The World Journal of Oncology recently retracted a February 2022 article that claimed nicotine e-cigarette users faced the same cancer riskiness as smokers, according to a media report, Jan. 5.
Following the publication of this article, the editors explained that concerns were raised about the article’s methodology, the treatment of source data including but not limited to statistical analysis, and the reliability of the conclusions. The manuscript was withdrawn at the request of the editor-in-chief immediately following the authors’ failure to provide a reasonable explanation and evidence in response to the questioning.
Some of the concerns raised by this article are similar to those of other studies linking e-cigarettes to smoking-related disease.
Most notably, the study failed to address the question of whether the diagnosis was made before or after everyone started using e-cigarettes, which is the minimum required to infer causation.
In 2020, the same issue led to the retraction of an article in the Journal of the American Heart Association that reported a link between e-cigarettes and heart attacks.
The World Journal of Oncology article – attributed to no fewer than 13 researchers at institutions such as the University of Missouri, Temple University Hospital, Mayo Clinic and the Icahn School of Medicine at Mount Sinai – had other glaring problems that should have been obvious before it was published. It has enough inconsistencies, writing errors, illogic, and failures of reasoning to make you wonder if peer reviewers and editors actually read it, let alone carefully assess its strengths and weaknesses.
As critics have pointed out, the publication of this type of study shows that the peer review process is biased against e-cigarettes, favoring articles that emphasize their potential harms, even if the science behind them is weak.
In an email, Brad Rodu, a professor of medicine at the University of Louisville who has been studying tobacco harm reduction for decades, said the seriously flawed research on e-cigarettes and cancer raises a troubling question: How does it pass peer review?
In the withdrawn study, University of Illinois internist Anusha Chidharla and her 12 co-authors analyzed data from the National Health and Nutrition Examination Survey.
The sample included, but was not limited to, 154,856 respondents surveyed from 2015 to 2018, of which 5% said they had been exposed to e-cigarettes, 31.4% said they were current smokers, and 63.6% said they were non-smokers and had never been exposed to e-cigarettes.
The survey also asked participants if they had ever been diagnosed with cancer.
Very importantly, the study did not include information on when e-cigarette users started smoking e-cigarettes. However, the authors noted that “e-cigarettes were used as a smoking cessation strategy for most cancer respondents,” suggesting that their diagnosis usually preceded e-cigarette use. If so, that would be consistent with what Rodu and University of Louisville research economist Nantaporn Plurphanswat found when they analyzed data on other smoking-related diseases from the Tobacco and Health Survey Population Assessment, including but not limited to information on diagnosis and timing of smoking.
Chidharla et al. stated that participants were categorized as e-cigarette users if they had ever smoked an e-cigarette and were currently non-smokers. The researchers did not consider whether the respondents in the group had a history of smoking, which is clearly problematic when you’re trying to distinguish correlation from causation.
“The authors reclassified former smokers as nonsmokers, thereby masking the effect of the former,” Rodu noted. “It also increased the cancers in their reference group, which is inappropriate.”
Keeping these points in mind, what did the researchers find? They seemed confused about it.
According to the abstract, e-cigarette users had a lower prevalence of cancer compared with traditional smoking (2.3% vs. 16.8%; P < 0.0001). This is consistent with the figures reported in Table 2. However, according to the results section of the article, “Respondents with cancer had a lower prevalence of e-cigarette use compared with traditional smoking (2.3% vs 16.8 %; P < 0.0001).” The discussion section reiterates that the prevalence of e-cigarette use was lower among respondents with cancer than among traditional smokers (2.3% vs. 16.8%).
All of these paragraphs cite the exact same numbers, but they talk about two different things: the prevalence of cancer among e-cigarette users and smokers (a secondary goal of the study) versus the prevalence of cancer among people diagnosed with cancer who use e-cigarettes and smoke (the primary goal of the study). “I made a serious attempt,” Rodu said. Rodu said, “but I couldn’t figure out how the authors shifted from cancer prevalence among e-cigarette users to e-cigarette prevalence among cancer participants.”
Neither peer reviewers nor journal editors appear to have noticed this inconsistency prior to publication.
Assuming that the versions of the results presented in the abstract and Table 2 are correct, 2.3% of e-cigarette users reported a cancer diagnosis, compared with 16.8% of current smokers and 9.5% of non-smokers. However, when the researchers conducted regression analyses that included several demographic variables and comorbidities (including other diagnoses and use of other drugs), they calculated that e-cigarette users” risk was 2.2 times higher and traditional smokers” risk was 1.96 times higher for developing cancer compared to nonsmokers.
In other words, the cancer rate for e-cigarette users was about one-fourth that of nonsmokers and one-seventh that of current smokers. However, after regression analysis, the risk for e-cigarette users was roughly the same as the risk for smokers – that is, about twice the risk for nonsmokers.
Since the retraction mentions concerns about “source data processing including statistical analysis,” we can speculate that the editors questioned this calculation after carefully examining the study. In any case, the lack of information on the duration of e-cigarette use makes it impossible to draw causal conclusions from any correlation supported by these survey data. Or, as in the case of Chidharla et al. In other words, “no causal or temporal associations could be established.
Despite this concession, the authors’ conclusions assume a risk they have not yet demonstrated. They write: Our study found that e-cigarette users developed cancer at an earlier age and had higher odds of developing cancer compared with nonsmokers. Prospective studies should be planned to reduce the risk.
Given the study’s fundamental weaknesses, even if the processing of the source data, including statistical analyses, were reliable, what value would it have? “Despite these limitations,” the authors said, “to our knowledge, this is the first large population-based study designed to discover a potential association between e-cigarette use and human cancer.”
Stanton Glantz, Distinguished Professor of Tobacco Control at the University of California, San Francisco, of the American Legacy Foundation, thinks that’s good enough. In a blog post, he praised the first epidemiological evidence linking e-cigarettes to human cancer.
Glantz, who co-authored the retracted American Heart Association Journal article that claimed a link between e-cigarettes and heart attacks, said the study by Chidharla et al. provides direct evidence that people who use e-cigarettes have an increased risk of developing certain cancers (emphasis his). He adds that “e-cigarette use is associated with a higher risk of certain cancers compared to smoking, including cervical cancer, leukemia, skin cancer (non-melanoma), skin cancer (other) and thyroid cancer” (again, emphasis his).
For those of us who are less inclined to undermine the case for e-cigarettes as a harm reduction alternative to smoking, what does it mean if this study is not withdrawn?
If you ignore the obvious methodological flaws, the study suggests that e-cigarette users and smokers face similar cancer risks. However, the authors note that “e-cigarettes emit vaporized nicotine that typically contains lower concentrations of carcinogens and is less carcinogenic than 1% of tobacco smoke.” In other words, e-cigarette aerosols are more than 99 percent less carcinogenic than cigarette smoke. The researchers added that “there was a decrease in average lifetime cancer risk from traditional smoking to e-cigarettes.”
Chidharla et al. said “the exponential growth in e-cigarette use is a dangerous threat and public health risk due to the widespread promotion of e-cigarettes as a safer alternative to traditional smoking. But they also describe e-cigarettes as a promising harm reduction tool.
“While smoking in any form is not safe, clinicians can recommend e-cigarettes as an alternative to traditional smoking for those with a history of cancer who would otherwise continue to smoke, or for those who want to start smoking at all costs.” the authors write. “This could greatly reduce the risk of serious disease in nicotine users and other high-risk groups.”
That’s the whole point of harm reduction. The dramatic decline in health risks for people who would otherwise smoke is certainly an improvement. So why do Chidharla et al. seem ambivalent, at best, about products that help people achieve this result?
The authors write that because of the high prevalence of certain types of cancer among e-cigarette users and the unknown consequences of e-cigarette use, more guidelines on e-cigarette use and its association with cancer are needed. Without stronger clinical evidence on their safety, e-cigarettes should not be considered a safe alternative to dual or traditional smoking.
But to reduce health risks, e-cigarettes do not have to be a safe alternative; they simply need to be a safer option, as suggested by Chidharla et al.
The authors sometimes seem eager to gloss over this point. “The recent outbreak of e-cigarette-associated lung injury (EVALI) in the United States suggests caution,” they write. “EVALI is largely attributable to vitamin E acetates in cannabis oil distributed through illicit channels.” How does this relate to the risks posed by legally marketed nicotine products discussed on the surface of the article?
Chidharla et al. are concerned about the growing popularity of e-cigarettes among never-smokers and adolescents. They add that the potential negative health effects of non-smokers exposed to nicotine or other chemicals in e-cigarettes are a concern.
E-cigarette use among teens has actually been declining in recent years. According to a survey cited by the researchers, never-smokers make up less than 9 percent of Americans who report having tried e-cigarettes. A recent survey found that less than 3 percent of Minnesota never-smokers reported “current” use of e-cigarettes, meaning they use e-cigarettes “every day or a few days.
Chidharla et al. are also concerned that e-cigarette products are often marketed as safe alternatives, and that “the long-term effects of e-cigarettes are not yet known. But as they acknowledge, the evidence suggests that e-cigarettes are far less harmful than smoking, even though they may pose some long-term risks.
Surveys show that Americans generally do not understand this, thanks in large part to deliberate obfuscation by anti-smoking activists and public health officials. In terms of public perception, the problem is not that people mistakenly believe e-cigarettes are completely risk-free; the problem is that less than 3 percent of Americans recognize that e-cigarettes are much less harmful than combustible cigarettes.
Brian King, director of the FDA’s Center for Tobacco Products, acknowledged the gap between what the evidence shows and what Americans generally think. I am fully aware of the misconceptions that exist there that are inconsistent with the known science,” he told the Associated Press in September. We do know that e-cigarettes, as a general category, are significantly less risky than combustible cigarette products.
Because these misconceptions discourage smokers from switching to e-cigarettes, they are a significant barrier to reducing smoking-related illness and death. Ill-conceived and poorly reasoned studies like this one exacerbate the problem.