A Smokeless Tobacco-Pancreatic Cancer Claim is Refuted

Snus use is not associated with pancreatic cancer, according to a study published in the International Journal of Cancer (abstract here).  Researchers combined data from nine cohort studies that involved 400,000 men in Sweden.  Compared with never users, the risk for current snus users, after adjustment for smoking, was 0.96 (95% confidence interval = 0.83 – 1.11).

The new work was conducted by the Swedish Collaboration on Health Effects of Snus Use, which includes researchers from several Swedish universities.  (In the past, snus research was largely performed by the Karolinska Institute, whose flawed studies I have previously documented here, here, here, and here.)  Their results are almost identical to those in a large study of smokeless use in North America and Europe published six years ago (discussed here), and to findings in another analysis published eight years ago (here).

Focus on a purported smokeless tobacco-pancreatic cancer link began after publication of a cherry-picked meta-analysis by Paolo Boffetta in 2008 (discussed here).  Dr. Boffetta contradicted his own finding in a later study (here), and epidemiologist Peter Lee refuted it in his comprehensive analysis in 2009 (here).  The fact is that there is no credible evidence that American or Swedish smokeless tobacco is linked to pancreatic cancer.      

Remarkably, the National Cancer Institute persists in asserting a pancreatic cancer link in its smokeless tobacco “fact sheet” (here).  That document also asks what should be a rhetorical question: “Is using smokeless tobacco less hazardous than smoking cigarettes?” 

The NCI’s answer is grossly misleading: “all tobacco products are harmful and cause cancer…There is no safe level of tobacco use.”  The agency’s source for this obfuscation is a 31-year-old Surgeon General report that has been eclipsed by three decades of epidemiologic studies.  

It should be noted that the U.S. Food & Drug Administration is equally culpable. That agency used the bogus smokeless-pancreatic cancer link as a talking point in last year’s $36 million campaign against smokeless tobacco (here).

We already knew that moist snuff and chewing tobacco have no measurable risk for mouth cancer (here).  Now there is scientific evidence that smokeless isn’t linked to pancreatic cancer.   

More Misinformation About Smokeless Tobacco From the American Cancer Society

American Cancer Society (ACS) investigators have just published results of a study on alcohol consumption and the development of pancreas cancer in the Archives of Internal Medicine (abstract here). Led by Susan M. Gapstur, the study found that, compared with never alcohol drinkers, consumers of three or more drinks per day had an elevated risk of pancreas cancer mortality. The higher risk was statistically significant for never smokers (Relative risk, RR = 1.36, 95% Confidence Interval, CI = 1.13 – 1.62) and for ever smokers (RR = 1.16, CI = 1.06 – 1.27). They did not detect higher risks for beer or wine drinkers, but only for consumption of liquor.

The article discussed the public health implications of the research:

“Alcoholic beverage consumption—a modifiable lifestyle factor—is causally related to several cancers, including oral cavity, pharynx, larynx, esophagus, liver, colorectum, and female breast. Findings from the prospective study presented herein strongly support the hypothesis that alcohol consumption, in particular heavy intake, also is an independent risk factor for pancreatic cancer, the fourth most common cause of cancer mortality in the United States. These results underscore the importance of adhering to the following guideline for cancer prevention by the American Cancer Society: ‘If you drink alcoholic beverages, limit consumption.’”

Thus, while the ACS acknowledges that alcohol is associated with considerable cancer risks, its advice to consumers emphasizes moderation. Historically, moderation has played no role in ACS messages to tobacco users: quit now and abstain completely and permanently.

The ACS web page on smokeless tobacco (available here) was revised on December 16, 2010; it is replete with misinformation, especially about cancer risks. Following are the cancers that the ACS claims, with no supporting data, are caused by smokeless tobacco use, followed by the actual scientific evidence derived from the most comprehensive study ever published (read about it here).

American Cancer Society Claim	Actual Scientific Evidence
Mouth, tongue and throat cancer	Not significantly elevated, RR = 1.07 (CI = 0.84-1.37)
Esophagus cancer	Not significantly elevated, RR = 1.13 (CI = 0.95-1.36)
Stomach cancer	Not significantly elevated, RR = 1.03 (CI = 0.88-1.20)
Pancreatic Cancer	Not significantly elevated, RR = 1.07 (CI = 0.71-1.60)

RR = Relative Risk.

Scientific evidence shows clearly that smokeless tobacco use only slightly elevates cancer risks, if at all. The reported elevations are so small that they are not statistically significant; in other words, they may have occurred purely by chance. It is also important to point out that small RRs (those under 2) should not be seen as reliable. The National Cancer Institute advises: “Relative risks or odds ratios less than 2 are viewed with caution,” because they “are sometimes difficult to interpret.”

Next week I will discuss ACS intransigence with respect to refusing to provide information in its possession about the health risks related to tobacco use.

The Revolving-Door Cohort at the Karolinska Institute

The Karolinska Institute (KI) in Stockholm is Sweden’s premier medical research institution, and among the most well known and respected in the world. For several years a group of researchers in the KI’s Department of Medical Epidemiology and Biostatistics has published numerous studies of the health risks related to snus use.

As I stated in a recent commentary published in Sweden (link here), “the health risks identified in the KI studies are the raison d’être for the ban on snus in the E.U. (except Sweden), but it has also had a profound impact on tobacco regulation in the U.S. and other countries,” making access to snus difficult or impossible.

The KI studies have profoundly influenced regulatory actions all over the world, but they are compromised by important, troubling and unresolved discrepancies that KI researchers have refused to address. This post describes the biggest problem in detail.

The KI studies are based on over 300,000 male Swedish construction workers who enrolled in a health program from 1971 to 1992, including roughly 135,000 workers who were enrolled in the program during the 1971-1974 period. This group is important, because there are potentially serious questions about the adequacy of tobacco use information for these workers. In fact, the information is so questionable that KI researchers have included and excluded them in a revolving door fashion in published analyses over the last several years.

The story goes back to 1994, when KI investigator Gunilla Bolinder and colleagues reported that snus use was a risk factor for cardiovascular diseases. (abstract here). In that study Dr. Bolinder studied only the construction workers from the 1971-74 group (hereafter, the “Bolinder” cohort). That report, one of only a few linking snus use with heart disease and stroke, had some obvious but inexplicable technical problems, which I raised in a 1995 letter to the editor of the journal (here). Dr. Bolinder did not resolve these problems.

Fast-forward 13 years to 2007, when KI investigators Luo et al. published a high profile study in The Lancet finding that snus use was a risk factor for pancreas cancer (here). In their analysis, Luo et al. excluded ALL of the workers in the Bolinder cohort “because of ambiguities in the coding of smoking status” of participants. In other words, Luo tossed out the 135,000 workers of the Bolinder cohort. The justification for these exclusions was an “unpublished” observation by Zendehdel, another KI investigator.

I published a letter to the editor of The Lancet (here) observing that, if the Bolinder cohort was deficient, then the validity of the Bolinder study was suspect. Luo et al. responded that perhaps the exclusions were not warranted (here), citing a KI study that was about to be published. That study, which found that snus use was associated with esophageal and stomach cancer, included the Bolinder cohort (here). The lead author on that study was Zendehdel.

Confusing? Absolutely. First, KI researchers cited Zendehdel as the justification for excluding the Bolinder cohort, but then Zendehdel included the Bolinder cohort in his published study.

To illustrate how many times KI researchers have subjected the Bolinder cohort to revolving door treatment, here is a list of publications.

The Bolinder Revolving Door Cohort At the Karolinska Institute
Year	First Author	Journal	Disease	Bolinder Cohort In/Out
1994	Bolinder	American Journal of Public Health	Cardiovascular	In
2005	Odenbro	British Journal of Cancer	Skin cancer	In
2007	Luo	Lancet	Pancreas cancer	Out
2007	Odenbro	British Journal of Dermatology	Melanoma	In
2007	Fernberg	Cancer Research	Leukemia	In
2007	Hergens	Journal of Internal Medicine	Heart attack	Out
2008	Zendehdel	International Journal of Cancer	Gastrointestinal cancer	In
2008	Hergens	Epidemiology	Stroke	Out
2008	Hergens	Journal of Internal Medicine	Hypertension	Out
2010	Carlens	American Journal of Respiratory and Critical Care Medicine	Inflammatory Diseases	Out
2011	Nordenvall	International Journal of Cancer	Colon-rectal cancer	In

This is unacceptable from a scientific perspective, but there are many other problems. For example, it appears that Dr. Bolinder’s definition of snus use was inconsistent with later definitions. I’ll have more to say about this in a future post.

New Study: Smokeless Tobacco is NOT Associated with Pancreatic Cancer

A new study documents that smokeless tobacco use is not associated with increased risk for pancreatic cancer. The study, from the International Pancreatic Cancer Case-Control Consortium and lead author Paolo Bertuccio of Milan, Italy, was published in Annals of Oncology (abstract here). It is a collaborative analysis of 6,000 cases of pancreatic cancer from 11 studies in North America and Europe.

With only 130 pancreatic cancer cases among ever smokeless tobacco users, the odds ratio (OR) is 0.98 (95% Confidence Interval, CI = 0.75 – 1.27). Twenty-three cases among exclusive users of smokeless tobacco produced an OR of 0.62 (CI = 0.37 – 1.04), which was almost significant for a PROTECTIVE EFFECT. Smokeless users who were also cigarette smokers had an OR of 1.36, which was not statistically significant (CI = 0.94 – 1.96) but confirms other studies that showed higher pancreatic cancer risks for smokers.

(The odds ratio is the measure used for case-control studies. Its interpretation is similar to that used for relative risks, which was discussed in this post.)

The importance of this study is hard to overestimate. First, it provides additional evidence that smokeless tobacco users are not at risk for pancreatic cancer. More importantly, it directly addresses a persistent question about the integrity of previous studies.

In September 2009, I described in detail the results of two meta-analyses of cancer risks among smokeless tobacco users (read my description here). The first report, published in 2008 by Paolo Boffetta and colleagues in Lancet Oncology, concluded that smokeless users had an increased risk for pancreatic cancer (RR = 1.6, CI = 1.1 – 2.2). But that study used cherry-picked data in an unscientific manner to artificially raise the cancer risks. The second study, by Peter Lee and Jan Hamling, using a more scientifically credible and valid approach, reported an RR for pancreatic cancer of 0.99 (CI = 0.71 – 1.60).

The results from the current study are in close agreement with the Lee-Hamling estimate, and at odds with the Boffetta estimate, which Bertuccio clearly acknowledges:

“Our results on smokeless tobacco use are in broad agreement with a recently published meta-analysis of all published data on the issue [Lee-Hamling], which reported NO EXCESS RISK OF PANCREATIC CANCER in case-control studies. They are, however, at variance with those from another meta-analysis [Boffetta], based mainly on data from two Nordic cohort studies, which suggested that smokeless tobacco is associated with an increased risk of pancreatic cancer.” (emphasis added)

Bertuccio actually cited a different Lee-Hamling publication (abstract here), but the data from this study is identical to the Lee-Hamling meta-analysis.

The Bertuccio study is significant because it endorses the Lee-Hamling analysis and clearly refutes the Boffetta analysis. But there is another, profound aspect to this report: Paolo Boffetta is a co-author. Thus, Dr. Boffetta is finally acknowledging that his 2008 meta-analysis was wrong.

American consumers have been deceived for decades by the myth that smokeless tobacco confers high risk for oral cancer (here ). Because of the misguided 2008 Boffetta meta-analysis, smokeless tobacco opponents have built a second unscientific line of attack around the issue of pancreatic cancer.

Regulatory authorities worldwide should now acknowledge that use of modern American and Swedish smokeless tobacco products is not a risk factor for cancers of the oral cavity or pancreas.