The relation between smokeless tobacco and cancer in Northern Europe and North America. A commentary on differences between the conclusions reached by two recent reviews

Abstract

Background: Smokeless tobacco is an alternative for smokers who want to quit but require nicotine. Reliable evidence on its effects is needed. Boffetta et al. and ourselves recently reviewed the evidence on cancer, based on Scandinavian and US studies. Boffetta et al. claimed a significant 60-80% increase for oropharyngeal, oesophageal and pancreatic cancer, and a non-significant 20% increase for lung cancer, data for other cancers being "too sparse". We found increases less than 15% for oesophageal, pancreatic and lung cancer, and a significant 36% increase for oropharyngeal cancer, which disappeared in recent studies. We found no association with stomach, bladder and all cancers combined, using data as extensive as that for oesophageal, pancreatic and lung cancer. We explain these differences.

Methods: For those cancers Boffetta et al. considered, we compared the methods, studies and risk estimates used in the two reviews.

Results: One major reason for the difference is our more consistent approach in choosing between study-specific never smoker and combined smoker/non-smoker estimates. Another is our use of derived as well as published estimates. We included more studies, and avoided estimates for data subsets. Boffetta et al. also included some clearly biased or not smoking-adjusted estimates. For pancreatic cancer, their review included significantly increased never smoker estimates in one study and combined smoker/non-smoker estimates in another, omitting a combined estimate in the first study and a never smoker estimate in the second showing no increase. For oesophageal cancer, never smoker results from one study showing a marked increase for squamous cell carcinoma were included, but corresponding results for adenocarcinoma and combined smoker/non-smoker results for both cell types showing no increase were excluded. For oropharyngeal cancer, Boffetta et al. included a markedly elevated estimate that was not smoking-adjusted, and overlooked the lack of association in recent studies.

Conclusion: When conducting meta-analyses, all relevant data should be used, with clear rules governing the choice between alternative estimates. A systematic meta-analysis using pre-defined procedures and all relevant data gives a lower estimate of cancer risk from smokeless tobacco (probably 1-2% of that from smoking) than does the previous review by Boffetta et al.

Figure 1

Variation in RR of ST-associated oropharyngeal cancer by study type and period of publication. For each of 19 studies, separated by study type and, for case-control studies, by period of publication, the individual study RR and 95% CI estimates, taken from the Lee and Hamling review [2] (see also Table 2), are shown numerically and also graphically on a logarithmic scale. In the graphical representation, the RR is indicated by a solid square, with the area of the square proportional to the weight (inverse-variance) of the estimate. Also shown are the combined estimates, derived by random-effects meta-analysis, for the three subgroups and overall. Here the sizes of the four squares corresponding to the RRs are also proportional to the weight of the estimate, though the constant of proportionality differs from that for the individual RRs.