Abstract
Coffee and caffeine consumption are thought to increase the risk of bladder cancer. However, few studies have stratified this risk by smoking status, which is a potential confounder. Here, we investigated the association between coffee, green tea (another major source of caffeine), and caffeine, and bladder cancer incidence in relation to smoking status. We conducted a population‐based prospective study in a cohort of Japanese, comprising a total of 49 566 men and 54 874 women aged 40–69 years who reported their coffee and green tea consumption at baseline. During follow‐up from 1990 through 2005, 164 men and 42 women were newly diagnosed with bladder cancer. Cigarette smoking was associated with an increased risk of bladder cancer, with a strong dose–response relationship. Coffee was positively associated with bladder cancer risk in men, without statistical significance. When stratified by smoking status, coffee and caffeine consumption were associated with an increased risk of bladder cancer in never‐ or former‐smoking men, with hazard ratios (95% confidence interval) in the highest categories of coffee (one or more cups per day) and caffeine consumption compared with the lowest of 2.24 (95% CI = 1.21–4.16) and 2.05 (95% CI = 1.15–3.66), respectively. In conclusion, cigarette smoking was confirmed as a risk factor for bladder cancer. Coffee and caffeine may be associated with an increased bladder cancer risk in never or former smokers among Japanese men. (Cancer Sci 2009; 100: 284–291)
The incidence of bladder cancer is increasing slightly worldwide, particularly in industrial countries, including Japan.( 1 , 2 ) Many epidemiological studies have suggested that bladder cancer is influenced by environmental factors, such as smoking, exposure to industrial chemicals, and several lifestyle factors.( 3 ) While the International Agency for Research on Cancer (IARC) reported that coffee is a possible carcinogenic agent (group 2B) in bladder cancer, it could not exclude the possibility that this was due to bias or confounding.( 4 ) In a recent meta‐analysis, Zeegers et al. demonstrated a small elevated risk (20%) of bladder cancer for current coffee drinkers,( 5 ) and a pooled analysis of 10 case‐control studies in European countries found that heavy coffee consumption showed a positive association with bladder cancer among non‐smokers.( 6 ) However, most of these previous studies were conducted in Western countries; and of the five conducted in Asian populations, results have been inconsistent: a prospective study in Japanese‐Americans reported that coffee consumption increased the risk of bladder cancer albeit without a dose–response,( 7 ) two case‐control( 8 , 9 ) and a prospective study( 10 ) among Japanese people found that the relative risk of coffee drinking was insignificant; while a case‐control study in Japanese‐American women showed an inverse association with coffee consumption.( 11 ) These findings indicate that the relationship between coffee consumption and bladder cancer in Asian populations is largely unknown.
Caffeine, which is contained in coffee, has been suggested to contribute to the increased risk of bladder cancer, although its carcinogenicity or otherwise in humans has not been classified (group 3).( 4 ) In Asian populations, green tea is a major source of caffeine, but only three studies have investigated the association between green tea and bladder cancer, and their results are inconsistent.( 8 , 9 , 10 )
Given that Asian populations have a low incidence of bladder cancer, and that their coffee and green tea consumption habits and amounts differ by geographic area, an understanding of the relationships between coffee, green tea or caffeine consumption and bladder cancer among Asian populations should be useful. Moreover, the distribution of phenotypes of N‐acetyltransferase,( 12 , 13 ) which metabolizes caffeine, differs between Asian and Caucasian populations.( 14 ) The effect of coffee, green tea, or caffeine on bladder cancer in Asian populations may therefore differ from that in other populations.
Here, we analyzed the association between coffee, green tea, or caffeine consumption, and bladder cancer in a population‐based prospective study in Japan. In addition, we explored these associations by smoking status, which is a known confounder between them.
Materials and Methods
Study population. The Japan Public Health Center‐based Prospective Study (JPHC study) started in 1990 for Cohort I and in 1993 for Cohort II. The study design has been described in detail previously.( 15 ) Cohort I consisted of five Public Health Center (PHC) areas (Iwate, Akita, Nagano, Okinawa, and Tokyo), and Cohort II of six PHC areas (Ibaraki, Niigata, Kochi, Nagasaki, Okinawa, and Osaka) across Japan. When analyzing the present data, we excluded all subjects in Tokyo, whose incidence data were not available. As a whole, this cohort consisted of 133 323 men and women aged 40–69 years at baseline who registered in the study areas. After excluding 239 subjects with non‐Japanese nationality (n = 51), late report of emigration occurring before the start of the follow‐up period (n = 178), incorrect birth date (n = 6), and duplicate enrollment (n = 4), a population‐based cohort of 133 084 subjects (65 660 men and 67 424 women) was established. This study was approved by the institutional review board of the National Cancer Center, Tokyo, Japan.
Baseline survey. A self‐administered questionnaire, which included information on coffee and green tea consumption, smoking history, medical history, and other lifestyle factors, was distributed to all registered residents at baseline. A total of 106 326 subjects returned valid responses (response rate 80%). After excluding subjects with self‐reported bladder cancer at baseline (11 persons) and incomplete data on coffee and green tea consumption, 104 440 subjects (49 566 men and 54 874 women) were included in analysis.
Information on coffee or green tea consumption was obtained in terms of frequency and amount of intake in six categories: almost none, 1–2 times/week, 3–4 times/week, 1–2 cups/day, 3–4 cups/day, and ≥5 cups/day. Based on the distribution in each category, we divided categories of coffee into the following four categories in men: almost none, 1–4 times/week, 1–2 cups/day, and ≥3 cups/day. The type of coffee consumed (decaffeinated or caffeinated) was not included in the questionnaire, because decaffeinated coffee is rarely consumed in Japan. Similarly, green tea consumption was divided into the following four categories in men: <1 cup/day, 1–2 cups/day, 3–4 cups/day, and ≥5 cups/day. For women, we classified coffee and green tea consumption by three categories because of the small numbers of cases. Caffeine consumption was summed as the total amount contained in coffee, green tea, black tea, and Chinese tea. Caffeine consumption from each was calculated by multiplying the amount per cup by the quantity of caffeine per cup for each beverage. Amount per cup for each beverage was determined as the median value in a validation study among subsamples using 28‐day dietary records,( 16 ) and found to be 150, 140, 150, and 120 mL in men, and 120, 130, 150, and 120 mL in women for coffee, green tea, black tea, and Chinese tea, respectively. Quantity of caffeine per cup for each beverage was taken from the fifth revised edition of the Standard Tables of Food Composition in Japan.( 17 )
The validity of coffee or green tea consumption was assessed among subsamples using 28‐day dietary records. Spearman's correlation coefficients between coffee or green tea consumption from the questionnaire and from dietary records in men and women were 0.42 and 0.38 (Cohort I) and 0.59 and 0.51 (Cohort II) for coffee, respectively, and 0.57 and 0.63 (Cohort I) and 0.37 and 0.43 (Cohort II) for green tea, respectively.( 16 )
Follow‐up. We followed subjects from the baseline survey until 31 December 2005. Changes in residence status including survival were identified annually through the residential registry in each area or, for those who had moved out of the study area, through the municipal office of the area to which they had moved. Generally, mortality data for residents included in the residential registry are forwarded to the Ministry of Health, Labour and Welfare and coded for inclusion in the National Vital Statistics. Residency and death registration are required by the Basic Residential Register Law and Family Registry Law, respectively, and the registries are believed to be complete. Among the study subjects, 8897 (8.5%) died, 5892 (5.6%) moved out of the study area, and 413 (0.4%) were lost to follow‐up during the study period.
The occurrence of cancer was identified by active patient notification from major local hospitals in the study area and data linkage with population‐based cancer registries, with permission from the local governments responsible for the registries. Cases were coded using the International Classification of Diseases for Oncology, third edition (ICD‐O‐3). Death certificate information was used as a supplementary information source, with 4.4% of cases of bladder cancer first notified by death certificate (DCN). The proportion of case patients with bladder cancer ascertained by death certificate only (DCO) was 1.9%. The mortality/incidence ratios were 0.19 for bladder cancer and 0.36 for all cancer except skin. These results were considered to be of adequate quality for the present study based on the international standard.( 18 )
For the present analysis, the earliest date of diagnosis was used in cases with multiple primary cancers at different times. A total of 206 newly diagnosed bladder cancer cases (164 men, 42 women) were identified by 31 December 2005.
Statistical analysis. Person‐years of follow‐up were calculated for each person from the date of completion of the baseline questionnaire to the date of bladder cancer diagnosis, the date of emigration from the study area, or the date of death, whichever came first; or if none of these occurred, follow‐up was through to the end of the study period (31 December 2005). Subjects who were lost to follow‐up were censored at the last confirmed date of presence in the study area. The hazard ratios (HRs) of bladder cancer were calculated in four categories for coffee and green tea or in quartiles for the categories of caffeine consumption, with the lowest consumption category as the reference. HRs and 95% confidence intervals (CIs) were calculated by the Cox proportional hazards model according to the SAS PHREG procedure (Version 9.1; SAS Institute, Cary, NC, USA). Covariates used in the model were age at enrollment, study area (10 PHC areas), smoking status (never, former [<10, 10–19, and ≥20 years since cessation of smoking], current [1–19, 20–29, 30–39, 40–49, and ≥50 pack‐years, defined by multiplying the years of smoking by the average number of cigarettes divided by 20] in men and never, former, current [<25 and ≥25 pack‐years] in women), alcohol consumption (non‐ or occasional drinkers, 1–150, ≥150 g/week), green tea, and coffee consumption. Moreover, we also calculated the HRs of bladder cancer for combined categories of coffee, green tea, or caffeine consumption and smoking status, and tested statistical interactions using the differences between two likelihood ratios of the models with and without the interaction terms between coffee, green tea, and caffeine consumption and smoking status. Interaction terms were generated by multiplying the ordinal of these consumption categories by ordinal smoking categories (never, former, or current smokers).
P‐values for trends for coffee, green tea, and caffeine consumption were calculated by treatment as ordinal variables in the proportional‐hazards model. All P‐values are two‐sided, and statistical significance was determined at the P < 0.05 level.
Results
During 1314 586 person‐years of follow‐up (average 12.6 years) of 104 440 subjects (49 566 men and 54 874 women), 164 men and 42 women were newly diagnosed with bladder cancer.
Baseline characteristics of subjects according to coffee and green tea consumption are shown in Table 1. Both men and women with high coffee consumption were younger than those who hardly drank. The proportion of current smokers increased as coffee consumption increased in both men and women. As coffee consumption increased, alcohol intake decreased in men and increased in women. Subjects with higher green tea consumption tended to be older, drink less alcohol, and consume less coffee in both men and women. The proportion of current smokers increased as green tea consumption increased in men, whereas that in women was high in both the lowest and highest categories of green tea consumption. As expected, caffeine consumption increased as coffee and green tea intake increased.
Table 1.
Baseline characteristics of study subjects according to coffee and green tea intake category
| Coffee intake | Green tea intake | |||||||
|---|---|---|---|---|---|---|---|---|
| Almost none | 1–4 times/week | 1–2 cups/day | ≥3 cups/day | <1 cup/week | 1–2 cups/day | 3–4 cups/day | ≥5 cups/day | |
| Men | ||||||||
| Number of subjects | 14 929 | 14 600 | 12 966 | 7071 | 12 868 | 11 679 | 13 092 | 11 927 |
| Proportion (%) | 30.1 | 29.5 | 26.1 | 14.3 | 26.0 | 23.6 | 26.4 | 24.0 |
| Age (years, mean) ± SD | 53.7 ± 7.8 | 52.1 ± 7.8 | 50.6 ± 7.9 | 48.3 ± 7.3 | 49.7 ± 7.4 | 50.7 ± 7.9 | 52.3 ± 8.1 | 53.9 ± 7.8 |
| Current smokers (%) | 43.3 | 49.7 | 55.9 | 71.3 | 51.4 | 52.9 | 51.7 | 54.1 |
| Regular drinkers (%) | 68.7 | 68.5 | 68.8 | 62.3 | 66.4 | 71.6 | 69.1 | 63.8 |
| Coffee intake (%), daily | – | – | – | – | 42.9 | 47.6 | 40.4 | 30.8 |
| Green tea intake (%), daily | 75.3 | 74.9 | 74.5 | 68.7 | – | – | – | – |
| Caffeine intake (g, mean) ± SD | 0.09 ± 0.06 | 0.12 ± 0.06 | 0.21 ± 0.06 | 0.43 ± 0.09 | 0.13 ± 0.13 | 0.16 ± 0.12 | 0.20 ± 0.12 | 0.23 ± 0.12 |
| Women | ||||||||
| Number of subjects | 17 509 | 15 968 | 15 994 | 5403 | 13 441 | 11 492 | 15 316 | 14 625 |
| Proportion (%) | 31.9 | 29.1 | 29.1 | 9.9 | 24.5 | 20.9 | 27.9 | 26.7 |
| Age (years, mean) ± SD | 55.0 ± 7.7 | 52.2 ± 7.8 | 49.8 ± 7.5 | 47.3 ± 6.7 | 49.8 ± 7.4 | 50.8 ± 7.9 | 52.7 ± 8.2 | 53.9 ± 7.9 |
| Current smokers (%) | 4.4 | 4.4 | 7.6 | 18.0 | 7.8 | 6.5 | 5.4 | 7.1 |
| Regular drinkers (%) | 8.6 | 10.5 | 15.8 | 19.6 | 12.7 | 13.6 | 12.1 | 11.3 |
| Coffee intake (%), daily | – | – | – | – | 43.3 | 48.8 | 38.4 | 27.9 |
| Green tea intake (%), daily | 76.8 | 77.7 | 75.0 | 66.2 | – | – | – | – |
| Caffeine intake (g, mean) ± SD | 0.09 ± 0.06 | 0.11 ± 0.06 | 0.19 ± 0.05 | 0.35 ± 0.08 | 0.10 ± 0.10 | 0.13 ± 0.09 | 0.17 ± 0.08 | 0.19 ± 0.09 |
Results for smoking status at baseline in relation to bladder cancer risk are showed in Table 2. Cigarette smoking was associated with an increased risk of bladder cancer, with a strong dose–response relationship in both men and women. Moreover, no increased risk was observed in men who had given up smoking for 10 or more years.
Table 2.
Hazard ratios (HRs) and 95% confidence intervals (CIs) of bladder cancer in relation to smoking
| Number of cases | Person‐years of follow up | HR † (95% CI) | HR ‡ (95% CI) | ||
|---|---|---|---|---|---|
| Men | |||||
| Never smoker | 26 | 147 111 | 1.0 (reference) | 1.0 (reference) | |
| Former smoker | 42 | 143 910 | 1.32 (0.80–2.16) | 1.28 (0.78–2.11) | |
| Current smoker | 92 | 316 526 | 1.69 (1.09–2.63) | 1.46 (0.92–2.31) | |
| P trend | 0.01 | 0.10 | |||
| Never smoker | 26 | 147 111 | 1.0 (reference) | 1.0 (reference) | |
| Years since cessation of smoking in former smokers | |||||
| <10 | 29 | 72 905 | 1.88 (1.10–3.21) | 1.82 (1.06–3.13) | |
| 10–19 | 7 | 48 324 | 0.71 (0.31–1.63) | 0.69 (0.30–1.60) | |
| ≥20 | 6 | 22 682 | 0.98 (0.40–2.40) | 0.98 (0.40–2.38) | |
| Pack‐years in current smokers | |||||
| <20 | 9 | 55 910 | 1.14 (0.53–2.44) | 0.85 (0.37–1.98) | |
| 20–29 | 16 | 83 959 | 1.39 (0.74–2.61) | 1.32 (0.70–2.49) | |
| 30–39 | 20 | 77 819 | 1.39 (0.77–2.50) | 1.23 (0.67–2.26) | |
| 40–49 | 22 | 45 221 | 2.24 (1.26–3.99) | 1.94 (1.06–3.56) | |
| ≥50 | 24 | 46 178 | 2.61 (1.49–4.56) | 2.24 (1.24–4.04) | |
| P trend | <0.01 | 0.04 | |||
| Women | |||||
| Never smoker | 26 | 147 111 | 1.0 (reference) | 1.0 (reference) | |
| Former smoker | 0 | 10 764 | – | – | |
| Current smoker | 9 | 43 315 | 5.45 (2.56–11.61) | 6.53 (3.02–14.11) | |
| Pack‐years in current smokers | |||||
| <25 | 7 | 28 118 | 6.91 (3.00–15.93) | 8.30 (3.55–19.43) | |
| ≥25 | 2 | 12 433 | 4.06 (0.96–17.17) | 5.27 (1.23–22.64) | |
| P trend | <0.01 | <0.01 | |||
Adjusted for age (continuous) and area (10 public health center areas).
Adjusted for age (continuous), area (10 public health center areas), alcohol drinking (non‐ or occasional drinkers, 1–150, ≥150 g/week), green tea (<1, 1–2, 3–4, ≥5 cups/day), and coffee (almost none, 1–4 times/week, 1–2, ≥3 cups/day).
Table 3 shows hazard ratios of bladder cancer in relation to coffee, green tea, and caffeine consumption among men. Most daily caffeine intake was derived from coffee (53%) and green tea (40%) in men. Although coffee drinking was associated with a marginally statistically significant increase in bladder cancer risk (age‐ and area‐adjusted HR for men who drank ≥ 3 cups/day vs men who hardly drank was 1.71, 95% CI = 0.99–2.96; P trend = 0.01), the results were attenuated after further adjustment for smoking status, alcohol drinking, and green tea consumption (multivariate HR = 1.37, 95% CI = 0.75–2.51; P trend = 0.09). In contrast, green tea and caffeine consumption were not associated with bladder cancer, and HRs did not change substantially after adjustment for all potential confounding factors.
Table 3.
Hazard ratios (HRs) and 95% confidence intervals (CIs) of bladder cancer in relation to consumption of coffee, green tea, and caffeine in men
| Category of intake | Coffee | ||||
|---|---|---|---|---|---|
| Almost none | 1–4 times/week | 1–2 cups/day | ≥3 cups/day | P trend | |
| Number of cases | 50 | 52 | 43 | 19 | |
| Person‐years of follow up | 185 405 | 183 367 | 157 544 | 83 713 | |
| HR † (95% CI) | 1.0 (reference) | 1.23 (0.83–1.82) | 1.60 (1.05–2.43) | 1.71 (0.99–2.96) | 0.01 |
| HR ‡ (95% CI) | 1.0 (reference) | 1.26 (0.84–1.88) | 1.53 (0.98–2.37) | 1.37 (0.75–2.51) | 0.09 |
| Green tea | |||||
|---|---|---|---|---|---|
| <1 cup/day | 1–2 cups/day | 3–4 cups/day | ≥5 cups/day | P trend | |
| Number of cases | 33 | 39 | 39 | 53 | |
| Person‐years of follow up | 161 557 | 140 218 | 158 952 | 149 301 | |
| HR † (95% CI) | 1.0 (reference) | 1.13 (0.70–1.82) | 0.83 (0.51–1.33) | 0.99 (0.63–1.56) | 0.67 |
| HR § (95% CI) | 1.0 (reference) | 1.18 (0.73–1.91) | 0.71 (0.43–1.18) | 0.90 (0.56–1.45) | 0.31 |
| Caffeine (median, mg/day) | |||||
|---|---|---|---|---|---|
| Lowest (0.04) | Second (0.13) | Third (0.18) | Highest (0.32) | P trend | |
| Number of cases | 47 | 34 | 43 | 40 | |
| Person‐years of follow up | 177 874 | 142 138 | 132 876 | 157 140 | |
| HR † (95% CI) | 1.0 (reference) | 0.72 (0.46–1.13) | 1.24 (0.82–1.89) | 1.26 (0.82–1.94) | 0.10 |
| HR ¶ (95% CI) | 1.0 (reference) | 0.67 (0.42–1.08) | 1.23 (0.80–1.89) | 1.05 (0.66–1.67) | 0.36 |
Adjusted for age (continuous) and area (10 public health center areas).
Adjusted for age (continuous), area (10 public health center areas), smoking status (never, former [<10, 10–19, ≥20 years since cessation of smoking], current [<20, 20–29, 30–39, 40–49, ≥50 pack‐years]), alcohol drinking (non‐ or occasional drinkers, 1–150, ≥150 g/week), and green tea (<1, 1–2, 3–4, ≥5 cups/day).
Adjusted for age (continuous), area (10 public health center areas), smoking status (never, former [<10, 10–19, ≥20 years since cessation of smoking], current [<20, 20–29, 30–39, 40–49, ≥50 pack‐years]), alcohol drinking (non‐ or occasional drinkers, 1–150, ≥150 g/week), and coffee (almost none, 1–4 times/week, 1–2, ≥3 cups/day).
Adjusted for age (continuous), area (10 public health center areas), smoking status (never, former [<10, 10–19, ≥20 years since cessation of smoking], current [<20, 20–29, 30–39, 40–49, ≥50 pack‐years]), and alcohol drinking (non‐ or occasional drinkers, 1–150, ≥150 g/week).
Table 4 presents the association between coffee, green tea, and caffeine consumption and bladder cancer in women. The proportions of coffee and green tea in caffeine were similar in women (43.3% for coffee and 46% for green tea). Coffee consumption tended to decrease the risk of bladder cancer in women who drank one or more cups of coffee per day (multivariate HR = 0.55, 95% CI = 0.23–1.33). In contrast, green tea dose‐dependently increased the risk of bladder cancer in women. Multivariate HR for women who drank 5 or more cups of green tea per day was 2.29 (95% CI = 1.06–4.92; P trend = 0.03). We observed no association between caffeine consumption and bladder cancer risk in women.
Table 4.
Hazard ratios (HRs) and 95% confidence intervals (CIs) of bladder cancer in relation to consumption of coffee, green tea, and caffeine in women
| Category of intake | Coffee | |||
|---|---|---|---|---|
| Almost none | 1–4 times/week | ≥1 cups/day | P trend | |
| Number of cases | 19 | 15 | 8 | |
| Person‐years of follow up | 226 689 | 207 355 | 270 514 | |
| HR † (95% CI) | 1.0 (reference) | 1.09 (0.55–2.16) | 0.63 (0.26–1.52) | 0.38 |
| HR ‡ (95% CI) | 1.0 (reference) | 1.03 (0.51–2.07) | 0.55 (0.23–1.33) | 0.23 |
| Green tea | ||||
|---|---|---|---|---|
| <3 cups/day | 3–4 cups/day | ≥5 cups/day | P trend | |
| Number of cases | 12 | 9 | 21 | |
| Person‐years of follow up | 324 123 | 193 066 | 187 369 | |
| HR † (95% CI) | 1.0 (reference) | 1.10 (0.45–2.68) | 2.21 (1.05–4.66) | 0.03 |
| HR § (95% CI) | 1.0 (reference) | 1.22 (0.49–3.00) | 2.29 (1.06–4.92) | 0.03 |
| Caffeine (median, mg/day) | ||||
|---|---|---|---|---|
| Lowest (0.05) | Middle (0.13) | Highest (0.24) | P trend | |
| Number of cases | 18 | 12 | 12 | |
| Person‐years of follow up | 260 765 | 227 409 | 216 383 | |
| HR † (95% CI) | 1.0 (reference) | 0.84 (0.40–1.76) | 1.23 (0.58–2.61) | 0.68 |
| HR ¶ (95% CI) | 1.0 (reference) | 0.88 (0.42–1.86) | 1.13 (0.52–2.46) | 0.81 |
Adjusted for age (continuous) and area (10 public health center areas).
Adjusted for age (continuous), area (10 public health centers), smoking status [never, former, current smokers (<25, ≥25 pack‐years)], alcohol drinking (non‐ or occasional drinkers, 1–150, ≥150 g/week), and green tea (<1, 1–2, 3–4, ≥5 cups/day).
Adjusted for age (continuous), area (10 public health centers), smoking status [never, former, current smokers (<25, ≥25 pack‐years)], alcohol drinking (non‐ or occasional drinkers, 1–150, ≥150 g/week), and coffee (almost none, 1–4 times/week, 1–2, ≥3 cups/day).
Adjusted for age (continuous), area (10 public health centers), smoking status [never, former, current smokers (<25, ≥25 pack‐years)], and alcohol drinking (non‐ or occasional drinkers, 1–150, ≥150 g/week).
We also assessed the effect of coffee, green tea, and caffeine consumption according to smoking status (Table 5). To avoid residual confounding by smoking, we first stratified smoking status to never, former, or current. Because the HRs of never and former smokers did not substantially differ, these were then combined. Coffee consumption was positively associated with bladder cancer risk in never or former smokers (for 1–4 times per week, multivariate HR = 1.47; for 1 cups or more per day, HR = 2.24, compared with men who hardly drank). For current smokers, coffee was not substantially associated with bladder cancer risk regardless of the amount of coffee consumption (HR = 1.13, 95% CI = 0.65–1.97 for men who drank 1 or more cups per day compared with men who hardly drank). In contrast, green tea was not statistically significant associated with bladder cancer in either never‐ or former‐smoking men. Among current smokers, green tea appeared to be associated with a decreased risk of bladder cancer. We also found a positive association between caffeine intake and bladder cancer in never‐ or former‐smoking men, with a HR (95% CI) in the highest category of caffeine consumption compared with the lowest of 2.05 (95% CI = 1.15–3.66). In addition, we observed that HRs slightly decreased as caffeine consumption increased among current smokers, and detected an interaction between caffeine consumption and smoking status (P interaction = 0.04).
Table 5.
Hazard ratios (HRs) and 95% confidence intervals (CIs) of bladder cancer in relation to consumption of coffee, green tea, and caffeine in men by smoking status
| Category of intake | Coffee | ||||
|---|---|---|---|---|---|
| Almost none | 1–4 times/week | ≥1 cups/day | P trend | P interaction | |
| Never smoker | |||||
| Number of cases | 6 | 9 | 11 | ||
| HR † (95% CI) | 1.00 (reference) | 1.89 (0.67–5.32) | 2.48 (0.88–7.05) | 0.09 | 0.25 |
| Former smoker | |||||
| Number of cases | 13 | 13 | 16 | ||
| HR † (95% CI) | 1.00 (reference) | 1.25 (0.58–2.71) | 2.09 (0.96–4.54) | 0.07 | |
| Never/Former smoker | |||||
| Number of cases | 19 | 22 | 27 | ||
| HR † (95% CI) | 1.00 (reference) | 1.47 (0.79–2.72) | 2.24 (1.21–4.16) | 0.01 | |
| Current smoker | |||||
| Number of cases | 29 | 30 | 33 | ||
| HR † (95% CI) | 1.00 (reference) | 1.11 (0.65–1.90) | 1.13 (0.65–1.97) | 0.67 | |
| Category of intake | Green tea | ||||
|---|---|---|---|---|---|
| <3 cups/day | 3–4 cups/day | ≥5 cups/day | P trend | P interaction | |
| Never smoker | |||||
| Number of cases | 13 | 6 | 7 | ||
| HR ‡ (95% CI) | 1.00 (reference) | 0.81 (0.30–2.19) | 0.85 (0.31–2.32) | 0.72 | 0.42 |
| Former smoker | |||||
| Number of cases | 14 | 12 | 16 | ||
| HR ‡ (95% CI) | 1.00 (reference) | 1.17 (0.53–2.56) | 1.40 (0.67–2.95) | 0.38 | |
| Never/Former smoker | |||||
| Number of cases | 27 | 18 | 23 | ||
| HR ‡ (95% CI) | 1.00 (reference) | 0.98 (0.53–1.79) | 1.14 (0.63–2.04) | 0.68 | |
| Current smoker | |||||
| Number of cases | 14 | 18 | 30 | ||
| HR ‡ (95% CI) | 1.00 (reference) | 0.44 (0.24–0.80) | 0.62 (0.37–1.04) | 0.05 | |
| Category of intake | Caffeine (median, mg/day) | ||||
|---|---|---|---|---|---|
| Lowest (0.06) | Middle (0.15) | Highest (0.28) | P trend | P interaction | |
| Never smoker | |||||
| Number of cases | 12 | 6 | 8 | ||
| HR § (95% CI) | 1.00 (reference) | 0.95 (0.35–2.58) | 1.66 (0.66–4.20) | 0.33 | 0.04 |
| Former smoker | |||||
| Number of cases | 13 | 13 | 16 | ||
| HR § (95% CI) | 1.00 (reference) | 1.19 (0.55–2.59) | 2.30 (1.08–4.87) | 0.03 | |
| Never/Former smoker | |||||
| Number of cases | 25 | 29 | 24 | ||
| HR § (95% CI) | 1.00 (reference) | 1.09 (0.59–2.00) | 2.05 (1.15–3.66) | 0.02 | |
| Current smoker | |||||
| Number of cases | 38 | 30 | 24 | ||
| HR § (95% CI) | 1.00 (reference) | 0.87 (0.53–1.44) | 0.72 (0.41–1.27) | 0.25 | |
Adjusted for age (continuous), area (10 public health center areas), smoking status (never, former [<10, 10–19, ≥20 years since cessation of smoking], current [<20, 20–29, 30–39, 40–49, ≥50 pack‐years]), alcohol drinking (non‐ or occasional drinkers, 1–150, = 150 g/week), and green tea (<1, 1–2, 3–4, ≥5 cups/day).
Adjusted for age (continuous), area (10 public health center areas), smoking status (never, former [<10, 10–19, ≥20 years since cessation of smoking], current [<20, 20–29, 30–39, 40–49, ≥50 pack‐years]), alcohol drinking (non‐ or occasional drinkers, 1–150, ≥150 g/week), and coffee (almost none, 1–4 times/week, 1–2, ≥3 cups/day).
Adjusted for age (continuous), area (10 public health center areas), smoking status (never, former [<10, 10–19, ≥20 years since cessation of smoking], current [<20, 20–29, 30–39, 40–49, ≥50 pack‐years]), and alcohol drinking (non‐ or occasional drinkers, 1–150, ≥150 g/week).
Discussion
In this study, coffee consumption was associated with an increased risk of bladder cancer, without statistical significance. In contrast, we found no association between green tea and caffeine consumption and bladder cancer risk in men. In never and former smokers, however, a positive association between coffee and caffeine and bladder cancer was observed. Additionally, significant interaction between caffeine and smoking was found (P interaction = 0.04), suggesting that the effects of the caffeine might be modified by smoking status.
Cigarette smoking is an established risk factor for bladder cancer.( 19 ) A meta‐analysis of 43 published case‐control and cohort studies reported that smoking amount and smoking duration were positively associated and that cessation of cigarette smoking was inversely associated with urinary tract cancer risk (most cases being bladder cancer).( 20 ) Our study confirmed these previous results.
Many previous studies have reported a positive association between coffee drinking and bladder cancer in Western countries,( 7 , 12 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ) although many others have reported no association.( 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ) However, several studies have shown higher risks in coffee drinkers who were non‐smokers,( 12 , 27 , 31 , 32 , 34 , 36 , 38 , 39 ) suggesting the necessity of separate interpretation by smoking status due to the difference in association between coffee consumption and bladder cancer according to smoking status. Our study showed that HRs of subjects who drank 3 or more cups of coffee were attenuated by adjustment for smoking status. Moreover, when we stratified these results by smoking status, we found a positive association between coffee and bladder cancer only in never or former smokers. Thus, our results suggest that the effect of coffee on bladder cancer risk in Japanese may be similar to that in other populations, notwithstanding that the type, strength, and amount of coffee drinking differ among countries.
In our study, caffeine consumption also showed a positive association with bladder cancer among never or former smokers. Given that a similar association was seen in the Netherlands cohort study,( 29 ) these findings suggest that caffeine contained in coffee might contribute to an increased risk of bladder cancer. Moreover, its ability to modify the apoptotic response and perturb cell checkpoint integrity( 40 , 41 ) suggest that caffeine might be a causative agent of bladder cancer.( 4 ) It is particularly noteworthy that the adverse effects of coffee and caffeine were observed among never or former smokers, and indeed plausible given a previous report that the clearance of caffeine in smokers is faster than that in non‐smokers,( 42 ) and that the urinary caffeine levels of smokers were approximately 70% lower than those of non‐smokers.( 43 ) In contrast, our study showed that the hazard ratio of current smokers who were in the highest tertile of caffeine consumption was lower than that of current smokers with lower caffeine consumption. Caffeine stimulates the production of cytochrome P450 (CYP) enzymes in the liver, such as CYP1A2 or NAT2, and these enzymes may increase the metabolic activation of carcinogens like polycyclic aromatic hydrocarbons in cigarette smoking.( 44 ) Thus, the adverse effects of coffee and caffeine may be more clearly expressed among never or former smokers and caffeine may modify the increased bladder cancer risk caused by smoking. However, it should be noted that smoking is a major independent risk of bladder cancer. HRs among current smokers who hardly drank coffee were higher than those among never smokers who hardly drank coffee (HR = 4.17 [95% CI = 1.59–10.96], data not shown). Even though our study appears to show a negative tendency between caffeine and bladder cancer among current smokers, the HRs among current smokers was higher than those among never smokers irrespective of caffeine intake (never smokers in lowest category of caffeine intake: reference, current smokers in lowest category of caffeine intake: HR = 3.23 [95% CI = 1.47–7.08], current smokers in highest category of caffeine intake: HR = 2.13 [95% CI = 0.95–4.79]; data not shown).
Of the few papers which have investigated the association between green tea and bladder cancer, one prospective study showed no relation with bladder cancer,( 10 ) a case‐control study showed an elevated risk in heavy drinkers of green tea (5–9 cups/day),( 9 ) while a third showed an inverse association with the consumption of matcha (powdered green tea) in women.( 8 ) In our study, green tea was not associated with bladder cancer risk among men. This result is supported by a recent meta‐analysis.( 5 ) We speculate that several polyphenolic components of green tea with antioxidant properties might mask the adverse effects of caffeine on bladder cancer in men. In addition, green tea appeared negatively associated with bladder cancer risk among smoking men. Nevertheless, hazard ratios in current smokers were relatively high independently of green tea drinking, indicating that green tea was unable to cancel all the adverse effects of smoking (HR = 1.72 [95%CI = 0.80–3.70] for current smokers who drank five or more cups of green tea per day versus never smokers who drank less than three cups; data not shown). In contrast, a positive association between green tea intake and bladder cancer was observed in women. This sex difference might suggest that the contribution of green tea to total caffeine intake in women is higher than that in men. In any case, the negative tendency in bladder cancer risk with increasing coffee consumption in women is difficult to explain. At present, a biological mechanism that might explain this discrepancy between men and women remains unclear, and may have arisen by chance due to the small sample size in women.
This study was a large prospective study in a general Japanese population. Among its strengths were the high rate of participation (approximately 80%) and negligible proportion of loss to follow‐up (0.4%), indicating that selection bias was unlikely. Another strength of the prospective design was that coffee and green tea intake were measured before the disease was diagnosed, thereby avoiding the probability of recall bias that is inherent to case‐control studies. On the other hand, several limitations also warrant mention. First, we could not evaluate the validity of caffeine consumption. The amount of caffeine depends on the quantity of coffee beans and tea leaf and the length of time of extraction. Unfortunately, we were unable to obtain such information. Second, we could not evaluate the large number of substances other than caffeine contained in coffee. The risk of bladder cancer might be attributable to ingredients other than caffeine or metabolic substances. Third, the number of bladder cancer cases was small, and that therefore the results in women might have occurred by chance. Fourth, coffee and green tea were sources of total fluid intake, which might be inversely associated with the risk of bladder cancer.( 35 , 45 ) However, we could not adjust for total fluid intake because we did not obtain such information. Finally, we were unable to determine exposure to chemical substances which might have increased the risk of bladder cancer. For example, coffee and green tea might be sources of potential exposure to drinking water contaminants such as chlorination by‐products and nitrates.( 28 ) However, any explanation of the different effects of coffee on bladder cancer in terms of smoking status by contaminants in drinking water would be difficult: if contaminants in coffee and green tea were a risk factor for bladder cancer, coffee consumption would be associated with dose‐related increase in risk even in current smokers.
In summary, we confirmed that cigarette smoking is major risk factor of bladder cancer and that coffee and caffeine are associated with an increased risk of bladder cancer in never‐ or former‐smoking men. Considerable research effort is required to clarify the effects of caffeine on carcinogenic processes in the bladder.
Appendix
Members of the Japan Public Health Center (JPHC) Study Group (principal investigator: S. Tsugane): S. Tsugane, M. Inoue, T. Sobue, and T. Hanaoka, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo; J. Ogata, S. Baba, T. Mannami, A. Okayama, and Y. Kokubo, National Cardiovascular Center, Suita; K. Miyakawa, F. Saito, A. Koizumi, Y. Sano, I. Hashimoto, and T. Ikuta, Iwate Prefectural Ninohe Public Health Center, Ninohe; Y. Miyajima, N. Suzuki, S. Nagasawa, Y. Furusugi, and N. Nagai, Akita Prefectural Yokote Public Health Center, Yokote; H. Sanada, Y. Hatayama, F. Kobayashi, H. Uchino, Y. Shirai, T. Kondo, R. Sasaki, Y. Watanabe, Y. Miyagawa, and Y. Kobayashi, Nagano Prefectural Saku Public Health Center, Saku; Y. Kishimoto, E. Takara, T. Fukuyama, M. Kinjo, M. Irei, and H. Sakiyama, Okinawa Prefectural Chubu Public Health Center, Okinawa; K. Imoto, H. Yazawa, T. Seo, A. Seiko, F. Ito, and F. Shoji, Katsushika Public Health Center, Tokyo; A. Murata, K. Minato, K. Motegi, and T. Fujieda, Ibaraki Prefectural Mito Public Health Center, Mito; T. Abe, M. Katagiri, M. Suzuki, and K. Matsui, Niigata Prefectural Kashiwazaki and Nagaoka Public Health Center, Kashiwazaki and Nagaoka; M. Doi, A. Terao, Y. Ishikawa, and T. Tagami, Kochi Prefectural Chuo‐higashi Public Health Center, Tosayamada; H. Doi, M. Urata, N. Okamoto, F. Ide, and H. Sueta, Nagasaki Prefectural Kamigoto Public Health Center, Arikawa; H. Sakiyama, N. Onga, H. Takaesu, and M. Uehara, Okinawa Prefectural Miyako Public Health Center, Hirara; F. Horii, I. Asano, H. Yamaguchi, K. Aoki, S. Maruyama, M. Ichii, and M. Takano, Osaka Prefectural Suita Public Health Center, Suita; S. Matsushima and S. Natsukawa, Saku General Hospital, Usuda; M. Akabane, Tokyo University of Agriculture, Tokyo; M. Konishi, K. Okada, and I. Saito, Ehime University, Toon; H. Iso, Osaka University, Suita; Y. Honda, K. Yamagishi, and S. Sakurai, Tsukuba University, Tsukuba; H. Sugimura, Hamamatsu University, Hamamatsu; Y. Tsubono, Tohoku University, Sendai; M. Kabuto, National Institute for Environmental Studies, Tsukuba; S. Tominaga, Aichi Cancer Center Research Institute, Nagoya; M. Iida, W. Ajiki, and A. Ioka, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka; S. Sato, Osaka Medical Center for Health Science and Promotion, Osaka; N. Yasuda, Kochi University, Nankoku; K. Nakamura, Niigata University, Niigata; S. Kono, Kyushu University, Fukuoka; K. Suzuki, Research Institute for Brain and Blood Vessels Akita, Akita; Y. Takashima, Kyorin University, Mitaka; E. Maruyama, Kobe University, Kobe; M. Yamaguchi, Y. Matsumura, S. Sasaki, and S. Watanabe, National Institute of Health and Nutrition, Tokyo; T. Kadowaki, Tokyo University, Tokyo; M. Noda, International Medical Center of Japan, Tokyo; Y. Kawaguchi, Tokyo Medical and Dental University, Tokyo; and H. Shimizu, Sakihae Institute, Gifu.
Acknowledgments
We wish to thank all staff members in each study area and in the central offices for their cooperation and technical assistance. We also wish to thank the Iwate, Aomori, Ibaraki, Niigata, Osaka, Kochi, Nagasaki, and Okinawa Cancer Registries for their provision of incidence data. This study was supported by Grants‐in‐Aid for Cancer Research (19shi‐2).
References
- 1. International Agency for Research on Cancer . Trends in Cancer Incidence and Mortality. IARC Press; 1993. [Google Scholar]
- 2. Marugame T, Kaneko S. Comparison of bladder cancer mortality in five countries: France, Italy, Japan, UK and USA from the WHO Mortality Database (1960–2000). Jpn J Clin Oncol 2005; 35: 357–60. [DOI] [PubMed] [Google Scholar]
- 3. Johansson SL, Cohen SM. Epidemiology and etiology of bladder cancer. Semin Surg Oncol 1997; 13: 291–8. [DOI] [PubMed] [Google Scholar]
- 4. International Agency for Research on Cancer, World Health Organization . Coffee, tea, mate, methylxanthines and methylglyoxal. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. IARC Monogr Eval Carcinog Risks Hum 1991; 51: 1–513. [PMC free article] [PubMed] [Google Scholar]
- 5. Zeegers MP, Tan FE, Goldbohm RA, Van Den Brandt PA. Are coffee and tea consumption associated with urinary tract cancer risk? A systematic review and meta‐analysis. Int J Epidemiol 2001; 30: 353–62. [DOI] [PubMed] [Google Scholar]
- 6. Sala M, Cordier S, Chang‐Claude J et al . Coffee consumption and bladder cancer in nonsmokers: a pooled analysis of case‐control studies in European countries. Cancer Causes Control 2000; 11: 925–31. [DOI] [PubMed] [Google Scholar]
- 7. Chyou PH, Nomura AM, Stemmermann GN. A prospective study of diet, smoking, and lower urinary tract cancer. Ann Epidemiol 1993; 3: 211–6. [DOI] [PubMed] [Google Scholar]
- 8. Ohno Y, Aoki K, Obata K, Morrison AS. Case‐control study of urinary bladder cancer in metropolitan Nagoya. Natl Cancer Inst Monogr 1985; 69: 229–34. [PubMed] [Google Scholar]
- 9. Wakai K, Hirose K, Takezaki T et al . Foods and beverages in relation to urothelial cancer: case‐control study in Japan. Int J Urol 2004; 11: 11–19. [DOI] [PubMed] [Google Scholar]
- 10. Nagano J, Kono S, Preston DL et al . Bladder‐cancer incidence in relation to vegetable and fruit consumption: a prospective study of atomic‐bomb survivors. Int J Cancer 2000; 86: 132–8. [DOI] [PubMed] [Google Scholar]
- 11. Nomura AM, Kolonel LN, Hankin JH, Yoshizawa CN. Dietary factors in cancer of the lower urinary tract. Int J Cancer 1991; 48: 199–205. [DOI] [PubMed] [Google Scholar]
- 12. Donato F, Boffetta P, Fazioli R, Aulenti V, Gelatti U, Porru S. Bladder cancer, tobacco smoking, coffee and alcohol drinking in Brescia, northern Italy. Eur J Epidemiol 1997; 13: 795–800. [DOI] [PubMed] [Google Scholar]
- 13. Hein DW, Doll MA, Fretland AJ et al . Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiol Biomarkers Prev 2000; 9: 29–42. [PubMed] [Google Scholar]
- 14. Hickman D, Sim E. N‐acetyltransferase polymorphism. Comparison of phenotype and genotype in humans. Biochem Pharmacol 1991; 42: 1007–14. [DOI] [PubMed] [Google Scholar]
- 15. Tsugane S, Sobue T. Baseline survey of JPHC study – design and participation rate. Japan Public Health Center‐based Prospective Study on Cancer and Cardiovascular Diseases. J Epidemiol 2001; 11: S24–9. [DOI] [PubMed] [Google Scholar]
- 16. Tsubono Y, Kobayashi M, Sasaki S, Tsugane S. Validity and reproducibility of a self‐administered food frequency questionnaire used in the baseline survey of the JPHC Study Cohort I. J Epidemiol 2003; 13: S125–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Science and Technology Agency , eds. Standard Tables of Food Composition in Japan. The Fifth Revised Edition (in Japanese). Tokyo: Printing Bureau, Ministry of Finance, 2000. [Google Scholar]
- 18. Parkin DM, Welan SL, Ferlay J, Teppo L, Thomas DB, eds. Cancer Incidence in Five Continents. Lyon: International Agency for Research on Cancer, 2002. [Google Scholar]
- 19. Zeegers MP, Kellen E, Buntinx F, Van Den Brandt PA. The association between smoking, beverage consumption, diet and bladder cancer: a systematic literature review. World J Urol 2004; 21: 392–401. [DOI] [PubMed] [Google Scholar]
- 20. Zeegers MP, Tan FE, Dorant E, Van Den Brandt PA. The impact of characteristics of cigarette smoking on urinary tract cancer risk: a meta‐analysis of epidemiologic studies. Cancer 2000; 89: 630–9. [DOI] [PubMed] [Google Scholar]
- 21. Claude J, Kunze E, Frentzel‐Beyme R, Paczkowski K, Schneider J, Schubert H. Life‐style and occupational risk factors in cancer of the lower urinary tract. Am J Epidemiol 1986; 124: 578–89. [DOI] [PubMed] [Google Scholar]
- 22. De Stefani E, Boffetta P, Deneo‐Pellegrini H et al . Non‐alcoholic beverages and risk of bladder cancer in Uruguay. BMC Cancer 2007; 7: 57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Howe GR, Burch JD, Miller AB et al . Tobacco use, occupation, coffee, various nutrients, and bladder cancer. J Natl Cancer Inst 1980; 64: 701–13. [PubMed] [Google Scholar]
- 24. Mettlin C, Graham S. Dietary risk factors in human bladder cancer. Am J Epidemiol 1979; 110: 255–63. [DOI] [PubMed] [Google Scholar]
- 25. Momas I, Daures JP, Festy B, Bontoux J, Gremy F. Relative importance of risk factors in bladder carcinogenesis: some new results about Mediterranean habits. Cancer Causes Control 1994; 5: 326–32. [DOI] [PubMed] [Google Scholar]
- 26. Pohlabeln H, Jockel KH, Bolm‐Audorff U. Non‐occupational risk factors for cancer of the lower urinary tract in Germany. Eur J Epidemiol 1999; 15: 411–9. [DOI] [PubMed] [Google Scholar]
- 27. Vena JE, Freudenheim J, Graham S et al . Coffee, cigarette smoking, and bladder cancer in western New York. Ann Epidemiol 1993; 3: 586–91. [DOI] [PubMed] [Google Scholar]
- 28. Villanueva CM, Cantor KP, King WD et al . Total and specific fluid consumption as determinants of bladder cancer risk. Int J Cancer 2006; 118: 2040–7. [DOI] [PubMed] [Google Scholar]
- 29. Zeegers MP, Dorant E, Goldbohm RA, Van Den Brandt PA. Are coffee, tea, and total fluid consumption associated with bladder cancer risk? Results from the Netherlands Cohort Study. Cancer Causes Control 2001; 12: 231–8. [DOI] [PubMed] [Google Scholar]
- 30. Bruemmer B, White E, Vaughan TL, Cheney CL. Fluid intake and the incidence of bladder cancer among middle‐aged men and women in a three‐county area of western Washington. Nutr Cancer 1997; 29: 163–8. [DOI] [PubMed] [Google Scholar]
- 31. Ciccone G, Vineis P. Coffee drinking and bladder cancer. Cancer Lett 1988; 41: 45–52. [DOI] [PubMed] [Google Scholar]
- 32. D’Avanzo B, La Vecchia C, Franceschi S, Negri E, Talamini R, Buttino I. Coffee consumption and bladder cancer risk. Eur J Cancer 1992; 28A: 1480–4. [DOI] [PubMed] [Google Scholar]
- 33. Demirel F, Cakan M, Yalcinkaya F, Topcuoglu M, Altug U. The association between personal habits and bladder cancer in Turkey. Int Urol Nephrol 2008; 40: 643–7. [DOI] [PubMed] [Google Scholar]
- 34. Escolar Pujolar A, Gonzalez CA, Lopez‐Abente G et al . Bladder cancer and coffee consumption in smokers and non‐smokers in Spain. Int J Epidemiol 1993; 22: 38–44. [DOI] [PubMed] [Google Scholar]
- 35. Michaud DS, Spiegelman D, Clinton SK et al . Fluid intake and the risk of bladder cancer in men. N Engl J Med 1999; 340: 1390–7. [DOI] [PubMed] [Google Scholar]
- 36. Risch HA, Burch JD, Miller AB, Hill GB, Steele R, Howe GR. Dietary factors and the incidence of cancer of the urinary bladder. Am J Epidemiol 1988; 127: 1179–91. [DOI] [PubMed] [Google Scholar]
- 37. Stensvold I, Jacobsen BK. Coffee and cancer. a prospective study of 43 000 Norwegian men and women. Cancer Causes Control 1994; 5: 401–8. [DOI] [PubMed] [Google Scholar]
- 38. Clavel J, Cordier S. Coffee consumption and bladder cancer risk. Int J Cancer 1991; 47: 207–12. [DOI] [PubMed] [Google Scholar]
- 39. Marrett LD, Walter SD, Meigs JW. Coffee drinking and bladder cancer in Connecticut. Am J Epidemiol 1983; 117: 113–27. [DOI] [PubMed] [Google Scholar]
- 40. Efferth T, Fabry U, Glatte P, Osieka R. Expression of apoptosis‐related oncoproteins and modulation of apoptosis by caffeine in human leukemic cells. J Cancer Res Clin Oncol 1995; 121: 648–56. [DOI] [PubMed] [Google Scholar]
- 41. Taylor WR, Stark GR. Regulation of the G2/M transition by p53. Oncogene 2001; 20: 1803–15. [DOI] [PubMed] [Google Scholar]
- 42. Campbell ME, Spielberg SP, Kalow W. A urinary metabolite ratio that reflects systemic caffeine clearance. Clin Pharmacol Ther 1987; 42: 157–65. [DOI] [PubMed] [Google Scholar]
- 43. Yang MKT, Katoh T, Matsuno K. Effects of lifestyle and genetic polymorphisms on consumption of coffee or black tea and urinary caffeine levels. Biomarkers 1998; 3: 367–77. [DOI] [PubMed] [Google Scholar]
- 44. Porta M, Vioque J, Ayude D et al . Coffee drinking: the rationale for treating it as a potential effect modifier of carcinogenic exposures. Eur J Epidemiol 2003; 18: 289–98. [DOI] [PubMed] [Google Scholar]
- 45. Michaud DS, Kogevinas M, Cantor KP et al . Total fluid and water consumption and the joint effect of exposure to disinfection by‐products on risk of bladder cancer. Environ Health Perspect 2007; 115: 1569–72. [DOI] [PMC free article] [PubMed] [Google Scholar]