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Association of nonsteroidal anti-inflammatory drugs and aspirin use and the risk of head and neck cancers: a meta-analysis of observational studies

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Oncotarget. 2016; 7:65196-65207. https://doi.org/10.18632/oncotarget.11239

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Lanhua Tang, Huabin Hu, Huai Liu, Chengzhu Jian, Hui Wang and Jin Huang _

Abstract

Lanhua Tang1,*, Huabin Hu2,*, Huai Liu3,4, Chengzhu Jian5, Hui Wang3,4, Jin Huang1

1Department of Oncology, Xiangya Hospital of Central South University, Changsha, China

2Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

3Department of Radiotherapy, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China

4Key Laboratory of Translational Radiation Oncology, Changsha, China

5Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, China

*Lanhua Tang and Huabin Hu contributed equally to this work

Correspondence to:

Jin Huang, email: jinhuang@csu.edu.cn

Keywords: head and neck cancer, nonsteroidal anti-inflammatory drugs, aspirin, chemoprevention, meta-analysis

Received: May 02, 2016    Accepted: July 28, 2016    Published: August 12, 2016

ABSTRACT

Purpose: Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, have emerged as the potential chemopreventive agents for a number of cancer types, however, previous studies of head and neck cancers (HNC) have yielded inconclusive results. We performed a meta-analysis of observational studies to quantitatively assess the association between NSAIDs use and the risk for HNC.

Methods: We searched Pubmed, Embase, Google scholar, and Cochrane library for relevant studies that were published in any language, from January 1980 to April 2016. We pooled the odds ratio (OR) from individual studies and performed subgroup, heterogeneity, and publication bias analyses.

Results: A total of eleven studies (eight case-control studies and three cohort studies), involving 370,000 participants and 10,673 HNC cases contributed to this meta-analysis. The results of these studies suggested that neither use of overall NSAIDs (OR=0.95; 95% CI, 0.81-1.11), aspirin (OR=0.93; 95% CI, 0.79-1.10), nor nonsteroidal NSAIDs (OR=0.92; 95% CI, 0.76-1.10) were associated with HNC risk. Similar nonsteroidal results were observed when stratified by HNC sites, study design, sample size, and varied adjustment factors. However, we found significant protective effect of ibuprofen (OR=0.85; 95% CI, 0.72-0.99) and long-term aspirin use (≧5years) (OR=0.75; 95% CI, 0.65-0.85) on HNC risk, with low heterogeneity and publication bias.

Conclusions: Our meta-analysis results do not support the hypothesis that overall use of NSAIDs significant reduces the risk of HNC. Whereas, we cannot rule out a modest reduction in HNC risk associated with ibuprofen and long-term aspirin use.


Association of nonsteroidal anti-inflammatory drugs and aspirin use and the risk of head and neck cancers: a meta-analysis of observational studies | Tang | Oncotarget

INTRODUCTION

Head and neck cancers (HNC) continues to be an important public health problem, with an estimated 700,000 new cases around the world in 2012 [1]. HNC includes a variety of cancers originating from different sites within the head and neck region, such as the oral cavity, oropharynx, hypopharynx and larynx. It is well documented that tobacco consumption and excessive alcohol drinking are independent major risk factors for the development of HNC [24]. Other possible risk factors include infection with human papilloma virus (HPV), poor oral hygiene, environmental carcinogens and genetic susceptibility [59]. Despite great advance in multidisciplinary treatment, approximately 30 - 50% patients with HNC survive over 5 years after initial diagnosis, and 15% - 20% patients will develop second primary malignancies after extensive therapy [10, 11]. Therefore, it is crucial that identifying potential chemopreventive measures other than tobacco and alcohol cessation should be further investigated.

Convincing laboratory evidence has emerged to demonstrate an association between chronic inflammation and cancer, which makes the anti-inflammatory drugs have emerged as the most potential chemopreventive agents [1215]. Nonsteroidal anti-inflammatory drugs (NSAIDs), have received increasing attention because of their inhibitive effect on the cyclo-oxygenase (COX) enzymes, which may prevent synthesis of prostaglandins that stimulate growth and play a role in promoting carcinogenesis [1619].

Several epidemiologic studies have observed use of aspirin and other NSAIDs have an association with reduced risk for cancers of the colon, stomach, prostate and breast [17, 2022]. Even though some studies supported NSAIDs use significantly decrease the risk of HNC [11, 23, 24], while other studies did not show a consistent benefit [25, 26]. On the basis of the previous systematic review by Wilson et al. in 2011 [27], no definitive conclusion can be reached on NSAID/aspirin use and HNC risk. In addition, no meta-analysis and quantitative analysis was conducted due to the limited case number and heterogeneity of the studies identified. The purpose of the present study was to summarize all available evidence on this issue using a meta-analysis of observational studies.

RESULTS

Eligible studies

The overview of our search process was illustrated in Figure 1. Eleven studies met the predetermined criteria for inclusion, with three cohort studies [24, 28, 29], and eight case-control studies [11, 23, 25, 26, 30-33]. The number of HNC cases ranged from 71 to 2,745 in the case-control studies, and from 68 to 185 in the cohort studies. Three studies were conducted in the United States [11, 24, 31], two in Denmark [28, 29], two in United Kingdom [26, 32], two in Italy [23, 33], one in Sweden [30] and the other one was coordinated by the International Agency for Research on Cancer (IARC) in fourteen European centers (in ten countries) [25]. These eleven studies were published between 2003 and 2015. The range of enrollment periods for participants across studies was 1982-2013. Table 1 and Supplementary Table S1 listed the study characteristics and corresponding estimated OR with 95%CIs.

The flow diagram of search strategy.

Figure 1: The flow diagram of search strategy.

Table 1: Characteristics of studies included in the meta-analysis of NSAIDs use and the risk of HNC

Study

Study design

Study location

Period

HNC sites

Cases

Controls or cohort size

Type of drugs

OR (95%CI)

Adjustment for covariates

Bosetti et al, 2003

Case-control

Italy

1992 - 2000

Combined sites (oral, pharynx and larynx)

965

1779

Aspirin (at least once a week for more than 6 months)

0.86 (0.46 - 1.61)a

Age, gender, centre, educational, smoking, alcohol drinking

935

1732

Long-term aspirin use (duration of use ≧ 5 years)

0.33 (0.13 - 0.82)

Friis et al, 2003

Cohort

Denmark

1989 - 1995

Combined sites

68

29470

Aspirin (75, 100 or 150 mg)

1.36 (1.04 - 1.77)b

Age, gender

Oral and oropharynx

48

1.30 (0.90 - 1.70)

Larynx

20

1.50 (0.90 - 2.40)

Rosenquist et al, 2005

Case-control

Sweden

2000 - 2004

Oral and oropharynx

132

320

Aspirin (75-150 mg/day)

1.00 (0.60 - 1.70)a

Smoking, alcohol drinking

Friis et al, 2006

Cohort

Denmark

1991 - 2002

Oral (month and tongue)

185

169589

NA-NSAIDs (≧ 2 prescriptions)

1.20 (1.00 - 1.60)

Age, gender

Jayaprakash et al, 2006

Case-control

United States

1982 - 1998

Combined sites

529

529

Aspirin (ever used)

0.75 (0.58 - 0.96)

Age, gender, smoking, alcohol drinking

Oral cavity

169

169

0.73 (0.51 - 1.05)

Nasopharynx

22

22

0.88 (0.36 - 2.15)

Oropharynx

102

102

0.68 (0.44 - 1.05)

Larynx

141

141

0.89 (0.58 - 1.35)

Hypopharynx

31

31

0.77 (0.35 - 1.66)

Combined sites

313

289

Long-term aspirin use (duration of use ≧ 10 years)

0.65 (0.52 - 0.82)c

Ahmadi et al, 2010

Case-control

United States

2003 - 2007

Combined sites

71

71

Any NSAIDs (ever used)

0.31 (0.11 - 0.88)

Educational, marital status

44

47

Any NSAIDs (daily)

0.14 (0.04 -0.54)

25

25

Aspirin (daily)

0.15 (0.02 - 1.30)

Macfarlane et al, 2012

Case-control

European

NR

Combined sites

1779

1993

Aspirin (at least once a week for one year)

0.92 (0.78 - 1.09) b

Age, gender, BMI, educational, smoking, alcohol drinking, fruit consumption

Oral cavity

510

1993

1.04 (0.76 - 1.41)

Oropharynx

474

1993

1.05 (0.76 - 1.46)

OP NOS

112

1993

1.29 (0.70 - 2.35)

Larynx

670

1993

0.74 (0.54 - 1.01)

Hypopharynx

183

1993

0.53 (0.28 - 1.02)

Combined sites

1588

1736

Long-term aspirin use (duration of use ≧ 5 years)

0.78 (0.58 - 1.05) d

Wilson et al, 2013

Cohort

United States

1993 - 2001

Combined sites

316

141718

Aspirin (regular use)

0.78 (0.62 - 0.98)

Age, gender, BMI, smoking

315

141550

Aspirin (daily)

0.85 (0.65 - 1.11)

316

141718

Ibuprofen (regular use)

0.97 (0.75 - 1.27)

Age, gender, BMI, smoking, aspirin use

Macfarlane et al, 2014

Case-control

United Kingdom

1996 - 2010

Combined sites

2392

7165

Aspirin (≧ 1 prescriptions)

0.93 (0.76 - 1.15)

Age, gender, carstairs deprivation category, coronary heart disease, stroke

2034

6094

Long-term aspirin use (time between last and first prescription ≧ 5.4 years)

0.85 (0.70 - 1.04)

2392

7165

NA-NSAIDs (≧ 1 prescriptions)

0.82 (0.70 - 0.96)

Becker et al, 2015

Case-control

United Kingdom

1995 - 2013

Combined sites

2238

13488

Aspirin (≧ 50 prescriptions)

1.21 (0.97 - 1.51)

BMI, smoking, alcohol drinking

1932

11657

Ibuprofen (≧ 6 prescriptions)

0.78 (0.64 - 0.96)

Di Maso et al, 2015

Case-control

Italy

1992 -2008

Nasopharynx

198

592

Aspirin (at least one aspirin a week for more than 6 months)

0.24 (0.07 -0.87)

Age, gender, area of residence, smoking, period of interview, years of education, occupation

Abbreviations: BMI, body mass index; CI, confidence interval; F, female; HNC, Head and Neck Cancers; M, male; NR, not reported; NA-NSAIDs, non-aspirin nonsteroidal anti-inflammatory drugs; NSAIDs, nonsteroidal anti-inflammatory drugs; OP NOS, Oral, pharynx not otherwise specified; OR, odds ratio.a, Cited from a systematic review by Wilson et al.; b, Pooled from all cancer sites except for esophagus; c, Pooled from the ORs of 10-20 years, 21-40 years and ≧40 years; d, Pooled from the ORs of 5-9 years and ≧10years.

Quality of study methodologies

Table 2 showed the quality of study methodology included in the meta-analysis. The range of quality scores was 5 - 8; the average score was 6.7. The average scores of cohort studies and case–control studies were 7.7 and 6.4, respectively, which suggests a reasonable good quality of the cohort and case–control studies.

Table 2: Methodological quality of included studies based on the Newcastle–Ottawa Scale

Cohort studies (n=3)

Representa-tiveness of the exposed cohort

Selection
of the unexposed cohort

Ascertainment of exposure

Outcome of interest not present at start of study

Control for Important factor or additional factor

Assessment of outcome

Follow-up long enough for outcomes to occur a

Adequacy of follow-up of cohorts

Total (0-9)

Friis et al, 2003

8

Friis et al, 2006

8

Wilson et al, 2013

-

7

Case-control studies (n=7)

Adequate definition of cases

Representa-tiveness of cases

Selection of contros

Definition of controls

Control for important factor or additional factor

Ascertainment of exposure

Same method of ascertainment for subjects

Nonresponse Rate b

Total (0-9)

Bosetti et al, 2003

-

★★

-

-

6

Rosenquist et al, 2005

-

-

6

Jayaprakash et al, 2006

★★

-

-

7

Ahmadi et al, 2010

-

-

-

5

Macfarlane et al, 2012

★★

-

-

7

Macfarlane et al, 2014

-

7

Becker et al, 2015

-

7

Di Maso et al, 2015

-

-

6

a, A cohort study with a follow-up time > 5 years was assigned one star; b, Same rate for both groups was assigned one star.

Overall use of NSAIDs and the risk for HNC

Figure 2 illustrated the forest plot of ORs estimates with 95%CIs from individual studies and overall meta-analysis of all eleven studies [11, 23-26, 28-33]. The overall summary ORs demonstrated no significant association between overall NSAIDs use and the risk of HNC (OR=0.95; 95%CI, 0.81-1.11), with statistical heterogeneity among studies (P=0.001; I2=67.4%). The tests for funnel plot asymmetry by Begg’s test and Egger’s test identified no publication bias (Begg’s test, P = 0.276; Egger’s test, P = 0.229).

Forest plots of meta-analysis of overall NSAIDs use and the risk of HNC.

Figure 2: Forest plots of meta-analysis of overall NSAIDs use and the risk of HNC.

Subgroup analyses

Table 3 showed the associations between NSAIDs use and the risk of HNC in subgroup meta-analyses by various factors. The subgroup analyses were conducted on the basis of different types of NSAIDs use. There was no significant association between use of aspirin [11, 23-26, 28, 30-33] or non-aspirin nonsteroidal anti-inflammatory drugs (NA-NSAIDs) [24, 26, 29, 32] and the risk of HNC, with OR of 0.93 (95%CI, 0.79-1.10) and OR of 0.92 (95%CI, 0.76-1.10), respectively. For the two studies evaluated exposure to ibuprofen and the risk of HNC [24, 32], a significant protective effect was observed (OR = 0.85; 95%CI, 0.72-0.99). We also found long- term usage of aspirin (≧5 years) has been associated with a significant 25% reduction in HNC risk from four studies [11, 23, 25, 26] (OR=0.75; 95%CI, 0.65-0.85) (Figure 3), and statistical heterogeneity was not detected.

Forest plots of meta-analysis of long-term usage of aspirin and the risk of HNC.

Figure 3: Forest plots of meta-analysis of long-term usage of aspirin and the risk of HNC.

Table 3: Associations between NSAIDs use and the risk of HNC in subgroup meta-analyses

Studies groups

No. of Studies

Summary OR (95% CI)

Homogeneity

Model used

Publication Bias

P-value

I2 (%)

Begg’sP-value

Egger’s P-value

Type of drugs use

 Aspirin

10

0.93 (0.79 - 1.10)

0.002

65.0%

Random-effects

0.474

0.255

 NA-NSAIDs

4

0.92 (0.76 - 1.10)

0.026

67.7%

Random-effects

0.734

0.342

 Ibuprofen

2

0.85 (0.72 - 0.99)

0.199

39.5%

Fixed-effects

1.000

NA

Long-term aspirin use

4

0.75 (0.65 - 0.85)

0.103

51.5%

Fixed-effects

0.308

0.313

HNC sites

 Oral and oropharynx

5

1.01 (0.85 - 1.20)

0.098

43.9%

Random-effects

0.230

0.139

 Larynx

3

0.96 (0.65 - 1.42)

0.059

64.7%

Random-effects

0.296

0.253

 Hypopharynx

2

0.62 (0.38 - 1.01)

0.469

0.0%

Fixed-effects

1.000

NA

 Nasopharynx

2

0.50 (0.14 - 1.76)

0.099

63.2%

Random-effects

1.000

NA

Study design

 Case-control

8

0.89 (0.74 - 1.07)

0.017

59.1%

Random-effects

0.108

0.130

 Cohort

3

1.08 (0.77 - 1.51)

0.003

82.4%

Random-effects

0.296

0.446

Sample sizes

 ≧ 1000

8

0.99 (0.85 - 1.15)

0.003

67.1%

Random-effects

0.711

0.897

 < 1000

3

0.47 (0.18 - 1.27)

0.031

71.1%

Random-effects

0.296

0.059

Exposure source

 Questionnaire

6

0.82 (0.73 - 0.92)

0.090

47.5%

Random-effects

0.060

0.040

 Prescription database

4

1.14(1.02 – 1.28)

0.118

48.9%

Fixed-effects

0.308

0.134

Adjustments for age

 Yes

8

0.93 (0.79 - 1.11)

0.003

68.0%

Random-effects

0.711

0.478

 No

3

0.89 (0.51 -1.53)

0.039

69.3%

Random-effects

0.296

0.233

Adjustments for gender

 Yes

8

0.93 (0.79 - 1.11)

0.003

68.0%

Random-effects

0.711

0.478

 No

3

0.89 (0.51 -1.53)

0.039

69.3%

Random-effects

0.296

0.233

Adjustments for smoking

 Yes

7

0.88 (0.73 - 1.06)

0.022

59.6%

Random-effects

0.230

0.382

 No

4

1.05 (0.78 - 1.40)

0.011

73.2%

Random-effects

1.000

0.454

Adjustments for alcohol

 Yes

5

0.95 (0.79 -1.14)

0.083

51.5%

Random-effects

1.000

0.908

 No

6

0.91 (0.69 -1.21)

<0.001

77.5%

Random-effects

1.000

0.229

Adjustments for BMI

 Yes

3

0.95 (0.76 - 1.20)

0.023

73.6%

Random-effects

1.000

0.939

 No

8

0.92 (0.72 - 1.17)

0.002

69.4%

Random-effects

0.386

0.164

Abbreviations: BMI, body mass index; CI, confidence interval; HNC, Head and Neck Cancers; NA, not available; NA-NSAIDs, non-aspirin nonsteroidal anti-inflammatory drugs; NSAIDs, nonsteroidal anti-inflammatory drugs; OR, odds ratio.

There are six studies provided results on the effect of NSAIDs for specific HNC sites. However, NSAIDs use was not associated with a reduced risk for cancer of oral and oropharynx [11, 25, 2830] (OR=1.01; 95%CI, 0.85 - 1.20), larynx [11, 25, 28] (OR=0.96; 95%CI, 0.65- 1.42), hypopharynx [11, 25] (OR=0.62; 95%CI, 0.38 - 1.01) and nasopharynx [11, 33] (OR=0.50; 95%CI, 0.14 - 1.76).

To examine consistency across varying study designs with different potential biases, we stratified data into subgroups on the basis of study design. The summary ORs were 0.89 (95%CI: 0.74 - 1.07) pooled from eight case-control studies [11, 23, 25, 26, 30-33] and 1.08 (95%CI: 0.77 - 1.51) across three cohort studies [24, 28, 29].

The impact of sample size on risk estimates was assessed. The summary ORs were 0.99 (95%CI: 0.85 - 1.15) in eight studies [11, 23-26, 28-32] with relatively large sample size (≧1,000) and 0.47 (95% CI: 0.18 - 1.27) from the other three studies with the sample size less than 1,000 [30, 31, 33].

Recorded prescription database, self-administered questionnaires and standardized interviews were used to obtain information on NSAIDs exposure. The summary ORs were 0.82 (95%CI: 0.73 - 0.92) pooled from six questionnaire-based studies [11, 23-25, 31, 33] and 1.14 (95%CI: 1.02 - 1.28) from four studies based on prescription [26, 28, 29, 32]. These results suggested a significant protective effect was observed only in studies based on questionnaire.

In subgroup analyses by varied adjustment factors including age, gender, smoking, alcohol drink and body mass index (BMI), the association between NSAIDs use and the risk of HNC were non-significant in all strata (Table 2).

DISCUSSION

The findings from this meta-analysis of eleven observational studies, including 370,000 participants and 10,673 HNC cases, did not indicate overall NSAIDs use was significantly associated with a decreased risk for HNC.

When stratified by type of drugs, there was no association between use of aspirin or NA-NSAIDs and the risk of HNC. However, we observed a significant risk reduction of 15% in HNC risk for users of ibuprofen alone (OR = 0.85; 95%CI, 0.72-0.99). It was suggested that different types of NSAIDs might have different effects due to biological mechanisms [34, 35]. Andrews et al. had demonstrated that ibuprofen was more effective at reducing cancer cell growth and survival across a variety of cancer cell lines compared to other NSAIDs [36, 37], which may explain our findings.

It is widely accepted that any potential protective effects of NSAIDs use against cancers are likely to involve a considerable duration [38]. Previous large randomized trials and cohort studies showed long-term use of aspirin and other NSAIDs have almost consistently been associated with a stronger reduced risk of colorectal cancer [3941]. The time-risk relations are similar to those described for colorectal cancer, our results also observed a significant association between long-term aspirin use and the risk of HNC (OR=0.78; 95%CI, 0.67-0.92).

A significant preventive effect of NSAIDs use on HNC risk was observed in questionnaire-based studies but not in prescription-based studies. Studies that use prescription databases have their own shortcomings. Generally, no data were available regarding the use of over-the-counter medications including aspirin and NSAIDs, which will have underestimated exposure to these drugs. However, results from questionnaire-based studies should be interpreted cautiously for recall bias or selection bias. If the relatively healthy aspirin users were more likely to participate in the study than non-users, and an overestimate inverse association could be observed.

The previous systematic review including 2 cohort studies [28, 29] and 3 case-control studies [11, 23, 30], conducted by Wilson et al. also suggested no definitive conclusion can be reached on the preventive effect of NSAIDs on HNC risk [27]. The strengths of our meta-analysis were as follows: First, our present study included sufficient cases and quantitatively analyzed the effect of NSAIDs/aspirin using a detailed meta-analysis of eleven observational studies; Second, we were more capable to investigate potentially different effects on risk by the type and duration of NSAIDs use. As mentioned in the conclusion of Wilson’s systematic review, aspirin may protect against HNC. We not only found a significant risk reduction in HNC risk for long-term aspirin but also ibuprofen user; Third, we performed the publication bias and more subgroup analyses, which reinforce our confidence in the validity of the conclusion.

There were some potential limitations that have to be considered when interpreting these results. First, this meta-analysis is based on observational studies, which are more susceptible to recall and selection biases, and could result in an underestimation or an overestimation of the true effect. However, It may be unfeasible to evaluate the long-term protective effects of NSAID from randomized clinical trials due to the large sample size required; Second, we did not take into account possible interactions with other drugs due to absence of data. Use of NSAIDs are often associated with other drugs use, which could have concealed a possible association with NSAIDs [42]. Third, none of the studies included adjusted the analyses for HPV infection, which has been shown to have an etiological role in HNC as well as smoking and heavy alcohol drink, and there was some evidence to suggest an up-regulation of COX-2 in HPV-infected tissues [43, 44]. Fourth, HNC are a heterogeneous group of neoplasms, and we conducted subgroup analyses separately for specific HNC sites, however no significant risk reduction was found; Fifth, the possibility of publication bias is always a concern in meta-analyses of published studies. This could bias the results of this review if negative studies were less likely to be published. In our meta-analysis, a significant publication bias in the subgroup of long-term aspirin use was observed from the Egger’s test (P=0.055) but not the Begg’s test (P=0.308). We consider the discrepancy was due to the small number of studies included.

In conclusion, our meta-analysis does not support the hypothesis that overall use of NSAIDs significant reduces the risk of HNC. Whereas, we cannot rule out a modest reduction in HNC risk associated with ibuprofen and long-term aspirin use. Further large-scale robust studies are required, in particular, those evaluating the duration of aspirin use that may be take a protective effect.

MATERIALS AND METHODS

Publication search

This meta-analysis was conducted according to the meta-analysis of Observational Studies in Epidemiology (MOOSE) Guidelines [45]. We systematically searched Pubmed, Embase, Google scholar, and Cochrane library for manuscripts that mentioned the relationship between the use of aspirin and NSAIDs and the risk of HNC without language restriction, from January 1980 to April 2016. Our search terms consisted of three main components, head and neck (head and neck OR oral OR oropharynx OR hypopharynx OR larynx OR upper aerodigestive tract) AND disease (cancer OR neoplasms OR carcinoma) AND the exposure factor (aspirin OR NSAIDs OR ibuprofen OR naproxen OR indomethacin OR meloxicam OR valdecoxib OR celecoxib OR rofecoxib). We also reviewed the reference lists of articles with information on the topic to retrieve additional pertinent studies. If necessary, we attempted to contact the authors if we required additional information.

Study selection

Studies that met the following criteria were eligible for inclusion: (1) use a case–control or cohort study design; (2) evaluate the association between NSAIDs use and the risk of HNC; (3) provided the odds ratio (OR) or relative risk (RR) with corresponding confidence interval (CI) or sufficient data to calculate them. When the same author reported results obtained from the same population in more than one publication, only the most recent report, or the most complete one, was included in the analysis. Data from review articles, case reports, abstracts, and letters were not included.

Data extraction and quality assessment

Two investigators (Lanhua Tang and Huabin Hu) extracted the following information from each eligible studies independently: the last name of the first author, year of publication, study design, country where the study was performed, enrollment periods, HNC sites, sample size (numbers of case patients and control subjects), types of NSAIDs use, the source of NSAIDs exposure information, the source of HNC diagnosis, the ORs or RRs with corresponding 95%CI and adjustment for covariates. Differences in data extraction were resolved by consensus, referring back to the original article.

The methodological quality of the included studies was assessed using the 9-star Newcastle–Ottawa scale for quality of nonrandomized studies in meta-analyses [46]. The Newcastle-Ottawa Scale consists of eight items, which are categorized three categories: selection (one star each), comparability (up to two stars), and exposure/outcome (one star each). A “star” presents a “high-quality” choice of individual study.

Statistical analysis

Odds ratio (OR) was used as a measure of the association between use of NSAIDs and risk of HNC. Because the absolute risk of HNC is low, the OR in case–control studies was considered reasonable approximations of the corresponding rate ratios in cohort studies [47]. The heterogeneity of the estimators of OR was tested by Cochran’s Q test at the P <0.10 level of significance [48]. We also calculated the quantity I2 that describes the percentage variation across studies that is attributed to heterogeneity [49, 50]. When significant heterogeneity was found, the random-effects model with the DerSimonian-Laird method was used for meta-analysis [51]. Otherwise, the fixed-effects model with Mantel–Haenszel method was adopted [52]. Publication bias was evaluated using the Begg’s adjusted rank correlation test [53], and the Egger’s regression asymmetry test [54]. P <0.10 was considered to represent statistically significant publication bias.

When study reported results separately for aspirin and non-aspirin NSAIDs (NA-NSAIDs), to avoid double counting of the cases, we included only the results for aspirin in the overall summary estimate. Use of NSAIDs has the definition as follows:“overall use” was all the reported intake levels of NSAIDs use,“long-term use” was defined the duration of NSAIDs use or the time between last and first prescription more than 5 years. We only calculated the results for combined sites of HNC in the overall estimate, if studies had results for specific site and combined sites of HNC.

Analysis was performed using the STATA version 11.0 (Stata Corporation, College Station, Texas)

.

ACKNOWLEDGMENTS AND GRANT SUPPORT

This work was supported by grants from the National Natural Science Foundation of China (No: 81502658); the National Key Clinical Specialty, Oncology Department (National Health and Family Planning Commission of the PRC 2013/544).

CONFLICTS OF INTEREST

The authors declare no potential conflicts of interest.

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