. more adjustment – effect estimates are available that take into account daily amount smoked, duration of smoking and/or their product (pack-years). Studies were categorised under D or E if smoking-adjusted effect estimates are available, regardless of whether some results for never smokers are also presented. The method used to adjust for smoking is not always clear. Studies where the authors merely report that they 'adjusted for cigarette smoking' are included in category D.

Based on the availability of relevant data, 13 cancer groupings (oropharyngeal, oesophagus, stomach, pancreas, other digestive, larynx and nasal, lung, prostate, bladder, kidney, haematopoietic and lymphoid, other and all), were selected, with results for each grouping tabulated in a standard way, with details given of the source, exposure to ST, smoking group, sex, number of cases and adjustment factors for each effect estimate or indication of association (see tables dealing with individual effects estimates, below). For each study the intent is to extract the relative risk (RR) or odds ratio (OR) adjusted for the most factors, relevant to current, former or ever exposure to chewing tobacco, snuff or overall/undefined ST. Where relevant results for a study are reported in more than one paper, those based on the greatest number of cases are used.

Results are included, where available, for the whole population and for never smokers, and for sexes separately. RR or OR estimates based on zero exposed cases (or controls) are not included as providing too little information and because a valid confidence interval (CI) cannot be calculated. Suitable estimates of effect (RR or OR) and precision (CI) provided by the authors are used if possible, estimates otherwise being calculated from available data presented in the source publication, based on methods [115‐118] summarised elsewhere [4]. Where an effect estimate cannot be calculated, statements made by the authors are summarised into terms such as 'no association' or 'no significant association'. Data are summarised for all types of cancer, except those relating to subdivision by type within site (for example, adenocarcinoma or squamous cell carcinoma of the lung, or t(14; 18)-positive and -negative non-Hodgkin's lymphoma or those relating to combined 'other' groups of cancers, which typically vary in definition from study to study).

Study-specific results for the different types of cancer are presented in an essentially identical format, with a standard set of information included for each effect estimate included. Points to note about the entries in the various columns are discussed below.

Estimates with no CI are not included in the meta-analyses. The standard error of the logarithm of estimates of effect size was calculated from its reported or estimated CI, assuming that the effect size was log-normally distributed. The logarithms of the effect sizes and their corresponding standard errors form the data points for fixed-effect and random-effects meta-analysis [116].

For most cancer groupings, results of nine random-effect meta-analyses are presented, subject to availability of data (see tables summarising meta-analysis results, below). In the first set of three, any, there is no restriction of estimates on type of exposure or region. In the second set, any ST use (USA), estimates are restricted to those from studies conducted in the USA (or on occasion in Puerto Rico), while in the third set, snuff (Scandinavia), estimates are restricted to those for snuff and for studies conducted in Scandinavia. Each of the three sets of meta-analyses is divided into overall data, smoking-adjusted and never smokers. In the overall data analyses, estimates are not restricted on smoking status or on adjustment for smoking. The smoking-adjusted analyses only include estimates that are for the whole population and adjusted for smoking or are for never smokers. The never smokers analyses are restricted to estimates for never smokers. For oropharyngeal cancer, where more estimates are available, some additional meta-analysis results are shown, based on estimates that are smoking and alcohol adjusted, and on estimates published since 1990.

To avoid double-counting multiple non-independent estimates from the same study, estimates from each study are selected for inclusion in the meta-analyses using order of preference lists for ST exposure (ever use/unspecified use/current use/former use), then smoking status (any – based on the combined population of smokers and non-smokers/never smokers), and then ST type (ST/snuff/chew), with each list being in order of most to least preferred. At each step we retain those estimates highest up the list, discarding any estimate lower in the preference order. If the procedure ends up with separate estimates for males and for females, both are included in the analysis. In one study [36], the results available are for males for chewing and for females for snuff (see Table 3). Although the procedure, strictly applied, selects only the snuff estimate, it was decided to include both in the relevant meta-analyses.

The presentation of the meta-analyses shows the number of estimates combined; the identification numbers of these estimates (so that they can be related to the preceding table of individual effect estimates); the combined random-effects estimate, with its 95% CI [116], the chi-squared and P value of homogeneity [119] and the I² statistic [120]. The meta-analyses conducted also include a test for publication bias [121] where five or more estimates are combined. Findings significant at P < 0.1 are indicated.

Forest plots are also included for most of the cancers. These are generally based on the smoking-adjusted analyses, with the estimates split by region and shown with cohort data first, then case-control, presented in order of publication year.

For each estimate included, the value of Q² is calculated by w (x - )², where w is the inverse-variance weight, x is the logarithm of the effect size and its mean. Q² is the contribution of the estimate to the heterogeneity chi-squared statistic [116]. Where there is significant (P < 0.05) heterogeneity of estimates, sensitivity to potentially outlying estimates is tested by removing that with the largest Q² value and rerunning the analyses. This process is continued until there is no longer significant heterogeneity.

Sensitivity to the criterion for including estimates based on ST exposure is also tested by rerunning the meta-analyses with the preference list for ST exposure changed from ever use/unspecified use/current use/former use to current use/ever use/unspecified use/former use.

Regression analyses are only conducted based on the overall data and smoking-adjusted data. The analyses successively introduce the most significant factor into the model, stopping when no further factor significant at P < 0.05 can be added. Significance is estimated by treating the ratio of the deviance per degree of freedom (d.f.) explained by the factor to the residual deviance per d.f. as an F statistic. For oropharyngeal cancer some additional analyses investigate the drop in deviance resulting from introducing each factor individually, and others are conducted having excluded 'outlying' observations with a very high Q² value.

RRs for current and former cigarette smokers (compared with never cigarette smokers) for men aged 35+ for seven major cancers caused by smoking (lip/oral cavity/pharynx, oesophagus, pancreas, larynx, lung, bladder, kidney/other urinary organs) were obtained from the American Cancer Society Cancer Prevention Study II (CPS-II) [122]. Numbers of deaths for these seven cancers occurring in US men aged 35+ in 2005 were obtained from WHO [123]. Estimates of the proportion of current and former cigarette smokers in US men aged 35+ in 2005 were obtained from the National Health Interview Survey [124].

Defining D_i as the number of deaths for cancer i (i = 1,..., 7), R_ci and R_fi as the RRs for current and former cigarette smokers for cancer i, and p_c and p_f as the proportions of current and former cigarette smokers in the population, the estimated number of deaths, , that would have occurred had the whole population the risk of never smokers, is then estimated by:

The number of deaths avoided from these seven cancers, had the whole population the risk of never smokers (that is, the deaths attributable to smoking) is then estimated by:

Let us further define R_si as the estimated relative risk from ST for cancer i based on the meta-analyses using smoking-adjusted effect estimates. Where R_si is estimated to be less than 1, it is taken to be 1 for the purposes of calculating deaths attributable to ST.

For a population of never smokers, the number of deaths from cancer i that would have occurred had the same proportion of men used ST as had ever smoked is then estimated by:

The increase in overall deaths from these seven cancers is then given by:

I₁ can then be compared with E as an indicator of the relative effects of ST and smoking.

Also for a population of never smokers, the number of deaths from cancer i that would have occurred had all the men used ST, is estimated by:

The increase, compared with E, is then calculated by:

Results relating ST use to mortality or incidence have been reported for nine cohort studies, with results provided by multiple publications for some studies. Six studies have been conducted in the USA and are based on the Lutheran Brotherhood cohort [11‐14], the US Veterans cohort [15‐19], the Iowa cohort [20], the First National Health and Nutrition Examination Survey (NHANES I) Follow-up cohort [21, 22], and the American Cancer Society Cancer Prevention Study I (CPS-I) [23] and Study II (CPS-II) [23‐25]. One study was based on two Norway cohorts [14, 26, 27] while the remaining two were conducted in Sweden; one based on construction workers [28‐34], and the other on a cohort in Uppsala County [35]. Fuller details of these studies are given in Table 1. A number of these studies (US Veterans, CPS-I, CPS-II, Swedish Construction Workers) are extremely large, involving at least 100,000 subjects, though the number of ST users is less than this, particularly in the CPS-I and CPS-II studies where the analyses of Henley et al. [23] restricted attention to never smokers of cigarettes. The US studies generally present results for combined ST use, the main exception being the analyses of CPS-II [23] where some separate analyses are presented for snuff and chewing tobacco. The results from the Swedish studies relate to snuff use, as do the main results from the Norwegian study [26].

Results relating ST use to cancer have been reported for 80 case-control studies, with Table 2 providing details for each study, in chronological order of publication, of the location, period and controls, as well as the exposures, cancer types and sexes studied. Eighteen were published between 1920 and 1975 [36‐52], 30 between 1976 and 1990 [53‐82] and 32 between 1991 and 2007 [83‐114]. In general there was one publication per study, but Bjelke [52] reported results from two studies, while the reference to Gross et al. [91] is to a review, which cites results from an unpublished study by Perry et al. Of the 80 studies, 56 were conducted in the USA, 11 in Sweden, three in each of Canada, Denmark and the UK, and one in each of Brazil, Norway and Puerto Rico, with one study conducted in five countries. Most of the studies involve only one or a small number of cancer types, but one study [55] involves a very wide range. The majority of the studies involve less than 1,000 cancer cases but 10 are larger than this [38, 55, 56, 66, 70, 74, 89, 97, 99, 106]. The numbers of cancers in ST-exposed subjects are typically much lower than this, as will become evident when the results for the individual sites are presented. Of the different cancer sites, oral cancer is by far the most often studied. Of the 56 US studies, 11 provide results only for chewing tobacco, five only for snuff, and 18 only for ST, with the remaining 22 results for more than one type. Seven of the 11 studies in Sweden restricted attention to snuff, with three also considering chewing and one only considering chewing.

ST use is not a major subject for many of the publications from which results have been extracted. While reference is made to ST in the title of one or more papers relating to six of the nine cohort studies (NHANES I, CPS-I, CPS-II, Norway Cohorts, Swedish Construction Workers and Uppsala County), the same is true for only 15 of the 80 case-control studies. For many of the other studies [39, 42, 59, 61, 66, 70, 89, 91, 102, 104, 108, 109, 111, 113, 114], the reports only provide limited information about ST use in the text, simply giving percentages of users in the cases and controls or even saying there was an association or no association, but without giving supportive data. Many papers consider ST independently of smoking, with no attempt to adjust ST effect estimates for smoking, even though for many of the cancers considered smoking is known to be a cause, and often a major cause.

To summarise the extent to which the available effect estimates were adjusted for smoking, the studies were divided into five groups (A = no information, B = no adjustment, C = never smokers, D = some adjustment, E = more adjustment) as described more fully in the methods. Of the nine cohort studies, the numbers in the five categories were, respectively, 0, 1, 3, 3 and 2. The Iowa study [20] failed to take smoking into account at all, while the CPS-I and CPS-II studies [23] and the main results from NHANES I [22] were restricted to never smokers. In the remaining five cohort studies, the extent of smoking adjustment varied from publication to publication, but amount smoked or duration of smoking were never taken into account in the US Veterans, Norway cohorts and Uppsala County studies so they are classified as group D. In the Lutheran Brotherhood study, amount smoked was taken into account in the analyses of pancreatic cancer [13] and stomach cancer [12], and in the Swedish Construction Workers study, amount smoked was adjusted for in the analyses of stomach and oesophageal cancer [34], and cutaneous squamous cell carcinoma [29], and they are therefore classified as group E.

Of the 80 case-control studies considered, details of the adjustment factors used are not provided in either of the studies reported by Bjelke [52] or in two other studies [93, 109] (category A). For a further 38 studies [36, 38‐40, 42, 44‐46, 49, 51, 53, 54, 56, 57, 59, 60, 63, 64, 67, 70‐73, 75, 78, 80‐82, 84‐86, 92, 95, 96, 98, 100, 103, 110] the results available for ST are for the whole population, with no adjustment for smoking (category B). In 14 studies [43, 47, 48, 66, 69, 74, 76, 83, 87, 88, 99, 101, 111, 112] the only relevant smoking-adjusted results reported are for never smokers (category C). In the remaining 24 studies, some smoking-adjusted results are available for the whole population. Fourteen of these [37, 41, 50, 58, 61, 62, 65, 94, 97, 102, 104, 107, 108, 114] can be classified into category D. In only 10 reports [55, 68, 77, 79, 89‐91, 105, 106, 113], is some account taken of daily dose and/or duration of smoking (category E).

Table 3 presents individual effect estimates from six cohort and 34 case-control studies, with 36 of the 40 studies providing estimates with CI that could be used in meta-analyses, the other four [40, 71, 86, 92] finding no significant relationship. Thirty-eight of the 41 estimates included in the first meta-analysis (see Table 4) are those given in our earlier review of ST and oral cancer [4], three recently published studies [32, 35, 113] being introduced into the current analysis. The overall data show an association with any ST use (1.79, 1.36–2.36) that, though highly significant, is based on an extremely heterogeneous set of estimates (P < 0.001). Limiting consideration to smoking-adjusted data, the estimate reduces substantially, to 1.36 (1.04–1.77, n = 19), though it is still significant, and marked heterogeneity remains (P < 0.001). Further limiting attention to estimates adjusted for both smoking and alcohol, the two major risk factors for oropharyngeal cancer [7, 8], eliminates both heterogeneity and excess risk (1.07, 0.84–1.37, n = 10). A significant relationship is seen in never smokers (1.72, 1.01–2.94, n = 9), though the estimates are heterogeneous (P = 0.044), and generally based on a very small number of oropharyngeal cancer cases that used ST.

When the analyses are restricted to US studies, the pattern is similar to that for the overall data, with the effect estimates reduced when attention is limited to those that are smoking-adjusted, and close to 1.0 when estimates that are adjusted both for smoking and alcohol are considered. The effect estimate for never smokers is significantly increased (3.33, 1.76–6.32), based on five small studies, in total involving 19 ST-exposed oropharyngeal cancer cases.

No real evidence of a relationship with snuff use is seen in studies conducted in Scandinavia, where seven estimates, all adjusted for smoking, and four additionally adjusted for alcohol, give a combined estimate of 0.97 (0.68–1.37). However some heterogeneity should be noted, a high RR of 3.1 (1.5–6.6) in the Uppsala County study [35] conflicting with six other estimates ranging from 0.67 to 1.10.

Many of the higher estimates seen in Table 4 come from older studies which often did not adjust for smoking. If attention is limited to studies published since 1990, which generally did adjust, no association is seen. Indeed, the combined estimate from the 14 smoking-adjusted studies published since 1990 is 1.00 (0.83–1.20), and shows no significant heterogeneity.

While the choice of 1990 as the cut-point was not defined a priori, the change in estimates about that time is very clear. As shown in Figure 2, smoking-adjusted estimates for case-control studies published between 1920 and 1988 are consistently high (overall 2.38, 95% CI 1.87–3.04), while estimates for case-control studies published between 1991 and 2005 show no association at all (0.98, 0.83–1.16). There is no evidence of heterogeneity within either period (P = 0.34 for pre-1990 and P = 0.93 for post-1990) and a highly significant (P < 0.001) difference between estimates in the two periods. Smoking-adjusted estimates for the cohort studies which, though published between 2005 and 2008, generally cover a long follow-up period extending from before 1990, give an intermediate result (1.32, 0.65–2.68).

The findings are very similar to those in an earlier review [4]. That review provides additional meta-analyses of the slightly smaller data set, further investigating variation by type of ST, sex, study design, study location and study period. It also provides full details of the various types of cancer that have been considered in the source papers.

The evidence presented suggests that snuff as used in Scandinavia has no effect on oropharyngeal cancer risk. Products used in the past in the USA may have increased the risk but any effect that exists now seems likely to be quite small.

Table 5 summarises the data from four cohort and 10 case-control studies. For five of these studies effect estimates with CI are not available, one of these [52] reporting a 'synergistic effect of tobacco chewing and alcohol', another [19] presenting a RR of 2.28, but not whether it was significant, and the others [14, 40, 60] showing no significant relationship. Of the remaining nine studies, six provide smoking-adjusted estimates, three of which are also adjusted for alcohol. Though estimates are generally somewhat above 1.0 in these nine studies, they are rarely significant, exceptions being the estimate of 1.92 (1.00–3.68) for snuff in never smokers in the Swedish Construction Workers study [34] and that for chewing of 2.39 (1.23–4.64) in the Wynder and Bross case-control study [44].

The meta-analyses (see Table 6 and Figure 3) show some indication of an association, though this is not always statistically significant. Based on all available smoking-adjusted data, the combined estimate for any ST use is 1.13 (0.95–1.36, n = 7), somewhat lower than when there is no restriction to smoking-adjusted data (1.25, 1.03–1.51, n = 10). The corresponding analyses show no real indication of an effect for snuff in Scandinavia, but are more suggestive for the USA. Even here, the smoking-adjusted estimate is not significant (1.89, 0.84–4.25), though this is based on only three small studies, involving a total of 11 cases using ST. The estimates based on all the available smoking-adjusted data include an any smoking RR of 1.00 (0.79–1.27) from the study with the largest weight, the Swedish Construction Workers study [34], this RR being derived by combining the findings for adenocarcinoma and squamous cell carcinoma. The meta-analyses for never smokers give a higher combined estimate of 1.91 (1.15–3.17, n = 4) for any ST use, mainly because they use a higher (combined adeno/squamous) estimate of 1.92 (1.00–3.68) for the Swedish Construction Workers study [34].

Overall, the data must be regarded as providing suggestive evidence of a possible weak relationship between ST use and oesophageal cancer.

Table 7 presents results from 12 studies, eight of which provide a total of 17 estimates which could be used in meta-analyses. Although the Swedish construction workers study [34] shows a significant increase in risk of stomach cancer associated with snuff use for never smokers (RR 1.33, 95% CI 1.03–1.72), no other significant associations are reported, and the meta-analyses conducted (see Table 8 and Figure 4) are all non-significant. Based on smoking-adjusted estimates from eight studies, the combined RR estimate is 1.03 (95% CI 0.88–1.20). Four studies did not provide detailed data. No association with stomach cancer was reported by Weinberg et al. [67] or for the US data considered by Bjelke [52]. However, Bjelke did report an "Association ... with tobacco chewing" for the Norwegian data, and a standardised mortality ratio of 1.51 was given for the US Veterans' Study [19], but not whether this was statistically significant.

The combined evidence does not indicate an effect of ST use on the risk of stomach cancer.

Table 9 presents results from four cohort and seven case-control studies. For four of the studies effect estimates that can be included in meta-analyses are not available; two [75, 84] of these studies merely reported finding no association, one [19] reported an elevated RR of 1.65 with no CI, and another [82] a reduced RR of 0.80, also with no CI. Of the other seven studies, significant increases have been reported in two. The Norway cohorts study [26] reports an increase in ever users of snuff in a smoking-adjusted analysis based on the whole population (1.67, 95% CI 1.12–2.50) but not in an analysis based on never smokers (0.85, 0.24–3.07). Conversely, the Swedish construction workers study shows no increase in a smoking-adjusted analysis based on the whole population (0.9, 0.7–1.2), but an increase in never smokers (2.0, 1.2–3.3). None of the three meta-analyses presented in Table 10 (see also Figure 5) for any ST use show any significant increase, though they all show evidence of heterogeneity. Smoking-adjusted overall population effect estimates are available for all seven studies considered, the combined estimate being 1.07 (0.71–1.60). For never smokers, the estimate is 1.23 (0.66–2.31, n = 5). No significant associations are seen in the separate meta-analyses for the USA and Scandinavia.

At most, the overall data weakly suggest a possible effect of ST on pancreatic cancer risk. A fuller discussion of these data is available elsewhere [5].

Table 11 summarises evidence relating to cancers of the digestive system other than those considered already in Tables 5, 7 and 9. Nine studies are considered, four cohort and five case-control, with one or two studies providing data for colon cancer, rectal cancer, colorectal cancer, small intestine cancer, liver cancer, gall bladder and bile duct cancer. These data, which are insufficient for meta-analysis, include two statistically significant effect estimates: an RR of 1.9 (1.2–3.1) for rectal cancer and ST use from the US Veterans study [18] and a remarkably high OR from the case-control study of Chow et al. [93] of 18.0 (1.4–227.7) for bile duct cancer and chewing tobacco, based on only three exposed cases.

There are rather more data for the combined category of all cancers of the digestive system. Of the four studies providing data, all conducted in the USA, NHANES I [22] and CPS-II [23] show no relationship, CPS-I [23] a weak, but significant, positive relationship, and the case-control study of Sterling et al. [89] a significant negative relationship. Overall, the combined estimate (see Table 12 and Figure 6), all based on smoking-adjusted data, is 0.86 (0.59–1.25, n = 5), with significant evidence of heterogeneity (P = 0.002). The analysis for never smokers removes the case-control study and eliminates the heterogeneity. However the combined estimate of 1.14 (0.99–1.33, n = 4) remains non-significant.

More data are needed before any conclusion can be drawn for these cancers.

The data shown in Table 13 are quite limited. The evidence for nasal cancer is based on only three studies, none reporting a significant association with ST use. Seven studies investigated the relationship of ST to larynx cancer, two providing no effect estimates and merely reporting a lack of association. Control for confounding variables is very limited, with only two studies providing estimates adjusted for smoking, only one adjusting for alcohol and no study presenting any results for never smokers. The only study to adjust for smoking and alcohol [102], which shows no relationship of snuff to risk of larynx cancer, is the only study conducted in Scandinavia. Two US studies [55, 56] report a significant relationship, however, and, as shown in Table 14 (see also Figure 7), an association is seen in the overall data (1.43, 1.08–1.89, n = 5).