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(Chest. 2005;127:748-754.)
© 2005 American College of Chest Physicians

Nonsteroidal Antiinflammatory Drug Use and Lung Cancer*

A Metaanalysis

Sadik A. Khuder, MPH, PhD; Nabeel A. Herial, MD, MPH; Anand B. Mutgi, MD, MSc and Douglas J. Federman, MD

* From the Department of Medicine, Medical College of Ohio, Toledo, OH.

Correspondence to: Sadik A. Khuder, PhD, Department of Medicine, Medical College of Ohio, 3120 Glendale Ave, Toledo, OH 43614-5809; e-mail: skhuder{at}mco.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: Studies done both in laboratory animals and humans suggest that nonsteroidal antiinflammatory drug (NSAID) use may reduce the risk of developing lung cancer. Many epidemiologic studies exploring this association lacked sufficient power to draw definitive conclusions. We conducted a metaanalysis to examine the effect of NSAID use on the risk of lung cancer.

Design: We searched the literature using MEDLINE, CANCERLIT, related conference abstracts, and bibliographies of selected studies. The estimators of relative risk (RR) and associated variances, adjusted for the greatest number of confounders, were abstracted and included in the metaanalysis. Combined estimators of RR were calculated using either fixed or random-effect models. Metaanalyses were performed on 14 studies (the number of cases ranged from 81 to 2,560) that examined the association between lung cancer and NSAIDs. Further, subgroup analyses were performed on the nine studies that had adjusted for the effects of smoking.

Results: The combined estimate of RR was 0.79 (95% confidence interval [CI], 0.66 to 0.95) when all the studies were included in the analysis, and was 0.68 (95% CI, 0.55 to 0.85) when the analysis was limited to the subgroup of studies adjusted for smoking. The combined estimates for case-control studies and cohort studies within this subgroup were 0.63 (95% CI, 0.47 to 0.86) and 0.78 (95% CI, 0.62 to 0.98), respectively. We also observed that small cell lung cancer was more inversely associated with NSAID use (RR, 0.48; 95% CI, 0.30 to 0.75) than non-small cell lung cancer (RR, 0.66; 95% CI, 0.56 to 0.79).

Conclusion: The findings of this study support an inverse association between NSAID use and risk of lung cancer, but do not suggest a causal relationship.

Key Words: aspirin • lung cancer • metaanalysis • nonsteroidal antiinflammatory drug • smoking


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Lung cancer is the most common cancer worldwide and is responsible for the death of an estimated one million people every year.1 In the United States, lung cancer continues to be the leading cause of cancer deaths in both men and women, with an estimated 173,770 new cases and 160,440 deaths in the year 2004.2 Approximately 87 to 90% of lung cancers are attributed to cigarette smoking; however, smoking cessation can tremendously reduce the lung cancer risk. A 30 to 50% decrease in the risk has been reported in former smokers compared to continuing smokers after 10 years of abstinence.3 Long-term heavy smokers retain a significant lung cancer risk despite smoking cessation, and half of newly diagnosed lung cancers are now found in former smokers. NSAIDs have received increasing attention owing to their potential as chemopreventive agents against colon cancer45 and carcinoma of the breast.6 Several epidemiologic studies have examined the relation between NSAID use and lung cancer, with inconsistent results. Combating lung cancer with NSAIDs appears a possibility, but the studies lacked sufficient statistical power to draw definitive conclusions. In this metaanalysis, we examined the epidemiologic studies on NSAID use and lung cancer.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The studies were located via a search of MEDLINE and CANCERLIT databases from 1966 through December 2003 using the key words "NSAID," "aspirin," "lung," and "cancer." Abstracts of research presented at related conferences (Society for Epidemiologic Research, European Cancer Research, British Cancer Research, and American Association for Cancer Research) were also searched. Additionally, we checked the references of the selected articles to detect additional eligible publications.

Studies were eliminated from the analyses if they included subjects used in other, more inclusive, studies. To avoid selection bias, studies were not rejected because of methodologic characteristics or any subjective quality criteria; however, differences in study methods were taken into account in the interpretation of our results.

The estimators of relative risk (RR) and associated variances, which have been adjusted for the greatest number of confounders, were abstracted and included in the metaanalysis. A series of metaanalyses were conducted, and the results were evaluated in the context of the published literature. The homogeneity of the estimators of RR was tested using the Cochran Q statistics.7 The fixed-effect model was used to obtain the combined estimator of RR and its SE. The random-effects model8 was used when significant heterogeneity within the groups of studies was detected.

Subgroup analyses were performed for studies that adjusted for the confounding effects of smoking in their statistical analyses. The dose-response relation was also evaluated for both frequency and the duration of NSAID use. At each dose, the odds ratio (OR) and 95% confidence interval (CI) were extracted. The SE was calculated from the CI. In studies in which CI was not provided, the OR and SE were calculated using the number of exposed cases and control subjects. An exponential random-effect approach was used for assessing the dose-response relation and the risk of lung cancer.9 For each study, a dose-response estimate was obtained by imposing a linear trend model for the natural logarithm of OR at each exposure level. The mid-interval score was assigned to dose level at each exposure category. A combined slope or trend was obtained by combining individual slope estimates. The equality of the response across dose levels was tested using a t test. Finally, the influence of individual studies was evaluated by estimating the average RR in the absence of each study. The potential for publication bias in published reports was investigated by constructing funnel plots of log OR against the size of the study. A Kendall {tau} rank correlation test10 was used to test for the statistical significance of publication bias. All the statistical analyses in this study were conducted using software (SAS version 8; SAS Institute; Cary, NC).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We identified 14 studies1112131415161718192021222324 published between 1988 and 2003 that evaluated the association between NSAID use and lung cancer. Six of the included studies were case-control studies and eight were cohort studies (Table 1 ). The number of cases of lung cancer in each study ranged from 81 to 2,560. Nine studies111213141518202123 provided data on aspirin use, and one study24 provided data on both aspirin and other NSAIDs. The estimator of RR for aspirin ranged from 0.32 to 1.10. Four of the estimators were significant, and three studies reported a nonsignificant RR that was > 1 (Fig 1 ). Of the 14 studies that were located, 3 studies111523 were restricted to men, 1 study18 was restricted to women, and 7 studies12131419202124 reported data stratified by gender.


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  		Table 1.. Summary of Studies Used in the Metaanalyses of NSAIDs Use and Lung Cancer*

 


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  		Figure 1.. Estimators of RR for studies both adjusted and not adjusted for smoking included in the metaanalysis of NSAID use and lung cancer.

 
The Q test of heterogeneity for the 14 studies was significant ({chi}2 = 82.58, p < 0.01), indicating that the results of the studies were not homogeneous. The combined estimate of RR using the random-effect model was 0.79 (95% CI, 0.66 to 0.95). Of the 14 studies that were identified, only 9 studies adjusted the analyses for smoking status of the study population (Table 1). An RR of 0.68 (95% CI, 0.55 to 0.85) was obtained when subgroup analysis was performed for the nine studies that had adjusted for the confounding effects of smoking. Further analyses and results reported in this metaanalysis pertain to these adjusted studies unless otherwise indicated. To account for heterogeneity, we conducted stratified metaanalysis by type of NSAID and study design. The results obtained from these analyses are presented in Table 2 . Significant heterogeneity was detected among the studies on aspirin ({chi}2 = 21.96, p < 0.01), and the combined estimate of RR was 0.73 (95% CI, 0.63 to 0.86). Significant heterogeneity was also detected among the case-control studies ({chi}2 = 44.55, p < 0.01), and the combined estimate of RR was 0.63 (95% CI, 0.47 to 0.86). The group of cohort studies was less heterogeneous ({chi}2 = 1.30, p = 0.51), and the estimate of RR using the fixed-effect model was 0.78 (95% CI, 0.62 to 0.98). Risk estimation after data were stratified by gender yielded combined RRs of 0.59 (95% CI, 0.47 to 0.77) for men and 0.59 (95% CI, 0.32 to 1.09) for women.


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  		Table 2.. Combined OR of Lung Cancer According to Study Design and Gender

 
Five of the 14 studies provided dose-response results on frequency of NSAID use; of these 5 studies, only 3 studies192024 were adjusted for smoking (Table 3 ). One study19 reported a significant trend in risk reduction with more pills per day. Six studies171820222324 provided dose-response results when medication use was grouped by duration, of which again only four studies18202324 were adjusted for the major risk factor (Table 4 ). Only one study20 reported a significant trend in risk reduction with a longer duration of NSAID use. The results obtained from the dose-response analysis are presented in Table 5 . The pooled dose-response test for tablet exposure indicated a trend in risk reduction, but the duration response indicated a clearly significant decrease in risk (p = 0.04). This could suggest that frequency of tablet use is not as good an indicator of effect as the duration of the drug use. The lack of significant pooled dose-response relation of frequency of tablet use could possibly be attributed to fewer studies (only three) that reported this information. Table 6 shows the results obtained from the analysis performed on the histologic types of lung cancer. Small cell lung cancer (SCLC) was more inversely associated with an OR of 0.48 (95% CI, 0.30 to 0.75) compared to non-small cell lung cancer (NSCLC) [OR, 0.66; 95% CI, 0.56 to 0.79]. The estimators of RR for all the 14 identified studies are plotted in Figure 1. The studies that reported a RR > 1 failed to adjust for the effects of smoking in the analyses. Notably, none of the nine studies adjusted for smoking reported an RR > 1. This demonstrates that inferences based on unadjusted data analyses could significantly weaken the association that may otherwise exist between NSAID use and the risk of lung cancer.


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  		Table 3.. Dose-Response Relation Reported in Studies Used in the Metaanalysis

 

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  		Table 4.. Duration of NSAID Use Reported in Studies Used in the Metaanalysis

 

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  		Table 5.. Dose-Response Analyses for Tablets per Day and Duration of Use

 

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  		Table 6.. Combined OR of NSCLC and SCLC

 
The studies of Peto et al11 and Lee et al15 were part of randomized trials. We investigated the effect of removing these studies on the inter-study variability and on the combined RR. The estimate did not change significantly when either of these studies was excluded from the analysis. The combined RRs were 0.78 (95% CI, 0.65 to 0.95) when the study of Lee et al15 was excluded from the analysis, and 0.79 (95% CI, 0.66 to 0.96) when the study of Peto et al11 was excluded. The studies of Paganini-Hill et al,12 Friis et al,21 and Sørensen et al22 were the studies that reported an increase in the risk of lung cancer with NSAID use. However, when they were excluded from the analysis, only a slight change in the RR from 0.79 to 0.71 was noted. Aspirin was the major NSAID type used in the studies that were included in this metaanalysis, and the reduction in the risk of lung cancer with aspirin use was not significantly different from other NSAIDs.

The distribution of the RRs in relation to their SEs, observed in a funnel graph, was symmetric, suggesting no indication for the presence of publication bias. The Kendall {tau} correlation coefficient test was not significant (p = 0.48), confirming no evidence of publication bias in studies included in this metaanalysis.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this metaanalysis, we found that NSAID use was associated with a small but statistically significant decrease in the risk of lung cancer. This finding was supported by the majority of studies included in the analysis. Specifically, seven studies11131418192024 suggested a strong inverse relationship between NSAID use and the risk of lung cancer.

The effect of NSAID on the risk of lung cancer was not consistent among the studies and differed according to the degree of adjustment for smoking. Studies that adjusted for smoking reported a stronger effect of NSAID use on the risk of lung cancer. It is well studied and established that smoking is strongly associated with lung cancer, and approximately 90% of the lung cancers are attributed to smoking. It is also documented that cigarette smokers are 22 times more likely to die from lung cancer than nonsmokers.25 Therefore, the findings of any study that failed to adjust for the effects of smoking can be questionable. We examined the association between NSAIDs and lung cancer with only those studies that had adjusted for smoking and excluded the studies that had failed to do so. The combined estimate of RR derived from all the 14 studies showed that regular use of NSAID was associated with 21% reduction in the risk of lung cancer; when the analysis was restricted to studies that adjusted for smoking, we found a 32% reduction in risk. We believe that smoking had confounded the relation between NSAID use and lung cancer, thus nullifying the likely protective effect of NSAIDs in those studies that failed to adjust for smoking. It is possible that NSAID use may affect the risk of lung cancer differently in current smokers and past smokers. One study suggests that people who have recently quit smoking may benefit the most from active chemoprevention.26

Many studies have contributed plausible evidence supporting the protective effects of NSAIDs against lung cancer. The roles of two isoforms of the cyclooxygenase (COX) enzyme—COX-1, which is constitutively expressed in tissues, and COX-2, induced by tumor oncogenes and promoters—have been extensively studied. It is possible that smoking might induce COX-2 expression, and studies in both animal and human models suggest that an increased expression of COX-2 is the basis for its chemopreventive role in carcinogenesis in addition to the well-known role in inflammatory reactions.27282930313233

The efficacy of NSAIDs is supposedly based on the type of NSAID being administered, its concentration, and also the target tissue. NSAIDs such as indomethacin, sulindac, and ibuprofen have inhibitory action on both isoforms of COX, while aspirin is more COX-1 selective than COX-2.34 The evidence accumulating from research clearly suggests a tremendous potential for COX-2 inhibitors in cancer pathogenesis.35

In this metaanalysis, the dose-response analysis revealed a significant relation between duration of use and the risk of lung cancer. A longer period of NSAID use was associated with greater reduction in lung cancer risk. However, no significant relationship was found between frequency of NSAID use and the risk of lung cancer. Of the five studies that evaluated frequency of NSAID use, only two studies1819 reported a significant dose-response relationship. This was expected since frequency of tablet use is not a good predictor of NSAID use compared to duration of use. This finding also suggests that the ability of NSAIDs to offset the carcinogenic mechanisms induced by cigarette smoke is manifested only after long-term use. Although both the duration of smoking and number of cigarettes are good predictors of lung cancer, a study36 that examined the participants of the Cancer Prevention Study II indicated that duration of smoking was a better predictor of lung cancer. Therefore, it is likely that duration of smoking as a predictor of lung cancer could be affected by the duration of NSAID use.

Regarding histology, NSAIDs inhibit the growth of different cancer cell types, which suggests a broad role for these drugs in preventing both tumor growth and spread. Only two studies2024 included in this metaanalysis provided data stratified by the histologic types of lung cancer. In one study,20 stronger association was observed in SCLC, while in the other study13 association was similar across all the histologic types. The combined RR revealed that NSAID use has resulted in a 52% reduction in SCLC risk and 34% reduction in NSCLC risk. Studies3738 have shown that smoking is more often associated with squamous cell carcinoma or SCLC than with adenocarcinoma. The pronounced protective effect from SCLC observed in this analysis further supports the possible association between smoking and NSAIDs. Alternatively, COX-2 expression was observed more commonly in smokers than in the nonsmokers,39 and higher levels of COX-2 expression were detected in atypical adenomatous hyperplasia, a possible precursor of adenocarcinoma of the lung.30 Studies4041 also suggest that an increase in COX-2 expression may be associated with the development of adenocarcinoma and possibly with acquisition of an invasive and metastatic phenotype. This possibly suggests that the inverse association of NSAIDs and NSCLC could be due to inhibition of the increased COX-2 expression observed in this cell type, while mechanisms other than COX inhibition may more be involved in the pathogenesis of SCLC.

The limitations of this metaanalysis stem mainly from the limitations inherent in studies that were included. Six studies had adopted the case-control design, and we cannot rule out the possibility of selection and recall bias in these studies. While misclassification of exposure is supposedly not a potential problem in cohort studies, none of the included cohort studies utilized an objective method of exposure assessment. Estimation of NSAID use was based on a self-report and therefore subject to recall bias. Survival bias is of concern for diseases characterized by poor prognosis (such as lung cancer). If NSAIDs were prescribed for cases with poor survival after diagnosis, the proportion of users among case survivors would be lower than among control subjects, leading to a spurious inverse association between NSAID use and risk of lung cancer. However, several studies4243 have shown that increased COX-2 is associated with poor prognosis in lung cancer, suggesting the effect of NSAIDs on survival in lung cancer is more likely to be beneficial than detrimental. Thus, the effect of survival bias would attenuate a real inverse association between NSAID use and lung cancer, suggesting that protective effect of NSAIDs could in fact be larger than that reported by studies included in this metaanalysis.

The likelihood of important selection or publication bias in our results is very small, because we did not exclude any article during the identification and selection process, and the statistical test of publication bias did not suggest a publication bias. We included 13 published studies and 1 meeting abstract.15 Exclusion of the unpublished study from the analysis resulted in minimal change of RR from 0.79 to 0.78.

The findings of this metaanalysis suggest that NSAIDs may have a chemopreventive value against lung cancer. However, the findings need to be interpreted with caution owing to the limitations of the studies included in the analysis. Finally, we emphasize the need for larger epidemiologic studies with adequate dose-response information and statistical adjustment of potential confounders particularly cigarette smoking. In addition to their general use as inhibitors of inflammation, pain, and fever, NSAIDs have an emerging utility in both chemoprevention and chemotherapy of human cancer.


   Footnotes
 
Abbreviations: CI = confidence interval; COX = cyclooxygenase; NSAID = nonsteroidal antiinflammatory drug; NSCLC = non-small cell lung cancer; OR = odds ratio; RR = relative risk; SCLC = small cell lung cancer

Received for publication March 19, 2004. Accepted for publication September 28, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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