Betel quid not containing tobacco and oral cancer: a report on a case-control study in Papua New Guinea and a meta-analysis of current evidence

Smoking and betel quid chewing are associated with increased risk of oral cancer but few studies have reported on associations in populations where betel quid does not contain tobacco. We conducted a case-control study in Papua New Guinea and a systematic review. Our case-control study recruited 143 cases with oral cancer and 477 controls. We collected information on smoking and betel quid chewing. Current smoking was associated with an increased risk of oral cancer with an adjusted odds ratio (OR) for daily smokers of 2.63 (95% confidence intervals (95% CI) 1.32, 5.22) and amongst heaviest smokers of 4.63 (95% CI 2.07, 10.36) compared to never-smokers. Betel chewing was associated with increased risk of oral cancer with an adjusted OR for current chewers of 2.03 (95% CI 1.01, 4.09) and in the heaviest chewers of 2.47 (95% CI 1.13, 5.40) compared to nonchewers. The OR in those who both smoked tobacco and chewed betel quid was 4.85 (95% 1.10, 22.25), relative to those who neither smoked nor chewed. The systematic review identified 10 previous studies that examined risk of oral cancer associated with betel quid chewing that controlled for smoking in populations where betel quid did not contain tobacco. In studies that reported results for non-smokers the combined OR was 2.14 (95% CI 1.06, 4.32) in betel quid chewers and in studies that adjusted for smoking the combined OR was 3.50 (95% CI 2.16, 5.65) in betel quid chewers. Preventive efforts should discourage betel quid chewing as well as smoking.     

Betel quid not containing tobacco and oral leukoplakia: a report on a cross-sectional study in Papua New Guinea and a meta-analysis of current evidence

Leukoplakia is an asymptomatic, potentially malignant change in the oral mucosa. Previous studies have reported that smoking and betel quid chewing are associated with increased risk of leukoplakia; few studies have reported on these associations in populations where betel quid does not contain tobacco. We conducted a case-control study nested in a cross-sectional study in Papua New Guinea and a systematic review of studies that included chewers of betel quid without tobacco. Our study recruited 1,670 adults. We recorded betel quid chewing and smoking. The prevalence of leukoplakia was 11.7%. In the nested case-control study of 197 cases and 1,282 controls, current betel chewing was associated with increased risk of leukoplakia with an adjusted odds ratio for current chewers of 3.8 (95% CI 1.7, 8.4) and in the heaviest chewers of 4.1 (95% CI 1.8, 9.1) compared to non-chewers. Current smoking was associated with an increased risk of leukoplakia with an adjusted odds ratio for current smokers of 6.4 (95% CI 4.1, 9.9) and amongst heaviest smokers of 9.8 (95% CI 5.9, 16.4) compared to non-smokers. The systematic review identified 5 studies examining risk of leukoplakia associated with betel quid chewing in populations where betel quid did not contain tobacco and that controlled for smoking. In studies that adjusted for smoking, the combined random effect odds ratio was 7.9 (95% CI 4.3, 14.6) in betel quid chewers. The results of this study and systematic review of similar studies provide evidence of the role of betel quid not containing tobacco and leukoplakia.     

High Prevalence of Lifestyle Factors Attributable for Oral Cancer,and of Oral Potentially Malignant Disorders in Rural Sri Lanka

Background: Oral Cancer is a major public health problem in most of the South East Asian countries including SriLanka. Use of tobacco in the form of smokeless tobacco and smoking, use of alcohol and betel quid chewing are themajor contributory factors for causation oral cancer. The aim of this study was to investigate the prevalence of lifestylefactors responsible for causation of oral cancer and Oral Potentially Malignant Disorders (OPMD) in the Sabaragamuwaprovince of Sri Lanka. Methods: A cross-sectional community based study was conducted in Sabaragamuwa provinceby interviewing, then conducting an oral examination, on 1029 subjects over 30 years of age, over a one year period fromNovember 2006. The study protocol included an interviewer-administered questionnaire to gather socio-demographicfactors, recording of habits that included areca/betel chewing, smoking, and alcohol consumption. A three-day food diarywas obtained, particularly to assess the consumption of tea, fruits and vegetables. The weight and height of residentswas taken for calculation of Body Mass Index (BMI). Results: One hundred and two individuals with one or moreOPMD were detected among these 1029 subjects. The prevalence of OPMD, weighted according to the estate sector andgender, was estimated as 11.3%. The prevalence of daily betel quid chewing in this study was 53.8%: 15.7% withouttobacco and 47.4% with tobacco. The prevalence of individuals who reported consumption of alcohol at least weeklywas 13.4%. A significant minority, 31.7%, were under nourished, with a BMI < 18.5. Forty six percent of the malespracticed combined habits of betel quid chewing, smoking and regular use of alcohol. Conclusions: This study discloseshigh prevalence of OPMD and of lifestyle factors for oral cancer in these communities. There is an urgent need fora comprehensive strategy to control the use of tobacco, betel quid chewing and alcohol for prevention of oral cancer.     

Different impact from betel quid, alcohol and cigarette: risk factors for pharyngeal and laryngeal cancer

The risks of betel quid chewing with or without tobacco, alcohol drinking and cigarette smoking have been well explored in the oral cavity but not in the pharynx and larynx. We conducted a case-control study to investigate the association of these three risk factors to cancers of the pharynx and larynx in Taiwan. A total cases of 148 pharyngeal cancer, 128 laryngeal cancer and 255 hospital controls, all men, were recruited. Betel quid chewing was a significant independent risk factor (adjusted odds ratio [aOR] = 7.7; 95% confidence interval [CI] = 4.1-15.0) similar to that of alcohol drinking (aOR = 6.6; 95% CI = 3.5-13.0) for pharyngeal cancer, but not for laryngeal cancer (aOR = 1.3; 95% CI = 0.7-2.5) on which cigarette smoking (aOR = 7.1) exerts a stronger significant independent risk than alcohol drinking (aOR = 3.8). For pharyngeal cancers, chewers who consumed >20 quid/day, chewed with inflorescence in the quid or swallowed the betel quid juice were at higher risks; significant dose-response effects were found in daily quantity of drinking and chewing, and cumulative quantity of drinking. Synergistic effects from the 3 risk factors existed both on the pharynx (aOR = 96.9) and the larynx (aOR = 40.3), and attributed for 93.1% and 92.9% respectively. Our study is the first evidence to show that betel quid chewing without tobacco has different impact on the pharynx (digestive tract) and the larynx (airway), and supports the concept that exposure quantity and direct mucosal contact with the betel quid juice may contribute to carcinogenesis. Our results show an important insight into the impact of betel quid chewing on other sites of the digestive tract other than the oral cavity.     

The Risk of Oral Cancer among Different Categories of Exposure to Tobacco Smoking in Sri Lanka

Background: The global incidence of oral squamous cell carcinoma (OSCC) is on the rise with no improvement seen in survival rates. Tobacco consumption varies depending on geographic location, ethnicity and culture. The present case-controlled study aimed to determine the relative risk of OSCC for different tobacco consumption patterns in a selected Sri Lankan population. Methods: One hundred and five patients with histopathologically confirmed OSCC attending the National Cancer Institute (Apeksha Hospital) of Sri Lanka and 210 age and gender-matched controls from the community responded to an interviewer-administered questionnaire regarding their smoking and betel-quid chewing (with/ without smokeless tobacco) habits were included in the study. The odds ratios (OR) and 95% confidence intervals (CI) were calculated. p<0.05 was considered as statistically significant. Results: The overall risk of OSCC increased 2.93-fold for smokers. Those smoking two packets of cigarettes or more per day (OR=5.56; 95% CI-2.822-10.984; p=0.000) had more than double the risk of OSCC than those smoking 1-2 packets per day. Smoking for more than 20 years had a 3.4-fold risk of OSCC. Consumption of betel quid containing tobacco (smokeless tobacco) had a 4.26-fold higher risk for OSCC (OR=4.26; 95% CI-2.21-8.21; p=0.000), and the risk increased when all four ingredients (betel leaf, slaked lime, areca nut, and tobacco) were consumed together (OR=4.26; 95% CI-2.34-7.74; p=0.000). The combined effect from concurrent smoking and betel chewing emerged as the highest risk for OSCC (OR=15.34) which significantly exceeded the risks evident for the two habits practised in isolation from each other. Conclusions: Use of smokeless tobacco, consumption of all four ingredients together, duration of smoking, the number of cigarettes smoked per day and combined consumption of betel quid and smoking are significant risk factors in the development of OSCC among Sri Lankans.     

Genetic cancer susceptibility and DNA adducts: studies in smokers, tobacco chewers, and coke oven workers

Preventive strategies require identification of cancer-susceptible individuals resulting from combinations of carcinogen exposure, cancer-predisposing genes, and lack of protective factors. To this aim, related to tobacco smoking and chewing (betel quid), we measured PAH-DNA adducts as exposure and susceptibility markers together with genetic polymorphism in drug-metabolizing enzymes related to CYP1A1, GSTM1, and GSTT1 genes in case-control studies. (+)-anti-Benzo(a)pyrene diol-epoxide (BPDE)-DNA adduct levels were quantitated in white blood cells (WBCs) and lung tissue DNA. CYP1A1 polymorphism and GSTM1 or GSTT1 gene deletion was analyzed in genomic DNA from lung parenchyma, WBCs, or oral biopsies (leukoplakia patients from India) and from oral exfoliated cells (healthy controls). Results from lung cancer patients and PAH-exposed coke oven workers correlated CYP1A1-GSTM1 genotype combinations with BPDE-DNA adduct levels. Smokers with homozygous CYP1A1 variant and GSTM1 null had the highest adduct levels and were, as shown in Japanese smokers, most susceptible to lung cancer. In oral premalignant leukoplakia cases associated with betel quid/tobacco chewing, the prevalence of the GSTM1 null and GSTT1 null genotypes was significantly higher, as compared to healthy controls. The combined GST null genotypes prevailed in 60% of the cases with none detected in controls. Based on this short review we conclude that (i) BPDE-DNA adduct levels resulting from "at risk" genotype combinations may serve as markers to identify most susceptible individuals; (ii) in Indian betel quid/tobacco chewers, the null genotypes of GSTM1 and GSTT1 greatly increased the risk for developing oral leukoplakia.     

Betel quid without tobacco as a risk factor for oral precancers

The IARC monographs recently classified chewing betel quid without tobacco as a human carcinogen. Several studies in Taiwan have reported that betel quid without tobacco may increase the risk of oral precancers such as oral leukoplakia and oral submucous fibrosis. However in India, since most betel quid chewers prefer to add tobacco to the quid, the independent effect of betel quid on the risk of oral precancers is difficult to assess and has not yet been fully explored. We conducted a large case-control study in Kerala, India, including 927 oral leukoplakia cases, 170 oral submucous fibrosis cases, 100 erythroplakia cases, 115 multiple oral precancer cases and 47,773 controls. The focus of this reanalysis is on the minority of individuals who chewed betel quid without tobacco. Among nonsmokers and nondrinkers, chewing betel quid without tobacco conferred ORs of 22.2 (95%CI = 11.3, 43.7) for oral leukoplakia, 56.2 (95%CI = 21.8, 144.8) for oral submucous fibrosis, 29.0 (95%CI = 5.63, 149.5) for erythroplakia and 28.3 (95%CI = 6.88, 116.7) for multiple oral precancers, after adjustment for age, sex, education and BMI. Dose-response relationships were observed for both the frequency and duration of betel quid chewing without tobacco on the risk of oral precancers. In conclusion, our study supports the hypothesis that chewing betel quid without tobacco elevates the risks of various oral precancers.     

Impact of RECK gene polymorphisms and environmental factors on oral cancer susceptibility and clinicopathologic characteristics in Taiwan

Oral cancer is the fourth common male cancer and causally associated with environmental carcinogens in Taiwan. The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) has a significant effect on tumorigenesis by limiting angiogenesis and invasion of tumors through the extracellular matrix. RECK downregulation has been confirmed in many human cancers and associated with lymph node metastasis clinically. In the present hospital-based case-controlled study, the demographic, RECK genotype and clinicopathologic data from 341 male oral cancer patients and 415 cancer-free controls were investigated. We found that RECK rs10814325, rs16932912, rs11788747 or rs10972727 polymorphisms were not associated with oral cancer susceptibility. Among 488 smokers, RECK polymorphisms carriers with betel quid chewing have a 7.62-fold [95% confidence interval (CI), 2.96-19.64] to 25.33-fold (95% CI, 9.57-67.02) risk to have oral cancer compared with RECK wild-type carrier without betel quid chewing. Among 352 betel quid chewers, RECK polymorphisms carriers with smoking have a 6.68-fold (95% CI, 1.21-36.93) to 18.57-fold (95% CI, 3.80-90.80) risk to have oral cancer compared with those who carried wild-type without smoking. In 263 betel quid chewing oral cancer patients, RECK rs10814325 polymorphism have a 2.26-fold (95% CI, 1.19-4.29) risk to have neck lymph node metastasis compared with RECK wild-type carrier. These results support that gene-environment interactions between the RECK polymorphisms, smoking and betel quid may alter oral cancer susceptibility and metastasis.     

Family History of Cancer and Head and Neck Cancer Risk in a Chinese Population

Background: The aim of this study was to investigate whether family history of cancer is associated with head and neck cancer risk in a Chinese population. Materials and Methods: This case-control study included 921 cases and 806 controls. Recruitment was from December 2010 to January 2015 in eight centers in East Asia. Controls were matched to cases with reference to sex, 5-year age group, ethnicity, and residence area at each of the centers. Results: We observed an increased risk of head and neck cancer due to first degree family history of head and neck cancer, but after adjustment for tobacco smoking, alcohol drinking and betel quid chewing the association was no longer apparent. The adjusted OR were 1.10 (95% CI=0.80-1.50) for family history of tobacco-related cancer and 0.96 (95%CI=0.75-1.24) for family history of any cancer with adjustment for tobacco, betel quid and alcohol habits. The ORs for having a first-degree relative with HNC were higher in all tobacco/ alcohol subgroups. Conclusions: We did not observe a strong association between family history of head and neck cancer and head and neck cancer risk after taking into account lifestyle factors. Our study suggests that an increased risk due to family history of head and neck cancer may be due to shared risk factors. Further studies may be needed to assess the lifestyle factors of the relatives.     

Association between Smokeless Tobacco Use and Waterpipe Smoking and the Risk of Lung Cancer: A Systematic Review and Meta-Analysis of Current Epidemiological Evidence

Background: Smokeless tobacco and waterpipes are used by hundreds of millions of people worldwide and consumption rates exceed that of cigarette smoking in much of South East Asia and parts of the Middle East. However, the cancer risks of these methods of tobacco consumption are less well-characterized than those of cigarette smoking. The objective of this study was to systematically review the epidemiological evidence on the association between smokeless tobacco use and waterpipe smoking and lung cancer risk. Methods: The MEDLINE, EMBASE, Web of Science and OpenSIGLE databases were searched to identify eligible case-control and cohort studies (published before 1st December 2020 in any language) that adjusted for cigarette smoking or included non-cigarette smokers only. Summary odds ratio/relative risk estimates and confidence intervals were extracted, and pooled risk ratios (RRs) for lung cancer were calculated using random effects meta-analysis. Results: The literature search identified 2,465 publications: of these, 26 studies including 6,903 lung cancer patients were included in the synthesis (20 studies of smokeless tobacco use, five of waterpipe smoking, one of both). Our results suggest that smokeless tobacco use is associated with an increased risk of lung cancer among non-cigarette smokers, and that betel quid tobacco may be particularly hazardous. The random effects meta-analysis showed that exclusive use of any type of smokeless tobacco (pooled RR = 1.53, 95%CI 1.09 – 2.14), betel quid chewing (pooled RR = 1.77, 95%CI 1.06 – 2.95), and waterpipe smoking (pooled RR = 3.25, 95%CI 2.01 – 5.25) were significantly associated with an increased risk of lung cancer. Conclusions: This meta-analysis of case-control/cohort studies supports the hypothesis that use of smokeless tobacco and waterpipe smoking is associated with increased risk of developing lung cancer. Considering the widespread and increasing use of smokeless tobacco in developing countries, and increasing prevalence of waterpipe smoking in almost all societies, these findings inform formulation of public health policy, legislation and tobacco control measures at national and international level to increase awareness and decrease the prevalence of smokeless tobacco use and waterpipe smoking.     

Expression of p53 in oral squamous cell carcinoma and its association with risk habits in southern Thailand

Tobacco smoking and alcohol drinking are the principal factors associated with p53 expression in oral squamous cell carcinomas (OSCC) in the west, whereas betel quid chewing and smokeless tobacco are important factors in the east. Variable results of p53 expression have been reported and it has been proposed that ethnic difference and a variation in the indigenous oral habit may be responsible for the finding. This study, therefore, investigated p53 expression among 106 OSCC patients from a southern Thailand population in which all four risk behaviours, tobacco smoking, alcohol drinking, betel quid chewing and use of smokeless tobacco, are practised. The associations of p53 expression with lifetime exposure to each risk behaviour were explored. Multivariate modelling showed that lifetime exposure to alcohol drinking was significantly positively associated with p53 expression (likelihood ratio P value 0.01). Betel quid chewing and tobacco smoking habit showed a trend of decreasing risk of p53 expression with increased lifetime exposure (OR 0.62, 95% CI 0.39-1.00 and OR 0.50, 95% CI 0.26-0.98, respectively). No significant association was found between p53 expression and clinico-pathological parameters. Further investigations are needed to study (1) the molecular alteration of p53 in each risk habit and (2) other possible pathways of oral carcinogenesis in betel quid- and tobacco smoking-associated OSCC in these group of patients.     

Betel quid and oral cancer: prospects for prevention.

Betel-quid chewing is an ancient and socially accepted practice. The introduction of tobacco reinforced this practice, and now almost all habitual chewers of betel quids include tobacco. It is well established that chewing of betel quid with tobacco causes oral cancer and is largely responsible for the high incidence of oral cancer in several South Asian countries. The feasibility of primary prevention of oral cancer was studied in a population-based prospective intervention study. A cohort of 12,212 betel-quid chewers and smokers was exposed to a programme of health education for stopping chewing and smoking and subjected to annual examinations for detection of oral precancerous lesions. Evaluations after one, five and eight years showed that primary prevention of oral cancer is feasible and practicable. Early detection of oral cancer is an important control measure. In a secondary prevention study, 53 basic health workers were trained in the detection and referral of lesions suspected of being oral cancer. Over one year, they examined more than 39,000 high-risk individuals, resulting in the detection of 20 cases of oral cancer. The sensitivity and specificity of their diagnoses was assessed through a re-examination of a 5% sample: we concluded that it was possible to incorporate a secondary prevention programme into the existing health care system.     

Assessment of risk factors for oral squamous cell carcinoma in Chidambaram, Southern India: a case-control study.

Oral squamous cell carcinoma, the fifth most common cancer worldwide, is a major cause of morbidity and mortality in India. The effect of lifestyle factors, including tobacco chewing, smoking and alcohol drinking, diet and dental care, on the risk of oral cancer was investigated in a case-control study conducted in Rajah Muthiah Dental College and Hospital, Annamalainagar, Annamalai University, Chidambaram, Tamil Nadu, India during the period 1991-2003. The study included 388 oral squamous cell carcinoma cases and an equal number (388) of age and sex-matched controls. All participants were interviewed using a structured questionnaire that contained data on demographic factors, family history of cancer, tobacco habits, use of alcohol, frequency, duration, cessation of these habits, dietary practices and oral hygiene. The data were analysed using multiple logistic regression model. Among people with chewing habits, those who chewed betel quid with tobacco [odds ratio (OR) 3.19, 95% confidence interval (CI): 0.48-2.13] and tobacco alone (OR 2.89) showed a greater risk than controls. Bidi smoking (OR 4.63) and alcohol drinking (OR 1.65) emerged as significant risk factors for oral cancer. These three habits showed increasing risk with increasing frequency and increase in duration of habits. Addition of alcohol to other habits also enhanced the risk for oral cancer. The combination of chewing and smoking together with alcohol drinking showed very high relative risk (OR 11.34). A positive association was observed between non-vegetarian diet, poor oral hygiene and poor dentition with the risk of oral squamous cell carcinoma. The fact that these risk factors are modifiable emphasizes the need for increasing awareness among the general public and policy makers as a first step in the prevention and control of oral squamous cell carcinoma.     

Impact of oral submucous fibrosis on chemotherapy-induced mucositis for head and neck cancer in a geographic area in which betel quid chewing is prevalent.

In Southeast Asia and Taiwan, betel quid chewing is prevalent. Patients with head and neck cancer who chewed betel quid habitually seem to experience more severe chemotherapy-induced mucositis in our clinical practice. To validate this issue, patients with untreated head and neck cancer who received cisplatin (cDDP) plus a 5-fluorouracil (5-FU)-based neoadjuvant chemotherapy were included in this analysis. Information on the consumption of betel quid, tobacco, and alcohol were recorded before chemotherapy. Oral submucous fibrosis (OSF) was diagnosed clinically according to the fibrotic appearance of the mucosa and trismus. Mucositis was scored according to the World Health Organization criteria, and the mucositis score of the first course of chemotherapy was used for analysis. From December 1993 to April 1996, 120 patients were enrolled in this trial. Neither the betel quid chewing nor the cancer of the oral cavity was to be a significant factor for mucositis. However, clinically diagnosed OSF was found to display a significant correlation with more severe mucositis (p = 0.02). We concluded that in betel quid chewing-prevalent areas, OSF was a risk factor of more severe mucositis in head and neck cancer patients treated by CDDP and 5-FU-based regimens.     

A novel single nucleotide polymorphism in ERCC6 gene is associated with oral cancer susceptibility in Taiwanese patients

The DNA repair gene ERCC6, an important caretaker of the overall genome stability, is thought to play a role in the development of human malignancy. However, the polymorphic variants of ERCC6, has never been reported about their association with oral cancer susceptibility. In this hospital-based case-control study, the association of ERCC6 codon 399, 1097 and 1413 polymorphisms with oral cancer risk in a Central Taiwanese population was first investigated. In total, 292 patients with oral cancer and 290 age- and gender-matched healthy controls recruited from the China Medical Hospital in Central Taiwan were genotyped. We found a significant different distribution in the frequency of the ERCC6 codon 399 genotypes, but not the ERCC6 codon 1097 or 1413 genotypes, between the oral cancer and control groups. Those who had homozygous A/A or heterozygous A/G at ERCC6 codon 399 showed a 1.82- and 1.22-fold (95% confidence interval=1.19-2.79 and 0.83-1.78, respectively) increased risk of oral cancer compared to those with G/G. As for ERCC6 codon 1097 or 1413, there was no difference in distribution between the oral cancer and control groups. Gene-environment interactions with smoking and betel quid chewing, but not alcohol drinking, were significant for ERCC6 polymorphisms. ERCC6 codon 399, G/A+A/A ever user groups exhibited an increased risk of 2.36 (95% CI=1.36-4.10) for smoking and 2.72 (95% CI=1.31-5.63) for betel quid chewing. Our results firstly suggest that the heterozygous and homozygous A allele of the ERCC6 codon 399 may be associated with the development of oral cancer and may be a novel useful marker for primary prevention and anticancer intervention.     

Chromosome-damaging activity of saliva of betel nut and tobacco chewers

Saliva of volunteers chewing betel quid, cured betel nut (Areca catechu), betel leaves (Piper betle), a mixture of quid ingredients (dried betel nut flakes, catechu, cardamon, lime, copra and menthol) and Indian tobacco was collected and examined for its genotoxic activity. Chromosome aberrations (chromatid breaks and chromatid exchanges) in Chinese hamster ovary (CHO) cells were used to estimate the genotoxic effect. No detectable levels of clastogenic activity were observed in the saliva of non-chewing individuals. After 5 min of chewing betel quid, betel nut, betel leaves, quid ingredients and Indian tobacco, the saliva samples showed relatively potent clastogenic activities. The addition of transition metals Mn²⁺ and Cu²⁺ to the saliva samples of betel nut and Indian tobacco chewers enhanced their clastogenic activities, whereas Fe³⁺ increased the clastogenicity of the betel nut saliva but decreased the genotoxic effect of the saliva of Indian tobacco chewers. After removal of the betel quid or its components from the mouth, the clastogenic activity disappeared within 5 min. The western-type chewing tobacco did not produce a genotoxic activity in the saliva of chewers. A possible association between the genotoxicity in the saliva of betel quid chewers and the development of oral, pharyngeal and esophageal carcinomas is discussed.     

Betel quid chewing and the risk of oral and oropharyngeal cancers: A meta‐analysis with implications for cancer control

We conducted a random‐effects meta‐analysis of 50 publications assessing the relationship between oral/oropharyngeal cancer and chewing betel quid, with (BQ+T) or without added tobacco (BQ‐T), a common practice in many parts of Asia and globally among Asian immigrants. Exposure‐response, by daily amount and years of BQ chewed, was assessed using spline models. Attributable fractions (PAF%) were calculated to estimate the public health impact if BQ were no longer chewed. The meta‐relative risk (mRR) for oral/oropharyngeal cancer in the Indian subcontinent was 2.56 (95%CI, 2.00–3.28; 15 studies) for BQ‐T and 7.74 (95%CI, 5.38–11.13; 31 studies) for BQ+T; in Taiwan, China, the mRR for BQ‐T was 10.98 (95%CI, 4.86–24.84; 13 studies). Restricting to studies that adjusted for tobacco and alcohol use had only a small effect on the risk estimates. For BQ+T in the Indian subcontinent, the mRR was much higher in women (mRR, 14.56; 95%CI, 7.63–27.76) than in men. Exposure‐response analyses showed that the risk of oral/oropharyngeal cancer increased with increasing daily amount and duration (years) of chewing BQ in India and Taiwan, China. Roughly half of oral cancers in these countries could be prevented if BQ were no longer chewed (PAF% = 53.7% for BQ‐T in Taiwan, China; PAF% = 49.5% for BQ+T in India). We demonstrate that betel quid chewing, with or without added tobacco, increases the risk of oral/oropharyngeal cancer in an exposure‐dependent manner, independently of tobacco and alcohol use. Further work is needed to explain the higher risks associated with chewing BQ‐T in Taiwan, China.     

Betel Quid Chewing and Upper Aerodigestive Tract Cancers: A Prospective Cohort Study in Khon Kaen,Thailand

Background: This study aimed to determine the association between betel quid chewing and the occurrenceof upper aerodigestive tract (UADT) cancers. Methods: A cohort of 17,388 subjects, recruited and interviewedover the 1990-2001 period, in Khon Kaen, Thailand, was followed up until 2011. The data were linked to theKhon Kaen Population-Based Cancer Registry. Results: The prevalence of betel quid chewing was 15.9%, with afemale predominance (97.7%); the mean age of chewers was 57.7 years (SD 6.6). The overall incidence of UADTcancers from the cohort was 14.7 per 100,000 person-years, whereas the incidence among the chewers was 45.7.Betel nut chewing was the only major risk factor for UADT cancers in this population (HR=5.26, 95%CI=2.51-11.0), while weak associations were found for tobacco smoking and alcohol (HR=1.16, 95%CI=0.45-3.01 and 1.47,95%CI=0.72-3.03 respectively). Conclusions: We found betel quid chewing to be a main risk factor for UADTcancers, resulting in a higher incidence in females. However, further study is required to explore the potentialr isk factors among non-chewers, non-smokers, and non-drinkers     

Independent and combined effects of alcohol intake, tobacco smoking and betel quid chewing on the risk of esophageal cancer in Taiwan

A multicenter case-control study was conducted in northern and southern Taiwan to clarify the independent and combined effects of alcohol intake, tobacco smoking and betel quid chewing on the risk of esophageal cancer. A total of 513 patients with newly diagnosed and histopathologically confirmed squamous cell carcinoma of the esophagus and 818 gender, age and study hospital-matched controls were included. We found a significant dose-response relationship between the duration and intensity of consumption of the 3 substances and the development of this neoplasm in this site. Although the amount of alcohol consumed had a stronger effect on the risk of esophageal cancer than the number of years it was consumed, however, the number of years one smoked had a stronger effect on the risk than the amount of cigarettes consumed. The strongest risk factor of esophageal cancer was alcohol intake, with highest risk (OR = 13.9) being for those who consumed more than 900 g/day-year. Combined exposure to any 2 of 3 substances brought the risks up to 8.8-19.7 fold and, to all 3 substances, to 41.2-fold. A multiplicative interaction effect for alcohol drinkers who smoked on cancer risk was detected, whereas an additive interaction effect was found among drinkers who chewed. The combined effect of all 3 substances accounted for 83.7% of the attributable fraction of contracting esophageal cancer in this population. In conclusion, these results suggest that the intensity and the length of time alcohol and tobacco are used play different roles in the etiology of esophageal cancer. Alcohol separately interacts with tobacco and betel quid in a differently synergistic way in determining the development of this site of cancer.     

Chewing areca nut, betel quid, oral snuff, cigarette smoking and the risk of oesophageal squamous-cell carcinoma in South Asians: a multicentre case-control study

Oesophageal cancer remains an important public health problem worldwide. This multicentre matched case-control study examined the chewing areca nut alone, betel quid with tobacco, oral snuff (snuff dipping) and cigarette smoking as the risk factors for oesophageal squamous-cell carcinoma. We enrolled 91 cases of oesophageal squamous-cell carcinoma and 364 matched controls from three tertiary-care hospitals in Karachi, Pakistan. A structured questionnaire was used to collect the data through face-to-face interview of the participants. Multivariable conditional logistic regression model showed that after adjusting for the effect of ethnicity, ever chewed areca nut alone (adjusted matched odds ratio (mOR(adj))=3.7; 95% confidence interval (CI): 1.6-8.5), ever chewed betel quid with tobacco (mOR(adj)=12.8; 95% CI: 6.3-26.2), ever practiced snuff dipping (mOR(adj)=4.3; 95% CI: 1.6-11.7) and ever smoked cigarettes (mOR(adj)=2.9; 95% CI: 1.4-5.9) were significantly and independently associated with oesophageal squamous-cell carcinoma status. The adjusted summary population attributable risk (PAR) percent for all four substances together was 67.0. Furthermore, despite incomplete synergy, there was manifold increase in the risk of oesophageal squamous-cell carcinoma, if the respondents ever smoked cigarettes and ever chewed betel quid with tobacco (mOR(adj)=21.4; 95% CI: 6.3-72.4) or if they ever smoked cigarettes and ever practiced snuff dipping (mOR(adj)=14.4; 95% CI: 2.3-91.1). The adjusted PAR (%) was higher for the dual practice of smoking cigarettes and chewing betel quid with tobacco (64.3) than the dual practice of smoking cigarettes and snuff dipping (32.2). Public awareness to curtail the addiction to these substances may result in a substantial reduction in the incidence of oesophageal squamous-cell carcinoma and related mortality in this and similar settings.