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.   

In the FDA’s New Anti-Smokeless Tobacco Campaign, #TheRealCost Is to Taxpayers and Public Health

The cost to taxpayers of the FDA’s new anti-smokeless tobacco campaign, dubbed The Real Cost, is $36 million.  FDA Center for Tobacco Products Director Mitch Zeller announced the campaign at the 8^th National Summit on Smokeless and Spit Tobacco, which was attended by a “coalition of organizations, agencies and individuals committed to reducing and eventually eliminating the use of smokeless and spit tobacco products.”

The zinger that Zeller focused on, however, was this: “Each year in the U.S., more than 2,300 people are diagnosed with oral, esophageal and pancreatic cancer due to smokeless tobacco use.”

I recently called on the CDC to release long-suppressed smokeless tobacco data (here).  The agency remains opaque on the matter, but Zeller did offer that one hard number.  Now we must ask: Is it accurate?

Surprisingly, the only source reference for the figure is found in the agency’s Tweet, here, which points to a 558-page report by the National Cancer Institute and the CDC (here).  The 2,300 figure, appearing on page 135, is the result of a calculation by Jane Henley and Michael Thun, epidemiologists at the CDC and the American Cancer Society.  They estimate that each year smokeless tobacco causes 1,601 oral cancers, 184 esophageal cancers and 530 pancreatic cancers, totaling 2,315. 

Drs. Henley and Thun estimated the number of current smokeless users in the U.S., and then applied relative risks (RR) from American studies of smokeless tobacco compiled by a 2008 article by Paolo Boffetta (here) – which I previously showed to be a classic case of data cherry picking (here).

Henley and Thun’s report of 700+ cases of esophageal and pancreatic cancers is unsubstantiated, as Boffetta’s RRs for these diseases among American smokeless users are not statistically significant. 

Boffetta reported an elevated RR of 2.6 (95% confidence interval = 1.3 – 5.2) for oral cancer among American smokeless users, but his risk analysis used only six studies, with no explanation of inclusion criteria.  The following table provides details about his results.

Epidemiologic Studies Used by Boffetta for U.S. Summary Risk Estimate = 2.6 (1.3 – 5.2), Smokeless Tobacco and Oral Cancer (Lancet Oncology, 2008)
Source Study (Author, Journal Year)	Includes smokers	Product, Number of Cases in Users	Relative Risk (95% Confidence Interval)
Men
Mashberg, Cancer 1993	Yes	Dip-Chew, 52	0.8 (0.4 – 1.9) Dip
			1.0 (0.7 – 1.4) Chew
Kabat, International Journal of Epidemiology 1994	No	Chew, 4	2.3 (0.7 – 7.3)
		Dip, 0	0
Henley, Cancer Causes and Control 2005	No	ST, 4	2.0 (0.5 – 7.7) CPS-I cohort
		ST, 1	0.9 (0.1 – 6.7) CPS-II cohort
Women
Winn, New England Journal of Medicine 1981	No	Dry Snuff, 79	4.2 (2.6 – 6.7) Whites
		Dry Snuff, 12	1.5 (0.5 – 4.8)
Blot, Cancer Research 1988	No	Dry Snuff, 6	6.2 (1.9 – 19.8)
Kabat, International Journal of Epidemiology 1994	No	Chew, 0	0
Men and Women Combined
Stockwell, Head and Neck Surgery 1986	Yes	ST, Men, 1: Women, 0	2.3 (0.2 – 12.9) Tongue
		ST, Men, 3; Women, 2	11.2 (4.1 – 30.7) Other Mouth
ST, smokeless tobacco unspecified
CPS I and II, American Cancer Society surveys

Some of the studies referenced by Boffetta included smokers, who are at much higher risk for oral cancer.  Additionally, men who dipped or chewed had no risk for oral cancer in any of the studies.  Boffetta’s elevated risk estimate of 2.6 was based almost entirely on women in the Winn and Blot studies.  As I have explained (here), elevated oral cancer risk among women in those studies was due to use of powdered dry snuff (here).  The table clearly shows the difference in risk between powdered dry snuff used by women and the dip/chew products used by men.  Boffetta’s estimate should never be applied to men who dip and chew.        

Unbiased epidemiologists would be appalled to learn that the FDA is basing its smokeless campaign on population cancer estimates derived from unreliable and inappropriate RRs.

Even if the FDA’s claim of 2,300 smokeless-related cancers was accurate, the number would pale in comparison to the 480,000 U.S. deaths per year due to smoking.

To deal with The Real Cost of tobacco use, the FDA should publish an honest estimate of the risks and consequences of smoking and smokeless use, and issue public messages that inform rather than mislead.  The current campaign wastes taxpayer resources, obfuscates the truth about smokeless tobacco and, ultimately, denies smokers information that could save their lives. 

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.

New Study Documents the Health Effects from Snus Use: Almost Zero

A detailed review of epidemiologic studies regarding snus use has just been published online by Regulatory Toxicology and Pharmacology (abstract here). Author Peter Lee, a UK epidemiologist, concludes: “Using snus is clearly much safer than smoking. While smoking substantially increases the risk of cancer and cardiovascular diseases, any increase from snus use is undemonstrated, and if it exists is probably about 1% of that from smoking.”

Dr. Lee confirms what I have been asserting since 1994: Smokeless tobacco use is 99% less hazardous than smoking, and the magnitude of risk, if it exists, is difficult to measure using modern epidemiologic methods.

Lee reviewed the evidence from over 150 studies covering many diseases. Previously, he published separate meta analyses involving smokeless tobacco use and all cancers (abstract here), dental problems (abstract here), pancreas cancer (here), oral cancer (here), and circulatory diseases (here).

The hallmark of Lee’s analytic approach is to use all of the published evidence in a systematic and unbiased manner. This is in direct contrast to anti-tobacco advocates like Dr. Paolo Boffetta, who cherry pick the data and use only numbers that confirm their pre-existing belief that smokeless tobacco causes disease. Pancreas cancer is an excellent example.

In 2008, Boffetta published a meta analysis (abstract here) in which he claimed that snus use is a risk factor for pancreas cancer. He cited two studies, one from Norway (here) and another from Sweden (here). The Norway study reported a risk increase among all snus users (Relative Risk = 1.7, Confidence Interval = 1.1 – 2.5) but not for a subset of snus users who were never smokers (RR = 0.9, CI = 0.2 – 3.1). The Swedish study reported exactly the opposite: There was virtually no risk among all snus users (RR = 0.9, CI = 0.7 – 1.2), but the subset of snus users who never smoked had an increased risk (RR = 2.0, CI = 1.2 – 3.3).

Dr. Boffetta chose only to use the elevated risks, even though they were from different groups. As Lee points out, “For pancreatic cancer, Boffetta cited only the increases for never smokers from the [Swedish] study and for the whole population from the [Norwegian] study, not mentioning the lack of increase for the whole population for the construction workers and for never smokers for the Norway cohorts.”

It is important to note Dr. Boffetta was an author of both studies; that makes his selective use of data from them even more objectionable.

Another issue raised by Lee about another Boffetta meta analysis (here) claiming that snus use is a risk factor for fatal – as opposed to non-fatal – heart attack and stroke. In a 2009 blog post, I noted that Boffetta’s claim was questionable (here): “Boffetta found that smokeless users had no significant risk for all heart attacks and strokes but had elevated risks for fatal cases. It logically follows that smokeless users probably had LOWER risks for NON-FATAL heart attacks and strokes.” Lee echoes my concern: “Anyway, an association for fatal cases but not for all cases seems unlikely unless implausibly snus protects against non-fatal cases.”

Finally, Lee reviewed epidemiologic studies to answer this question: Does snus encourage initiation of smoking or discourage quitting? His conclusion: “There is no good evidence that introducing snus in a population would encourage smoking initiation or discourage cessation.”

This is an especially important point, because RJ Reynolds has just launched a campaign encouraging smokers to switch completely to Camel Snus (article here). While apparently in full compliance with FDA tobacco regulations, the ads have enraged prohibitionists like Matt Myers, who said that Reynolds should “stop its insidious marketing of tobacco products in ways that seek to discourage smokers from quitting and keep them hooked on nicotine...The ads are trying to take advantage of people trying to end all uses of tobacco.”

Myers is wrong about many things. Most smokers are not trying to achieve abstinence, but they are interested in enjoying tobacco in a safer manner. As Dr. Lee documents, snus is a vastly safer cigarette substitute.

Magnifying Smokeless Tobacco Risks By Cherry Picking Data: A Case Study

A month ago, I discussed in this blog the definitive study of cancer risks among smokeless tobacco users. This comprehensive meta-analysis, which produced a series of summary relative risks for cancer among smokeless tobacco users by systematically combining all of the primary epidemiologic studies, was completed by Peter Lee and Jan Hamling. They concluded that there is very little evidence that smokeless tobacco use is associated with any cancer.

The results in the Lee-Hamling study were surprisingly different from an earlier meta-analysis performed by Paolo Boffetta, an epidemiologist at the International Agency for Research on Cancer, and co-authors, which was published in the journal Lancet Oncology. The Boffetta team had produced relative risk estimates for cancers of the oral cavity and pharynx, esophagus and pancreas that were considerably higher than those from Lee and Hamling, as illustrated in the following table:

Cancer Site	Boffetta Relative Risk Estimate (95% CI)	Lee-Hamling Relative Risk Estimate (95% CI)
Oral cavity/pharynx	1.8 (1.1 – 2.9)	1.36 (1.04 – 1.77)
Esophagus	1.6 (1.1 – 2.3)	1.13 (0.95 – 1.36)
Pancreas	1.6 (1.1 – 2.2)	0.99 (0.71 – 1.60)

Why did the Boffetta meta-analysis always produce higher risk estimates than the Lee-Hamling study if both were using essentially the same data? A commentary published by Lee and Hamling in the journal BMC Cancer provides the answer to that question. The answer is simple and disturbing.

First, let me give you some background information. Most primary epidemiologic studies report results for many different sets of circumstances. For example, a study about smokeless tobacco might report risk estimates for all users and these subgroups: current users, former users, exclusive users who never smoked, and users who also smoked. So it is important for investigators conducting meta-analyses to develop specific rules for combining estimates from different studies. Lee and Hamling developed rules and followed them systematically in their meta-analyses. In contrast, Boffetta did not specify any rules but appears to have followed one: Use only the highest risk estimate.

The Lee/Hamling commentary focused on the inherent contradictions in Boffetta’s approach, the best example of which is illustrated in the table below. There are two important primary epidemiologic studies on pancreatic cancer among smokeless tobacco users, one published in the Lancet and the other in the International Journal of Cancer. Each study provided risk estimates for exclusive smokeless users (i.e., those who never smoked) and for users who might also have smoked, as seen in this table:

Primary Study Journal, Year	Risk Among Exclusive Users (95% CI)	Risk Among Users +/- Smoking
Lancet, 2007	1.8 (1.1 – 2.9)	0.9 (0.7 – 1.2)
Int J Cancer, 2005	0.85 (0.24 – 3.07)	1.67 (1.12 – 2.50)

Lee and Hamling make it clear that they produced their summary estimates by either combining risks for exclusive users (i.e. 1.8 and 0.85), or risks for users who might have smoked (0.9 and 1.67). This is both logical and scientifically valid. But which estimates did Boffetta use? The highest, of course. For the Lancet study he used the estimate of 1.8 in exclusive users, but for the International Journal of Cancer study he used the estimate of 1.67 in smokeless users who might have smoked. His goal was to maximize the health risks from smokeless tobacco use, thereby feeding scaremongers who portray smokeless tobacco as deadly, despite decades of research to the contrary. The scientific term for this epidemiologic method is cherry picking.

This is just one example of the unscientific manner in which the Boffetta meta-analysis was conducted. The Lee/Hamling commentary describes many others.

According to its website, the International Agency for Research on Cancer places emphasis on “elucidating the role of environmental and lifestyle risk factors” in cancer development. The IARC should not condone the fabrication of estimates misrepresenting the scientific evidence that cancer risks from smokeless tobacco use in Sweden and the U.S. are minimal to nonexistent. Kudos to Peter Lee and Jan Hamling for documenting this travesty.