Cancer risks from betel quid chewing beyond oral cancer: a multiple-site carcinogen when acting with smoking
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- Wen, C.P., Tsai, M.K., Chung, W.S.I. et al. Cancer Causes Control (2010) 21: 1427. doi:10.1007/s10552-010-9570-1
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This cohort study is to assess the extent of cancer risks of betel quid chewing (without tobacco added) beyond oral cancer, as such information was limited from case–control studies.
The cohort, selected from participants in a medical screening program since 1994, consisted of 177,271 adult men with 19.2% chewers of betel quid. As of 2006, out of 4,840 deaths, 1,901 cancer deaths were identified. Mortality hazard ratios (HR) were estimated by Cox proportional hazard model. Life expectancy was calculated by life table method.
One-third of smokers chewed (33%) but most of chewers smoked (90%). Risk for all cancer doubled among chewers (HR = 2.00). Risks of at least six cancer sites were increased among chewers: oral cavity (HR = 12.52), esophagus (HR = 5.64), liver (HR = 2.27), pancreas (HR = 2.67), larynx (HR = 6.24), and lung (HR = 2.43) with risks increased with increasing betel quid amount consumed. All-cancer age-adjusted mortality rates in Taiwan increased 25%, including 223% increase in oral cancer, during the last 20 years when chewing rate increased five- to tenfolds. Chewing on top of smoking increased the risks synergistically, and these two were responsible for at least half (50%) of all cancer deaths among 2 million chewers in Taiwan. Life expectancy of chewers was shorter than non-chewers by 5.93 years at age 20 and 5.55 years at age 40.
In addition to oral cancer, significant increases were seen among chewers for cancer of the esophagus, liver, pancreas, larynx, lung, and all cancer. Chewing and smoking, as combined by most chewers, interacted synergistically and was responsible for half of all cancer deaths in this group. They were responsible for the recent increases in oral, esophageal, pancreatic, and liver cancer in Taiwan. Chewing and smoking shortened their life span by nearly 6 years.
The habit of betel quid (BQ) chewing or “paan” as known in Hindi word  is one of the four most commonly used psychoactive substances, involving 600 million people around the world [1–3]. Reasons for chewers to chew are complex , but they were reportedly to seek pharmacologically addictive stimulants from BQ or from tobacco to keep them awake or to relieve stress [3, 5].
Male adults in Taiwan chew BQ without tobacco added, different from the majority of global chewers adding tobacco to the BQ and chew together [1–3, 6]. In contrast, most chewers in Taiwan use tobacco in the form of smoking . Betel quid chewers (chewers) alternate chewing with smoking, which might incur health risks from both chewing and smoking. The differences in health risks between adding tobacco before chewing (consuming BQ with tobacco) and adding tobacco after chewing by smoking (consuming BQ without tobacco) have not been well studied until recently partly because chewers of few locations other than Taiwan consume BQ without tobacco added [2, 8]. BQ is distinctly different from cigarettes in the nature of the products, production process, the addictive mechanisms, and in the way they are consumed [7, 9]. As a result, chewing and smoking, two highly prevalent behaviors in Taiwan, have been viewed and managed as two different and remotely related behaviors . The International Agency of Research on Cancer (IARC) determined in 1985 and 2004 that “BQ without tobacco causes oral cancer (only), while BQ with tobacco causes oral cancer, and cancer of the pharynx and esophagus.”(IARC 2004 vol. 85, p. 238) [2, 6]. Assessing the health risks of chewing (BQ without tobacco) and smoking is scientifically important, but most studies so far relied on case–control design and were not able to identify cancer risks other than oral cavity [10, 11].
The purpose of this cohort study was to examine the extent of cancer risks of chewers beyond oral cancer. With a large healthy cohort from Taiwan, this study analyzed the site-specific cancer risks of the role of BQ per se and its interaction with the habit of smoking.
There were 231,935 non-institutionalized males aged 20 and over from a range of backgrounds participated in a medical screening program run by a private firm (MJ Health Screening Center) since 1994. They went through a series of medical tests on blood, urine, body measurements, functional tests, physical examination and medical history. Identical screening procedures with the same model of instruments were used in all four clinics, and results were centrally managed and stored. Overnight fasting blood was collected and analyzed by a Hitachi 7150 auto-analyzers. Carrying statuses of Hepatitis B surface antigen (HBsAg) and antibody against hepatitis C virus (anti-HCV) were determined by using enzyme immunoassay kits. Each participant completed a self-administered questionnaire, asking for demographic, socioeconomic, medical, and lifestyle information. Participants at earlier stages operated by the MJ Health Management Institution did not receive questionnaires, and data were therefore missing for specific elements. A total of 177,271 participants with data on BQ and smoking history were included in the analysis. A more detailed description has been documented elsewhere .
Chewers were those who self-reported having had the habit of consuming BQ regularly at the initial intake of the medical screening. Smokers, including current and ex-smokers, were those who self-reported to smoke regularly (exceeding 100 cigarettes in their life time). The number of years and number of cigarettes smoked were also recorded. Drinking was defined as drinking alcohol three times or more a week and two or more drinks each time. Education levels were classified as low education levels (middle school or below) and high education levels (high school, junior college, and college or above). Physical activity was grouped into none or little (<1 h/week), occasional (1–2 h/week), or often (>2 h/week). Screened systolic hypertension was defined as systolic blood pressure ≧140 mmHg measured and screened diabetes was defined as fasting blood glucose ≧126 mg/dL. Screened hyperlipidemia was defined as triglyceride ≧200 mg/dL, total cholesterol ≧240 mg/dl, or high-density lipoproteins (HDL) <35 mg/dL. Central obesity was defined as waist circumference ≧90 cm, and obesity was defined as body mass index (BMI) ≧25 Kg/m2.
Taiwan has a computer file for all deaths of citizens, which are coded from death certificates. Through linking unique ID number with the computerized file, the cohort identified 4,840 deaths as of 31 December 2006. Analyzed causes of death, classified according to International Classification of Diseases, 9th version (ICD-9), consisted of all cause (001–999), all cancer (140–208), and oral cancer (140–141, 143–146,148, and 149), nasopharyngeal cancer (147), esophageal cancer (150), stomach cancer (151), colo-rectal cancer (153,154), liver cancer (155), pancreatic cancer (157), larynx cancer (161), lung cancer (162), prostate cancer (185), bladder cancer (188), and kidney cancer (189). A total of 1,901 cancer deaths were identified.
Additionally, the attributable fractions (AF) for chewing and smoking were calculated by using HRs. The equation is AF = (HR−1)/HR . Statistical analyses were performed using SAS 9.1 (SAS Institute Inc, Cary, NC). All reported p-values are two sided; p less than 0.05 is considered statistically significant. Life expectancy was calculated by Chiang’s life table method [16, 17].
Each participant has signed a consent form authorizing MJ Health Screening Center for processing the data generated from medical screening. Ethical reviews (IRB) have been processed and approved both at MJ Health Screening Center and at National Health Research Institutes.
Baseline characteristics of male cohort subjects by chewing and smoking status
Smoking and chewing status
(n = 177,271)
Middle school or below
College or above
Number of cigarettes smoked per daya
10 or less
21 or more
None or little (< 1 h/week)
Occasional (1–2 h/week)
Often (>2 h/week)
Body mass index
Hazard ratios (HR) and 95% confidence interval (95% CI) for all-cause and causes of cancer deaths among chewers and smokers when compared against non-smoking, non-chewers
Number of subjects
Cause of death
Number of deaths
Hazard ratios (HR) and 95% confidence interval (95% CI) for chewing smokers when compared against non-chewing smokers
Number of subjects
Cause of death
Figure 2 compared HRs for selected cancer deaths between chewers and smokers, as well as those with both habits, with those with neither habit as reference group. The general pattern showed increased risks for both chewers and smokers, but when both habits co-existed, synergistic interaction was observed for all cancer, oral cancer, esophageal cancer, liver cancer, and laryngeal cancer. We used both Rothman’s synergy index [(RR11−1)/(RR10 + RR01−2) with S > 1 indicating synergistic effects] and Cox model to test the effect of adding chewing among smokers. In Fig. 2, HRs for oral cancer by smoking or chewing status, for example, were presented in a two by two fashion, with smoking only (2.09), chewing only (3.81), and both (9.49). The resulting synergy index, 2.18, showed the presence of synergistic interaction. Significant interaction was found for all-cancer, oral cancer, esophageal cancer, and liver cancer analyzed by Cox model, with p < 0.05.
Figure 3 shows the cancer mortality effect of increasing the daily amount of BQ chewed (left side of figure) or increasing the daily amount of cigarettes smoked (right side of figure) among chewers. When BQ consumption increased from 1 to 5 pieces, 6–9 pieces to ten or more pieces, the cancer risks increased. This included all-cancer, oral cancer, esophagus cancer, liver cancer, and lung cancer. Similar pattern was observed for the daily amount of cigarettes smoked, increasing from half a pack or less (10 or less cigarettes), more than half pack (11–20 cigarettes) to more than a pack (>20 cigarettes).
Smoking was responsible for more than one-third (39%) of all cancer deaths among smokers, with HR being 1.65, but when chewing was added, with HR being 2.00, both habits were responsible for at least half (50%) of all cancer deaths among chewers (attributable fraction calculation data not shown).
Remaining years of life at different ages between chewers and non-chewers
In this study, we showed that the risks of chewing BQ were more than oral cancer, as chewing had additional significant increases in risks for cancer of the esophagus, liver, pancreas, larynx, and lung. Most of these increases showed dose-dependent relationship, with risks increased with increasing the daily amount of BQ consumed. Chewers as a whole, 2 million in Taiwan, shortened their life span by an average of nearly 6 years. In this manner, chewing BQ without tobacco behaved as a multiple-site carcinogen, and the health concerns of chewers should not be limited to oral cancer in Taiwan. This is in contrast to the two IARC monographs, 1985 and 2004, which concluded that “BQ without tobacco (added) causes oral cancer” [2, 6]. Although both BQ and areca nut were considered as human Group 1 carcinogen, and liver and esophageal cancer were mentioned based on limited case–control studies, the conclusion in the final IARC evaluation did not address cancer sites other than oral .
This has policy implications for Taiwan, as efforts by the government have been primarily focused on screening oral cancer among chewers . Consumption of BQ took off right after 1986 when cigarette market in Taiwan was forced open [19, 20]. Ever since the stepwise increase in the number of chewers, from a prevalence of 2–3% to 15–20% between 1986 and 2006 , the age-adjusted mortality in Taiwan has increased 37% for esophageal cancer, 18% for liver cancer, 90% for pancreatic cancer, and 25% for all cancer, in addition to 223% increase for oral cancer . These large increases in cancer mortality coincided with the sharp increase in the per capita BQ consumption in the society, from 2.8 kg/capita to 9.5 kg/capita . While a sharp increase in BQ chewing was responsible for most of these cancer increases, these increases resulted from the combined effects of smoking and chewing. This was reflected in the dose–response relationship between the amount of BQ chewed or the number of cigarettes smoked and the intensity of cancer risks.
Chewing increased mortality risks of several cancer sites among smokers, significantly over and above smoking, showing synergistic interaction. In addition to cancer, all-cause mortality was also increased, by 47% (Table 3). This implied that the combination of chewing and smoking was doubly deadly, not only for cancer as a whole but also for all causes, shortening their life span. Unfortunately, majority of chewers in Taiwan, more than 2 million adult males, who came largely from lower socioeconomic class, belonged to this high-risk group. The proportion of chewers without smoking, either in our cohort or in Taiwan, was relatively small (1–2%), and its public health significance was overshadowed by those with combined habits. When comparing the hazards of smoking with hazards of chewing with smoking, one yard stick is to quantify its attributable fraction . Smoking alone was responsible for one out of three cancer deaths among smokers (AF: 39%). In contrast, chewing was responsible for one out of two cancer deaths among those with two habits (AF: 55%). That every other cancer deaths was the result of a common lifestyle habit prevalent in a large segment of the population was rarely encountered in any developed country.
Nearly nine out of ten chewers were smokers, but chewers without smoking were relatively rare. Smoking chewers should be the center of public health focus. Chewers without smoking, constituting less than 2% of adult males, may have represented more of those chewers in transition on their way to quitting, when one has already quit smoking, and therefore, assessing the independent cancer effect of chewing among the small number of non-smoking chewers is of more academic interest but difficult to reach statistical significance.
In a meta-analysis of oral cancer without tobacco added , the smoking-adjusted odds ratio was 3.50 (95% CI: 2.16; 5.65), much smaller than 12.52 found in this study. In contrast, most of the studies from India or Pakistan had much lower oral cancer risks than those from Taiwan [2, 11]. There could be at least two reasons for the fact that combination of chewing and smoking in Taiwan was much more deadly than when tobacco was added to BQ for chewing as practiced in most parts of the world: First, the act of smoking created burns and injured the oral mucosa and chewing caused local irritation and trauma, leading to chronic inflammation, oxidative stress, and cytokine production , and the wound provided easier access to the system for carcinogens contained in BQ. Perhaps this is the reason for the observed synergistic effect when chewing was added to smoking. Second, the frequency of an individual with both habits in smoking and in chewing was high and the number additive, 15–20 times each, yielding a combined total of 35–40 times of assaults to the oral cavity every day . Chewers alternated the two behaviors throughout the day, providing ample opportunities for chemical interaction between the ingredients of BQ and combustion substances of cigarettes.
There has been a steady increase in rates for esophageal cancer in many countries unrelated to betel quid chewing [25, 26]. However, there was a marked difference in the presentation of esophageal cancer between Taiwan and those countries with increases. First, the global increase in esophageal cancer was mainly adenocarcinoma, while the increase in Taiwan was limited to squamous cell cancer [27, 28] reported in cancer registry . Secondly, the former was located in the lower third of esophagus, while the latter was more in the upper segment, as a direct insult by the BQ exposure. These differences made the observed increase in esophageal cancer increase in Taiwan a unique phenomenon .
The large sample size and the cohort design are the strengths of this study, enabling the findings of cancer increases in multiple sites. Most of the reported studies reviewed in the IARC monograph were case–control in nature, which examined one cancer at a time. Nevertheless, there are limitations in this study. First, the cohort came from those paid participants who belonged to a higher social class, and this could have accounted for the lower chewing rate observed for the cohort (19.2%) than the one collected from the national data (24%) . The hazard ratios calculated from Cox proportional model, however, were internally valid and suffered less of the non-representative issue. Second, cancers such as oral and esophageal cancer were known to be associated with alcohol drinking [10, 30, 31]. Chewers in our cohort drank more than non-chewers, but our results yielded essentially the same pattern whether drinking was adjusted or not. Drinking seemed to be a minor issue as the number of chewers involved (1/4 of chewers drank) was far less than those involved with smoking (9/10 of chewers smoked). Besides, drinking in this Asian population was known to be more of social nature, with occasional binge drinking. The cancer effect from this drinking pattern, different from those characteristics of chronic alcoholics, should be limited to a small group of people with heaviest drinking . Third, smoking and chewing relied on self-reported information at the time of baseline examination, and not independently validated. Furthermore, any subsequent changes in the chewing habits were not updated. Nevertheless, misclassification, if present, would have made the results toward null. Fourth, the HR in this study was based on mortality and not on incidence. In this society, death ascertainment was far more reliable and complete than incidence reporting. By law, all deaths should have been identified if died in Taiwan. There could be a portion of subjects moved out of Taiwan and later died abroad. Because the study was internally standardized, the bias should be minimal. In fact, because of the available National Health Insurance Program, those who had cancer, requiring expensive treatment, would be more likely to return to Taiwan for treatment.
In conclusion, the risks of chewing BQ were more than oral cancer, as chewing BQ without tobacco had additional risks for cancer of the esophagus, liver, pancreas, larynx, and lung. Chewing interacted with smoking and significantly increased cancer risks. Helping chewers to quit, both smoking and chewing, should be the number one priority in cancer control policy.
Conflict of interest statement
We declare that we have no conflict of interest.