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Aspirin use and risk for lung cancer: a meta-analysis
original article
Annals of Oncology 22: 2456–2465, 2011 doi:10.1093/annonc/mdq779 Published online 8 March 2011
Aspirin use and risk for lung cancer: a meta-analysis S.-W. Oh1, S.-K. Myung2*, J. Y. Park3, C. M. Lee1 & H. T. Kwon1 Korean Meta-analysis (KORMA) Study Group 1 Department of Family Medicine, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul; 2Cancer Epidemiology Branch, Research Institute, National Cancer Center, Goyang; 3Department of Family Medicine, Kwangdong Oriental Hospital, Seoul, Korea
Received 4 November 2010; revised 17 December 2010; accepted 20 December 2010
original article
Background: Aspirin has received increasing attention owing to its potential as a chemopreventive agent against lung cancer. Previous observational studies have reported inconsistent findings on this issue. We investigated the association between aspirin use and risk for lung cancer by conducting a meta-analysis. Patients and methods: Relevant studies were identified by searching Medline, EMBASE, and Cochrane Library to December 2009. We also reviewed relevant bibliographies from the retrieved articles. Two authors independently extracted data and assessed study quality. Disagreements were resolved by consensus. Results: Fifteen studies (six case–control studies and nine prospective cohort studies) were included in the final meta-analysis. When all studies were pooled, the odds ratio (OR) of aspirin use for lung cancer risk was 0.86 [95% confidence interval (CI) 0.76–0.98]. In subgroup meta-analyses, there was no association between aspirin use and lung cancer risk among cohort studies (relative risk, 0.97; 95% CI 0.87–1.08), while there was a significant association among case–control studies (OR, 0.74; 95% CI 0.57–0.99). In a subgroup meta-analysis by quality of study methodology, a significant protective effect of aspirin use on lung cancer was observed only among eight low-quality studies (OR, 0.82; 95% CI 0.68–0.99), but not among seven high-quality studies (OR, 0.90; 95% CI 0.76–1.07). Conclusions: Overall, the findings of this meta-analysis support that there was no association between aspirin use and lung cancer risk. Our findings should be confirmed in future prospective cohort studies or randomized, controlled trials. Key words: aspirin, lung cancer, meta-analysis, NSAIDs
introduction Lung cancer is the leading cause of cancer deaths worldwide. Although smoking is a well-established etiological factor for lung cancer [1], other causes remain unclear. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have received increasing attention owing to their potential as chemopreventive agents against cancer. It has been proposed that aspirin influences cancer risk primarily through its effect on cyclooxygenase (COX) activity [2–9]. In experimental animal models, aspirin and other NSAIDs have been reported to suppress tumor growth [2, 3]. Observational epidemiological investigations and meta-analyses suggested that regular aspirin use is associated with a reduced risk for cancers of the esophagus [4], stomach [5, 6], colon [7, 8], prostate [9], and breast [10]. Several observational studies have examined the relationship between aspirin and other NSAIDs use and lung cancer, with inconsistent results. According to a meta-analysis of 14 observational studies between 1998 and 2003, the odds ratio *Correspondence to: Dr S.-K. Myung, Cancer Epidemiology Branch, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do 410-769, Korea. Tel: +82-31-920-0479; Fax: +82-31-920-2606; E-mail: [email protected]
(OR) was 0.73 [95% confidence interval (CI) 0.63–0.86] for aspirin use and 0.79 (95% CI 0.66–0.95) for NSAID use [11]. In a quantitative review concerning aspirin use and lung cancer risk in 2006, a pooled relative risk (RR) was 0.70 (95% CI 0.56–0.88) for two case–control studies and 0.96 (95% CI 0.91–1.02) for six cohort studies [12]. Recently, two large randomized trials with post-trial follow-up for >20 years have reported no association between regular aspirin use and lung cancer risk [13]. The purpose of the current study was to investigate the association between aspirin use and lung cancer risk by conducting a meta-analysis of observational studies such as case–control studies and cohort studies by type of study design, quality of study methodology, aspirin dose, duration of aspirin use, smoking status, and histology of lung cancer.
methods search strategy We searched Medline (PubMed) (from 1968 to December 2009), EMBASE (from 1977 to December 2009), and the Cochrane Library (from 1953 to December 2009) using selected common key words regarding aspirin, NSAIDs, and lung cancer in observational epidemiological studies such as
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original article
Annals of Oncology
case–control studies and cohort studies; these searches were carried out by one of the authors (S-WO) and then confirmed by another author (S-KM). We also scanned the bibliographies of relevant articles to identify additional studies. As the key words for the literature search, we selected ‘aspirin’, ‘nonsteroidal anti-inflammatory drugs’, and ‘NSAIDs’ for the exposure factors, and ‘lung cancer’ and ‘pulmonary neoplasm’ for the outcome factors.
eligibility criteria We included case–control studies and cohort studies reporting an association between aspirin use and lung cancer risk using ORs or RRs. The current study included only articles written in English. We excluded those studies with no available data for outcome measures, having the same population as other studies (in this case, the first published or more comprehensive study was included in the analysis), having data on mortality only, and reporting standardized incidence ratios (SIRs).
data extraction All studies retrieved from databases and bibliographies were independently evaluated by two authors of this article (S-WO and S-KM). Disagreements between the evaluators concerning the selected studies were resolved by consensus or in consultation with the third author (JYP). Of the articles found in the three databases, duplicate articles and those that did not meet the selection criteria were excluded. We extracted the following data from the remaining studies: study name (first author, year of publication), journal name, country and design, years enrolled, characteristics and study population age range, exposure assessment, definition of aspirin use, OR or RR with 95% CI, and adjustments. Data abstraction was also carried out by two evaluators, as was study selection. The methodological quality of the included studies was assessed using the 9-star Newcastle–Ottawa scale for quality of nonrandomized studies in meta-analyses [14]. We considered a high-quality study as one awarded star more than the average stars of the included studies with the same study design since there are no established standard criteria to date. The mean value for the 15 studies assessed was 6.4 stars.
statistical analysis Adjusted data (adjusted OR or RR with 95% CI) were used for the metaanalysis whenever possible. For the exposure factor, we chose the highest and lowest levels of aspirin use among the various categories in each study (Table 1). We also carried out subgroup analyses by quality of study methodology, gender, study design type (case–control studies versus cohort studies; for the selection of cases and controls, we classified a nested case– control study into a cohort study in the current study), aspirin dose [low dose (£100 mg) or high dose (>100 mg)], duration of aspirin use [short term (<5 years) or long term (‡5 years)], smoking status (current, former, or never smokers), and histology of lung cancer (adenocarcinoma, squamous cell carcinoma, or small-cell carcinoma). The test of heterogeneity in results across studies was carried out using Higgins I2, which measures the percentage of total variation across the studies. I2 is calculated as follows:
I 2 =100% · ðQ2df Þ=Q where Q is the Cochran’s heterogeneity statistic and df the degrees of freedom. Negative values of I2 are set at zero so that I2 exists between 0% (no observed heterogeneity) and 100% (maximal heterogeneity) [30]. An I2 value >50% was considered to show substantial heterogeneity. We estimated a pooled OR or RR with a 95% CI on the basis of both fixedeffects and random-effects models. When substantial heterogeneity was not found (i.e. if I2 £50%), the pooled estimate based on the fixed-effects model
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was represented. When substantial heterogeneity was found (i.e. if I2 >50%), the pooled estimate based on the random-effects model was represented. The Woolf’s method (inverse variance method) was used for a fixedeffects analysis [31] and the DerSimonian–Laird’s method for a randomeffects analysis [32]. We used Begg’s funnel plot and Egger’s test to identify publication bias. If the funnel plot was asymmetrical or the P value was <0.05 by Egger’s test, then we assessed that there was publication bias. We used the Stata SE version 10.0 software package (StataCorp, College Station, TX) for the statistical analysis.
results literature search In total, 15 studies (6 case–control studies and 9 prospective cohort studies) published between 1989 and 2009 were included in the final analysis. Figure 1 shows a flow diagram, identifying the relevant studies. We identified 1244 articles from the three databases and the bibliographies of relevant articles. After the exclusion of duplicates (n = 139), all remaining articles screened (n = 1105) were reviewed according to their titles and abstracts. Of the 1105 articles, we excluded 1079 articles that did not meet the selection criteria. After reviewing the full text for the remaining 26 articles, we included 15 articles in the final analysis. The main reasons for excluding studies from the final review (n = 11) were as follows: insufficient data (n = 6) [33–38], identical cohort (n = 1) [39], mortality data only (n = 2) [40, 41], and use of SIRs as an outcome measure (n = 2) [42, 43]. study characteristics Table 1 shows the main characteristics of all the studies included in the final analysis. The study design types were as follows: hospital-based case–control studies (n = 4) [15–18], populationbased case–control studies (n = 2) [19, 20], nested case–control studies (n = 2) [23, 26], and prospective cohort studies (n = 7) [21, 22, 24, 25, 27–29]. The countries where the studies had been carried out were as follows: the United States (n = 13) [15–18, 20–25, 27–29], the UK (n = 1) [26], and Denmark (n = 1) [19]. The range of enrollment periods for participants across studies was 1971–2007. In the nine cohort studies (nested case–control studies and prospective cohort studies), we identified a total of 9262 cases among 467 831 participants. quality of study methodologies Table 2 shows the quality of study methodology included in the final meta-analysis. The range of quality scores was 4–8; the average score was 6.5. The average scores (standard deviation) of case–control studies and cohort studies were 5.5 (0.57) and 7.1 (0.98), respectively. The high-quality studies (above each study type average) included three of six case–control studies and four of nine cohort studies. overall use of aspirin and the risk for lung cancer Figure 2 shows the effect of aspirin use on lung cancer risk in a meta-analysis of all studies, including both case–controls studies and prospective cohort studies. In a random-effects meta-analysis of all 15 studies, the overall use of aspirin
doi:10.1093/annonc/mdq779 | 2457
Study (reference)
Country; design
Years enrolled
Population (age, years)
Exposure assessment
Definition of use (highest category)
OR or RR (95% CI)
Adjustments
Case–control studies 1 Moysich et al. [15]
BMC Cancer
1982–1998
868 cases and 935 controls (62)
Questionnaire
>1 tablet/week for at least 1 year
0.57 (0.41–0.78)
Age, education, and pack-years of cigarettes
2
Muscat et al. [16]
Cancer
1992–2000
1038 cases and 1002 controls
Interview
3 tablets/week for ‡1 year
0.84 (0.62–1.14)
3
Harris et al. [17]
Int J Biol Sci
United States; case–control (hospital based) United States; case–control (hospital based) United States; case–control (hospital based)
2002–2004
492 cases and 984 controls
Interview
‡2 times/week for ‡2 years
0.53 (0.34–0.82)
4
Kelly et al. [18]
Pharmacoepidemiol Drug Saf
United States; case–control (hospital based)
1976–2007
1883 cases and 6251 controls (18–79)
Interview
5
Olsen et al. [19]
Br J cancer
Denmark; case–control (population based)
2002–2005
573 cases and 857 controls (64)
6
Van Dyke et al. [20]
Cancer Epidemiol Biomarkers Prev
United States; case–control (hospital based)
2001–2005
581 cases and 541 controls; women (18–74)
Interview, mailed questionnaire, and database Interview
At least 4 days/ week for at least 3 continuous months ‡0.5 prescriptions/ year in 1–3 years before index date
Age, gender, years of education, and packyears of smoking Pack-years of cigarette smoking, age, body mass, gender, ethnicity, family history, arthritis, and alcohol intake Age, sex, study region, interview year, years of education, alcohol use, and cigarette pack-years Age, sex, study, smoking habit, education, and use of acetaminophen Age, race, education, smoking pack-years, BMI, family history of lung cancer, COPD, arthritis, and cardiovascular disease
BMJ
United States; prospective cohort United States; prospective cohort
1981–1985
111 cases among 13 987 residents (73) 163 cases among a population of 12 668 (25–74)
Cohort studies 1 Paganini-Hill et al. [21] 2 Schreinemachers et al. [22]
Epidemiology
1971–1975
1.1 (0.9–1.4)
0.75 (0.49–1.14)
‡3 times/week for at least 1 month
0.66 (0.46–0.94)
Mailed questionnaire Interview
Daily use at start date Ever use in past 30 days
0.92 (0.54–1.55)
Age
0.68 (0.49–0.94); women: 1.40 (0.74–2.66); men: 0.54 (0.37–0.80) 0.66 (0.34–1.28)
Age and gender; women: age; men: age, race, education, smoking, and alcohol Age, menopausal status, dates of enrollment and follow-up, smoking, and educational status Age, age at started to smoke regularly, and smoking status
3
Akhmedkhanov et al. [23]
Br J cancer
United States; nested case–control (population based)
1985–1991
81 cases and 808 controls; women (35–69)
Mailed questionnaire
‡3 times/week for at least 6 months
4
Holick et al. [24]
Br J Cancer
United States; prospective cohort
1989–1995
328 cases among 51 529 male (40–75)
Mailed questionnaire
‡2 times/week at start date
0.89 (0.47–1.67)
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Journal
original article
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Table 1. Characteristics of studies of aspirin and lung cancer risk included in the final analysis (n = 15)
Journal
Country; design
Years enrolled
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Population (age, years)
Exposure assessment
Definition of use (highest category)
OR or RR (95% CI)
Adjustments
5
Hayes et al. [25]
Cancer Epidemiol Biomarkers Prev
United States; prospective cohort
1986
403 cases among 41 836 women (55–69)
Mailed questionnaire
Frequency of use (‡6 times/week)
1.08 (0.81–1.45)
1995–2004
4336 cases and 10 000 controls (40–84)
Database
For >1 year, 1-year lag time
1.15 (0.99–1.34)
United States; prospective cohort
1976
1360 cases among 109 348 women (36–82)
Mailed questionnaire
1.00 (0.86–1.16)
J Natl Cancer Inst
United States; prospective cohort
1992–1993
1815 cases among 69 810 men and 76 303 women
Mailed questionnaire
At least 1 tablet/ week or 1 day/ week of regular use for the past 2 years Days per month (current daily use, ‡5 year)
Age, education, alcohol intake, smoking status, pack-years, BMI, total fruit servings, and history of heart disease Age, sex, smoking, smoking cessation advice by general practitioner, smoking cessation treatment, BMI, alcohol intake, COPD, hypertension, CVD, IHD, arthritis, number of visits to general practitioner, number of referrals, and use of oral corticosteroids, antihypertensives, and statins Age, smoking status, age at start of smoking, years since quit smoking, and cigarettes per day
6
Herna´ndez-Dı´az et al. [26]
Int J Cancer
UK; nested case–control (population based)
7
Feskanich et al. [27]
Br J Cancer
8
Jacobs et al. [28]
9
Slatore et al. [29]
Cancer Epidemiol Biomarkers Prev
United States; prospective cohort
2000–2002
665 cases among a population of 77 125 (50–76)
Mailed questionnaire
10-year average use (third tertile)
0.90 (0.71–1.15)
0.98 (0.76–1.25)
Age, sex, race, education, smoking, BMI, physical activity level, use of HRT, use of nonaspirin NSAIDs, and history of heart attack, diabetes, and hypertension Age, sex, years smoked, packyears, pack-years squared, and acetaminophen use
OR, odds ratio; RR, relative risk; CI, confidence interval; BMI, body mass index; NSAIDs, non-steroidal anti-inflammatory drugs; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; IHD, ischemic heart disease; HRT, hormone replacement therapy.
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Table 1. (Continued)
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Figure 1. Flow diagram of identification of relevant studies. RR, relative risk.
significantly decreased lung cancer risk (OR, 0.86; 95% CI 0.76– 0.98; I2 = 61.8%). In a subgroup meta-analysis of case–control studies, aspirin use significantly decreased lung cancer risk (OR, 0.74; 95% CI 0.57–0.99; I2 = 70.4%) based on a random-effects model. However, no association between aspirin use and lung cancer risk was observed in a subgroup meta-analysis of cohort studies (RR, 0.97; 95% CI 0.87–1.08; I2 = 30.0%) based on a fixedeffects model. When a study without adjustment for smoking [21] was excluded from the analysis of cohort studies, the result was not changed (data not shown). A significant publication bias was found in the selected 15 studies (Begg’s funnel plot, asymmetrical; Egger’s test, P for bias = 0.006) (Figure 3). There was also a significant publication bias in the six case–control studies (Egger’s test, P for bias = 0.042), while there was no publication bias in the nine cohort studies (Egger’s test, P for bias = 0.082).
subgroup meta-analyses Table 3 shows the effects of aspirin use on lung cancer risk in subgroup meta-analyses by quality of study methodology, gender, aspirin dose, duration of aspirin use, smoking status, and lung cancer histology. Significant protective effects of aspirin use on lung cancer were observed among the eight low-quality studies (OR, 0.82; 95% CI 0.68–0.99) but not among the seven high-quality studies (OR, 0.90; 95% CI 0.76–1.07) (Table 3). There was no significant association between aspirin use and lung cancer risk regardless of the duration of aspirin use (short term, <5 years; long term, ‡5 years), aspirin dose (low dose, <100 mg; high dose ‡100 mg), smoking status (current, former,
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or never), or lung cancer histology (adenocarcinoma, squamous cell carcinoma, or small-cell carcinoma). Aspirin use was associated with a decreased lung cancer risk for men (OR, 0.62; 95% CI 0.48–0.62), while there was no evidence of a preventive effect for women (OR, 0.73; 95% CI 0.50–1.06).
discussion The findings from this meta-analysis of epidemiological studies, including case–control and cohort studies, indicate that aspirin use was associated with a decreased risk for lung cancer. However, in the subgroup meta-analyses by study design, cohort studies showed no significant decreased risk for lung cancer with aspirin use, while case–control studies showed a significant preventive effect. These inconsistent findings between two different study designs can be explained by the quality of the study methodologies, included in the current study. Overall, case– control studies had a lower mean score than cohort studies, namely, 5.5 and 7.1, respectively. In the subgroup meta-analyses by study quality, significant protective effects of aspirin use on lung cancer were observed only among low-quality studies. Additionally, most of the included studies in our study used self-administered questionnaires or interviews for the assessment of aspirin use, regarding the item of ‘ascertainment of exposure’. Results from observational studies that collected exposure information through questionnaires or retrospective personal interviews without blinding are susceptible to recall bias or selection bias. If the relatively healthy aspirin users were more likely to participate in the study than nonusers, especially
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Table 2. Methodological quality of studies included in the final analysis, based on the Newcastle–Ottawa scale for assessing the quality of case–control studies and cohort studies Case–control studies (n = 6)
Selection Adequate definition of cases
1 2 3 4 5 6
Moysich et al. [15] Muscat et al. [16] Harris et al. [17] Kelly et al. [18] Olsen et al. [19] Van Dyke et al. [20]
Representativeness of cases
Cohort Selection studies (n = 9) Representativeness of the exposed cohort
a
Definition of controls
Comparability Control for important factor or additional factor
Exposure Ascertainment of exposure (blinding)
Total (0–9) Same method of ascertainment for subjects
Nonresponse ratea 5 6 6 6 5 5
Selection of the Ascertainment Outcome of interest not nonexposed cohort of exposure present at start of study
Comparability Outcome Total (0–9) Control for important Assessment Follow-up long Adequacy factor or additional of outcome enough form of follow-up factor outcomes to occur of cohorts
Paganini-Hill et al. [21] Schreinemachers et al. [22] Akhmedkhanov et al. [23] Holick et al. [24] Hayes et al. [25] Herna´ndez-Dı´az et al. [26] Feskanich et al. [27] Jacobs et al. [28] Slatore et al. [29]
If there was no significant difference in the response rate between both groups using a chi-square test (P > 0.05), one point was awarded.
4 8 7 7 7 8 7 8 8
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1 2 3 4 5 6 7 8 9
Selection of controls
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Figure 2. Association between aspirin use and lung cancer risk by type of study design.
Figure 3. Begg’s funnel plot and Egger’s test risk for identifying publication bias.
as controls, a spurious protective association could be observed. Likewise, the item of ‘selection of controls’ is related to selection bias in the case–control studies. For example, four of six case–control studies used hospital controls. The use of hospital controls might introduce bias due to the possibility that some controls were suffering from conditions that would make them more likely to use aspirin. Especially, three case– control studies classified in the low-quality category did not satisfy the validity for the item of ‘adequate definition of lung cancer cases’. These studies used record linkage or self-reports for the case definition, while the other studies reviewed individual pathology reports. Our findings are inconsistent with a previous meta-analysis of observational studies, including case–control studies and cohort studies, regarding the use of NSAIDs and lung cancer. The previous meta-analysis reported that the OR of lung cancer
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risk was 0.73 (95% CI 0.63–0.86) for aspirin use and 0.79 (95% CI 0.66–0.95) for NSAID use, and that the subgroup metaanalysis of cohort studies also showed a significant positive effect [11]. However, only three cohort studies were included in the subgroup meta-analysis and the analysis of the methodological quality were not reported. Another quantitative review reported the protective effect of aspirin on lung cancer from two case–control studies (OR, 0.70; 95% CI 0.56–0.88), while there was no significant effect from six cohort studies (OR, 0.96; 95% CI 0.91–1.02) [12]. Although these results are consistent with our meta-analysis, there is a limitation that few studies were included. Furthermore, previously mentioned meta-analyses included cohort studies of lung cancer mortality [40, 41] that were excluded from our final analysis. However, when we added mortality data in the analysis of cohort studies with incidence data, its finding was similar to that of only incidence data (RR, 1.00; 95% CI 0.92–1.08). When we combined both case–control and cohort studies, we identified a publication bias. From the results of the funnel plot, we could interpret that studies having a null association between aspirin use and lung cancer risk were not included (or published) in our meta-analysis. This publication bias might lead to the overall overestimated positive association between them. However, when we assessed publication bias by type of study, publication bias was observed only in the case–control studies and not in the cohort studies. Aspirin and other NSAIDs inhibit COX enzymes, which convert arachidonic acid into prostaglandins [44]. The proposed mechanism for aspirin’s effect on cancer lies with its inhibition of the COX-2 enzyme, which is induced early in the development of numerous tumors through its effect on apoptosis, cell migration, and angiogenesis [1, 45]. Observational studies and meta-analyses have suggested that regular aspirin use is associated with reduced risk for cancers of the esophagus [3], stomach [4, 5], colon [6, 7], prostate [8], and breast [9]. However, in contrast with the observational
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Table 3. Association between aspirin use and lung cancer risk in subgroup meta-analyses by quality of study methodology, dose of aspirin, duration of aspirin use, smoking status, and histology of lung cancer Category
No. of studies (reference)
Summary RR (95% CI)
Heterogeneity, I2 (%)
Model used
All Except a study unadjusted for smoking Quality of study methodology High quality Low quality Gender Male Female Dose of aspirin (mg) Low dose (<100) High dose (‡100) Duration of aspirin use (years) Short-term (<5) Long-term (‡5) Smoking status Current smokers Former smokers Never smokers Histology of lung cancer Adenocarcinoma Squamous cell carcinoma Small-cell carcinoma
15 14 [1–20, 22–53]
0.86 (0.76–0.98) 0.85 (0.74–0.97)
61.8 68.1
Random effects Random effects
7 [16–18, 22, 26, 28, 29] 8 [15, 19–21, 23–25, 27]
0.90 (0.7621.07) 0.82 (0.6820.99)
68.6 54.8
Random effects Random effects
3 [15, 22, 24] 4 [15, 20, 22, 23]
0.62 (0.48–0.79) 0.73 (0.50–1.06)
0.0 46.4
Fixed effects Fixed effects
3 [17, 20, 26] 3 [17, 26, 28]
0.94 (0.81–1.09) 0.96 (0.57–1.61)
48.9 89.7
Fixed effects Random effects
6 [16–18, 20, 23, 26] 6 [15–18, 20, 23]
0.95 (0.84–1.07) 0.84 (0.67–1.07)
40.6 50.2
Fixed effects Random effects
3 [16, 18, 26] 2 [16, 18] 5 [16, 18, 20, 25, 26]
1.06 (0.87–1.30) 0.88 (0.56–1.39) 1.11 (0.88–1.40)
0.0 65.7 42.7
Fixed effects Random effects Fixed effects
4 [15, 16, 18, 25] 4 [15, 16, 18, 25] 4 [15, 16, 18, 25]
0.95 (0.71–1.26) 0.86 (0.68–1.09) 0.77 (0.42–1.44)
50.2 0.0 73.2
Random effects Fixed effects Random effects
RR, relative risk; CI, confidence interval.
evidence on cancer incidence, data from randomized trials have been more limited. The Physicians’ Health Study found no effect on colorectal cancer after the administration of aspirin 325 mg every alternate day over a 5-year period [46]. Results from the Women’s Health Study (WHS) also reported that alternate-day use of low-dose aspirin (100 mg) for an average 10 years of treatment did not lower risk for total, breast, colorectal, or other site-specific cancer incidences [47]. In the WHS, a marginally statistically significant protective effect on lung cancer was observed (RR, 0.78; 95% CI 0.59–1.03; P = 0.08), which was significant for lung cancer mortality. In contrast, two UK large randomized trials with post-trial follow-up for >20 years reported a significant protective effect of aspirin use on colorectal cancer incidence, using ‡300 mg for 5 years, with a latency of 10 years [13]. However, in this study, there were no significant effects of aspirin use on lung cancer (hazard ratio, 0.96; 95% CI 0.70–1.32). More recently, a long-term follow-up of three large trials of daily low-dose aspirin (75–300 mg) reported that allocation to aspirin reduced the 20-year risk for colon cancer [48]. Even though the results from previously mentioned randomized, controlled trials (RCTs) are suggestive of a reduction in colorectal cancer risk, we have an insufficient amount of RCTs data to draw definite conclusions in noncolorectal cancers, including lung cancer. In subgroup meta-analyses, a significant protective effect of aspirin use on lung cancer was observed among men but not among women. Some biological evidence has suggested that there is an association between sexual hormones and lung cancer risk. Estrogen receptors are expressed in both normal
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lung tissue and lung tumors, and these receptors may influence the association between aspirin use and lung cancer [49–52]. However, these findings should be evaluated further, given the small number of studies. Our meta-analysis has several limitations. First, definitions of aspirin use in each study were quite heterogeneous. For the exposure definition, we used the highest and lowest levels of aspirin use among the various categories in each study. Dose and duration of aspirin use were various according to the definition of each study. It could lead to heterogeneity across the included studies. Secondly, even though there was no association between duration or dose of aspirin use and the risk for lung cancer in our analysis, more trials are required to conclude their association because of the paucity of data published on this issue. Thirdly, the exclusion of non-English language articles might bias our findings. However, there have been few studies on this topic written in languages other than English. Upon reviewing their English abstracts, none of them met our main eligibility criteria; therefore, this exclusion criterion would not have substantially altered our results. Finally, we should mention common limitations of metaanalysis, i.e. ‘pooled results could incorporate the biases of individual studies and embody new sources of bias, mostly because of the selection studies and the inevitable heterogeneity among them’ [53]. In summary, our meta-analysis indicates that there is no association between aspirin use and risk for lung cancer on the basis of the findings of cohort studies, which generally give a higher level of evidence than case–control studies. Although a subgroup meta-analysis of case–control studies showed
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original article a preventive effect of aspirin use on lung cancer, interpretation should be cautious because of the potential biases of lowquality case–control studies. The findings from these observational studies need to be confirmed in future research, such as in more prospective cohort studies or RCTs providing the highest level of evidence.
disclosure The authors declare no conflict of interest.
references 1. Mannino DM, Ford E, Giovino GA et al. Lung cancer deaths in the United States from 1979 to 1992: an analysis using multiple-cause mortality data. Int J Epidemiol 1998; 27 (2): 159–166. 2. Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part I). J Natl Cancer Inst 1998; 90: 1529–1536. 3. Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part II). J Natl Cancer Inst 1998; 90: 1609–1620. 4. Corley DA, Kerlikowske K, Verma R, Buffler P. Protective association of aspirin/ NSAIDs and esophageal cancer: a systematic review and meta-analysis. Gastroenterology 2003; 124: 47–56. 5. Ridaura R. Effects of non-steroidal anti-inflammatory drugs on cancer sites other than the colon and rectum: a meta-analysis. BMC Cancer 2003; 3: 28. 6. Wang WH, Huang JQ, Zheng GF et al. Non-steroidal anti-inflammatory drug use and the risk of gastric cancer: a systematic review and meta-analysis. J Natl Cancer Inst 2003; 95 (23): 1784–1791. 7. Asano TK, McLeod RS. Nonsteroidal anti-inflammatory drugs and aspirin for the prevention of colorectal adenomas and cancer: a systematic review. Dis Colon Rectum 2004; 47: 665–673. 8. Garcia Rodriguez LA, Huerta-Alvarez C. Reduced risk of colorectal cancer among long-term users of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs. Epidemiology 2001; 12: 88–93. 9. Mahmud S, Franco E, Aprikian A. Prostate cancer and use of nonsteroidal antiinflammatory drugs: systematic review and meta-analysis. Br J Cancer 2004; 90: 93–99. 10. Khuder SA, Mutgi AB. Breast cancer and NSAID use: a meta-analysis. Br J Cancer 2001; 84: 1188–1192. 11. Khuder SA, Herial NA, Mutgi AB, Federman DJ. Nonsteroidal antiinflammatory drug use and lung cancer: a metaanalysis. Chest 2005; 127: 748–754. 12. Bosetti C, Gallus S, La Vecchia C. Aspirin and cancer risk: an updated quantitative review to 2005. Cancer Causes Control 2006; 17: 871–888. 13. Flossmann E, Rothwell PM. British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 2007; 369: 1603–1613. 14. Wells GA, Shea B, O’Connell D et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http:// www.ohri.ca/programs/clinical_epidemiology/oxford.htm (3 March 2010, date last accessed). 15. Moysich KB, Menezes RJ, Ronsani A et al. Regular aspirin use and lung cancer risk. BMC Cancer 2002; 2: 31. 16. Muscat JE, Chen S, Richie JP et al. Risk of lung carcinoma among users of nonsteroidal anti-inflammatory drugs. Cancer 2003; 97: 1732–1736. 17. Harris RE, Beebe-Donk J, Alshafie GA. Reduced risk of human lung cancer by selective cyclooxygenase 2 (Cox-2) blockade: results of a case control study. Int J Biol Sci 2007; 3: 328–334. 18. Kelly JP, Coogan P, Strom BL, Rosenberg L. Lung cancer and regular use of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs. Pharmacoepidemiol Drug Saf 2008; 17: 322–327. 19. Olsen JH, Friis S, Poulsen AH et al. Use of NSAIDs, smoking and lung cancer risk. Br J Cancer 2008; 98: 232–237.
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20. Van Dyke AL, Cote ML, Prysak G et al. Regular adult aspirin use decreases the risk of non-small cell lung cancer among women. Cancer Epidemiol Biomarkers Prev 2008; 17: 148–157. 21. Paganini-Hill A, Chao A, Ross RK, Henderson BE. Aspirin use and chronic disease: a cohort study of the elderly. BMJ 1989; 299: 1247–1250. 22. Schreinemachers DM, Everson RB. Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology 1994; 5: 138–146. 23. Akhmedkhanov A, Toniolo P, Zeleniuch-Jacquotte A et al. Aspirin and lung cancer in women. Br J Cancer 2002; 87: 49–53. 24. Holick CN, Michaud DS, Leitzmann MF et al. Aspirin use and lung cancer in men. Br J Cancer 2003; 89: 1705–1708. 25. Hayes JH, Anderson E, Folsom AR. Association between nonsteroidal anti-inflammatory drug use and the incidence of lung cancer in the Iowa women’s health study. Cancer Epidemiol Biomarkers Prev 2006; 15: 2226–2231. 26. Herna´ndez-Dı´az S, Rodriguez G. Nonsteroidal anti-inflammatory drugs and risk of lung cancer. Int J Cancer 2007; 120: 1565–1572. 27. Feskanich D, Bain C, Chan AT et al. Aspirin and lung cancer risk in a cohort study of women: dosage, duration and latency. Br J Cancer 2007; 97: 1295–1299. 28. Jacobs EJ, Thun MJ, Bain EB et al. A large cohort study of long-term daily use of adult-strength aspirin and cancer incidence. J Natl Cancer Inst 2007; 99: 608–615. 29. Slatore CG, Au DH, Littman AJ et al. Association of nonsteroidal antiinflammatory drugs with lung cancer: results from a large cohort study. Cancer Epidemiol Biomarkers Prev 2009; 18: 1203–1207. 30. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–1558. 31. Woolf B. On estimating the relation between blood group and disease. Ann Hum Genet 1955; 19: 251–253. 32. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188. 33. Rosenberg L. Nonsteroidal anti-inflammatory drugs and cancer. Prev Med 1995; 24: 107–109. 34. Skriver MV, Nørgaard M, Poulsen AH et al. Use of nonaspirin NSAIDs and risk of lung cancer. Int J Cancer 2005; 117: 873–876. 35. Harris RE, Beebe-Donk J, Schuller HM. Chemoprevention of lung cancer by nonsteroidal anti-inflammatory drugs among cigarette smokers. Oncol Rep 2002; 9: 693–695. 36. Langman MJ, Cheng KK, Gilman EA, Lancashire RJ. Effect of anti-inflammatory drugs on overall risk of common cancer: case-control study in general practice research database. BMJ 2000; 320: 1642–1646. 37. Wall RJ, Shyr Y, Smalley W. Nonsteroidal anti-inflammatory drugs and lung cancer risk: a population-based case control study. J Thorac Oncol 2007; 2: 109–114. 38. Peto R, Gray R, Collins R et al. Randomised trial of prophylactic daily aspirin in British male doctors. BMJ 1988; 296: 313–316. 39. Harris RE, Beebe-Donk J, Alshafie GA. Cancer chemoprevention by cyclooxygenase 2 (COX-2) blockade: results of case control studies. Subcell Biochem 2007; 42: 193–212. 40. Thun MJ, Namboodiri MM, Calle EE et al. Aspirin use and risk of fatal cancer. Cancer Res 1993; 53: 1322–1327. 41. Ratnasinghe LD, Graubard BI, Kahle L et al. Aspirin use and mortality from cancer in a prospective cohort study. Anticancer Res 2004; 24: 3177–3184. 42. Sørensen HT, Friis S, Nørga˚rd B et al. Risk of cancer in a large cohort of nonaspirin NSAID users: a population-based study. Br J Cancer 2003; 88: 1687–1692. 43. Friis S, Sørensen HT, McLaughlin JK et al. A population-based cohort study of the risk of colorectal and other cancers among users of low-dose aspirin. Br J Cancer 2003; 88: 684–688. 44. Awtry EH, Loscalzo J. Aspirin. Circulation 2000; 101: 1206–1218. 45. Thun MJ. Beyond willow bark: aspirin in the prevention of chronic disease. Epidemiology 2000; 11: 371–374.
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46. Sturmer T, Glynn RJ, Lee IM et al. Aspirin use and colorectal cancer: post-trial follow-up from the Physicians’ Health Study. Ann Intern Med 1998; 128: 713–720. 47. Cook NR, Lee IM, Gaziano JM et al. Low-dose aspirin in the primary prevention of cancer: the Women’s Health Study: a randomized controlled trial. JAMA 2005; 294: 47–55. 48. Rothwell PM. Wilson M, Elwin CE et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010; 376: 1741–1750. 49. Kabat GC, Miller AB, Rohan TE. Reproductive and hormonal factors and risk of lung cancer in women: a prospective cohort study. Int J Cancer 2007; 120: 2214–2220.
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original article 50. Rodriguez C, Feigelson HS, Deka A et al. Postmenopausal hormone therapy and lung cancer risk in the cancer prevention study II nutrition cohort. Cancer Epidemiol Biomarkers Prev 2008; 17: 655–660. 51. Mollerup S, Jorqensen K, Berge G, Hauqen A. Expression of estrogen receptors alpha and beta in human lung tissue and cell lines. Lung Cancer 2002; 37: 153–159. 52. Omoto Y, Kobayashi Y, Nishida K et al. Expression, function, and clinical implications of the estrogen receptor beta in human lung cancers. Biochem Biophys Res Commun 2001; 285: 340–347. 53. LeLorier J, Gregoire G, Benhaddad A et al. Discrepancies between metaanalyses and subsequent large randomized controlled trials. New Engl J Med 1997; 337: 536–542.
doi:10.1093/annonc/mdq779 | 2465
Annals of Oncology 22: 2456–2465, 2011 doi:10.1093/annonc/mdq779 Published online 8 March 2011
Aspirin use and risk for lung cancer: a meta-analysis S.-W. Oh1, S.-K. Myung2*, J. Y. Park3, C. M. Lee1 & H. T. Kwon1 Korean Meta-analysis (KORMA) Study Group 1 Department of Family Medicine, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul; 2Cancer Epidemiology Branch, Research Institute, National Cancer Center, Goyang; 3Department of Family Medicine, Kwangdong Oriental Hospital, Seoul, Korea
Received 4 November 2010; revised 17 December 2010; accepted 20 December 2010
original article
Background: Aspirin has received increasing attention owing to its potential as a chemopreventive agent against lung cancer. Previous observational studies have reported inconsistent findings on this issue. We investigated the association between aspirin use and risk for lung cancer by conducting a meta-analysis. Patients and methods: Relevant studies were identified by searching Medline, EMBASE, and Cochrane Library to December 2009. We also reviewed relevant bibliographies from the retrieved articles. Two authors independently extracted data and assessed study quality. Disagreements were resolved by consensus. Results: Fifteen studies (six case–control studies and nine prospective cohort studies) were included in the final meta-analysis. When all studies were pooled, the odds ratio (OR) of aspirin use for lung cancer risk was 0.86 [95% confidence interval (CI) 0.76–0.98]. In subgroup meta-analyses, there was no association between aspirin use and lung cancer risk among cohort studies (relative risk, 0.97; 95% CI 0.87–1.08), while there was a significant association among case–control studies (OR, 0.74; 95% CI 0.57–0.99). In a subgroup meta-analysis by quality of study methodology, a significant protective effect of aspirin use on lung cancer was observed only among eight low-quality studies (OR, 0.82; 95% CI 0.68–0.99), but not among seven high-quality studies (OR, 0.90; 95% CI 0.76–1.07). Conclusions: Overall, the findings of this meta-analysis support that there was no association between aspirin use and lung cancer risk. Our findings should be confirmed in future prospective cohort studies or randomized, controlled trials. Key words: aspirin, lung cancer, meta-analysis, NSAIDs
introduction Lung cancer is the leading cause of cancer deaths worldwide. Although smoking is a well-established etiological factor for lung cancer [1], other causes remain unclear. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have received increasing attention owing to their potential as chemopreventive agents against cancer. It has been proposed that aspirin influences cancer risk primarily through its effect on cyclooxygenase (COX) activity [2–9]. In experimental animal models, aspirin and other NSAIDs have been reported to suppress tumor growth [2, 3]. Observational epidemiological investigations and meta-analyses suggested that regular aspirin use is associated with a reduced risk for cancers of the esophagus [4], stomach [5, 6], colon [7, 8], prostate [9], and breast [10]. Several observational studies have examined the relationship between aspirin and other NSAIDs use and lung cancer, with inconsistent results. According to a meta-analysis of 14 observational studies between 1998 and 2003, the odds ratio *Correspondence to: Dr S.-K. Myung, Cancer Epidemiology Branch, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do 410-769, Korea. Tel: +82-31-920-0479; Fax: +82-31-920-2606; E-mail: [email protected]
(OR) was 0.73 [95% confidence interval (CI) 0.63–0.86] for aspirin use and 0.79 (95% CI 0.66–0.95) for NSAID use [11]. In a quantitative review concerning aspirin use and lung cancer risk in 2006, a pooled relative risk (RR) was 0.70 (95% CI 0.56–0.88) for two case–control studies and 0.96 (95% CI 0.91–1.02) for six cohort studies [12]. Recently, two large randomized trials with post-trial follow-up for >20 years have reported no association between regular aspirin use and lung cancer risk [13]. The purpose of the current study was to investigate the association between aspirin use and lung cancer risk by conducting a meta-analysis of observational studies such as case–control studies and cohort studies by type of study design, quality of study methodology, aspirin dose, duration of aspirin use, smoking status, and histology of lung cancer.
methods search strategy We searched Medline (PubMed) (from 1968 to December 2009), EMBASE (from 1977 to December 2009), and the Cochrane Library (from 1953 to December 2009) using selected common key words regarding aspirin, NSAIDs, and lung cancer in observational epidemiological studies such as
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original article
Annals of Oncology
case–control studies and cohort studies; these searches were carried out by one of the authors (S-WO) and then confirmed by another author (S-KM). We also scanned the bibliographies of relevant articles to identify additional studies. As the key words for the literature search, we selected ‘aspirin’, ‘nonsteroidal anti-inflammatory drugs’, and ‘NSAIDs’ for the exposure factors, and ‘lung cancer’ and ‘pulmonary neoplasm’ for the outcome factors.
eligibility criteria We included case–control studies and cohort studies reporting an association between aspirin use and lung cancer risk using ORs or RRs. The current study included only articles written in English. We excluded those studies with no available data for outcome measures, having the same population as other studies (in this case, the first published or more comprehensive study was included in the analysis), having data on mortality only, and reporting standardized incidence ratios (SIRs).
data extraction All studies retrieved from databases and bibliographies were independently evaluated by two authors of this article (S-WO and S-KM). Disagreements between the evaluators concerning the selected studies were resolved by consensus or in consultation with the third author (JYP). Of the articles found in the three databases, duplicate articles and those that did not meet the selection criteria were excluded. We extracted the following data from the remaining studies: study name (first author, year of publication), journal name, country and design, years enrolled, characteristics and study population age range, exposure assessment, definition of aspirin use, OR or RR with 95% CI, and adjustments. Data abstraction was also carried out by two evaluators, as was study selection. The methodological quality of the included studies was assessed using the 9-star Newcastle–Ottawa scale for quality of nonrandomized studies in meta-analyses [14]. We considered a high-quality study as one awarded star more than the average stars of the included studies with the same study design since there are no established standard criteria to date. The mean value for the 15 studies assessed was 6.4 stars.
statistical analysis Adjusted data (adjusted OR or RR with 95% CI) were used for the metaanalysis whenever possible. For the exposure factor, we chose the highest and lowest levels of aspirin use among the various categories in each study (Table 1). We also carried out subgroup analyses by quality of study methodology, gender, study design type (case–control studies versus cohort studies; for the selection of cases and controls, we classified a nested case– control study into a cohort study in the current study), aspirin dose [low dose (£100 mg) or high dose (>100 mg)], duration of aspirin use [short term (<5 years) or long term (‡5 years)], smoking status (current, former, or never smokers), and histology of lung cancer (adenocarcinoma, squamous cell carcinoma, or small-cell carcinoma). The test of heterogeneity in results across studies was carried out using Higgins I2, which measures the percentage of total variation across the studies. I2 is calculated as follows:
I 2 =100% · ðQ2df Þ=Q where Q is the Cochran’s heterogeneity statistic and df the degrees of freedom. Negative values of I2 are set at zero so that I2 exists between 0% (no observed heterogeneity) and 100% (maximal heterogeneity) [30]. An I2 value >50% was considered to show substantial heterogeneity. We estimated a pooled OR or RR with a 95% CI on the basis of both fixedeffects and random-effects models. When substantial heterogeneity was not found (i.e. if I2 £50%), the pooled estimate based on the fixed-effects model
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was represented. When substantial heterogeneity was found (i.e. if I2 >50%), the pooled estimate based on the random-effects model was represented. The Woolf’s method (inverse variance method) was used for a fixedeffects analysis [31] and the DerSimonian–Laird’s method for a randomeffects analysis [32]. We used Begg’s funnel plot and Egger’s test to identify publication bias. If the funnel plot was asymmetrical or the P value was <0.05 by Egger’s test, then we assessed that there was publication bias. We used the Stata SE version 10.0 software package (StataCorp, College Station, TX) for the statistical analysis.
results literature search In total, 15 studies (6 case–control studies and 9 prospective cohort studies) published between 1989 and 2009 were included in the final analysis. Figure 1 shows a flow diagram, identifying the relevant studies. We identified 1244 articles from the three databases and the bibliographies of relevant articles. After the exclusion of duplicates (n = 139), all remaining articles screened (n = 1105) were reviewed according to their titles and abstracts. Of the 1105 articles, we excluded 1079 articles that did not meet the selection criteria. After reviewing the full text for the remaining 26 articles, we included 15 articles in the final analysis. The main reasons for excluding studies from the final review (n = 11) were as follows: insufficient data (n = 6) [33–38], identical cohort (n = 1) [39], mortality data only (n = 2) [40, 41], and use of SIRs as an outcome measure (n = 2) [42, 43]. study characteristics Table 1 shows the main characteristics of all the studies included in the final analysis. The study design types were as follows: hospital-based case–control studies (n = 4) [15–18], populationbased case–control studies (n = 2) [19, 20], nested case–control studies (n = 2) [23, 26], and prospective cohort studies (n = 7) [21, 22, 24, 25, 27–29]. The countries where the studies had been carried out were as follows: the United States (n = 13) [15–18, 20–25, 27–29], the UK (n = 1) [26], and Denmark (n = 1) [19]. The range of enrollment periods for participants across studies was 1971–2007. In the nine cohort studies (nested case–control studies and prospective cohort studies), we identified a total of 9262 cases among 467 831 participants. quality of study methodologies Table 2 shows the quality of study methodology included in the final meta-analysis. The range of quality scores was 4–8; the average score was 6.5. The average scores (standard deviation) of case–control studies and cohort studies were 5.5 (0.57) and 7.1 (0.98), respectively. The high-quality studies (above each study type average) included three of six case–control studies and four of nine cohort studies. overall use of aspirin and the risk for lung cancer Figure 2 shows the effect of aspirin use on lung cancer risk in a meta-analysis of all studies, including both case–controls studies and prospective cohort studies. In a random-effects meta-analysis of all 15 studies, the overall use of aspirin
doi:10.1093/annonc/mdq779 | 2457
Study (reference)
Country; design
Years enrolled
Population (age, years)
Exposure assessment
Definition of use (highest category)
OR or RR (95% CI)
Adjustments
Case–control studies 1 Moysich et al. [15]
BMC Cancer
1982–1998
868 cases and 935 controls (62)
Questionnaire
>1 tablet/week for at least 1 year
0.57 (0.41–0.78)
Age, education, and pack-years of cigarettes
2
Muscat et al. [16]
Cancer
1992–2000
1038 cases and 1002 controls
Interview
3 tablets/week for ‡1 year
0.84 (0.62–1.14)
3
Harris et al. [17]
Int J Biol Sci
United States; case–control (hospital based) United States; case–control (hospital based) United States; case–control (hospital based)
2002–2004
492 cases and 984 controls
Interview
‡2 times/week for ‡2 years
0.53 (0.34–0.82)
4
Kelly et al. [18]
Pharmacoepidemiol Drug Saf
United States; case–control (hospital based)
1976–2007
1883 cases and 6251 controls (18–79)
Interview
5
Olsen et al. [19]
Br J cancer
Denmark; case–control (population based)
2002–2005
573 cases and 857 controls (64)
6
Van Dyke et al. [20]
Cancer Epidemiol Biomarkers Prev
United States; case–control (hospital based)
2001–2005
581 cases and 541 controls; women (18–74)
Interview, mailed questionnaire, and database Interview
At least 4 days/ week for at least 3 continuous months ‡0.5 prescriptions/ year in 1–3 years before index date
Age, gender, years of education, and packyears of smoking Pack-years of cigarette smoking, age, body mass, gender, ethnicity, family history, arthritis, and alcohol intake Age, sex, study region, interview year, years of education, alcohol use, and cigarette pack-years Age, sex, study, smoking habit, education, and use of acetaminophen Age, race, education, smoking pack-years, BMI, family history of lung cancer, COPD, arthritis, and cardiovascular disease
BMJ
United States; prospective cohort United States; prospective cohort
1981–1985
111 cases among 13 987 residents (73) 163 cases among a population of 12 668 (25–74)
Cohort studies 1 Paganini-Hill et al. [21] 2 Schreinemachers et al. [22]
Epidemiology
1971–1975
1.1 (0.9–1.4)
0.75 (0.49–1.14)
‡3 times/week for at least 1 month
0.66 (0.46–0.94)
Mailed questionnaire Interview
Daily use at start date Ever use in past 30 days
0.92 (0.54–1.55)
Age
0.68 (0.49–0.94); women: 1.40 (0.74–2.66); men: 0.54 (0.37–0.80) 0.66 (0.34–1.28)
Age and gender; women: age; men: age, race, education, smoking, and alcohol Age, menopausal status, dates of enrollment and follow-up, smoking, and educational status Age, age at started to smoke regularly, and smoking status
3
Akhmedkhanov et al. [23]
Br J cancer
United States; nested case–control (population based)
1985–1991
81 cases and 808 controls; women (35–69)
Mailed questionnaire
‡3 times/week for at least 6 months
4
Holick et al. [24]
Br J Cancer
United States; prospective cohort
1989–1995
328 cases among 51 529 male (40–75)
Mailed questionnaire
‡2 times/week at start date
0.89 (0.47–1.67)
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Journal
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Table 1. Characteristics of studies of aspirin and lung cancer risk included in the final analysis (n = 15)
Journal
Country; design
Years enrolled
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Population (age, years)
Exposure assessment
Definition of use (highest category)
OR or RR (95% CI)
Adjustments
5
Hayes et al. [25]
Cancer Epidemiol Biomarkers Prev
United States; prospective cohort
1986
403 cases among 41 836 women (55–69)
Mailed questionnaire
Frequency of use (‡6 times/week)
1.08 (0.81–1.45)
1995–2004
4336 cases and 10 000 controls (40–84)
Database
For >1 year, 1-year lag time
1.15 (0.99–1.34)
United States; prospective cohort
1976
1360 cases among 109 348 women (36–82)
Mailed questionnaire
1.00 (0.86–1.16)
J Natl Cancer Inst
United States; prospective cohort
1992–1993
1815 cases among 69 810 men and 76 303 women
Mailed questionnaire
At least 1 tablet/ week or 1 day/ week of regular use for the past 2 years Days per month (current daily use, ‡5 year)
Age, education, alcohol intake, smoking status, pack-years, BMI, total fruit servings, and history of heart disease Age, sex, smoking, smoking cessation advice by general practitioner, smoking cessation treatment, BMI, alcohol intake, COPD, hypertension, CVD, IHD, arthritis, number of visits to general practitioner, number of referrals, and use of oral corticosteroids, antihypertensives, and statins Age, smoking status, age at start of smoking, years since quit smoking, and cigarettes per day
6
Herna´ndez-Dı´az et al. [26]
Int J Cancer
UK; nested case–control (population based)
7
Feskanich et al. [27]
Br J Cancer
8
Jacobs et al. [28]
9
Slatore et al. [29]
Cancer Epidemiol Biomarkers Prev
United States; prospective cohort
2000–2002
665 cases among a population of 77 125 (50–76)
Mailed questionnaire
10-year average use (third tertile)
0.90 (0.71–1.15)
0.98 (0.76–1.25)
Age, sex, race, education, smoking, BMI, physical activity level, use of HRT, use of nonaspirin NSAIDs, and history of heart attack, diabetes, and hypertension Age, sex, years smoked, packyears, pack-years squared, and acetaminophen use
OR, odds ratio; RR, relative risk; CI, confidence interval; BMI, body mass index; NSAIDs, non-steroidal anti-inflammatory drugs; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; IHD, ischemic heart disease; HRT, hormone replacement therapy.
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Table 1. (Continued)
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Figure 1. Flow diagram of identification of relevant studies. RR, relative risk.
significantly decreased lung cancer risk (OR, 0.86; 95% CI 0.76– 0.98; I2 = 61.8%). In a subgroup meta-analysis of case–control studies, aspirin use significantly decreased lung cancer risk (OR, 0.74; 95% CI 0.57–0.99; I2 = 70.4%) based on a random-effects model. However, no association between aspirin use and lung cancer risk was observed in a subgroup meta-analysis of cohort studies (RR, 0.97; 95% CI 0.87–1.08; I2 = 30.0%) based on a fixedeffects model. When a study without adjustment for smoking [21] was excluded from the analysis of cohort studies, the result was not changed (data not shown). A significant publication bias was found in the selected 15 studies (Begg’s funnel plot, asymmetrical; Egger’s test, P for bias = 0.006) (Figure 3). There was also a significant publication bias in the six case–control studies (Egger’s test, P for bias = 0.042), while there was no publication bias in the nine cohort studies (Egger’s test, P for bias = 0.082).
subgroup meta-analyses Table 3 shows the effects of aspirin use on lung cancer risk in subgroup meta-analyses by quality of study methodology, gender, aspirin dose, duration of aspirin use, smoking status, and lung cancer histology. Significant protective effects of aspirin use on lung cancer were observed among the eight low-quality studies (OR, 0.82; 95% CI 0.68–0.99) but not among the seven high-quality studies (OR, 0.90; 95% CI 0.76–1.07) (Table 3). There was no significant association between aspirin use and lung cancer risk regardless of the duration of aspirin use (short term, <5 years; long term, ‡5 years), aspirin dose (low dose, <100 mg; high dose ‡100 mg), smoking status (current, former,
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or never), or lung cancer histology (adenocarcinoma, squamous cell carcinoma, or small-cell carcinoma). Aspirin use was associated with a decreased lung cancer risk for men (OR, 0.62; 95% CI 0.48–0.62), while there was no evidence of a preventive effect for women (OR, 0.73; 95% CI 0.50–1.06).
discussion The findings from this meta-analysis of epidemiological studies, including case–control and cohort studies, indicate that aspirin use was associated with a decreased risk for lung cancer. However, in the subgroup meta-analyses by study design, cohort studies showed no significant decreased risk for lung cancer with aspirin use, while case–control studies showed a significant preventive effect. These inconsistent findings between two different study designs can be explained by the quality of the study methodologies, included in the current study. Overall, case– control studies had a lower mean score than cohort studies, namely, 5.5 and 7.1, respectively. In the subgroup meta-analyses by study quality, significant protective effects of aspirin use on lung cancer were observed only among low-quality studies. Additionally, most of the included studies in our study used self-administered questionnaires or interviews for the assessment of aspirin use, regarding the item of ‘ascertainment of exposure’. Results from observational studies that collected exposure information through questionnaires or retrospective personal interviews without blinding are susceptible to recall bias or selection bias. If the relatively healthy aspirin users were more likely to participate in the study than nonusers, especially
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Table 2. Methodological quality of studies included in the final analysis, based on the Newcastle–Ottawa scale for assessing the quality of case–control studies and cohort studies Case–control studies (n = 6)
Selection Adequate definition of cases
1 2 3 4 5 6
Moysich et al. [15] Muscat et al. [16] Harris et al. [17] Kelly et al. [18] Olsen et al. [19] Van Dyke et al. [20]
Representativeness of cases
Cohort Selection studies (n = 9) Representativeness of the exposed cohort
a
Definition of controls
Comparability Control for important factor or additional factor
Exposure Ascertainment of exposure (blinding)
Total (0–9) Same method of ascertainment for subjects
Nonresponse ratea 5 6 6 6 5 5
Selection of the Ascertainment Outcome of interest not nonexposed cohort of exposure present at start of study
Comparability Outcome Total (0–9) Control for important Assessment Follow-up long Adequacy factor or additional of outcome enough form of follow-up factor outcomes to occur of cohorts
Paganini-Hill et al. [21] Schreinemachers et al. [22] Akhmedkhanov et al. [23] Holick et al. [24] Hayes et al. [25] Herna´ndez-Dı´az et al. [26] Feskanich et al. [27] Jacobs et al. [28] Slatore et al. [29]
If there was no significant difference in the response rate between both groups using a chi-square test (P > 0.05), one point was awarded.
4 8 7 7 7 8 7 8 8
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1 2 3 4 5 6 7 8 9
Selection of controls
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Figure 2. Association between aspirin use and lung cancer risk by type of study design.
Figure 3. Begg’s funnel plot and Egger’s test risk for identifying publication bias.
as controls, a spurious protective association could be observed. Likewise, the item of ‘selection of controls’ is related to selection bias in the case–control studies. For example, four of six case–control studies used hospital controls. The use of hospital controls might introduce bias due to the possibility that some controls were suffering from conditions that would make them more likely to use aspirin. Especially, three case– control studies classified in the low-quality category did not satisfy the validity for the item of ‘adequate definition of lung cancer cases’. These studies used record linkage or self-reports for the case definition, while the other studies reviewed individual pathology reports. Our findings are inconsistent with a previous meta-analysis of observational studies, including case–control studies and cohort studies, regarding the use of NSAIDs and lung cancer. The previous meta-analysis reported that the OR of lung cancer
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risk was 0.73 (95% CI 0.63–0.86) for aspirin use and 0.79 (95% CI 0.66–0.95) for NSAID use, and that the subgroup metaanalysis of cohort studies also showed a significant positive effect [11]. However, only three cohort studies were included in the subgroup meta-analysis and the analysis of the methodological quality were not reported. Another quantitative review reported the protective effect of aspirin on lung cancer from two case–control studies (OR, 0.70; 95% CI 0.56–0.88), while there was no significant effect from six cohort studies (OR, 0.96; 95% CI 0.91–1.02) [12]. Although these results are consistent with our meta-analysis, there is a limitation that few studies were included. Furthermore, previously mentioned meta-analyses included cohort studies of lung cancer mortality [40, 41] that were excluded from our final analysis. However, when we added mortality data in the analysis of cohort studies with incidence data, its finding was similar to that of only incidence data (RR, 1.00; 95% CI 0.92–1.08). When we combined both case–control and cohort studies, we identified a publication bias. From the results of the funnel plot, we could interpret that studies having a null association between aspirin use and lung cancer risk were not included (or published) in our meta-analysis. This publication bias might lead to the overall overestimated positive association between them. However, when we assessed publication bias by type of study, publication bias was observed only in the case–control studies and not in the cohort studies. Aspirin and other NSAIDs inhibit COX enzymes, which convert arachidonic acid into prostaglandins [44]. The proposed mechanism for aspirin’s effect on cancer lies with its inhibition of the COX-2 enzyme, which is induced early in the development of numerous tumors through its effect on apoptosis, cell migration, and angiogenesis [1, 45]. Observational studies and meta-analyses have suggested that regular aspirin use is associated with reduced risk for cancers of the esophagus [3], stomach [4, 5], colon [6, 7], prostate [8], and breast [9]. However, in contrast with the observational
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Table 3. Association between aspirin use and lung cancer risk in subgroup meta-analyses by quality of study methodology, dose of aspirin, duration of aspirin use, smoking status, and histology of lung cancer Category
No. of studies (reference)
Summary RR (95% CI)
Heterogeneity, I2 (%)
Model used
All Except a study unadjusted for smoking Quality of study methodology High quality Low quality Gender Male Female Dose of aspirin (mg) Low dose (<100) High dose (‡100) Duration of aspirin use (years) Short-term (<5) Long-term (‡5) Smoking status Current smokers Former smokers Never smokers Histology of lung cancer Adenocarcinoma Squamous cell carcinoma Small-cell carcinoma
15 14 [1–20, 22–53]
0.86 (0.76–0.98) 0.85 (0.74–0.97)
61.8 68.1
Random effects Random effects
7 [16–18, 22, 26, 28, 29] 8 [15, 19–21, 23–25, 27]
0.90 (0.7621.07) 0.82 (0.6820.99)
68.6 54.8
Random effects Random effects
3 [15, 22, 24] 4 [15, 20, 22, 23]
0.62 (0.48–0.79) 0.73 (0.50–1.06)
0.0 46.4
Fixed effects Fixed effects
3 [17, 20, 26] 3 [17, 26, 28]
0.94 (0.81–1.09) 0.96 (0.57–1.61)
48.9 89.7
Fixed effects Random effects
6 [16–18, 20, 23, 26] 6 [15–18, 20, 23]
0.95 (0.84–1.07) 0.84 (0.67–1.07)
40.6 50.2
Fixed effects Random effects
3 [16, 18, 26] 2 [16, 18] 5 [16, 18, 20, 25, 26]
1.06 (0.87–1.30) 0.88 (0.56–1.39) 1.11 (0.88–1.40)
0.0 65.7 42.7
Fixed effects Random effects Fixed effects
4 [15, 16, 18, 25] 4 [15, 16, 18, 25] 4 [15, 16, 18, 25]
0.95 (0.71–1.26) 0.86 (0.68–1.09) 0.77 (0.42–1.44)
50.2 0.0 73.2
Random effects Fixed effects Random effects
RR, relative risk; CI, confidence interval.
evidence on cancer incidence, data from randomized trials have been more limited. The Physicians’ Health Study found no effect on colorectal cancer after the administration of aspirin 325 mg every alternate day over a 5-year period [46]. Results from the Women’s Health Study (WHS) also reported that alternate-day use of low-dose aspirin (100 mg) for an average 10 years of treatment did not lower risk for total, breast, colorectal, or other site-specific cancer incidences [47]. In the WHS, a marginally statistically significant protective effect on lung cancer was observed (RR, 0.78; 95% CI 0.59–1.03; P = 0.08), which was significant for lung cancer mortality. In contrast, two UK large randomized trials with post-trial follow-up for >20 years reported a significant protective effect of aspirin use on colorectal cancer incidence, using ‡300 mg for 5 years, with a latency of 10 years [13]. However, in this study, there were no significant effects of aspirin use on lung cancer (hazard ratio, 0.96; 95% CI 0.70–1.32). More recently, a long-term follow-up of three large trials of daily low-dose aspirin (75–300 mg) reported that allocation to aspirin reduced the 20-year risk for colon cancer [48]. Even though the results from previously mentioned randomized, controlled trials (RCTs) are suggestive of a reduction in colorectal cancer risk, we have an insufficient amount of RCTs data to draw definite conclusions in noncolorectal cancers, including lung cancer. In subgroup meta-analyses, a significant protective effect of aspirin use on lung cancer was observed among men but not among women. Some biological evidence has suggested that there is an association between sexual hormones and lung cancer risk. Estrogen receptors are expressed in both normal
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lung tissue and lung tumors, and these receptors may influence the association between aspirin use and lung cancer [49–52]. However, these findings should be evaluated further, given the small number of studies. Our meta-analysis has several limitations. First, definitions of aspirin use in each study were quite heterogeneous. For the exposure definition, we used the highest and lowest levels of aspirin use among the various categories in each study. Dose and duration of aspirin use were various according to the definition of each study. It could lead to heterogeneity across the included studies. Secondly, even though there was no association between duration or dose of aspirin use and the risk for lung cancer in our analysis, more trials are required to conclude their association because of the paucity of data published on this issue. Thirdly, the exclusion of non-English language articles might bias our findings. However, there have been few studies on this topic written in languages other than English. Upon reviewing their English abstracts, none of them met our main eligibility criteria; therefore, this exclusion criterion would not have substantially altered our results. Finally, we should mention common limitations of metaanalysis, i.e. ‘pooled results could incorporate the biases of individual studies and embody new sources of bias, mostly because of the selection studies and the inevitable heterogeneity among them’ [53]. In summary, our meta-analysis indicates that there is no association between aspirin use and risk for lung cancer on the basis of the findings of cohort studies, which generally give a higher level of evidence than case–control studies. Although a subgroup meta-analysis of case–control studies showed
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original article a preventive effect of aspirin use on lung cancer, interpretation should be cautious because of the potential biases of lowquality case–control studies. The findings from these observational studies need to be confirmed in future research, such as in more prospective cohort studies or RCTs providing the highest level of evidence.
disclosure The authors declare no conflict of interest.
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