American Journal of Epidemiology © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: [email protected].

Vol. 182, No. 5 DOI: 10.1093/aje/kwv089 Advance Access publication: August 4, 2015

Original Contribution Associations of Body Mass Index, Smoking, and Alcohol Consumption With Prostate Cancer Mortality in the Asia Cohort Consortium

Jay H. Fowke*, Dale F. McLerran, Prakash C. Gupta, Jiang He, Xiao-Ou Shu, Kunnambath Ramadas, Shoichiro Tsugane, Manami Inoue, Akiko Tamakoshi, Woon-Puay Koh, Yoshikazu Nishino, Ichiro Tsuji, Kotaro Ozasa, Jian-Min Yuan, Hideo Tanaka, Yoon-Ok Ahn, Chien-Jen Chen, Yumi Sugawara, Keun-Young Yoo, Habibul Ahsan, Wen-Harn Pan, Mangesh Pednekar, Dongfeng Gu, Yong-Bing Xiang, Catherine Sauvaget, Norie Sawada, Renwei Wang, Masako Kakizaki, Yasutake Tomata, Waka Ohishi, Lesley M. Butler, Isao Oze, Dong-Hyun Kim, San-Lin You, Sue K. Park, Faruque Parvez, Shao-Yuan Chuang, Yu Chen, Jung Eun Lee, Eric Grant, Betsy Rolland, Mark Thornquist, Ziding Feng, Wei Zheng, Paolo Boffetta, Rashmi Sinha, Daehee Kang, and John D. Potter * Correspondence to Dr. Jay H. Fowke, Department of Medicine, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 1200, Nashville, TN 37203 (e-mail: [email protected]).

Initially submitted June 26, 2014; accepted for publication December 23, 2014.

Many potentially modifiable risk factors for prostate cancer are also associated with prostate cancer screening, which may induce a bias in epidemiologic studies. We investigated the associations of body mass index (weight (kg)/height (m)2), smoking, and alcohol consumption with risk of fatal prostate cancer in Asian countries where prostate cancer screening is not widely utilized. Analysis included 18 prospective cohort studies conducted during 1963–2006 across 6 countries in southern and eastern Asia that are part of the Asia Cohort Consortium. Body mass index, smoking, and alcohol intake were determined by questionnaire at baseline, and cause of death was ascertained through death certificates. Analysis included 522,736 men aged 54 years, on average, at baseline. During 4.8 million person-years of follow-up, there were 634 prostate cancer deaths (367 prostate cancer deaths across the 11 cohorts with alcohol data). In Cox proportional hazards analyses of all cohorts in the Asia Cohort Consortium, prostate cancer mortality was not significantly associated with obesity (body mass index >25: hazard ratio (HR) = 1.08, 95% confidence interval (CI): 0.85, 1.36), ever smoking (HR = 1.00, 95% CI: 0.84, 1.21), or heavy alcohol intake (HR = 1.00, 95% CI: 0.74, 1.35). Differences in prostate cancer screening and detection probably contribute to differences in the association of obesity, smoking, or alcohol intake with prostate cancer risk and mortality between Asian and Western populations and thus require further investigation. alcohol drinking; Asia; mortality; obesity; prostate cancer; prostate-specific antigen; smoking

Abbreviations: ACC, Asia Cohort Consortium; BMI, body mass index; HR, hazard ratio; OR, odds ratio; PSA, prostate-specific antigen.

Editor’s note: An invited commentary on this article appears on page 390.

United States, prostate cancer remains the leading cancer diagnosis and the second leading cause of cancer-related death (2). Prostate tumors tend to grow slowly, providing time and an opportunity to intervene. Unfortunately, established risk factors such as age, race, or inherited genetic variants do not lend themselves to intervention or advice on how to reduce risk or slow progression (3). Alternatively, accumulating evidence

Worldwide, prostate cancer is the second most prevalent cancer among men (after lung cancer), but there is wide geographical heterogeneity in incidence and mortality (1). In the 381

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382 Fowke et al.

suggests that several modifiable lifestyle factors may hold a modest association with prostate cancer. For example, recent studies suggest that obesity and tobacco smoking may be associated with the risk of advanced prostate cancer (4–6). In contrast, while alcohol intake has been associated with several cancers (7, 8), the associations between alcohol consumption and prostate cancer risk and mortality are unclear (9, 10). Identifying nongenetic prostate cancer risk factors that have perhaps a modest association at most can be markedly complicated by the broad-based prostate cancer screening practiced in the United States (2). In the current era of widespread prostate-specific antigen (PSA) testing, small, localized prostate lesions of uncertain clinical relevance are routinely diagnosed (11, 12). In this situation, any association between a candidate risk factor and prostate cancer may be confounded if the risk factor is also associated with prostate cancer screening itself. Indeed, in past studies of candidate modifiable risk factors such as obesity and tobacco smoking, as well as health insurance, income, and comorbid conditions such as dyslipidemia and diabetes, investigators have consistently reported associations with prostate cancer screening and detection practices (6, 13–17). The magnitude and direction of these associations with prostate cancer detection may be population-specific, such that any epidemiologic investigation of behavioral or lifestyle factors in prostate cancer could be biased toward the null or perhaps result in a spurious stageor grade-specific association. Asian regions have a substantially lower incidence of prostate cancer than Western nations; for example, there is a 19-fold difference in incidence between China (5.3 per 100,000 men) and the United States (98.2 per 100,000 men) (1). Furthermore, most countries in Asia have not yet undertaken widespread prostate cancer screening programs or have only recently initiated feasibility efforts (18). Asian men are also more likely to be diagnosed with advanced-stage prostate cancer, and in most Asian countries the majority of men diagnosed with prostate cancer are likely to die from the disease within 5 years of diagnosis (19). For example, almost 60% of prostate cancer patients diagnosed in some regions of China may be expected to die from the disease within a year of diagnosis, whereas 5-year survival in the United States approaches 100% (20, 21). Investigation of potentially modifiable risk factors for prostate cancer in populations with no systematic prostate cancer screening may allow the clear identification of risk factors that have universal applicability. Conversely, the absence of such findings in Asian populations would suggest that the findings reported above are a consequence of something else, including confounding by screening and detection. We investigated the associations of prostate cancer mortality with obesity, tobacco smoking, and alcohol intake in the Asia Cohort Consortium (ACC). Only through a consortium such as the ACC is it possible to conduct a prospective investigation of prostate cancer mortality in those areas of the world where prostate cancer is a rare or emerging disease and where screening is not widely performed. We chose to analyze obesity, tobacco smoking, and alcohol consumption because there is biological plausibility related to carcinogen exposure or proinflammatory signaling (22–24), because they have inconsistent associations with prostate cancer in the US population (4–10), because there is an increasing or

substantial prevalence of these factors in Asian populations (25–27), and because there is some evidence supporting an association of these factors with prostate cancer in an Asian population (28, 29). There is a strong possibility that prostate cancer screening will increase in Asian countries in the future (30, 31). This study within the ACC offers what is probably a singular opportunity to determine the prospective association between these modifiable risk factors and fatal prostate cancer without concern that the risk factor is more strongly associated with detection and treatment than with etiology. METHODS

The ACC has been described in detail elsewhere (32). Briefly, it is a consortium of cohort studies in Asian countries developed to create sufficient sample sizes and statistical power to explore the etiology of cancer and other diseases. Recruitment was initiated across these cohorts from 1963 to 2001, with follow-up of the final cohort ending in 2006. The ACC has recruited 22 cohorts to date. One cohort recruited women only, 1 had no prostate cancer deaths, and 2 other cohorts had no cause-of-death information. Thus, our analysis involved 18 cohorts with information on death from prostate cancer during follow-up. The ACC was approved by the ethics committee overseeing each of the participating cohort studies and by the Institutional Review Board of the Fred Hutchinson Cancer Research Center; this analysis was also approved by the Institutional Review Board of Vanderbilt University Medical Center. Height and weight were directly measured in 7 cohorts and assessed by self-report in 11 cohorts. Body mass index (BMI; weight (kg)/height (m)2) was categorized as 12–19.9, 20– 22.4, 22.5–24.9, and ≥25 to explore the association with low BMI as well as high BMI. Information on smoking status, alcohol intake, and other covariates at baseline was obtained through baseline questionnaires. Alcohol consumption was calculated in grams per week to unify data on alcohol intake across studies, assuming standard serving sizes (beer = 355 mL, wine = 125 mL, spirits = 35 mL), a standard portion of ethanol per drink (beer = 5%, wine = 12%, spirits = 40%), and 0.789 g of ethanol per mL. Prostate cancer mortality during follow-up was ascertained from death certificates. There were 542,188 male participants enrolled in 18 ACC cohorts with available information on cause of death. To focus on incident prostate cancer diagnosed during followup, we excluded 24 persons with a history of cancer at enrollment and who died of prostate cancer. Another 14,319 persons were excluded for missing data on age, cigarette smoking, or BMI. Persons who had a BMI greater than 50 or less than 12 (n = 197) and those with invalid or missing data on survival (n = 224) were also excluded. After removal of subjects meeting 1 or more of these criteria, the final study population included 522,736 individuals. Data on alcohol intake were not collected in 7 cohorts, and alcohol intake was missing for another 13,502 persons in the remaining 11 cohorts; this left 294,389 ACC participants for the analysis of alcohol and prostate cancer mortality. Hazard ratios for associations with BMI, smoking, and alcohol intake were derived from a Cox proportional hazards model. Rather than fitting a time-to-event model, we fitted Am J Epidemiol. 2015;182(5):381–389

Am J Epidemiol. 2015;182(5):381–389

Table 1. Characteristics of Studies From the Asia Cohort Consortium Included in an Analysis of the Association of Body Mass Index, Smoking, and Alcohol Consumption With Prostate Cancer Mortality, 1963–2006 Country and Cohort Studya

No. of Subjects

Date(s) of Study

Mean No. of Years Followed (SD)

Mean Age at Study Entry, years (SD)

Mean BMIb at Study Entry (SD)

Method of Height and Weight Ascertainment

% Who Had Ever Smoked at Study Entry

Alcohol Intake at Study Entry, g/week

No. of Deaths

No. of PC Deaths

% of PC Deathsc

India Mumbai

87,397

1991–1997

5.0 (1.6)

52.6 (10.9)

22.0 (3.8)

DM

31.3

NA

9,559

24

0.25

Trivandrum

49,598

1995–2002

7.2 (2.3)

50.9 (12.0)

21.3 (3.6)

DM

58.7

NA

6,025

9

0.15

CHEFS

75,379

1990–1992

7.2 (2.4)

55.1 (10.5)

22.4 (3.4)

DM

63.6

131

10,036

12

0.12

SCS

18,100

1986–1989

16.3 (4.4)

55.3 (5.7)

22.2 (3.0)

SA

57.2

92

4,983

36

0.72

SMHS

61,377

2001–2006

3.1 (1.2)

54.9 (9.7)

23.7 (3.1)

DM

69.6

82

946

7

0.74

11,943

1991–1992

15.0 (3.0)

48.1 (10.2)

24.0 (3.2)

DM

56.4

NA

1,837

14

0.76

2262

1990–1993

14.5 (3.5)

48.5 (16.0)

23.7 (3.3)

DM

53.9

27

476

3

0.63

27,937

1993–1998

11.1 (3.2)

56.7 (8.0)

23.0 (3.2)

SA

57.9

25

6,134

64

1.04

3-Pref Aichi

14,984

1985

11.2 (5.3)

55.6 (11.0)

22.3 (2.8)

SA

84.2

NA

3,155

38

1.20

JACC

34,795

1988–1990

12.5 (3.7)

57.4 (10.2)

22.6 (2.8)

SA

79.4

NA

7,304

119

1.63

JPHC1

20,397

1990–1992

14.2 (3.7)

49.5 (5.9)

23.6 (2.8)

SA

75.9

208

2,270

26

1.15

JPHC2

26,294

1992–1995

11.2 (3.1)

54.0 (8.8)

23.5 (2.9)

SA

75.9

210

3,558

36

1.01

3-Pref Miyagi

10,162

1984

11.2 (5.2)

56.0 (11.1)

23.1 (3.0)

SA

77.3

NA

2,358

27

1.15

Miyagi

20,984

1990

12.6 (2.7)

51.6 (7.6)

23.5 (2.8)

SA

81.5

186

2,240

19

0.85

Ohsaki

21,837

1995

9.8 (3.8)

59.3 (10.6)

23.3 (2.9)

SA

81.4

188

4,180

74

1.77

RERF

19,556

1963–1993

19.7 (9.8)

52.1 (11.2)

21.8 (3.1)

SA

86.2

150

11,829

120

1.01

5,966

1994–2004

5.9 (3.0)

55.8 (12.5)

23.1 (3.0)

DM

79.5

NA

711

3

0.42

13,768

1992–1993

14.7 (1.7)

49.2 (5.2)

23.4 (2.3)

SA

77.3

176

827

3

0.36

522,736

1963–2006

9.0 (5.5)

53.7 (10.4)

22.6 (3.3)

63.7

129

78,428

634

0.85

China

Taiwan CBCSP CVDFACTS Singapore Japan

KMCC Seoul Total

Abbreviations: BMI, body mass index; CBCSP, Community-Based Cancer Screening Project; CHEFS, China National Hypertension Survey Epidemiology Follow-up Study; CVDFACTS, Cardiovascular Disease Risk Factor Two-Township Study; DM, direct measurement; JACC, Japanese Collaborative Cohort Study; JPHC1, Japan Public Health Center-based Prospective Study 1; JPHC2, Japan Public Health Center-based Prospective Study 2; KMCC, Korea Multi-Center Cancer Cohort; Miyagi, Miyagi Cohort Study; Mumbai, Mumbai Cohort Study; NA, not available; Ohsaki, Ohsaki National Health Insurance Cohort Study; PC, prostate cancer; 3-Pref Aichi, Three-Prefecture Cohort Study Aichi; 3-Pref Miyagi, Three-Prefecture Cohort Study Miyagi; RERF, Radiation Effects Research Foundation; SA, self-assessment; SCS, Shanghai Cohort Study; Seoul, National Cancer Center Screenee Cohort; Singapore, Singapore Chinese Health Study; SMHS, Shanghai Men’s Health Study; Trivandrum, Trivandrum Oral Cancer Screening Study. a Restricted to men meeting study eligibility criteria (see Methods). b Weight (kg)/height (m)2. c Vital status records which did not have an International Classification of Diseases cause-of-death code were excluded.

Prostate Cancer Mortality in the ACC 383

South Korea

384 Fowke et al. Table 2. Risk of Prostate Cancer Mortality According to Level of Cigarette Smoking, Overall and by Region, Asia Cohort Consortium, 1963–2006a Level of Cigarette Smoking Never Smoking (Referent)

Ever Smoking ≥21 Pack-Years

1–20 Pack-Years

P for Trend

No. of PC Deaths

0.42

463

HR

95% CI

No. of PC Deaths

HR

No. of PC Deaths

171

1.00

186

China

54

1.00

39

0.92 0.60, 1.41

43

0.78 0.51, 1.18

0.24

88

1.11 0.79, 1.57

Japan

98

1.00

139

1.14 0.88, 1.48

211

1.01 0.79, 1.30

0.92

361

0.94 0.75, 1.18

152

1.00

178

1.07 0.86, 1.34

254

0.94 0.76, 1.17

0.60

449

0.99 0.82, 1.20

19

1.00

8

0.56 0.24, 1.30

4

0.49 0.12, 1.96

0.32

14

1.31 0.64, 2.71

Total (all cohorts)

HR

95% CI

1.03 0.83, 1.28

No. of PC Deaths

258

HR

95% CI

0.92 0.74, 1.13

1.00 0.84, 1.21

Region

East Asia South Asia

Abbreviations: CI, confidence interval; HR, hazard ratio; PC, prostate cancer. a Covariates included age, education, population density, marital status, and history of severe cancer, heart disease, or stroke at baseline.

baseline hazard functions in the Cox proportional hazards model by naming cohorts as strata.

a left-truncated survival-time model with risk sets based on respondent age. The left-truncated model incorporates an age-specific baseline hazard function rather than assuming that the baseline hazard function at time t is the same for all men regardless of age. BMI (12–19.9, 20–22.4, 22.5–24.9, or 25–50) and smoking status (never, ever) were simultaneously included in every model. Alcohol intake (0, 1–155 g/week, or ≥156 g/week) was excluded when examining BMI and smoking associations because 7 cohorts did not have data on alcohol intake. Adjustment covariates included age at baseline; education; marital status; history of incident or prevalent cancer (other than noninvasive skin lesions), heart disease, or stroke; and population density. Hazard ratios for the exposures of interest were estimated for all cohorts combined and for cohorts aggregated on the basis of major Asian ethnicity regions: South Asia (cohorts from India); Japan and China (which for these analyses included South Korea and Singapore); and East Asia (Japan, China, South Korea, and Singapore combined). In all analyses, we allowed cohort-specific

RESULTS

Table 1 shows the characteristics of the ACC studies evaluated for this analysis. The final analysis included 522,736 men contributing 4,773,847 person-years of accumulated follow-up across ACC cohorts. The average age at baseline was approximately 54 years, and average BMI ranged from 21.3 to 24.0 across these cohorts. With the exception of the Mumbai, India, cohort, the majority of men were current smokers. There were 634 prostate cancer deaths during followup, with 9 of the 18 cohorts contributing fewer than 25 prostate cancer deaths to the analysis. In the subset of men with known alcohol intake, there were 367 prostate cancer deaths during follow-up. Smoking status, scored as ever/never smoking or as packyears of smoking, was not significantly associated with prostate

Table 3. Risk of Prostate Cancer Mortality According to Body Mass Index Category, Overall and by Region, Asia Cohort Consortium, 1963–2006a Body Mass Indexb 12.0–19.9 No. of PC Deaths

Total (all cohorts)

HR

22.5–24.9 (Referent)

20.0–22.4 95% CI

No. of PC Deaths

HR

95% CI

P for Trend

25.0–50.0

No. of PC Deaths

HR

No. of PC Deaths

HR

95% CI

142

0.98 0.78, 1.23

188

0.92 0.75, 1.13

184

1.0

120

1.08 0.85, 1.36

0.58

13

0.51 0.25, 1.04

23

1.01 0.56, 1.83

21

1.0

15

0.75 0.38, 1.46

0.14

China

20

0.59 0.35, 1.00

34

0.70 0.46, 1.08

56

1.0

32

0.86 0.56, 1.34

0.04

Japan

113

1.18 0.91, 1.54

142

0.98 0.77, 1.26

122

1.0

82

1.15 0.87, 1.52

0.42

East Asia

133

1.01 0.80, 1.28

176

0.90 0.73, 1.11

178

1.0

114

1.07 0.84, 1.35

0.73

9

0.75 0.26, 2.12

12

1.56 0.58, 4.15

6

1.0

6

1.32 0.42, 4.10

0.67

Alternate body mass index measurementc Region

South Asia

Abbreviations: CI, confidence interval; HR, hazard ratio; PC, prostate cancer. a Covariates included age, education, population density, marital status, and history of severe cancer, heart disease, or stroke at baseline. b Weight (kg)/height (m)2. c Body mass index calculated from measured weight and height rather than self-reported weight and height.

Am J Epidemiol. 2015;182(5):381–389

Prostate Cancer Mortality in the ACC 385

Table 4. Risk of Prostate Cancer Mortality According to Level of Alcohol Consumption, Overall and by Region, Asia Cohort Consortium, 1963–2006a Level of Alcohol Consumption 1–155 g/week (Referent)

None

P for Trend

≥156 g/week

No. of PC Deaths

HR

95% CI

No. of PC Deaths

HR

No. of PC Deaths

HR

95% CI

182

1.02

0.78, 1.34

80

1.0

105

1.00

0.74, 1.35

0.98

China

86

0.97

0.63, 1.50

28

1.0

11

0.69

0.33, 1.38

0.27

Japan

96

1.03

0.72, 1.46

52

1.0

94

1.08

0.77, 1.52

0.75

182

1.02

0.78, 1.34

80

1.0

105

1.00

0.74, 1.35

0.87

Total (all cohorts) Region

East Asia

Abbreviations: CI, confidence interval; HR, hazard ratio; PC, prostate cancer. a Covariates include age, education, population density, marital status, and history of severe cancer, heart disease, or stroke at baseline.

cancer mortality (Table 2); most hazard ratios were close to 1.0 and without suggestion of a trend with increasing packyears of smoking. Similarly, prostate cancer mortality was not significantly associated with increasing BMI category across all studies or within those studies with direct measurement of weight and height (Table 3). There was a marginally significant protective association between BMI 30 to permit adequate investigation of obesity in disease mortality. Although BMI estimates body adiposity, Asian populations may be more susceptible to abdominal and visceral fat accumulation (25, 45). Hsing et al. (46) reported a stronger case-control association between waist:hip ratio and localized prostate cancer (odds ratio (OR) = 4.20, 95% CI: 1.88, 9.36) than between waist:hip ratio and regional prostate cancer (OR = 2.09, 95% CI: 1.18, 3.70) among Chinese men, perhaps suggesting an alternative explanation in that centralized obesity has greater relevance earlier in the process of prostate carcinogenesis than would be identified in this analysis of BMI and prostate cancer mortality. Although tobacco is known to affect steroid levels and to contain multiple carcinogens, including N-nitroso compounds, past epidemiologic studies on the relationship between smoking status and prostate cancer risk have been decidedly mixed (22). Zu and Giovannucci (5) recently reviewed the heterogeneity from 26 studies and observed that smokers had more advanced disease at diagnosis and an approximately 30% increased mortality compared with nonsmokers. In a meta-analysis, Huncharek et al. (47) concluded that heavy tobacco use was associated with overall incidence of prostate cancer (relative risk = 1.22, 95% CI: 1.01, 1.46)

386 Fowke et al.

and more strongly with fatal prostate cancer (relative risk = 1.30, 95% CI: 1.16, 1.46). In the NIH-AARP Diet and Health Study, Watters et al. (6) reported that current smokers were at lower risk of localized prostate cancer (HR = 0.82, 95% CI: 0.77, 0.88) but at greater risk of fatal prostate cancer (HR = 1.69, 95% CI: 1.25, 2.27). This pattern of associations (inverse for localized disease but positive for advanced disease) may suggest that tobacco use is associated with progression of prostate cancer, but this would also be consistent with lower blood PSA levels or lower rates of PSA testing or digital rectal examination among tobacco users, perhaps confounded by BMI, leading to delayed detection. Our results are consistent with a past analysis from the Singapore Chinese Health Study (n = 27,293 men), in which Butler et al. (29) reported a statistically nonsignificant association between smoking and fatal prostate cancer (HR = 1.51, 95% CI: 0.80, 2.86; 47 deaths) in Asian men. The association with alcohol may be dose-dependent, since light-to-moderate alcohol consumption may be antiinflammatory and antiandrogenic whereas heavy alcohol intake may increase inflammatory responses and oxidative stress or alter sex hormone levels (48–50). Recent analyses of data from the Prostate Cancer Prevention Trial (51) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) Trial (52) suggested that the risk of prostate cancer was associated with alcohol intake among men randomized to receive a steroid reductase inhibitor, a type of antiandrogen therapy, further suggesting that alcohol may affect steroid hormone activity to increase prostate cancer risk. Breslowand Weed (10) reported that low-to-moderate alcohol intake was not associated with prostate cancer risk, but they could not evaluate the associations with heavy drinking. Dennis (9) concluded that there was little association overall between alcohol intake and prostate cancer, but she also found a statistically significant relationship among men who consumed 4 or more drinks per day. Associations specific to liquor (53) or wine (53, 54) have also been identified. In a recent review by Middleton Fillmore et al. (23), there was a statistically significant overall association between alcohol and prostate cancer in populationbased case-control studies ( per drink/day, OR = 1.27, 95% CI: 1.17, 1.38) but not in prospective cohort analyses (OR = 1.16, 95% CI: 0.58, 2.32), suggesting selection bias, recall bias, or the possibility that alcohol consumption proximal to the time of diagnosis may be most relevant. It may also be possible that light alcohol consumption affects prostate cancer detection if alcohol intake decreases blood PSA levels (55) or the severity of lower urinary tract symptoms that often lead to contact with a physician and a subsequent prostate cancer diagnosis. Indeed, light alcohol intake has been associated with decreased risk of benign prostatic hyperplasia, whereas heavy alcohol intake has been associated with increased risk of benign prostatic hyperplasia (56, 57). Thus, alcohol has an inconsistent association with prostate cancer risk and may also be associated with prostate cancer detection. We found no evidence that alcohol consumption was associated with prostate cancer mortality in the ACC, which included a large Asian study population. The most innovative aspect of this study was the use of the ACC to prospectively investigate prostate cancer mortality without systematic prostate cancer screening. Compared with the United States and some other parts of the world, there is a

substantially lower prevalence of screening in eastern and southern Asia (18, 58–61). Furthermore, we focused on those clinically relevant prostate cancers leading to mortality rather than incidental prostate cancers commonly found through screening. As such, our results are less likely to have been a consequence of recall bias or a detection bias due to any relationship between obesity, smoking, or alcohol use with PSA testing or digital rectal examination practices. There are also several limitations to consider. Despite an analysis of over 500,000 men, only 634 prostate cancer deaths were identified overall, and only 367 were included in our analysis of alcohol intake. In post hoc power calculations, we estimated that we had sufficient statistical power to identify a hazard ratio of 1.2 or greater, assuming a 30% prevalence and type I and type II errors of 5% and 20%, respectively. We found a pattern to suggest that our results would reveal a significantly increased risk of fatal prostate cancer with an increase in population size or duration of follow-up. Harmonization of data across cohort studies required analyses that limited our ability to separate former smokers from never smokers or to evaluate duration of tobacco use, patterns of alcohol intake (such as binge drinking), or type of alcohol consumed. Similarly, most of the cohort studies included did not collect data on waist or hip circumference, lower urinary tract symptoms, PSA test history, prostate cancer incidence, or prostate cancer treatment. We further recognize that the epidemiology of prostate cancer in Asian nations may be in the process of changing (62). In Japan, for example, prostate cancer mortality increased almost linearly with time between 1955 and 1985 (20), and prostate cancer mortality in South Korea was 5-fold higher in 2000 than in 1985 (21). We found that stratification by date of prostate cancer mortality did not modify associations. However, data on changes in BMI or other factors after baseline and during follow-up were not collected, and thus the influence of temporal changes in exposure on prostate cancer mortality could not be fully addressed. In summary, past analyses in Western regions have found a consistent association between obesity and prostate cancer mortality, and a subset of studies have also found increased risk with smoking or alcohol intake. In a prospective analysis of over 500,000 men living in Asian countries, we found no association between prostate cancer mortality and BMI, smoking, or alcohol consumption. Differences in results between Asian and Western populations may be related, perhaps in part, to differences in clinical practices regarding prostate cancer screening and detection or treatment. Confounding between these risk factors and the likelihood of screening is a distinct possibility, which would rule out these modifiable risk factors as relevant to prevention of prostate cancer mortality, not only in Asia but also elsewhere. However, there are many other reasons to promote smoking cessation, moderation of alcohol intake, and weight control. Investigators should monitor these associations in future studies, as the number of prostate cancer screening programs in Asia may increase.

ACKNOWLEDGMENTS

Author affiliations: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (Jay H. Am J Epidemiol. 2015;182(5):381–389

Prostate Cancer Mortality in the ACC 387

Fowke, Xiao-Ou Shu, Wei Zheng); Fred Hutchinson Cancer Research Center, Seattle, Washington (Dale F. McLerran, Betsy Rolland, Mark Thornquist, John D. Potter); HealisSekhsaria Institute for Public Health, Navi Mumbai, India (Prakash C. Gupta, Mangesh Pednekar); Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana (Jiang He); Division of Radiation Oncology, Regional Cancer Center, Medical College Campus, Trivandrum, India (Kunnambath Ramadas); Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan (Shoichiro Tsugane, Manami Inoue, Norie Sawada); AXA Department of Health and Human Security, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (Manami Inoue); Department of Public Health, Graduate School of Medicine, Hokkaido University, Sapporo, Japan (Akiko Tamakoshi); Duke-NUS Graduate Medical School Singapore and Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore (Woon-Puay Koh); Division of Cancer Epidemiology and Prevention, Miyagi Cancer Center Research Institute, Sendai, Japan (Yoshikazu Nishino); Division of Epidemiology, Department of Public Health and Forensic Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan (Ichiro Tsuji, Yumi Sugawara, Masako Kakizaki, Yasutake Tomata); Department of Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan (Kotaro Ozasa, Waka Ohishi, Eric Grant); University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (Jian-Min Yuan, Renwei Wang); Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (Jian-Min Yuan, Lesley M. Butler); Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan (Hideo Tanaka, Isao Oze); Department of Preventive Medicine, College of Medicine, Seoul National University, Seoul, South Korea (Yoon-Ok Ahn, Keun-Young Yoo, Sue K. Park, Daehee Kang); Genomics Research Center, Academia Sinica, Taipei, Taiwan (Chien-Jen Chen); Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan (Chien-Jen Chen, Wen-Harn Pan); Departments of Health Studies, Medicine, and Human Genetics, Comprehensive Cancer Center, University of Chicago, Chicago, Illinois (Habibul Ahsan); Division of Preventive Medicine and Health Services Research, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan (Wen-Harn Pan, ShaoYuan Chuang); Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (Wen-Harn Pan); Department of Evidence Based Medicine and Department of Population Genetics and Prevention, Fu Wai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (Dongfeng Gu); Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China (Yong-Bing Xiang); Screening Group, International Agency for Research on Cancer, Lyon, France (Catherine Sauvaget); Department of Social and Preventive Medicine, College of Medicine, Hallym University, Seoul, South Korea (Dong-Hyun Kim); Department of Public Health, Fu Jen Catholic University, Taipei, Taiwan (San-Lin Am J Epidemiol. 2015;182(5):381–389

You); Cancer Research Institute, Department of Biomedical Science, Seoul National University Graduate School, Seoul, South Korea (Sue K. Park, Daehee Kang); Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York (Faruque Parvez); Department of Population Health, School of Medicine, New York University, New York, New York (Yu Chen); Department of Food and Nutrition, Sookmyung Women’s University, Seoul, South Korea (Jung Eun Lee); Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas (Ziding Feng); Tisch Cancer Institute and Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, New York (Paolo Boffetta); International Prevention Research Institute, Lyon, France (Paolo Boffetta); Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland (Rashmi Sinha); Centre for Public Health Research, Massey University, Wellington, New Zealand (John D. Potter); and Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington (John D. Potter). This research was funded by grant RO3CA159398 (Principal Investigator: J.H.F.) from the National Cancer Institute (US National Institutes of Health). The funding agency played no role in the implementation of the study or the interpretation of these results. Conflict of interest: none declared.

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Appendix Table 1. Risk of Prostate Cancer Mortality According to Body Mass Index Category, Overall and by Date of Prostate Cancer Death, Asia Cohort Consortium, 1963–2006a Body Mass Indexb 12.0–19.9

Date of PC Death

No. of PC Deaths

Total (all cohorts)

142

HR

22.5–24.9 (Referent)

20.0–22.4 95% CI

No. of PC Deaths

0.98 0.78, 1.23

188

HR

95% CI

0.92 0.75, 1.13

P for Trend

25.0–50.0

No. of PC Deaths

HR

No. of PC Deaths

184

1.00

120

HR

95% CI

1.08 0.85, 1.36

0.58

Before January 1, 2000

91

1.06 0.79, 1.44

114

1.05 0.79, 1.38

91

1.00

65

1.22 0.88, 1.68

0.95

On or after January 1, 2000

51

0.95 0.67, 1.35

74

0.80 0.59, 1.10

93

1.00

55

0.92 0.66, 1.30

0.62

Abbreviations: CI, confidence interval; HR, hazard ratio; PC, prostate cancer. a Covariates included age, education, population density, marital status, and history of severe cancer, heart disease, or stroke at baseline. b Weight (kg)/height (m)2.

Am J Epidemiol. 2015;182(5):381–389

Associations of body mass index, smoking, and alcohol consumption with prostate cancer mortality in the Asia Cohort Consortium.

Many potentially modifiable risk factors for prostate cancer are also associated with prostate cancer screening, which may induce a bias in epidemiolo...
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