Non-linear dose–response relationship between cigarette smoking and pancreatic cancer risk: Evidence from a meta-analysis of 42 observational studies

https://doi.org/10.1016/j.ejca.2013.08.014Get rights and content

Abstract

Background

Question remains about the shape of the dose–response relationship between cigarette smoking and pancreatic cancer risk.

Methods

Relevant studies were identified by searching PubMed, ISI Web of Science and China National Knowledge Infrastructure (CNKI) databases and by reviewing the reference lists of retrieved articles. Random-effects models were applied to estimate summary relative risks (RRs).

Results

Forty-two publications were finally included. The overall meta-analysis showed evidence of non-linear association between smoking intensity and pancreatic cancer risk (P for non-linearity = 0.000). Compared with non-smokers, the summary RRs were 1.5 (95% confidence interval (CI): 1.4, 1.6) for 10 cigarettes/day, 1.9 (95% CI: 1.8, 2.0) for 20 cigarettes/day, 2.0 (95% CI: 1.9, 2.1) for 30 cigarettes/day and 2.1 (95% CI: 1.9, 2.3) for 40 cigarettes/day with marginal between-study heterogeneity (I2 = 29%). Similar results were also found for smoking duration and cumulative amount of cigarettes smoked. Besides, the summary RR for former smokers reduced with increasing time since quitting smoking compared with current smokers without heterogeneity (P for non-linearity = 0.008, I2 = 0%). The results of stratified analysis by study design were comparable to those of overall meta-analysis. When stratified by sex, non-linear dose–response associations were detected for all metrics of cigarette smoking in women, while linear relationships were observed for smoking duration and cumulative amount of cigarettes smoked in men except for smoking intensity.

Conclusion

This meta-analysis reveals a non-linear dose–response association between cigarette smoking and pancreatic cancer risk, but it might differ between sexes.

Introduction

Pancreatic cancer, as one of the most lethal human cancers, accounts for 266,000 deaths per year worldwide [1]. According to the epidemiological data, pancreatic cancer is the fourth leading cause of cancer death in United States [2], the fifth in Europe [3] and the sixth in China [4]. Since there are no effective methods for early detection and treatment as yet, less than 6% of cases survive 5 years after diagnosis [2], [5], emphasising the importance of primary prevention through alteration of modifiable risk factors.

To date, cigarette smoking is the most consistent aetiological factor for pancreatic cancer, responsible for approximately 20% of pancreatic cancer cases [6]. In addition, ample evidence has shown that smoking is an independent risk factor for chronic pancreatitis and diabetes mellitus which are suggested to confer the risk of pancreatic cancer [7], [8], [9]. A meta-analysis conducted in 2007 indicated that compared with never smokers, the overall risk of pancreatic cancer was 1.7 (95% confidence interval (CI): 1.6, 1.9) for current smokers and persisted for a minimum of 10 years after smoking cessation. Besides, its linear dose–response analysis showed that the risk increased with the number of cigarettes smoked and the duration, although limited estimates (e.g. 1 or 20 cigarette(s)/day for smoking intensity) were obtained [6]. Then another meta-analysis synthesising the publications on observational studies up to 2008 suggested that the magnitude of the positive association between cigarette smoking and pancreatic cancer greatly relied on the quality of included studies [10]. In a pooled-analysis comprising eight nested case-control studies in 2009, the risk of pancreatic cancer was observed to significantly increase with greater intensity (⩾30 cigarettes/day), duration (⩾50 years) and cumulative amount (⩾40 pack-years), whereas null association was found in lower categories. The odds ratio (OR) for those who had abstained from smoking for more than 15 years decreased to that for never smokers [11]. Additionally, Matsuo et al. reported a relative risk (RR) for ever smokers relative to never smokers of 1.7 (95% CI: 1.4, 2.1) in the Japanese population by combining four cohort and three case-control studies in 2011 [12]. Moreover, a pooled-analysis from the International Pancreatic Cancer Case-Control Consortium in 2012 demonstrated that the OR was 2.2 (95% CI: 1.7, 2.8) for current smokers. Among current smokers, a significant increasing trend in risk was detected with increasing number of cigarettes smoked, however, a significant decreasing trend was found with increasing time since quitting smoking [13]. Although multiple meta- and pooled-analyses have confirmed the role of cigarette smoking in pancreatic cancer risk, the association between lower exposure to cigarettes and the risk remains elusive. Besides, given that accumulating evidence has shown non-linear dose–response relationships between cigarette smoking and oesophageal [14], gastric [15] and lung cancers [16], this relationship is also speculated to be present in pancreatic cancer. Thus, we performed a dose–response meta-analysis of retrospective and prospective studies to provide a more precise evaluation for the potential non-linear association between cigarette smoking and pancreatic cancer risk.

Section snippets

Literature search and selection

Pertinent English-language articles were identified by searches of PubMed and ISI Web of Science databases from their inception to 14th November 2012 using the key words cigarette, smoking or tobacco combined with pancreatic tumour, pancreatic cancer or pancreatic neoplasia. To expand the coverage of our retrieval, we further performed searches in China National Knowledge Infrastructure (CNKI) database based on the above searching strategy. Besides, the reference lists of retrieved articles

Study characteristics

Fig. S1 shows the literature search and study selection procedures. Our literature search identified 1256 publications, of which 1071 were excluded after review of title and abstract. 147 publications were further excluded after review of full-text because of the following reasons: no report of the association between cigarette smoking and pancreatic cancer risk (19 studies), without a case-control, nested case-control or cohort design (32 studies), data duplication (17 studies) and lack of

Discussion

Findings from the overall meta-analysis comprising 30 retrospective and 12 prospective studies indicated that there were non-linear dose–response associations between intensity and duration of smoking, cumulative amount of cigarettes smoked, time since quitting smoking and pancreatic cancer risk. The RRs of pancreatic cancer increased with cigarette consumption, but then leveled off at high intensities. Our study, to the best of our knowledge, firstly explores the precise effect of cigarette

Role of the funding source

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest statement

None declared.

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    Funding: This work was supported by the National Natural Science Foundation of China [NSFC-81001275, 81171878, 81222038 to Xiaoping Miao].

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