International Journal of (2005) 29, 1267–1274 & 2005 Nature Publishing Group All rights reserved 0307-0565/05 $30.00 www.nature.com/ijo PAPER Obesity and overweight in relation to organ-specific cancer mortality in London (UK): findings from the original Whitehall study

GD Batty1,2*, MJ Shipley3, RJ Jarrett4, E Breeze3, MG Marmot3 and G Davey Smith5

1MRC Social and Public Health Sciences Unit, University of Glasgow, 4 Lilybank Gardens, Glasgow, UK; 2Department of Psychology, University of Edinburgh, UK; 3Department of and Public Health, University College London, London, UK; 4Bishopsthorpe Road, London, UK; and 5Department of Social Medicine, University of Bristol, Bristol, UK

OBJECTIVE: To examine the relation of obesity and overweight with organ-specific cancer mortality. METHODS: In the Whitehall prospective cohort study of London-based government employees, 18 403 middle-age men participated in a medical examination between 1967 and 1970. Subjects were followed up for cause-specific mortality for up to 35 y (median: interquartile range (25th–75th centile); 28.1 y: 18.6–33.8). RESULTS: There were over 3000 cancer deaths in this cohort. There was a raised risk of mortality from carcinoma of the rectum, bladder, colon, and liver, and for lymphoma in obese or overweight men following adjustment for range of covariates, which included socioeconomic position and physical activity. These relationships held after exclusion of deaths occurring in the first 20 y of follow-up. CONCLUSION: Avoidance of obesity and overweight in adult life may reduce the risk of developing some cancers. International Journal of Obesity (2005) 29, 1267–1274. doi:10.1038/sj.ijo.0803020; published online 28 June 2005

Keywords: overweight; cancer; Whitehall; cohort study

Introduction women), endometrium, kidney, colon (strongest in men), Although elevated rates of cancer mortality in individuals oesophagus and pancreas.3,4 However, studies examining the with higher body weight were first documented almost a influence of obesity and overweight on other malignan- century ago,1 most attention has focused on the role of ciesFprostate, liver, stomach, bladder, lymphoma and obesity in the aetiology of coronary heart disease (CHD). In leukaemiaFreveal inconclusive findings.3–5 These discre- large-scale prospective studies, findings are generally con- pant results may be explained by variability in definition of sistent: a positive association is apparent such that obese and obesity and overweight across reports, so complicating overweight persons, as indexed by their body mass index comparison; and a failure to adjust for important covariates, (BMI), experience a higher risk of CHD than their leaner such as socioeconomic position6 and physical activity.7 counterparts.2 This relation may be largely ascribed to Additionally, in cohort studies, the presence of subclinical mediation via the established CHD risk indicators of blood malignancy at baseline may lead to low body weight. It is pressure, blood lipids and glucose tolerance.2 likely, therefore, that the positive obesity/overweight–cancer In the last two decades, the cohort studies on which these gradient seen for some sites would, in fact, be steeper if observations are based have matured, so accumulating deaths occurring in the early years of follow-up were sufficient events to allow investigators to examine the link excluded from analyses. However, the few extant prospective between obesity and some organ-specific cancers. There is a cohort studies have a sufficiently high number of cancer consensus that obesity and overweight are associated with cases with which to examine this issue of reverse causality. an increased risk of cancer of the breast (in postmenopausal In the Whitehall study, over 18 000 middle-aged London- based government employees participated in a medical examinationinthelate1960s,whichincludedanassessment *Correspondence: Dr GD Batty, MRC Social and Public Health Sciences of their BMI and a range of covariate data.8 In an extended Unit, University of Glasgow, 4 Lilybank Gardens, Glasgow G12 8RZE, UK. (maximum 35 y) mortality surveillance of this cohort, there E-mail: [email protected] Received 4 August 2004; revised 7 January 2005; accepted 16 March 2005; have been over 3000 cancer deaths, enabling us to address published online 28 June 2005 these issues of data scarcity and methodological shortcomings. Obesity, overweight and cancer GD Batty et al 1268 In earlier (r15y)follow-upsofthiscohort,raisedrisksoftotal 140–208; ICD9: 140–209; ICD10: C00–C97)Freferred to as mortality,9,10 cardiovascular disease9,11 and total cancers9 were ‘all-cancers’Fwas divided into individual organs. These reported in overweight and obese groups. In this most recent were: oesophagus (ICD8/9: 150; ICD10: C15); stomach follow-up we examine, for the first time, the link between (ICD8/9: 151; ICD10: C16); colon (ICD8/9: 153; ICD10: obesity and a range of organ-specific malignancies. C18); rectum (ICD8/9: 154; ICD10: C19); liver (ICD8/9: 155– 156; ICD10: C22-C24); pancreas (ICD8/9: 157; ICD10: C25); trachea, bronchus and lung (ICD8/9: 162; ICD10: C33–C34; Materials and methods referred to as ‘lung cancer’); prostate (ICD8/9: 185; ICD10: In the Whitehall study, data were collected on 18 403 non- C61); bladder (ICD8/9: 188; ICD10: C67); kidney (ICD8/9: industrial London-based male government employees aged 189; ICD10: C64–C66, C68); brain (ICD8/9: 191; ICD10: from 40 to 64 y when examined between September 1967 C71); lymphoma (ICD8/9: 200–203; ICD10: C81–C90); and and January 1970, representing a 74% response. This leukaemia (ICD8: 204–207; ICD9: 204–208; ICD 10: C91– involved the completion of a study questionnaire and C95). participation in a medical examination, both of which have been described in detail elsewhere.8 In brief, the question- naire included enquiries regarding civil service employment Data analyses grade (an indicator of socio-economic position),12 smoking A total of 17 347 men identified in the NHSCR had data for habits,13 intermittent claudication,14 ,15,16 chronic BMI and all potential covariates. The cause of death for 41 of bronchitis,17 marital status,18 physical activity,19 unex- these was unknown and they were excluded from all plained weight loss in the preceding year and the use of analyses. In addition, we excluded 204 men classified as drug therapy for heart problem or high blood pressure.8 underweight (see later explanation) leaving an analytical

Forced expiratory volume in one second (FEV1) adjusted for sample of 17 102 men (92.9% of those recruited). In analyses height,20 ischaemia,21 fasting plasma cholesterol,22 post- of baseline characteristics according to the level of obesity challenge 2-h blood glucose,23 blood pressure,24 and triceps and overweight, the prevalence of the former was adjusted skinfold thickness8 were determined using standardised for age (5 y age groups) by the direct standardisation method. protocols. In addition, in a representative sample of the Trends in proportions were tested for statistical significance cohort, 1669 men participated in a dietary survey. This using the Mantel–Haenszel test; for continuous variables, involved the completion of a 3-day semiquantitative record least-squares means were used to present the age-adjusted of all food and drink consumed.25 means, and tests for trend across obesity, overweight and normal weight groups were computed by fitting a linear trend term. In the examination of the relation of dietary Assessment of obesity and overweight characteristics with weight in a subsample of the present Height was measured with the subject wearing shoes and cohort, the distribution of alcohol intake was highly skewed; standing with his back to a measuring rod; readings were therefore, analysis was conducted on the logarithmically 1 8 transformed data after adding 0.5 to all data points to taken to the nearest 2 in. (approximately 12.7 mm) below. Weight was recorded with the subject wearing shoes but with overcome values of zero. 1 Models fitted with a BMI by follow-up time interaction jacket removed; readings were taken to the nearest 2 lb (227 g).8 Following conversion from imperial to metric units, term confirmed that the proportional hazards assumption BMI (weight (kg) divided by height squared (m2)) was was not violated. Thus, hazard ratios and accompanying computed. To facilitate comparability of our findings with confidence intervals were computed for the relation of those from other studies,26–28 we defined underweight obesity/overweight with each mortality outcome using Cox’s 33 (o18.5 to 25.0 kg/m2), normal weight (BMI 18.5 to proportional hazards regression model with follow-up o25.0 kg/m2), overweight (25.0–29.99 kg/m2) and obesity period as the time scale. These models were initially adjusted (Z30.0 kg/m2), according to criteria advanced by the World for age and then for other potential covariates. For the Health Organisation.29 purposes of statistical adjustment, age, triceps skinfold thickness, plasma cholesterol, height-adjusted FEV1 and systolic blood pressure were fitted as continuous variables; Ascertainment of cancer mortality while unexplained weight loss in the last year (two levels), The records of 18 245 men (99.1% of subjects) were traced employment grade (5), marital status (4), blood pressure- and flagged using the procedures of the National Health lowering medication (2), blood glucose levels (3), disease at Service Central Registry (NHSCR) until 31 December 2002. study entry (2) and physical activity (6) were fitted as Among the 11 710 men who died, 91.6% of death certificates categorical variables. During the baseline study, the physical were coded according to the eighth revision of the Interna- activity enquiries on the questionnaire were modified. Levels tional Classification of Diseases (ICD),30 7.0% according to of this behaviour were therefore determined from either an the ninth revision31 and 1.4% according to the tenth item about travel activity19 (administered to approximately revision.32 The category of all malignant neoplasms (ICD8: two-thirds of men) or from leisure activities34 (administered

International Journal of Obesity Obesity, overweight and cancer GD Batty et al 1269 to the remainder). Analyses of the obesity/overweight– have occurred within this time frame.35 All statistical cancer relation indicated that there was no confounding analyses were conducted using SAS computer software.36 effect due to questionnaire type. Smoking status was grouped into four categories (never, ex-smoker, current pipe or cigar smoker, current cigarette smoker) together with additional adjustment for the number of cigarettes smoked per day in Results current smokers. Existing disease at study entry was defined In Table 1 the relation of obesity and overweight with as a positive response to enquiries regarding a range of health baseline characteristics are presented. Men with obesity conditions: myocardial ischaemia, intermittent claudication, comprised 4.2% (717) of the analytical sample. The most physician-diagnosed heart problems or high blood pressure unfavourable level of each baseline characteristic was (one question), dyspnoea and bronchitis. The existence of apparent in the obese and overweight study participants, ischaemia was determined from ischaemic signs on an ECG the only exception being cigarette smoking where normal trace, or positive responses to either the Rose angina weight men had the highest prevalence. questionnaire or a report of severe pain across the front of In Table 2 the relations of overweight and obesity to a the chest lasting 30 min or more.15 Men with range of dietary characteristics, assessed in a subgroup of the comprised those who gave a positive response to the study population, are depicted. Higher quantities of alcohol questionnaire enquiry ‘are you, or have you been, diabetic?’, consumption were apparent in the men classified as obese, or those who had blood glucose level 2 h after the glucose while lower levels of fibre and fat (total and saturated) intake load of Z11.1 mmol/l (Z200 mg/100 ml). A blood glucose of were seen. 5.4–11.0 mmol/l (96–199 mg/100 ml) was used to designate In 17 102 men there were 10 901 (63.7%) deaths over a participants with glucose intolerance, with all remaining maximum of 35 y follow-up. Of these, 3051 deaths were men termed normoglycaemic.23 ascribed to all-cancers, the most common site being that of To address the problem of reverse causalityFfor some the lung (26% of all cancer fatalities). Of all cancers, 498 cancers, tumour presence may lead to weight loss, so occurred within the first 10 y of follow-up and 1401 within attenuating the obesity–cancer relationshipFwe took three the first 20 y of follow-up. In Tables 3 and 4 the relationships approaches. Firstly, we dropped the underweight group from between obesity, overweight and mortality from various our analyses on the understanding that this group would cancer sites are presented. contain some men with undetected cancer that may have The suggestion of a raised rate of total cancers in the obese resulted in weight loss. Secondly, we adjusted for unex- and overweight groups in the age- and multiply-adjusted plained weight loss in the preceding year and existing illness analyses was essentially eliminated when deaths occurring in at study entry. Finally, in subsequent analyses, we excluded the first 20 y of follow-up were excluded from the analysis. deaths in the first 10 and 20 y of mortality surveillance. In so Owing to the low prevalence of obesity in the present study doing, we reasoned that a significant proportion of deaths population, there were few cancer deaths in this group for attributable to cancer, if present at study induction, would some anatomical sites; some of our findings should therefore

Table 1 Obesity and overweight in relation to baseline characteristics (1967–70)a

Normal weight (18.5–24.9 kg/m2) Overweight (25.0–29.9 kg/m2) Obese (Z30 kg/m2)

Number (%) 9288 (54.3) 7097 (41.5) 717 (4.2)

Mean (s.e.) Age (y) 51.1 (0.1) 52.0 (0.1) 52.6 (0.2) Triceps skinfold thickness (mm) 39.4 (0.2) 50.3 (0.2) 64.0 (0.5) Plasma cholesterol (mmol/l) 5.04 (0.01) 5.21 (0.01) 5.15 (0.05) b FEV1 (l/s) 3.13 (0.01) 3.16 (0.01) 3.09 (0.02) Systolic blood pressure (mmHg) 133.1 (0.2) 138.9 (0.2) 148.7 (0.7)

Percent (s.e.) Physically inactive 15.3 (0.4) 16.2 (0.4) 23.8 (1.6) Unintentional weight loss in last year 3.1 (0.2) 0.9 (0.1) 0.3 (0.2) Current cigarette smoker 44.1 (0.5) 37.4 (0.6) 36.9 (1.8) Low work grade 23.3 (0.4) 23.0 (0.5) 30.1 (1.7) No partner 12.4 (0.3) 10.7 (0.4) 14.2 (1.3) Disease at study entryc 19.6 (0.4) 21.5 (0.5) 24.7 (1.6) Blood pressure-lowering medication 1.2 (0.1) 1.9 (0.2) 2.2 (0.5) Glucose intolerancec 4.7 (0.2) 5.8 (0.3) 7.9 (1.0) Diabeticc 1.2 (0.1) 1.2 (0.1) 2.1 (0.5) a b c Adjusted for age (age is unadjusted). FEV1 ¼ forced expiratory volume in one second (adjusted for height). See Materials and methods section for definitions.

International Journal of Obesity Obesity, overweight and cancer GD Batty et al 1270 Table 2 Overweight and obesity in relation to self-reported dietary intake over a 3-day period (N ¼ 1652)

Dietary characteristic (g) Normal (18.5–24.9 kg/m2) Overweight (25.0–29.9 kg/m2) Obese (Z30 kg/m2) P-value for trend

Number of men 873 710 69 F

Alcohola 3.70b (3.21,4.18) 4.07 (3.51,4.70) 4.26 (2.64,6.73) 0.24 Total fibre 16.7 (16.4,17.1) 16.2 (15.8,16.6) 16.2 (15.1,17.4) 0.05 Total fat 112.6 (110.6,114.5) 109.2 (107.0,111.3) 110.1 (103.2,117.0) 0.05 Saturated fat 58.1 (57.1,59.1) 55.9 (54.8,57.0) 56.2 (52.6,59.8) 0.008 Monounsaturated fat 46.1 (45.3,46.9) 45.0 (44.1,45.9) 45.6 (42.6,48.5) 0.16 Polyunsaturated fat 7.96 (7.77,8.15) 7.97 (7.77,8.18) 8.03 (7.37,8.70) 0.75

aMeans for alcohol are geometric means (see Materials and methods). bResults are mean (95% CI).

viewed with caution. In an age-adjusted analysis, the lowest however, owing to their dissimilar epidemiology,37 separa- risk of lung cancer deaths was apparent in obese men; tion is warranted. Previous studies in men suggest a direct however, following adjustment for confounding factors obesity/overweight–colon cancer association,3,4 as apparent which included smokingFthe highest prevalence of this herein, although this is not a universal result.38 We also behaviour was evident in the normal weight groupFthis found a positive non-significant gradient for rectal cancer, relation was lost. There was a suggestion of elevated rates of an association that has previously been suggested to be carcinoma of colon and lymphoma in the obese and null.39,40 Three other studies26,41,42 have reported an excess overweight groups following full adjustment and exclusion occurrence of malignant neoplasm of the liver in overweight of deaths in the first 20 y of follow-up, although statistical persons. While we made the same observation in the present significance at conventional levels was not always evident. study, these findings should be viewed with caution owing to Of the individual cancer sites depicted in Table 4, there the very low number of cases; a caveat that should also be were raised rates of carcinoma of liver, rectum and bladder in applied to some of our other results. In a recent meta- the obese or overweight groups, although most confidence analysis of observational studies, adiposity was associated intervals included unity. In contrast, there was a suggestion with increased pancreatic cancer risk.28 That this effect was of a non-significant inverse weight–kidney cancer relation modestFHR (95% CI); 1.19 (1.10, 1.29)Fimplicates un- although confidence intervals were wide owing to a low measured or residual confounding as a likely alternative number of cases. There was little evidence of an obesity/ explanation.28 Indeed, in the present analyses in which we overweight–malignancy gradient for any other cancer site utilised a wide range of confounding factors, we found no featured in Tables 3 and 4. When we included the under- evidence of an association between BMI and this cancer. weight group in age-adjusted analyses with total cancers as the end point of interest (data not shown), we found an

elevated rate in this group (HRunderweight vs normal weight (95% Plausible mechanisms CI): 1.61 (1.21, 2.13)) that was heavily attenuated when Several mechanisms have been invoked for the higher remaining covariates were added to the multivariable model occurrence of some cancers in the obese or overweight. (1.22 (0.91, 1.62)). There were too few site-specific cancer Differences in incidence of some cancers across body weight cases in the underweight group (N ¼ 204 men) to facilitate categories may reflect differences in dietary characteristics, further analyses. such as fat and fibre intake.43 In the Whitehall study, a small representative subgroup of 1669 participants completed a 3- day dietary record during the period of baseline examina- tion.25 While there were insufficient site-specific cancer cases Discussion to examine the potential confounding effect of dietary The main finding of this study was an elevated risk of characteristics on the obesity/overweight–cancer association mortality from carcinoma of the rectum, bladder, colon, and in this group, when we related intake to overweight and liver, and for lymphoma in men who were obese or obesity, the differences across these groups were small and overweight in comparison to those in the normal weight not always most favourable in the leanest subjects. It is group, although statistical significance was not always unlikely, therefore, that these small and inconsistent apparent. There was little evidence of an weight–cancer differences in diet were large enough to explain differences gradient for other malignancies. in later cancer risk across the body weight groups. A more specific explanation for the obesity/overweight– cancer relation that has received much recent attention Comparison with other studies concerns the role of insulin and insulin-like growth factors. Some investigators combine colon and rectal cancer into a These hypotheses suggests that obesity precipitates insulin single disease category when examining their aetiology; resistance and the resulting prolonged hyperinsulinaemia in

International Journal of Obesity Obesity, overweight and cancer GD Batty et al 1271 Table 3 Mortality rates and hazard ratios for selected site–specific cancer deaths in relation to obesity and overweight

Type of cancer (total no. of deaths) Normal (18.5–24.9 kg/m2) Overweight (25.0–29.9 kg/m2) Obese (Z30 kg/m2) P for trend

Number of subjects 9288 7097 717 F

All cancers (3051) Mortality ratea (no. of deaths) 7.66 (1648) 7.53 (1279) 7.88 (124) F Age adjustedb 1.0 (ref) 1.00 (0.93,1.07) 1.14 (0.95,1.37) 0.69 Multiply adjustedc 1.0 1.05 (0.97,1.13) 1.21 (1.00,1.48) 0.08 Multiply adjustedFexcluding first 10 yd 1.0 1.04 (0.95,1.13) 1.17 (0.94,1.45) 0.20 Multiply adjustedFexcluding first 20 ye 1.0 1.09 (0.98,1.22) 1.09 (0.81,1.47) 0.13

Lung (783) (no. of deaths) 2.20 (450) 1.85 (308) 1.55 (25) Age adjusted 1.0 0.85 (0.73, 0.98) 0.77 (0.51, 1.15) 0.007 Multiply adjusted 1.0 0.99 (0.85, 1.16) 1.00 (0.65, 1.53) 0.98 Multiply adjustedFexcluding first 10 y 1.0 0.96 (0.80, 1.15) 1.15 (0.72, 1.83) 0.98 Multiply adjustedFexcluding first 20 y 1.0 1.01 (0.79, 1.30) 1.07 (0.53, 2.16) 0.85

Prostate (431) Mortality rate (no. of deaths) 1.14 (243) 1.02 (175) 0.81 (13) Age adjusted 1.0 0.93 (0.76, 1.12) 0.88 (0.50, 1.54) 0.42 Multiply adjusted 1.0 0.92 (0.75, 1.13) 0.91 (0.51, 1.63) 0.45 Multiply adjustedFexcluding first 10 y 1.0 0.91 (0.74, 1.13) 0.80 (0.43, 1.51) 0.33 Multiply adjustedFexcluding first 20 y 1.0 0.95 (0.74, 1.22) 0.76 (0.35, 1.67) 0.54

Colon (279) Mortality rate (no. of deaths) 0.64 (139) 0.72 (122) 1.18 (18) Age adjusted 1.0 1.14 (0.89, 1.46) 2.00 (1.22, 3.26) 0.03 Multiply adjusted 1.0 1.20 (0.93, 1.56) 2.21 (1.29, 3.79) 0.02 Multiply adjustedFexcluding first 10 y 1.0 1.20 (0.90, 1.60) 2.14 (1.15, 3.99) 0.05 Multiply adjustedFexcluding first 20 y 1.0 1.42 (1.01, 2.01) 1.37 (0.53, 3.56) 0.07

Stomach (190) Mortality rate (no. of deaths) 0.48 (100) 0.49 (81) 0.56 (9) Age adjusted 1.0 1.02 (0.76, 1.37) 1.27 (0.64, 2.52) 0.70 Multiply adjusted 1.0 1.05 (0.76, 1.44) 1.23 (0.59, 2.58) 0.60 Multiply adjustedFexcluding first 10 y 1.0 1.13 (0.78, 1.62) 1.80 (0.81, 3.99) 0.22 Multiply adjustedFexcluding first 20 y 1.0 0.92 (0.55, 1.51) 1.30 (0.38, 4.51) 0.95

Lymphoma (158) Mortality rate (no. of deaths) 0.33 (77) 0.42 (74) 0.44 (7) Age adjusted 1.0 1.30 (0.94, 1.79) 1.46 (0.67, 3.16) 0.08 Multiply adjusted 1.0 1.34 (0.95, 1.89) 1.49 (0.65, 3.42) 0.10 Multiply adjustedFexcluding first 10 y 1.0 1.25 (0.86, 1.81) 1.61 (0.69, 3.74) 0.18 Multiply adjustedFexcluding first 20 y 1.0 1.33 (0.84, 2.09) 1.92 (0.70, 5.25) 0.15

Pancreas (147) Mortality rate (no. of deaths) 0.36 (75) 0.41 (69) 0.20 (3) Age adjusted 1.0 1.19 (0.86, 1.66) 0.61 (0.19, 1.93) 0.77 Multiply adjusted 1.0 1.18 (0.83, 1.68) 0.58 (0.18, 1.91) 0.80 Multiply adjustedFexcluding first 10 y 1.0 1.13 (0.77, 1.66) 0.43 (0.10, 1.84) 0.90 Multiply adjustedFexcluding first 20 y 1.0 1.24 (0.76, 2.03) 0.86 (0.19, 3.76) 0.57 aAge-adjusted mortality rates per 1000 person-years; bResults are hazards ratio (95% CI). cMultiply adjusted modelFadjusted for age, plus employment grade, physical activity, smoking habit, marital status, disease at entry, weight loss in the last year, blood pressure-lowering medication, height adjusted FEV1, triceps skinfold thickness, systolic blood pressure, plasma cholesterol, glucose intolerance and diabetes status. dDeaths in the first 10 y of surveillance are excluded. eDeaths in the first 20 y of surveillance are excluded. itself acts as a tumour growth promoter.44 Additionally, elevated risk of colon and rectal cancer mortality in the higher levels of insulin-like growth factor (IGF-I)Fa multi- obese and overweight groups herein, there was no evidence functional, circulating peptide that encourages tumour of a relationship with prostate cancer. growth through its mitosis and antiapoptosis properties45 Fare positively associated with prostate and colorectal cancer risk,46 both energy-related malignancies. While IGF- Study strengths and limitations I is also positively related to BMI, the gradient is in fact non- The strengths of the present study include its sizeFsuperior linear (at obese levels it decreases).47 Although we found an to most, if not all,48 reports in the literatureFwhich

International Journal of Obesity Obesity, overweight and cancer GD Batty et al 1272 Table 4 Mortality rates and hazard ratios for selected site-specific cancer deaths in relation to obesity and overweight

Type of cancer (total no. of deaths) Normal (18.5-24.9 kg/m2) Overweight (25.0–29.9 kg/m2) Obese (Z30 kg/m2) P for trend

Number of subjects 9288 7097 717 F

Bladder (144) Mortality ratea (no. of deaths) 0.36 (75) 0.38 (65) 0.26 (4) Age adjustedb 1.0 (ref) 1.11 (0.80, 1.55) 0.83 (0.30, 2.28) 0.80 Multiply adjustedc 1.0 1.21 (0.84, 1.73) 0.94 (0.33, 2.69) 0.46 Multiply adjustedFexcluding first 10 yd 1.0 1.27 (0.86, 1.85) 0.57 (0.13, 2.41) 0.51 Multiply adjustedFexcluding first 20 ye 1.0 1.68 (1.06, 2.65) 1.19 (0.27, 5.18) 0.05

Oesophagus (121) Mortality rate (no. of deaths) 0.25 (58) 0.34 (58) 0.33 (5) Age adjusted 1.0b 1.33 (0.92, 1.91) 1.40 (0.56, 3.49) 0.16 Multiply adjusted 1.0 1.39 (0.94, 2.06) 1.48 (0.56, 3.90) 0.13 Multiply adjustedFexcluding first 10 y 1.0 1.27 (0.84, 1.90) 0.84 (0.25, 2.81) 0.51 Multiply adjustedFexcluding first 20 y 1.0 1.12 (0.69, 1.81) 0.00f 0.75

Leukaemia (108) Mortality rate (no. of deaths) 0.28 (61) 0.27 (45) 0.13 (2) Age adjusted 1.0 0.95 (0.65, 1.40) 0.50 (0.12, 2.04) 0.48 Multiply adjusted 1.0 0.93 (0.61, 1.41) 0.44 (0.10, 1.91) 0.42 Multiply adjustedFexcluding first 10 y 1.0 0.93 (0.59, 1.48) 0.53 (0.12, 2.32) 0.53 Multiply adjustedFexcluding first 20 y 1.0 1.18 (0.68, 2.03) 0.48 (0.06, 3.72) 0.89

Rectum (104) Mortality rate (no. of deaths) 0.24 (52) 0.26 (46) 0.40 (6) Age adjusted 1.0 1.17 (0.79, 1.74) 1.80 (0.77, 4.19) 0.20 Multiply adjusted 1.0 1.20 (0.78, 1.83) 1.97 (0.79, 4.91) 0.21 Multiply adjustedFexcluding first 10 y 1.0 1.44 (0.90, 2.29) 1.81 (0.61, 5.42) 0.09 Multiply adjustedFexcluding first 20 y 1.0 1.45 (0.82, 2.59) 2.92 (0.82, 10.4) 0.08

Kidney (61) Mortality rate (no. of deaths) 0.16 (36) 0.11 (20) 0.34 (5) Age adjusted 1.0 0.73 (0.42, 1.27) 2.12 (0.83, 5.41) 0.99 Multiply adjusted 1.0 0.58 (0.32, 1.04) 1.20 (0.41, 3.52) 0.31 Multiply adjustedFexcluding first 10 y 1.0 0.55 (0.29, 1.07) 1.14 (0.31, 4.23) 0.24 Multiply adjustedFexcluding first 20 y 1.0 0.62 (0.28, 1.35) 0.46 (0.05, 3.88) 0.20

Brain (55) Mortality rate (no. of deaths) 0.12 (30) 0.14 (24) 0.05 (1) F Age adjusted 1.0 1.08 (0.63, 1.85) 0.50 (0.07, 3.66) 0.94 Multiply adjusted 1.0 0.95 (0.53, 1.69) 0.42 (0.05, 3.32) 0.59 Multiply adjustedFexcluding first 10 y 1.0 0.73 (0.32, 1.66) 0.00f 0.24 Multiply adjustedFexcluding first 20 y 1.0 0.61 (0.20, 1.85) 0.00f 0.24

Liver (51) Mortality rate (no. of deaths) 0.11 (27) 0.10 (18) 0.37 (6) Age adjusted 1.0 0.91 (0.50, 1.65) 3.55 (1.46, 8.63) 0.29 Multiply adjusted 1.0 0.99 (0.53, 1.88) 3.76 (1.36, 10.4) 0.17 Multiply adjustedFexcluding first 10 y 1.0 0.98 (0.48, 2.01) 3.02 (0.80, 11.4) 0.50 Multiply adjustedFexcluding first 20 y 1.0 0.89 (0.39, 2.06) 3.88 (0.96, 15.7) 0.48

aAge-adjusted mortality rates per 1000 person-years. bResults are hazards ratio (95% CI). cMultiply adjusted modelFadjusted for age, plus employment grade,

physical activity, smoking habit, marital status, disease at entry, weight loss in the last year, blood pressure-lowering medication, height adjusted FEV1, triceps skinfold thickness, systolic blood pressure, plasma cholesterol, glucose intolerance and diabetes status. dDeaths in the first 10 y of surveillance are excluded. eDeaths in the first 20 y of surveillance are excluded. fNo cases with which to compute a hazards ratio.

facilitated an examination of reverse causality; its prospec- adiposity. Although skinfold thickness was measured in the tive design; the measurement of a range of covariate data Whitehall study participants, readings were only taken at the including physical activity and socio-economic position; and triceps, rendering the data of little practical use. In contrast the definition of obesity and overweight which matches to many previous reports that focus on a single cancer site WHO criteria. These strengths notwithstanding, this study is rather than a range (perhaps in the interest of generating a not without its weaknesses. The assessment of obesity and greater number publications), we related obesity and over- overweight was based on BMI, an imperfect measure of weight to 16 mortality outcomes. Clearly, not all of the

International Journal of Obesity Obesity, overweight and cancer GD Batty et al 1273 relationships we examined were hypothesis driven. In so 3 World Cancer Research Fund/American Institute for Cancer doing we wished to gain insight into specificity of associa- Research. Food, nutrition and the prevention of cancer: a global tion,49 an important determinant of causality in observa- perspective. American Institute for Cancer Research: Washington; 50 1997. tional epidemiology. However, one disadvantage of this 4 IARC handbooks of cancer prevention. Weight control and physical approach is that some of our findings may have arisen by activity Vol 6. International Agency for Research on Cancer: chance. Additionally, the cancer outcomes reported herein Lyons, France; 2002. were based on mortality surveillance. Thus, our results reflect 5 Bianchini F, Kaaks R, Vainio H. Overweight, obesity, and cancer risk. Lancet Oncol 2002; 3: 565–574. the combined effect of weight on survival and incidence. 6 Batty GD. Confounding effect of socioeconomic position in the The suggestion has been made that the relation of weight to study of height in relation to prostate cancer risk (letter). Br J survival may be higher than that for incidence of some Cancer 2004; 90: 1875. cancers (eg breast).48 7 Batty GD, Thune I. Does physical activity prevent cancer? Evidence suggests protection against colon cancer and probably In conclusion, an elevated risk of mortality from carcino- breast cancer (editorial). BMJ 2000; 321: 1424–1425. ma of the rectum, bladder, colon, and liver, and for 8 Reid DD, Hamilton PJS, McCartney P, Rose G, Jarrett RJ, Keen H, lymphoma in men who were obese or overweight in Rose G. Cardiorespiratory disease and diabetes among middle- comparison to those in the normal weight group was aged male civil servants. Lancet 1974; i: 469–473. 9 Jarrett RJ, Shipley MJ, Rose G. Weight and mortality in the apparent in this cohort of London-based government Whitehall Study. Br Med J (Clin Res Edn) 1982; 285: 535–537. employees. Avoidance of obesity and overweight in adult 10 Jarrett RJ. Is there an ideal body weight? Br Med J (Clin Res Edn) life may therefore reduce the risk of developing these 1986; 293: 493–495. cancers. However, prevention and treatment of obesity is 11 Fitzgerald AP, Jarrett RJ. Body weight and coronary heart disease unlikely to be achieved through attempts to alter physical mortality: an analysis in relation to age and smoking habit. 15 51 years follow-up data from the Whitehall Study. Int J Obes Relat activity and dietary habits at the level of the individual. Metab Disord 1992; 16: 119–123. Rather, fundamental changes in environmental structure 12 Davey Smith G, Leon D, Shipley MJ, Rose G. Socioeconomic that includes ready access to amenities conducive to physical differentials in cancer among men. Int J Epidemiol 1991; 20: 339– activity (eg parkland) and retail outlets that provide a range 345. 52 13 Reid DD, Hamilton PJ, McCartney P, Rose G, Jarrett RJ, Keen H. of micronutrient-dense food sources is crucial. Smoking and other risk factors for coronary heart-disease in British civil servants. Lancet 1976; 2: 979–984. 14 Davey Smith G, Shipley MJ, Rose G. Intermittent claudication, Contributions heart disease risk factors, and mortality. The Whitehall Study. Circulation 1990; 82: 1925–1931. David Batty generated the idea for this paper; Martin Shipley 15 Rose G, McCartney P, Reid DD. Self-administration of a conducted all data analyses. David Batty wrote the first draft questionnaire on chest pain and intermittent claudication. Br J of the manuscript to which co-authors contributed. Prev Soc Med 1977; 31: 42–48. 16 Rose GA. The diagnosis of ischaemic heart pain and intermittent claudication in field studies. Bull World Health Organ 1962; 27: 645–658. Acknowledgements 17 Committee on the aetiology of chronic bronchitis. Definition We are grateful to the civil servants who gave of their time to and classification of chronic bronchitis. Lancet 1965; i: 775–779. 18 Ben Shlomo Y, Davey Smith G, Shipley M, Marmot MG. take part in the baseline study. The original screening of Magnitude and causes of mortality differences between married participants in the Whitehall study was funded by the and unmarried men. J Epidemiol Commun Health 1993; 47: 200– Department of Health and Social Security and the Tobacco 205. Research Council. Martin Shipley and Elizabeth Breeze are 19 Batty GD, Shipley M, Marmot M, Davey Smith G. Physical supported by the British Heart Foundation; activity and cause-specific mortality in men: further evidence from the Whitehall study. Eur J Epidemiol 2002; 17: 863–869. by the UK Medical Research Council (MRC). When work on 20 Batty GD, Shipley MJ, Marmot M, Davey Smith G. Physical this report began, David Batty was financed by the UK MRC activity and cause-specific mortality in men with type 2 diabetes/ at the London School of Hygiene and Tropical Medicine and impaired glucose tolerance: evidence from the Whitehall study. subsequently by a University Senior Research Fellowship at Diabetes Med 2002; 19: 580–588. 21 Rose G, Hamilton PS, Keen H, Reid DD, McCartney P, Jarrett RJ. the University of Copenhagen. He is now the recipient of a Myocardial ischaemia, risk factors and death from coronary Wellcome Advanced Training Fellowship. heart-disease. Lancet 1977; 1: 105–109. 22 Davey Smith G, Shipley MJ, Marmot MG, Rose G. Plasma cholesterol concentration and mortality. The Whitehall Study. JAMA 1992; 267: 70–76. References 23 Batty GD, Shipley M, Marmot M, Davey Smith G. Diabetes status 1 Actuarial Society of America and Association of Life Insurance and post-load plasma glucose concentration in relation to site- Directors. Medico-actuarial mortality investigation. Spector Com- specific cancer mortality: findings from the original Whitehall pany: New York; 1913. study. Cancer Causes Control 2004; 15: 873–881. 2 Whitlock G, Lewington S, Ni Mhurchu C. Coronary heart disease 24 Batty GD, Shipley MJ, Marmot MG, Davey Smith G. Blood and body mass index: a systematic review of the evidence from pressure and site-specific cancer mortality: evidence from the larger prospective cohort studies. Seminars in vascular medicine original Whitehall study. Br J Cancer 2003; 89: 1243–1247. (classical and emerging risk factors for , Part 2 25 Keen H, Thomas BJ, Jarrett RJ, Fuller JH. Nutrient intake, 2002. Vol 4, pp 369–381. adiposity, and diabetes. Br Med J 1979; 1: 655–658.

International Journal of Obesity Obesity, overweight and cancer GD Batty et al 1274 26 Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Over- 40 Chyou PH, Nomura AM, Stemmermann GN. A prospective study weight, obesity, and mortality from cancer in a prospectively of weight, body mass index and other anthropometric measure- studied cohort of US adults. N Engl J Med 2003; 348: 1625–1638. ments in relation to site-specific cancers. Int J Cancer 1994; 57: 27 Henley SJ, Flanders WD, Manatunga A, Thun MJ. Leanness and 313–317. lung cancer risk: fact or artifact? Epidemiology 2002; 13: 268–276. 41 Wolk A, Gridley G, Svensson M, Nyren O, McLaughlin JK, 28 Berrington dG, Sweetland S, Spencer E. A meta-analysis of obesity Fraumeni JF, Adam HO. A prospective study of obesity and cancer and the risk of pancreatic cancer. Br J Cancer 2003; 89: 519–523. risk (Sweden). Cancer Causes Control 2001; 12: 13–21. 29 World Health Organisation. Physical status: the use and interpreta- 42 Moller H, Mellemgaard A, Lindvig K, Olsen JH. Obesity and tion of anthropometry: report of a WHO expert committee WHO cancer risk: a Danish record-linkage study. Eur J Cancer 1994; 30A: Technical Report Series. WHO: Geneva; 1995. 344–350. 30 Anon. Manual of the international statistical classification of 43 Hill MJ. Nutrition and human cancer. Ann NY Acad Sci 1997; 833: diseases, injuries, and causes of death (8th revision). World Health 68–78. Organisation: Geneva; 1967. 44 Giovannucci E. Insulin and colon cancer. Cancer Causes Control 31 Anon. Manual of the international statistical classification of 1995; 6: 164–179. diseases, injuries, and causes of death (9th revision). WHO: Geneva; 45 Jones JI, Clemmons DR. Insulin-like growth factors and 1977. their binding proteins: biological actions. Endocr Rev 1995; 16: 32 Anon. International statistical classification of diseases and related 3–34. health problems (10th revision). WHO: Geneva; 1992. 46 Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM, 33 Cox DR. Regression models and life-tables. J Roy Stat Soc Ser B Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein- 1972; 34: 187–220. 3, and cancer risk: systematic review and meta-regression 34 Davey Smith G, Shipley MJ, Batty GD, Morris JN, Marmot M. analysis. Lancet 2004; 363: 1346–1353. Physical activity and cause-specific mortality in the Whitehall 47 Thissen JP, Ketelslegers JM, Underwood LE. Nutritional regulation study. Public Health 2000; 114: 308–315. of the insulin-like growth factors. Endocr Rev 1994; 15: 80–101. 35 Coleman MP, Rachet B, Woods LM, Mitry E, Riga M, Cooper N, 48 Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Quinn MJ, Brenner H, Esteve J. Trends and socioeconomic Overweight, obesity, and mortality from cancer in a prospectively inequalities in cancer survival in England and Wales up to studied cohort of US adults. N Engl J Med 2003; 348: 2001. Br J Cancer 2004; 90: 1367–1373. 1625–1638. 36 SAS Institute Inc. SAS/STAT(R) user’s guide Version 6, volumes 1 & 49 Weiss NS. Can the ‘specificity’ of an association be rehabilitated 2. SAS Institute Inc.: Cary, NC; 1989. as a basis for supporting a causal hypothesis? Epidemiology 2002; 37 Haenszel W, Correa P. Cancer of the large intestine: epidemiolo- 13: 6–8. gic findings. Dis Colon Rectum 1973; 16: 371–377. 50 Bradford Hill A. The environment and disease: association or 38 Tamakoshi K, Wakai K, Kojima M, Watanabe Y, Hayakawa N, causation? Proc Roy Soc Med 1965; 58: 295–300. Toyoshima H, Yatsuya H, Kondo T, Tokudome S, Hashimoto S, 51 Batty GD, Lee IM. Physical activity and coronary heart disease. Suzuki K, Ito Y, Tamakoshi A, JACC Study Group. A prospective BMJ 2004; 328: 1089–1090. study of body size and colon cancer mortality in Japan: The JACC 52 Davey Smith G, Gunnell D, Ben-Shlomo Y. Life-course ap- Study. Int J Obes Relat Metab Disord 2004; 28: 551–558. proaches to socio-economic differentials in cause-specific adult 39 Nomura A, Heilbrun LK, Stemmermann GN. Body mass index as mortality. In: Leon D, Walt G (eds) Poverty, inequality and health. a predictor of cancer in men. J Natl Cancer Inst 1985; 74: 319–323. An international perspective 2001. OUP: Oxford.

International Journal of Obesity