When preference is given to overall population smoking-adjusted estimates of pancreatic cancer risk associated with ST, on the basis that these provide greater power to detect a possible association, the meta-analyses (Table 4) show no clear evidence of any increase in risk associated with ST use. In contrast, when preference is given to risk estimates for never smokers, on the basis that these avoid possible confounding by smoking, the meta-analyses (Table 5) show more indication of an increase in risk. While no increased risk is demonstrated in studies in North America or in case-control studies (all of which were in North America), there is some evidence of an increased risk in studies in Sweden or Norway and in the cohort studies. This is also suggested by an analysis excluding the unusually low estimate from the Third National Cancer Survey , a study which in any case suffers from a weakness we describe later.
Of the three cohort studies contributing to the analysis in Table 5, one conducted in the USA, one in Sweden and one in Norway, the Norway Cohorts Study  shows no increase at all (RR 0.85, 95% CI 0.24–3.07) in never smokers, but the estimate is based on only three pancreatic cancer cases in snuff users, while the Lutheran Brotherhood Study  shows a non-significant increase (1.70, 0.90–3.10) based on 16 cases in ST users in an analysis for smokers and non-smokers combined adjusted for smoking (and also age and alcohol).
The major contributor to the observed increase derives from the recently reported Swedish Construction Workers Study , where the RR was 2.00 (1.20–3.30), based on 20 cases of pancreatic cancer in snuff-using never smokers. In considering this report by Luo et al, a number of points should be made.
First, the study was based on follow-up until the end of 2004, based on exposure information obtained at the first health check-up of those cohort members with at least one visit in the 1978–1992 period. The authors reported that a proportion of subjects classified on their first visit as never smoking were recorded in a later visit as having smoked, and that this proportion was greater in subjects who initially reported use of snus (12% vs 7%). They stated (based on an analysis not reported in detail) that bias due to this misclassification would have had little effect on the risk estimates. However, the estimated bias may have been greater, had account been taken of the possibility of subjects taking up smoking later in the follow-up period, when data were not collected.
Second, as pointed out by Rodu , the authors excluded workers enrolled in their cohort from 1971 to 1975 because of "ambiguities" in questionnaire coding, despite an earlier report on snus and cardiovascular disease from this cohort  being based only on workers enrolled in the years excluded by Luo et al (1971 to 1974).
Finally, the study provided no indication of an increase in the overall population of smokers and non-smokers combined, with the RR adjusted for age, smoking and body mass index estimated as 0.90 (95% CI 0.70–1.20). Though this estimate would have been based on considerably more snuff-using pancreatic cancer cases, Luo et al tended to dismiss this finding, and placed far more reliance on the estimate for never smokers, as this avoids residual confounding by smoking. They noted that "previous evidence, reinforced by observed data in the present study (not shown), suggests that individuals who combine smoking with snus use smoke less and might increase their overall chances of subsequent abstinence, compared with those who only smoke". While some bias may be present for this reason, it seems implausible that it could possibly explain the huge difference between the estimates for ever vs. never snuff use of 0.90 (0.70–1.20) for smokers and non-smokers combined and that of 2.00 (1.20–3.30) for never smokers. The same publication  also reports corresponding results for lung cancer of 0.70 (0.60–0.70) for smokers and non-smokers combined and of 0.80 (0.50–1.30) for never smokers. Given that smoking has a much greater effect on lung cancer risk than on pancreatic cancer risk [36, 37], any residual confounding in the estimated ever vs. never snuff use for smokers and non-smokers combined should be substantially greater for lung cancer than for pancreatic cancer. The lack of any marked difference between the two estimates for lung cancer suggests residual confounding cannot explain more than a minor part of the difference between the two estimates for pancreas cancer. The high estimate in snuff users for never smokers in the Swedish Construction Workers Study seems therefore likely to be due to other reasons, including possibly chance.
No epidemiological study is perfect, and there are weaknesses in those studies that showed no evidence of an association of ST use with pancreatic cancer (see below). However, given the reliance that has been placed on the Swedish Construction Workers Study in a recent review (), it is not inappropriate to have focused on some particular weaknesses of this study, as well as to have pointed out that estimates for other comparisons in this study do not show an association of ST with increased pancreatic cancer risk.
Considering the evidence as a whole, there are a number of limitations which should be pointed out. These include the small number of exposed cases, with the main analysis for never smokers based on a total of only 63 exposed cases from the seven studies providing data, limited control of confounding with, for example, no study at all having taken diet into account (other than alcohol) in their analyses of risk from ST, and the very limited reporting of results relating to ST use for a number of the studies, either because only an abstract was available , or because ST was not a major issue in the publication [9, 12, 13, 15, 20].
Individual study weaknesses are also an issue. The Louisiana Study and the Quebec Study [20, 21] used surrogate respondents markedly more often for cases than for controls. The analysis of the Third National Cancer Survey data  included in its control group of cancers not associated with smoking some (e.g. kidney cancer, stomach cancer and leukaemia) for which there is now evidence of a moderate relationship . The Louisiana Study  used a control group where exclusions were based on whether the conditions were suspected of altering diet, rather than on grounds of an association with tobacco use. Reliance, in the four cohort studies [9–11, 19], all involving follow-up of at least 15 years, on exposure data recorded at baseline, as already noted for the Swedish Construction Workers Study , is also a problem. In regard to the Norway Cohorts Study , this issue has also been referred to by Ramström , who comments on the considerable changes in snus use and smoking over the long follow-up period.
Other general points affecting the overall interpretation are the lack of evidence of any dose-response relationship, and possible publication bias, not only due to failure to publish data that show no effect, but also to failure to present data in a form suitable for meta-analysis where no relationship is seen [12, 20, 21].
While it remains possible that ST may increase the risk of pancreatic cancer, more evidence is clearly needed to demonstrate this. In any event, any excess risk is highly likely to be less than that associated with active smoking, where there is clear evidence that the risk increases with daily cigarette consumption and the number of years of smoking, and RRs range from three up to five at the highest levels of smoking [36, 37].
Our conclusions are not in line with those of the SCENIHR report  or of IARC Monograph 89 . The SCENIHR report, as already noted, was limited by emphasis on specific results from the Norway Cohorts Study  and from the Swedish Construction Workers Study  without citing other relevant results from these two studies. IARC Monograph 89  did not include some recent studies [11, 15] and based its conclusions on four studies; one of these  did not report a significant relationship with ST use, one of these  reported a marginally significant association with chewing tobacco but not snuff, one of these  reported no overall association with ST use, but a marginally significant trend with amount used in an analysis that, as explained above, is biased, and one of these  reported an association with snuff use in an analysis which effectively assumed that such use would not change over a follow-up period of over 30 years, and also found no association with snuff use in never smokers. Both reviews omitted some relevant references [19–21] and neither included any meta-analyses. Taking into account the limitations of the SCENIHR report  and of IARC Monograph 89 , and also the weaknesses of the available data, we consider that our analysis more accurately reflects the present evidence regarding the risk of pancreatic cancer associated with smokeless tobacco use, and indicates that an effect has not been demonstrated.