4b

Hot Tea Consumption and Its Interactions With Alcohol and Tobacco Use on the Risk for Esophageal Cancer A Population-Based Cohort Study Canqing Yu, PhD*; Haijing Tang, PhD*; Yu Guo, MSc; Zheng Bian, MSc; Ling Yang, PhD; Yiping Chen, DPhil; Aiyu Tang, MD; Xue Zhou, PhD; Xu Yang, PhD; Junshi Chen, MD; Zhengming Chen, DPhil; Jun Lv, PhD; and Liming Li, MD, MPH; on behalf of the China Kadoorie Biobank Collaborative Group†

Background: Although consumption of tea at high- temperatures has been suggested as a risk factor for esophageal cancer, an association has not been observed consistently, and whether any relationship is independent of alcohol and tobacco exposure has not been evaluated.

Objective: To examine whether high-temperature tea drinking, along with the established risk factors of alcohol consumption and smoking, is associated with esophageal cancer risk.

Design: China Kadoorie Biobank, a prospective cohort study established during 2004 to 2008.

Setting: 10 areas across China.

Participants: 456 155 persons aged 30 to 79 years. Those who had cancer at baseline or who reduced consumption of tea, al- cohol, or tobacco before baseline were excluded.

Measurements: The usual temperature at which tea was con- sumed, other tea consumption metrics, and lifestyle behaviors were self-reported once, at baseline. Outcome was esophageal cancer incidence up to 2015.

Results: During a median follow-up of 9.2 years, 1731 incident esophageal cancer cases were documented. High-temperature tea drinking combined with either alcohol consumption or smok-

ing was associated with a greater risk for esophageal cancer than hot tea drinking alone. Compared with participants who drank tea less than weekly and consumed fewer than 15 g of alcohol daily, those who drank burning-hot tea and 15 g or more of alcohol daily had the greatest risk for esophageal cancer (hazard ratio [HR], 5.00 [95% CI, 3.64 to 6.88]). Likewise, the HR for cur- rent smokers who drank burning-hot tea daily was 2.03 (CI, 1.55 to 2.67).

Limitation: Tea consumption was self-reported once, at base- line, leading to potential nondifferential misclassification and at- tenuation of the association.

Conclusion: Drinking tea at high temperatures is associated with an increased risk for esophageal cancer when combined with excessive alcohol or tobacco use.

Primary Funding Source: National Natural Science Foundation of China and National Key Research and Development Program.

Ann Intern Med. 2018;168:489-497. doi:10.7326/M17-2000 Annals.org For author affiliations, see end of text. This article was published at Annals.org on 6 February 2018. * Drs. Yu and Tang contributed equally to this work. † The members of the China Kadoorie Biobank Collaborative Group and its steering committee are listed in the Appendix (available at Annals.org).

Esophageal cancer remains a global concern be- cause of its increasing incidence and persistently

poor survival rates (1, 2). It poses a bigger threat to less-developed regions and to men. Both alcohol con- sumption and tobacco smoking are well-established causes of esophageal squamous cell cancer (ESCC) (3), the most common histologic subtype globally (2). Lim- ited evidence suggests that the risk for ESCC decreases with greater intake of vegetables and fruits and an in- crease in physical activity and rises with higher con- sumption of processed meat (3).

Tea, one of the most common beverages world- wide, usually is consumed at elevated temperatures. Existing evidence remains inconclusive regarding whether hot tea drinking is associated with esophageal cancer risk. Although several studies have demon- strated inhibitory effects of tea against tumorigenesis in the digestive tract (4), chronic thermal injury to the esophageal mucosa may initiate carcinogenesis. The International Agency for Research on Cancer recently classified the intake of scalding beverages (>65 °C) as “probably carcinogenic to humans” (3, 5). A few epide- miologic studies addressed the association between esophageal cancer and tea drinking with regard to fre- quency, amount consumed, or tea temperature, with

substantially conflicting results (6–12). Except for a few prospective investigations with limited incident cases (13–16), the vast majority of studies followed a case– control design. Such studies are particularly vulnerable to several biases, including recall bias and reverse cau- sality due to participants changing their drinking habits after symptoms develop or they receive an esophageal cancer diagnosis.

China is among the countries with the highest inci- dence of esophageal cancer. Tea drinkers, especially Chinese men, are more likely to smoke and to drink alcohol. Tobacco smoking and alcohol consumption, as well as the chemical compounds and adverse thermal effect of hot tea, considerably complicate the associa- tion between tea drinking and esophageal cancer risk. In the China Kadoorie Biobank (CKB) study of 0.5 mil-

See also:

Editorial comment . . . . . . . . . . . . . . . . . . . . . . . . . 519 Summary for Patients . . . . . . . . . . . . . . . . . . . . . . . I-22

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lion adults, we prospectively examined the joint associ- ation of tea-drinking metrics, especially beverage tem- perature, and the established risk factors of smoking and alcohol consumption with esophageal cancer risk.

METHODS Study Population

The CKB cohort was established in 10 study re- gions throughout China, including 5 urban and 5 rural areas. From 2004 to 2008, the study enrolled 512 891 adults aged 30 to 79 years with valid baseline data, including a completed questionnaire, physical mea- surements, and written informed consent. Trained staff entered baseline information directly into a laptop- based data entry system developed with built-in func- tions to avoid missing items and to minimize logic er- rors during the interview. A more detailed description is available elsewhere (17, 18). The Ethical Review Committee of the Chinese Center for Disease Control and Prevention (Beijing, China) and the Oxford Tropical Research Ethics Committee, University of Oxford (United Kingdom) approved the study.

For the present analysis, we excluded persons with previously diagnosed cancer (n = 2577) and those who had missing data for body mass index (n = 2) or were lost to follow-up shortly after baseline (n = 1). To avoid potential reverse causality, we further excluded per-

sons who reduced their tea (n = 11 578) or alcohol (n = 20 952) intake from at least weekly to less than weekly and former smokers (n = 30 563) who had stopped smoking 6 or more months ago. The final analysis in- cluded 456 155 participants.

Assessment of Tea Consumption Our baseline questionnaire asked participants to

report their usual frequency of tea drinking (never, only occasionally, only at certain seasons, monthly but less than weekly, or at least once a week) during the past 12 months. Those who drank tea less than weekly were asked whether they had ever consumed tea weekly for at least 1 year. Participants who reported weekly con- sumption were asked how many days in a typical week they drank tea (1 to 2, 3 to 5, or 6 to 7 days), how many (300-mL) cups they consumed in 1 drinking day, the volume of tea leaves (in grams) they added each time, how many times they changed the leaves in 1 drinking day, the type of tea they drank most commonly (for example, green, oolong, or black tea), the usual tem- perature of the tea (room temperature or warm, hot, or burning hot), and the age at which they started drinking tea weekly. We provided the participants with a picto- rial guide showing a standard-sized cup and different quantities of tea leaves in grams. The quantity of leaves added in 1 drinking day was calculated by multiplying the weight (in grams) of the leaves added each time by

Table 1. HRs (95% CIs) for Esophageal Cancer According to Tea Temperature Preference

Variable Less Than Weekly

Weekly Daily P for Trend

Warm Hot Burning Hot All* Daily†

Men (n � 164 531) Esophageal cancer cases, n 648 60 106 188 104 PYs 697 248 151 440 209 462 290 694 118 899 Cases per 1000 PYs, n 0.93 0.40 0.51 0.65 0.87 HR (95% CI)

Age adjusted 1.00 1.04 (0.78–1.38) 1.44 (1.13–1.83) 1.60 (1.31–1.96) 1.97 (1.52–2.57) <0.001 0.058 Multivariable adjusted‡ 1.00 1.06 (0.79–1.41) 1.50 (1.17–1.92) 1.62 (1.32–1.99) 1.93 (1.48–2.52) <0.001 0.117

Further adjusted for tobacco smoking§

1.00 1.01 (0.76–1.34) 1.38 (1.08–1.77) 1.49 (1.21–1.83) 1.75 (1.34–2.28) <0.001 0.153

Further adjusted for alcohol consumption��

1.00 0.93 (0.70–1.24) 1.17 (0.91–1.50) 1.30 (1.05–1.59) 1.55 (1.19–2.02) <0.001 0.100

Women (n � 291 624) Esophageal cancer cases, n 583 5 14 16 7 PYs 2 083 035 146 512 204 331 174 264 50 476 Cases per 1000 PYs, n 0.28 0.03 0.07 0.09 0.14 HR (95% CI)

Age adjusted 1.00 0.48 (0.20–1.17) 0.97 (0.51–1.85) 1.21 (0.69–2.10) 1.08 (0.49–2.38) 0.73 0.54 Multivariable adjusted‡ 1.00 0.51 (0.21–1.25) 1.03 (0.53–1.98) 1.29 (0.74–2.26) 1.12 (0.51–2.48) 0.55 0.60

Further adjusted for tobacco smoking§

1.00 0.52 (0.21–1.27) 1.05 (0.54–2.02) 1.31 (0.75–2.30) 1.14 (0.52–2.52) 0.50 0.58

Further adjusted for alcohol consumption��

1.00 0.52 (0.21–1.27) 1.04 (0.54–2.02) 1.30 (0.74–2.29) 1.13 (0.51–2.51) 0.51 0.57

HR = hazard ratio; PY = person-year. * Calculated by assigning consecutive integers to 5 tea consumption categories. † Restricted to daily tea consumers and calculated by assigning consecutive integers to 3 tea consumption categories. ‡ Adjusted for age (in years); education (no formal school, primary school, middle school, high school, or college or university or higher); marital status (married, widowed, divorced/separated, or never married); household income (<2500, 2500–4999, 5000–9999, 10 000–19 999, 20 000– 34 999, or ≥35 000 Chinese renminbi/y); physical activity (in metabolic equivalent of task-hours daily); intake of red meat, fresh fruits and vegeta- bles, and preserved vegetables (in days per week, calculated by assigning participants to the midpoint of their intake category); body mass index (in kg/m2); family history of cancer (presence or absence); and menopausal status (premenopausal, perimenopausal, or postmenopausal [for women only]). § Nonsmokers or current smokers of 1–9, 10–19, 20–29, or ≥30 cigarettes or equivalents per day. �� Less than weekly; weekly; or <15, 15–29, 30–59, or ≥60 g/d of pure alcohol.

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the number of times the leaves were changed. Among 4405 weekly tea drinkers who completed the same questionnaire twice, at an average interval of 2.6 years between the baseline and subsequent survey (17), the Spearman correlation coefficient was 0.35 for tea tem- perature preference, 0.53 for cups of tea consumed, and 0.63 for tea leaves added.

Assessment of Tobacco Smoking, Alcohol Consumption, and Other Covariates

We asked ever-smokers how many times a day they smoked, along with the type and amount of tobacco used (in cigarettes or an equivalent amount of tobacco: 1 cigarette = 1 g of tobacco = 0.5 cigars) (19); we asked former smokers how long it had been since they quit. Participants who reported that they had stopped smok- ing less than 6 months earlier were considered current smokers and included in the present analysis. We asked participants who used alcohol at least once a week in the past 12 months how often they typically drank, the type of alcoholic beverages they consumed habitually, and the amount of alcohol they consumed on a typical drinking day. On the basis of this informa- tion, we calculated pure alcohol intake in grams on a typical drinking day (20). We also asked participants who drank alcohol less than weekly whether they had ever consumed alcohol weekly for at least 1 year.

The baseline questionnaire also included other covariates, such as sociodemographic characteristics (age, sex, education, marital status, and household in- come), lifestyle behaviors (physical activity and intakes of red meat, fresh fruits and vegetables, and preserved

vegetables), menopausal status (for women), and family history of cancer. Trained staff measured weight and height using calibrated instruments.

Ascertainment of Esophageal Cancer Cases We ascertained incident esophageal cancer cases

among participants from the time they enrolled in the study by linking to local disease and death registries and to the national health insurance system, as well as by active follow-up (17). Trained staff, blinded to the baseline information, coded all cases using the Interna- tional Classification of Diseases, 10th Revision. For the present analysis, esophageal cancer cases were de- fined by code C15. In the CKB study, retrieval of med- ical records from participants with incident cases is ongoing. Trained staff review medical records for diag- nosis validation and collect additional clinical informa- tion, such as pathology subtype. So far, we retrieved medical records pertaining to 870 esophageal cancer cases reported during follow-up; of these cases, 843 (96.9%) were confirmed as esophageal cancer, 569 (65.4%) of which had pathology reports. After 37 cases with “unknown” subtype were excluded, 91.9% of the cases (489 of 532) were ESCC.

Statistical Analysis We calculated person-years at risk from the base-

line date to diagnosis of esophageal cancer, death, loss to follow-up, or 31 December 2015, whichever oc- curred first. In the CKB study, loss to follow-up refers to participants who moved their permanent registered residence out of the jurisdiction of the Regional Coor-

Table 2. HRs (95% CIs) for Esophageal Cancer in Relation to Tea Temperature Preference, by Alcohol Consumption (n = 456 155)

Variable Less Than Weekly Weekly Daily P for Trend

Warm Hot Burning Hot All* Daily†

Less than daily alcohol consumption or <15 g/d of pure alcohol

Esophageal cancer cases, n 1095 32 43 79 61 PYs 2 665 904 264 453 353 163 372 308 140 262 Cases per 1000 PYs, n 0.41 0.12 0.12 0.21 0.43 HR (95% CI)‡

1§ 1.00 0.97 (0.67–1.39) 1.17 (0.81–1.67) 1.41 (1.09–1.84) 1.42 (1.04–1.95) 0.003 0.78 2�� 1.00 0.82 (0.57–1.18) 0.92 (0.66–1.30) 1.23 (0.96–1.59) 1.36 (1.00–1.86)

>15 g/d of pure alcohol Esophageal cancer cases, n 136 33 77 125 50 PYs 114 379 33 498 60 630 92 651 29 113 Cases per 1000 PYs, n 1.19 0.99 1.27 1.35 1.72 HR (95% CI)‡

1§ 1.00 0.99 (0.66–1.47) 1.37 (1.00–1.88) 1.54 (1.16–2.04) 2.16 (1.49–3.14) <0.001 0.065 2�� 1.90 (1.57–2.31) 2.60 (1.79–3.76) 3.74 (2.86–4.90) 3.84 (3.06–4.83) 5.00 (3.64–6.88)

HR = hazard ratio; PY = person-year. * Calculated by assigning consecutive integers to 5 tea consumption categories. † Restricted to daily tea consumers and calculated by assigning consecutive integers to 3 tea consumption categories. ‡ Multivariable model was adjusted for age (in years); sex (male or female); education (no formal school, primary school, middle school, high school, or college or university or higher); marital status (married, widowed, divorced/separated, or never married); household income (<2500, 2500–4999, 5000–9999, 10 000–19 999, 20 000–34 999, or ≥35 000 Chinese renminbi/y); physical activity (metabolic equivalent of task-hours daily); intake of red meat, fresh fruits and vegetables, and preserved vegetables (in days per week, calculated by assigning participants to the midpoint of their intake category); body mass index (kg/m2); family history of cancer (presence or absence); and tobacco smoking (nonsmokers or current smokers of 1–9, 10–19, 20–29, or ≥30 cigarettes or equivalents per day). § Calculated within strata of alcohol consumption, with participants who consumed tea less than weekly as the reference category. �� Calculated with participants who consumed tea less than weekly and consumed <15 g/d of pure alcohol as the reference category.

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dinating Center. By 31 December 2015, of the 512 891 participants, 37 289 (7.3%) had died and 4875 (<1%) were lost to follow-up. We used a Cox proportional hazards model to estimate the hazard ratio (HR) and 95% CI, with age as the underlying time scale and strat- ified jointly by 10 study areas and age at baseline in 5-year intervals. A test and graph based on Schoenfeld residuals showed that the proportional hazards as- sumption was satisfied.

Multivariable models were adjusted for age; sex; education; marital status; household income; tobacco smoking; alcohol consumption; physical activity; in- takes of red meat, fresh fruits and vegetables, and pre- served vegetables; body mass index; family history of cancer; and menopausal status (for women). Forty women had missing data for menopausal status; we in- cluded an indicator for the missing-data category. No data were missing for the other variables. We tested the linear trend of esophageal cancer risk across vari- ous metrics of tea consumption by modeling the levels of ordered categorical variables as a continuous vari- able in a separate model.

We examined whether the association between tea temperature preference and esophageal cancer risk differed by tobacco smoking or alcohol consumption. We tested multiplicative interaction by using a likeli- hood ratio test comparing models with and without cross-product terms. We also plotted the covariate- adjusted cumulative incidences of esophageal cancer on the basis of the Cox model for participants with dif- ferent combinations of tea-drinking temperature, to- bacco use, and alcohol consumption separately, ac- counting for death as a competing risk. Specifically, after fitting the competing risks regression model

(stcrreg procedure), we used the stcurve procedure for plotting (21).

We performed all statistical analyses using Stata, version 14.2 (StataCorp).

Role of the Funding Source The funders had no role in the study design, data

collection, data analysis and interpretation, writing of the report, or decision to submit the manuscript for publication.

RESULTS Participants in the present analysis had a mean age

of 50.9 ± 10.5 years. Of 456 155 participants, 42.1% of the men and 16.1% of the women drank tea daily. Both men and women who reported preferring burning-hot tea were more likely to be current smokers, consume alcohol daily, drink more cups of tea, and add more tea leaves per day (Supplement Table 1, available at Annals.org).

Tea Temperature Preference, Other Metrics of Tea Consumption, and Esophageal Cancer

During a median follow-up of 9.2 years (4.1 million person-years), we documented 1106 incident esopha- geal cancer cases in men and 625 in women. In the multivariable-adjusted model of the male participants, daily tea consumption was associated with increased esophageal cancer risk, with greater risk seen in those who said they preferred hotter tea (Table 1). The asso- ciation exhibited a clear attenuation after further adjust- ment for tobacco smoking and alcohol consumption.

Table 3. HRs (95% CIs) for Esophageal Cancer in Relation to Tea Temperature Preference, by Tobacco Smoking (n = 456 155)

Variable Less Than Weekly Weekly Daily P for Trend

Warm Hot Burning Hot All* Daily†

Nonsmokers Esophageal cancer cases, n 781 10 28 32 15 PYs 2 316 170 186 506 248 152 226 924 63 446 Cases per 1000 PYs, n 0.34 0.05 0.11 0.14 0.24 HR (95% CI)‡

1§ 1.00 0.62 (0.33–1.18) 1.42 (0.91–2.22) 1.34 (0.90–1.99) 1.49 (0.86–2.61) 0.044 0.85 2�� 1.00 0.48 (0.25–0.90) 1.02 (0.68–1.52) 1.00 (0.69–1.45) 1.21 (0.71–2.06)

Current smokers Esophageal cancer cases, n 450 55 92 172 96 PYs 464 113 111 445 165 642 238 034 105 928 Cases per 1000 PYs, n 0.97 0.49 0.56 0.72 0.91 HR (95% CI)‡

1§ 1.00 0.94 (0.69–1.28) 1.09 (0.83–1.42) 1.30 (1.04–1.62) 1.53 (1.15–2.03) 0.001 0.038 2�� 1.04 (0.89–1.21) 1.28 (0.94–1.75) 1.52 (1.16–1.99) 1.76 (1.41–2.21) 2.03 (1.55–2.67)

HR = hazard ratio; PY = person-year. * Calculated by assigning consecutive integers to 5 tea consumption categories. † Restricted to daily tea consumers and calculated by assigning consecutive integers to 3 tea consumption categories. ‡ Multivariable model was adjusted for age (in years); sex (male or female); education (no formal school, primary school, middle school, high school, or college or university or higher); marital status (married, widowed, divorced/separated, or never married); household income (<2500, 2500–4999, 5000–9999, 10 000–19 999, 20 000–34 999, or ≥35 000 Chinese renminbi/y); physical activity (in metabolic equivalent of task-hours daily); intake of red meat, fresh fruits and vegetables, and preserved vegetables (in days per week, calculated by assigning participants to the midpoint of their intake category); body mass index (in kg/m2); family history of cancer (presence or absence); and alcohol consumption (less than weekly; weekly; or <15, 15–29, 30–59, or ≥60 g/d of pure alcohol). § Calculated within strata of smoking, with participants who consumed tea less than weekly as the reference category. �� Calculated with participants who consumed tea less than weekly and did not smoke as the reference category.

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Compared with men who drank tea less than weekly, the HRs for esophageal cancer were 1.17 (95% CI, 0.91 to 1.50), 1.30 (CI, 1.05 to 1.59), and 1.55 (CI, 1.19 to 2.02) for daily tea drinkers who preferred their bever- age warm, hot, and burning hot, respectively. No statis- tically significant association was found between tea temperature and esophageal cancer in women (P < 0.001 for interaction with sex).

We also observed a statistically significant increase in men's esophageal cancer risk with more cups of tea consumed, more tea leaves added, a longer duration of tea consumption, and green tea drinking (all P < 0.001 for interaction with sex) (Supplement Tables 2 to 5, available at Annals.org). Information on various metrics of tea consumption was available only for regular tea drinkers; therefore, we made further adjust- ments for tea temperature preference and other met- rics of tea consumption mutually among men who drank tea daily. After we mutually adjusted the metrics for one another, we found no statistically significant association between the number of cups consumed per day, volume of tea leaves added, duration of tea

drinking, type of tea consumed, or beverage tempera- ture and the risk for esophageal cancer in men who drank tea daily (Supplement Table 6, available at Annals.org).

Association of Tea Temperature Preference and Alcohol Consumption or Smoking With Esophageal Cancer Risk

We observed important differences in the associa- tion between tea temperature preference and esopha- geal cancer risk across the stratum for alcohol con- sumption (P < 0.001 for interaction) (Table 2) or tobacco smoking (P = 0.001 for interaction) (Table 3), with a stronger association in participants who drank 15 g or more of alcohol per day and in current smokers. Compared with participants who consumed tea less than weekly and drank less than 15 g of alcohol daily, those who drank burning-hot tea and 15 g or more of alcohol per day had the greatest risk for esophageal cancer (HR, 5.00 [CI, 3.64 to 6.88]). Likewise, the HR for current smokers who drank burning-hot tea daily was 2.03 (CI, 1.55 to 2.67).

Figure. Adjusted cumulative incidences of esophageal cancer for participants with different combinations of tea, alcohol, and tobacco consumption.

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B. Tobacco+, Alcohol− D. Tobacco+, Alcohol+

A. Nonsmokers who drank alcohol less than daily or drank fewer than 15 g of alcohol per day. B. Current smokers who drank alcohol less than daily or drank fewer than 15 g of alcohol per day. C. Nonsmokers who drank 15 g or more of alcohol per day. D. Current smokers who drank 15 g or more of alcohol per day. Nonsmokers who drank tea less than daily and alcohol less than daily or drank fewer than 15 g of alcohol per day were the reference group. The multivariable model was adjusted for age; sex; study area; education; marital status; household income; physical activity; intakes of red meat, fresh fruits and vegetables, and preserved vegetables; body mass index; and family history of cancer.

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Joint Association of Tea Temperature Preference, Alcohol Consumption, and Smoking With Esophageal Cancer

We further examined the joint association of the 3 factors (tea temperature, alcohol consumption, and smoking) on esophageal cancer risk. The Figure shows the adjusted cumulative incidences of esophageal can- cer by combined categories of tea temperature, to- bacco use, and alcohol consumption. In the absence of smoking and excessive alcohol consumption, daily tea drinking was not associated with an increased risk for esophageal cancer, regardless of tea temperature (Ta- ble 4) or other consumption metrics (Supplement Ta- ble 7, available at Annals.org). The esophageal cancer risk increased for daily tea drinkers who preferred hot or burning-hot tea in the presence of either smoking (HR, 1.56 [CI, 1.21 to 2.02]) or excessive alcohol con- sumption (HR, 2.27 [CI, 1.16 to 4.45]). The strongest association was seen in the combination of daily high- temperature tea drinking with both smoking and exces- sive alcohol consumption (HR, 5.01 [CI, 4.00 to 6.28]). Other metrics of tea drinking showed less clear pat- terns of joint association with smoking and excessive alcohol consumption.

Sensitivity Analysis (Data Not Shown) The association between tea temperature prefer-

ence and esophageal cancer risk persisted after exclu- sion of patients who received an esophageal cancer diagnosis during the first 2 (n = 339) or 4 (n = 706) years of follow-up. The results also did not change ap- preciably when we tried more comprehensive adjust- ments for tobacco use by using pack-years and for alcohol consumption by adding years of alcohol con- sumption. When we used competing risk regression to account for the competing risk for death, the subhazard ratios obtained in the competing risk regression were similar when compared with the HRs obtained in the Cox regression.

DISCUSSION In this large prospective Chinese cohort, we found

that the association between high-temperature tea drinking and esophageal cancer risk was dependent on alcohol and tobacco consumption. A synergistic asso- ciation was found between hot tea drinking with exces- sive alcohol consumption or smoking and the risk for esophageal cancer. Participants who drank high- temperature tea, consumed alcohol excessively, and smoked had an esophageal cancer risk more than 5 times greater than those who had none of those 3 hab- its. However, in the absence of both excessive alcohol consumption and smoking, daily tea drinking was not associated with esophageal cancer risk, regardless of tea temperature or other consumption metrics.

A few prospective studies examined the associa- tion between esophageal cancer risk and the tempera- ture (13) or amount (14–16) of tea consumed and showed inconsistent findings. Several systematic re- views and meta-analyses of principally case–control studies suggested no clear pattern of association be- tween the amount of tea consumed and esophageal cancer risk, although higher-temperature tea drinking has been associated with increased esophageal cancer risk (6–12). Previous studies also found an association between consumption of hot food and beverages and the risk for ESCC but not esophageal adenocarcinoma (12, 22). In the current Chinese population, in which ESCC is the predominant histologic subtype, we ob- served that high-temperature tea drinking was pro- spectively associated with esophageal cancer risk in the presence of excessive alcohol consumption or smok- ing; however, we found no such association in the ab- sence of both habits.

The synergistic effects of high-temperature tea drinking, excessive alcohol consumption, and tobacco use on esophageal cancer risk are biologically plausi- ble. Research has suggested that thermal injury may

Table 4. HRs (95% CIs) for Joint Associations Among Tea Temperature Preference, Tobacco Smoking, and Alcohol Consumption and Risk for Esophageal Cancer (n = 456 155)

Tea Temperature Preference Consumption of >15 g/d of Pure Alcohol

No Yes

Esophageal Cancer Cases, n

Cases per 1000 PYs, n

HR (95% CI)* Esophageal Cancer Cases, n

Cases per 1000 PYs, n

HR (95% CI)*

Nonsmokers Less than daily 775 0.31 1.00 16 0.45 1.14 (0.69–1.89) Daily, warm 23 0.10 1.00 (0.64–1.56) 5 0.59 2.28 (0.94–5.56) Daily, hot/burning hot 38 0.14 1.05 (0.74–1.48) 9 0.62 2.27 (1.16–4.45)

Current smokers Less than daily 352 0.76 1.03 (0.88–1.21) 153 1.36 2.47 (2.01–3.04) Daily, warm 20 0.18 0.93 (0.58–1.50) 72 1.38 4.59 (3.45–6.10) Daily, hot/burning hot 102 0.43 1.56 (1.21–2.02) 166 1.55 5.01 (4.00–6.28)

HR = hazard ratio; PY = person-year. * Multivariable model was adjusted for age (in years); sex (male or female); education (no formal school, primary school, middle school, high school, or college or university or higher); marital status (married, widowed, divorced/separated, or never married); household income (<2500, 2500–4999, 5000–9999, 10 000–19 999, 20 000–34 999, or ≥35 000 Chinese renminbi/y); physical activity (in metabolic equivalent of task-hours daily); intake of red meat, fresh fruits and vegetables, and preserved vegetables (in days per week, calculated by assigning participants to the midpoint of their intake category); body mass index (in kg/m2); and family history of cancer (presence or absence).

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damage the epithelium and impair barrier function, subsequently augmenting the risk for damage from other risk factors, such as excessive alcohol consump- tion and smoking (22). The release of N-nitroso com- pounds, which are formed as a result of inflammatory processes associated with chronic thermal irritation of the esophageal mucosa, also may contribute to esoph- ageal cancer development (22, 23). The mechanism for the joint association of hot tea drinking, excessive alco- hol consumption, and tobacco use with esophageal cancer warrants further elucidation.

Various tea-drinking metrics were interrelated in the population studied, making it difficult to identify the most relevant metric in relation to esophageal cancer risk. The present study found evidence of increased esophageal cancer risk with higher tea temperatures. Additional studies are needed to confirm our findings.

In contrast to the strong and relatively consistent evidence from experimental studies showing potential anticarcinogenic properties of bioactive compounds in tea (4), results from epidemiologic studies have not convincingly demonstrated that tea drinking has pre- ventive effects against esophageal cancer in humans (6–12). Most of the inverse associations between tea drinking and esophageal cancer risk were found in case–control studies in East Asian countries, especially China. The protective effects of tea drinking, if any, on esophageal cancer development were thought to be overshadowed by alcohol consumption and smoking as well as the thermal effect of hot tea (24). However, in the present population, when we restricted our analy- ses to the subgroup of nonsmokers who were not heavy alcohol users, daily tea drinking, regardless of consumption metrics or tea type, was not associated with a decreased risk for esophageal cancer. In an early randomized controlled trial with 200 participants from Henan, China, decaffeinated green tea did not show a benefit in alleviating precancerous lesions or abnormal cell proliferation patterns after 11 years of follow-up (25). A nested case–control study in a cohort of men from Shanghai also found no association between uri- nary biomarkers of tea polyphenol and the risk for esophageal cancer (26). The reason for the difference between the results from animal research and those from human studies with high-quality evidence is prob- ably that humans were exposed to tea polyphenols at levels 1 to 2 orders of magnitude lower than those used in animal studies (4).

To the best of our knowledge, this study is the first to provide compelling evidence of joint associations between high-temperature tea drinking with estab- lished risk factors of excessive alcohol and tobacco use and esophageal cancer risk. Strengths of the study in- clude its prospective design, a population geographi- cally spread across urban and rural China, and careful adjustment for potential confounders. To avoid reverse causality bias, we excluded persons who had reduced their consumption of tea, alcohol, or tobacco and, sub- sequently, participants who received an esophageal cancer diagnosis during the first several years of follow- up. The CKB study collected detailed information on

several metrics of tea consumption, including fre- quency, amount, duration, type of tea, and qualitative gradation of tea temperature, allowing us to analyze them comprehensively and to mutually adjust them for one another.

Some limitations also warrant mention. Tea- drinking patterns were self-reported and collected once, at baseline, although consumption habits may change over time. Nevertheless, misclassification of ex- posure may have been nondifferential with regard to subsequent disease status, attenuating our findings. Tea temperatures relied on qualitative self-report data and were not validated by actual measurement. We did not ask participants about sip size, which together with initial tea temperature, determines intraesophageal temperature (27); this may have led to differences in subjective perception of temperature. Obtaining a valid and reliable estimate of the temperature at which study participants typically drink tea is a challenge for most epidemiologic research. The present study lacked information regarding the histologic subtype of each esophageal cancer case. However, ESCC accounts for more than 90% of the subset of esophageal cancer cases documented in the CKB study population as well as in China (28). Hot tea drinking may be correlated with a preference for consuming other beverages and foods at high temperature, but we did not collect this information or adjust for it in our analyses. Thus, thermal injury from other beverages and foods may have contrib- uted to the observed associations. Despite the large sam- ple size, few women in the CKB cohort smoked or drank alcohol, leading to wide CIs for the effect estimates and inconclusive results for women and precluding further sex-specific joint analysis of relevant factors. In addition, when we further examined the 3-way associations—that is, the association among tea temperature, alcohol con- sumption, and tobacco smoking and tea temperature, frequency of tea drinking per day, and alcohol con- sumption (or tobacco smoking)—the cases were too small to obtain reliable effect estimates for the 3 cate- gories of tea temperature.

Our findings show a noticeable increase in esoph- ageal cancer risk associated with a combination of high-temperature tea drinking, excessive alcohol con- sumption, and tobacco smoking. They suggest that ab- staining from hot tea might be beneficial for preventing esophageal cancer in persons who drink alcohol exces- sively or smoke. More prospective studies are war- ranted to confirm the interactions observed in this study. Studies that directly measure tea temperature are particularly encouraged.

From Peking University Health Science Center, Beijing, China; Beijing Institute of Technology, Beijing, China; Chinese Acad- emy of Medical Sciences, Beijing, China; University of Oxford, Oxford, United Kingdom; Suzhou Center for Disease Control and Prevention, Suzhou, Jiangsu, China; Heilongjiang Center for Disease Control and Prevention, Harbin, Heilongjiang, Chi- na; China National Center for Food Safety Risk Assessment, Beijing, China; Peking University Health Science Center and Peking University Institute of Environmental Medicine, Beijing,

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China; and Peking University Health Science Center and Chi- nese Academy of Medical Sciences, Beijing, China.

Acknowledgment: The authors thank the study participants and members of the survey teams in each of the 10 regional centers, as well as the project development and management teams based in Beijing, Oxford, and the regional centers.

Grant Support: By the National Natural Science Foundation of China (grants 81530088, 81390540, 81390544, and 81390541) and National Key Research and Development Pro- gram of China (grants 2016YFC0900500, 2016YFC0900501, and 2016YFC0900504). The CKB baseline survey and first re- survey were supported by a grant from the Kadoorie Charita- ble Foundation in Hong Kong. The long-term follow-up is sup- ported by Wellcome Trust, United Kingdom (grants 202922/ Z/16/Z, 088158/Z/09/Z, and 104085/Z/14/Z), and the Chinese Ministry of Science and Technology (grant 2011BAI09B01).

Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje /ConflictOfInterestForms.do?msNum=M17-2000.

Reproducible Research Statement: Study protocol: Cohort description and questionnaires are available at www .p3gobservatory.org/questionnaire/list.htm. Statistical code: Available from Dr. Lv (e-mail, [email protected]). Data set: See study Web site (www.ckbiobank.org) for data access pol- icy and procedures.

Requests for Single Reprints: Jun Lv, PhD, or Liming Li, MD, MPH, Department of Epidemiology and Biostatistics, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China; e-mail, [email protected] or [email protected] .com.

Current author addresses and author contributions are avail- able at Annals.org.

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AD LIBITUM Provisions

I spot you first in floral, reaching past purple gladiolas and petite roses to score a sassy bunch of sunflowers. On to bakery to claim a glossy cake—your daughter's favorite, I overhear—announcing her name in yellow icing.

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The final sighting at checkout, where I grin as you fasten three roiling balloons to your basket. You chat with the checker, offer the bagger an encouraging aside— something about perseverance, the doors it can open.

The I Love You balloon bobs merrily above the others as you swipe your card. Then, one last remark to the checkout team before you turn to go: “So glad it's pretty today. That cemetery gets muddy in the rain.”

Outside, in sunlight, you're on the other side of the wide parking lot. I return your brief wave as you wrangle balloons, now dancing madly to escape backseat confinement. Then you're gone, pulling away, a silent riot of color in your wake.

Sylvia S. Villarreal, MEd, MPH McGovern Center for Humanities and Ethics Houston, Texas

Current Author Address: Sylvia S. Villarreal, MEd, MPH; e-mail, [email protected].

© 2018 American College of Physicians

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Current Author Addresses: Drs. C. Yu, J. Lv, and L. Li: Depart- ment of Epidemiology and Biostatistics, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China. Drs. H. Tang and X. Yang: School of Software, Beijing Institute of Technology, 5 South Zhongguancun Street, Beijing 100081, China. Drs. Y. Guo and Z. Bian: Chinese Academy of Medical Sci- ences, Beijing 102300, China. Drs. L. Yang, Y. Chen, and Z. Chen: Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Depart- ment of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Oxford OX3 7LF, United Kingdom. Dr. A. Tang: Suzhou Center for Disease Control and Preven- tion, Suzhou 215006, China. Dr. X. Zhou: Heilongjiang Center for Disease Control and Pre- vention, Harbin 150030, China. Dr. J. Chen: China National Center for Food Safety Risk As- sessment, Beijing 100738, China.

Author Contributions: Conception and design: J. Lv, L. Li. Analysis and interpretation of the data: C. Yu, H. Tang, X. Yang, J. Lv. Drafting of the article: C. Yu, J. Lv. Critical revision for important intellectual content: J. Lv, L. Li. Final approval of the article: C. Yu, H. Tang, Y. Guo, Z. Bian, L. Yang, Y. Chen, A. Tang, X. Zhou, X. Yang, J. Chen, Z. Chen, J. Lv, L. Li. Obtaining of funding: J. Chen. Z. Chen, L. Li. Administrative, technical, or logistic support: Y. Guo, J. Chen, Z. Chen, L. Li. Collection and assembly of data: Y. Guo, Z. Bian, L. Yang, Y. Chen, A. Tang, X. Zhou.

APPENDIX: CKB COLLABORATIVE GROUP Members of the CKB International Steering Com-

mittee are Junshi Chen, Zhengming Chen (Principal In- vestigator [PI]), Robert Clarke, Rory Collins, Yu Guo, Liming Li (PI), Jun Lv, Richard Peto, and Robin Walters.

The CKB Collaborative Group members who authored this work are Canqing Yu (National Co- ordinating Centre, Beijing), Yu Guo (National Co- ordinating Centre, Beijing), Zheng Bian (National Co-ordinating Centre, Beijing), Ling Yang (International Co-ordinating Centre, Oxford), Yiping Chen (Interna- tional Co-ordinating Centre, Oxford), Aiyu Tang (Su- zhou CDC), Xue Zhou (Heilongjiang Provincial CDC), Junshi Cheng, Zhengming Chen (PI, International Co- ordinating Centre, Oxford), Jun Lv (National Co- ordinating Center, Beijing), and Liming Li (PI, National Co-ordinating Center, Beijing).

The CKB Collaborative Group members who con- tributed to this work but did not author it are as follows:

International Co-ordinating Centre, Oxford Daniel Avery, Ruth Boxall, Derrick Bennett, Yumei

Chang, Robert Clarke, Huaidong Du, Simon Gilbert, Alex Hacker, Mike Hill, Michael Holmes, Andri Iona, Christiana Kartsonaki, Rene Kerosi, Ling Kong, Om

Kurmi, Garry Lancaster, Sarah Lewington, Kuang Lin, John McDonnell, Iona Millwood, Qunhua Nie, Jay- akrishnan Radhakrishnan, Paul Ryder, Sam Sansome, Dan Schmidt, Paul Sherliker, Rajani Sohoni, Becky Ste- vens, Iain Turnbull, Robin Walters, Jenny Wang, Lin Wang, Neil Wright, and Xiaoming Yang.

National Co-ordinating Centre, Beijing Xiao Han, Can Hou, Pei Pei, Chao Liu, and Yunlong

Tan. Regional Co-ordinating Centres Qingdao CDC: Zengchang Pang, Ruqin Gao, Shan-

peng Li, Shaojie Wang, Yongmei Liu, Ranran Du, Yajing Zang, Liang Cheng, Xiaocao Tian, Hua Zhang, Yaoming Zhai, Feng Ning, Xiaohui Sun, and Feifei Li.

Licang CDC: Silu Lv, Junzheng Wang, and Wei Hou.

Heilongjiang Provincial CDC: Mingyuan Zeng and Ge Jiang.

Nangang CDC: Liqiu Yang, Hui He, Bo Yu, Yanjie Li, Qinai Xu, Quan Kang, and Ziyan Guo.

Hainan Provincial CDC: Dan Wang, Ximin Hu, Jin- yan Chen, Yan Fu, Zhenwang Fu, and Xiaohuan Wang.

Meilan CDC: Min Weng, Zhendong Guo, Shukuan Wu, Yilei Li, Huimei Li, and Zhifang Fu.

Jiangsu Provincial CDC: Ming Wu, Yonglin Zhou, Jinyi Zhou, Ran Tao, Jie Yang, and Jian Su. Suzhou CDC: Fang Liu, Jun Zhang, Yihe Hu, Yan Lu, Liangcai Ma, Shuo Zhang, Jianrong Jin, and Jingchao Liu.

Guangxi Provincial CDC: Zhenzhu Tang, Naying Chen, and Ying Huang.

Liuzhou CDC: Mingqiang Li, Jinhuai Meng, Rong Pan, Qilian Jiang, Jian Lan, Yun Liu, Liuping Wei, Liyuan Zhou, Ningyu Chen, Ping Wang, Fanwen Meng, Yulu Qin, and Sisi Wang.

Sichuan Provincial CDC: Xianping Wu, Ningmei Zhang, Xiaofang Chen, and Weiwei Zhou.

Pengzhou CDC: Guojin Luo, Jianguo Li, Xiaofang Chen, Xunfu Zhong, Jiaqiu Liu, and Qiang Sun.

Gansu Provincial CDC: Pengfei Ge, Xiaolan Ren, and Caixia Dong.

Maiji CDC: Hui Zhang, Enke Mao, Xiaoping Wang, Tao Wang, and Xi Zhang.

Henan Provincial CDC: Ding Zhang, Gang Zhou, Shixian Feng, Liang Chang, and Lei Fan. Huixian CDC: Yulian Gao, Tianyou He, Huarong Sun, Pan He, Chen Hu, Xukui Zhang, Huifang Wu, and Pan He.

Zhejiang Provincial CDC: Min Yu, Ruying Hu, and Hao Wang.

Tongxiang CDC: Yijian Qian, Chunmei Wang, Kaixu Xie, Lingli Chen, Yidan Zhang, Dongxia Pan, and Qijun Gu.

Hunan Provincial CDC: Yuelong Huang, Biyun Chen, Li Yin, Huilin Liu, Zhongxi Fu, and Qiaohua Xu.

Liuyang CDC: Xin Xu, Hao Zhang, Huajun Long, Xianzhi Li, Libo Zhang, and Zhe Qiu.

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CORRECTION: HOT TEA CONSUMPTION AND ITS INTERACTIONS

WITH ALCOHOL AND TOBACCO USE ON THE RISK FOR

ESOPHAGEAL CANCER: A POPULATION-BASED COHORT STUDY

“Effect of” was incorrectly added to the title of the pre- ceding article (1) during the copyediting process. It was not our intent to imply causality, and we apologize for any confusion.

Reference 1. Yu C, Tang H, Guo Y, Bian Z, Yang L, Chen Y, et al. Hot tea consumption

and its interactions with alcohol and tobacco use on the risk for esophageal

cancer: a population-based cohort study. Ann Intern Med. 2018;168:487-97.

[PMID: 29404576] doi: 10.7326/M17-2000

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