Risk factors for pancreatic cancer mortality: extended follow-up of the original Whitehall study

Abstract

Given the well-established links between diabetes and elevated rates of pancreatic cancer, there are reasons to anticipate that other markers of metabolic abnormality (raised body mass index, plasma cholesterol, and blood pressure) and their correlates (physical activity and socio-economic status) may also confer increased risk of pancreatic cancer. However, to date, the results of a series of population-based cohort studies are inconclusive. We examined these associations in the original Whitehall cohort study of 17,898 men. A maximum of thirty-eight years of follow-up gave rise to 163 deaths due to carcinoma of the pancreas. While Poisson regression analyses confirmed established risk factor disease associations for increasing age, smoking and type II diabetes, there was essentially no evidence that body mass index (rate ratio; 95% confidence interval per one SD increase: 1.01; 0.86, 1.18), plasma cholesterol (per one SD increase: 0.91; 0.78, 1.07), diastolic blood pressure (per one SD increase: 0.93; 0.78, 1.09), systolic blood pressure (per one SD increase: 0.98; 0.83, 1.15), physical activity (sedentary vs. high: 1.37; 0.89, 2.12), or socio-economic status (clerical[low] vs. professional/executive: 0.95; 0.59, 1.51) offered any predictive value for pancreatic cancer mortality. These results were unchanged following control for a range of covariates.

Introduction

Pancreatic cancer is a relatively rare malignancy but a major cause of cancer mortality worldwide (1;2): because conventional treatments are essentially ineffective (3), fewer than 4% of cases survive five years after diagnosis (4;5). Despite the crucial importance of primary prevention for such a near-lethal neoplasm, little is known about its risk factors beyond increased age, family history, smoking, and diabetes (3). Obesity and physical activity, by dint of their link with diabetes, have been implicated in pancreatic cancer aetiology, but findings suggest that any increased occurrence of this neoplasm in the obese may be modest (6), particularly in men (7), and evidence for physical exertion is inconclusive with both inverse (8;9) and null (10-12) associations reported. Other metabolic abnormalities such as raised levels of blood pressure (13-15) and blood cholesterol (15-17), although examined in few studies, generally show no effect. Furthermore, the evidence that socio-economic disadvantage, by which all of the afore described risk factors are patterned, may confer increased risk of carcinoma of the pancreas is uncertain with opposing gradients reported (10;18).

We contribute to this highly inconclusive and scant literature, much of which is derived from under-powered studies, by focusing on the role of obesity, physical activity, raised blood pressure, elevated cholesterol and socio-economic disadvantage as potential risk factors for pancreatic cancer in an extended follow-up of a large prospective cohort of male office workers.

Materials and Methods

In the Whitehall study, data were collected on 19,019 male, non-industrial, government employees aged from 40 to 69 years when examined between 1967 and 1970 in London (UK), representing a 77% response (19). This involved the completion of a study questionnaire and participation in a medical examination, both of which have been described in detail elsewhere (19). In brief, the questionnaire included enquiries regarding civil service employment grade (an indicator of socio-economic status (20)), smoking habits (21), marital status (22), and physical activity(23;24). Blood pressure (13), height (25), weight (26), pulmonary function (indexed by forced expiratory volume in one second, FEV1) (27), and, following an overnight fast, plasma cholesterol (17) and post-challenge blood glucose concentration (28), were all determined using standard protocols (19). Body mass index (BMI) was computed using the standard formulae (weight[kg]/height²[m²]).

A total of 18,863 men (99.2% of participants in baseline survey) were traced using the UK National Health Service Central Registry and pancreatic cancer deaths were ascertained from death certificates (coded as ICD 8/9: 157, ICD 10: C25). The present analyses are based on 17,898 men with complete data. The person years of follow-up for each man was partitioned by age at risk using 5-years age groups. To summarise the relationship between each risk factor and pancreatic cancer we used Poisson regression which produced rate ratios (RRs) with accompanying 95% confidence intervals. These analyses were first adjusted for age at risk and then fully adjusted for all potential confounding and mediating factors (BMI, plasma cholesterol, diastolic and systolic blood pressure, physical activity, socio-economic status, diabetes/blood glucose, marital status, FEV1, height, age at risk, smoking).

Results

During a maximum of 38 years of follow-up there were 12,797 deaths from all-causes in the present analytical sample, 163 (1.3%) of which were ascribed to pancreatic cancer. We were able to replicate the few well established risk factor disease associations for pancreatic cancer. Thus, in age-adjusted analyses, current (RR; 95% confidence interval: 1.52; 0.94, 2.46) and former smokers (1.72; 1.07, 2.77) relative to non-smokers, and men with type II diabetes (2.47; 0.79, 7.75) relative to those who were free of this condition, all experienced an elevated risk of this malignancy. Age itself also revealed the expected positive association with pancreatic cancer mortality (RR per 10 y increase: 2.10; 1.79, 2.46).

In table 1 we show the associations between a series of other potential risk factors for carcinoma of the pancreas. Body mass index, plasma cholesterol and socio-economic position were all unrelated to pancreatic cancer risk. Similarly, neither component of blood pressure predicted the occurrence of this malignancy. There was a modest elevated risk in the least physically active men that, again, did not attain statistical significance at conventional levels, and there was no evidence of a dose-response effect across the exercise groups.

Table 1.

Risk factors for pancreatic cancer mortality in the original Whitehall Study (N=17,898)

		No. deaths / no. men	Rate ratio (95% confidence intervals)
			Age-adjusted	Multiple-adjustment*
Body mass index (kg/m2)	Tertile 1	53 / 5969	1.0	1.0
	Tertile 2	54 / 5994	0.98 (0.67, 1.43)	1.02 (0.69, 1.50)
	Tertile 3	56 / 5935	1.10 (0.75, 1.60)	1.18 (0.79, 1.75)
	Per 1 SD (2.98 kg/m2) increase		1.01 (0.86, 1.18)	1.03 (0.87, 1.23)
Plasma cholesterol (mmol/l)	Tertile 1	56 / 6124	1.0	1.0
	Tertile 2	69 / 5733	1.32 (0.93, 1.88)	1.32 (0.93, 1.88)
	Tertile 3	38 / 6041	0.71 (0.47, 1.07)	0.73 (0.48, 1.10)
	Per 1 SD (1.21mmol/l) increase		0.91 (0.78, 1.07)	0.92 (0.78, 1.08)
Diastolic blood pressure (mmHg)	Tertile 1	63 / 5687	1.0	1.0
	Tertile 2	50 / 6219	0.75 (0.52, 1.09)	0.75 (0.52, 1.10)
	Tertile 3	50 / 5991	0.88 (0.61, 1.28)	0.89 (0.60, 1.31)
	Per 1 SD (13.8 mmHg) increase		0.93 (0.78, 1.09)	0.92 (0.77, 1.10)
Systolic blood pressure (mmHg)	Tertile 1	59 / 5870	1.0	1.0
	Tertile 2	57 / 6042	0.97 (0.67, 1.39)	0.96 (0.67, 1.39)
	Tertile 3	47 / 5986	0.92 (0.63, 1.36)	0.93 (0.62, 1.38)
	Per 1 SD (21.2 mmHg) increase		0.98 (0.83, 1.15)	0.98 (0.83, 1.17)
Physical activity	High	33 / 2955	1.0	1.0
	Moderate	78 / 9339	0.93 (0.66, 1.33)	0.92 (0.65, 1.30)
	Sedentary	52 / 5604	1.37 (0.89, 2.12)	1.32 (0.84, 2.06)
Socio-economic position	Administrative (highest SES)	13 / 908	1.43 (0.80, 2.54)	1.43 (0.80, 2.55)
	Professional/executive	106 / 11652	1.0	1.0
	Clerical	21 / 2823	0.95 (0.59, 1.51)	1.00 (0.62, 1.63)
	Other (lowest SES)	16 / 1678	1.29 (0.76, 2.18)	1.29 (0.74, 2.25)
	BC & DS‡	7 / 837	0.94 (0.44, 2.02)	0.99 (0.46, 2.13)

^#Person years at risk are shown for age at risk categories.

^‡British Council & Diplomatic Service included as a separate category since grade levels are not comparable with other civil service departments.

^*multiple adjustment is adjustment for BMI. plasma cholesterol, physical activity, socio-economic status, diabetes/blood glucose, marital status, FEV1, height, age at risk, smoking, and diastolic and systolic blood pressure (estimates for components of blood pressure are not mutually adjusted).

Discussion

In this large prospective cohort study with almost complete follow-up of its members, there was little suggestion that a series of indicators of metabolic abnormalities, or their correlates, all of which have been hypothesised, by us and other groups, to influence pancreatic cancer risk, actually revealed any relationships, either with or without adjustment for potential confounders. These results accord with the generally null findings from a series of other studies for body mass index (in men) (7), plasma cholesterol (15-17), blood pressure (13-15), physical activity (10-12) and socioeconomic position (18) – including those from earlier follow-ups of the present cohort for some of these risk factors which were based on substantially fewer deaths (13;20;23;26).

This study has several strengths, including: its large sample size which leads to a greater number of pancreatic cancer events than many other studies, prospective design, statistical control of a range of potential mediating and confounding variables, and almost complete follow-up for mortality. Weaknesses include the absence of measurement of other potential risk factors such as dietary characteristics, including alcohol and meat consumption (29). While three day food intake diaries were in fact administered in the present study, this was only in a subset of fewer than 2000 men (26) in which the number of pancreatic cancer deaths is too low to facilitate analyses. A second study limitation is the absence of repeat measurement of these risk factors over time, a common shortcoming in this field. However, given that this dataset revealed the established risk factor--disease gradients for age, diabetes and smoking in relation to pancreatic cancer, there is a suggestion that our null results should be trusted.

In conclusion, while confirming previously well demonstrated risk factors, we found little or no evidence that potentially modifiable risk factors (body mass index, plasma cholesterol, blood pressure, physical activity) or socio-economic status were associated with pancreatic cancer mortality. Examination of other potential risk factors, including dietary characteristics, is important in order to increase understanding of the aetiology of pancreatic cancer and to identify targets for primary prevention.