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Meta-Analysis:

Association between nonsteroidal anti-inflammatory drugs use and risk of central nervous system tumors: a dose-response meta analysis

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Oncotarget. 2017; 8:102486-102498. https://doi.org/10.18632/oncotarget.21829

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Tao Zhang _, Xiaowen Yang, Pei Liu, Jianrui Zhou, Jie Luo, Hui Wang, Anrong Li and Yi Zhou

Abstract

Tao Zhang1,*, Xiaowen Yang2,*, Pei Liu3, Jianrui Zhou4, Jie Luo1, Hui Wang1, Anrong Li1 and Yi Zhou1

1Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, China

2Department of Clinical Laboratory, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, China

3Department of Dermatology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, China

4Department of Rehabilitation Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, China

*These authors contributed equally to this work and are co-first authors

Correspondence to:

Tao Zhang, email: ta0__zhang@sina.com

Keywords: central nervous system tumors, nonsteroidal anti-inflammatory drugs, dose-response relationship, meta analysis

Received: July 31, 2017     Accepted: September 23, 2017     Published: October 11, 2017

ABSTRACT

Although studies have examined the association between nonsteroidal anti-inflammatory drugs (NSAIDs) use and central nervous system (CNS) tumors risk, the results are inconclusive. Here, we conducted a dose-response meta-analysis in order to investigate the correlation between NSAIDs use and CNS tumors risk. Up to July 2017, 12 studies were included in current meta-analysis. NSAIDs use was significantly associated with a lower risk of CNS tumors. Furthermore, non-aspirin NSAIDs or aspirin use are significantly associated with a lower risk of CNS tumors. Additionally, NSAIDs use was associated with significantly a lower risk of glioma, glioblastoma but not meningioma. Subgroup analysis showed consistent findings. Furthermore, a significant dose-response relationship was observed between NSAIDs use and CNS tumors risk. Increasing cumulative 100 defined daily dose of NSAIDs use was associated with a 5% decrement of CNS tumors risk, increasing NSAIDs or non-aspirin NSAIDs or aspirin use (per 3 prescriptions increment) was associated with a 7%, 7%, 10% decrement of CNS tumors risk, increasing per 2 year of duration of NSAIDs or non-aspirin NSAIDs or aspirin use was associated with a 6%, 8%, 6% decrement of CNS tumors risk. Considering these promising results, NSAIDs use might provide helpful for reducing CNS tumors risk. Large sample size and different ethnic population are warranted to validate this association.


INTRODUCTION

Central nervous system (CNS) tumors are the second leading cause of death from neurological diseases worldwide, and costs on patients, caregivers and society [1]. Survival chances have improved gradually over the last 30 years but remain poor compared to many other cancers, and 30% glioma survived to one year and 15% glioma survived to five years of patients after diagnosis in adults [2, 3]. These data reveal the poor prognosis of CNS tumors, and thus to prevent the occurrence of CNS tumors is essential. The etiology of CNS tumors involves both genetic and environmental factors. Compared with many other cancers, there are only a few identified risk factors for glioma, including increasing age, male, rare genetic syndrome, and high levels of ionizing radiation [4]. Meanwhile, previous studies investigating have showed nonsteroidal anti-inflammatory drugs (NSAIDs) have a chemopreventive potential in the CNS tumors in vitro and in vivo [5].

NSAIDs are a non-steroidal anti-inflammatory drugs, including aspirin, acetaminophen, indomethacin, naproxen, diclofenac, ibuprofen, nimesulide, rofecoxib and celecoxib. The main function of NSAIDs is anti-inflammatory, antirheumatic, relieve pain and anticoagulation [6, 7]. At present, NSAIDs is one of the most widely used drugs in the world. About 30 million people use it every day around the world. As people using NSAIDs increases, clinicians, pharmacists, patients, and society and governments pay more attention to the safety of these drugs.

Previous studies have examined the relationship between NSAIDs use and risk of colorectal cancer [8], stomach cancer [9], prostate cancer [10] and breast cancer [11], have found that NSAIDs use is significantly reduce cancer risk. Even though some studies supported NSAIDs use significantly decrease the risk of CNS tumors [1223]. However, the result remains controversial. Additionally, no study to quantitative assessed NSAIDs use in relation to CNS tumors. Thus, we performed this dose-response meta-analysis to clarify and quantitative assessed the correlation between NSAIDs use and CNS tumors risk.

RESULTS

Literature search results

Figure 1 shows literature research and selection. A total of 2215 studies from PubMed and 2547 studies from Embase. After exclusion of duplicates and studies that did not fulfill the inclusion criteria, 12 studies were chosen, and the data were extracted. These studies were published update to July 2017.

Flow diagram of the study selection process.

Figure 1: Flow diagram of the study selection process.

Study characteristics

The characteristics of the included studies of NSAIDs use and CNS tumors risk are shown in the Table 1 and 2. Results in different subgroups were treated as two separate reports. Finally, thirty-three independent reports from twelve studies investigated the association between NSAIDs use and CNS tumors risk. Among the selected reports, twenty-two reports investigated the association between non-aspirin NSAIDs use and CNS tumors risk, eleven reports investigated the association between aspirin use and CNS tumors risk. A total of 667085 participants with 19394 incident cases from three countries were included in this meta-analysis.

Table 1: Characteristics of participants in included studies of nonsteroidal anti-inflammatory drugs using in relation to risk of central nervous system tumor

Author(year)

Study design

Country

Sex of population

Age at baseline (years)

No of participants

Endpoints (cases)

Quality score

Bannon et al. (2013)

Case-control

United Kingdom

Mix

58.0

47730

Brain tumours (5052)

Gliomas (2313)

Meningiomas (861)

7

Gaist et al. (2013)

Case-control

Denmark

Mix

20–85

21536

Gliomas (2688)

7

Sivak-Sears et al. (2004)

Case-control

USA

Mix

51–71.5

637

Glioblastoma (236)

7

Scheurer et al. (2008)

Case-control

USA

Mix

50

925

Gliomas (325)

6

Scheurer et al. (2011)

Case-control

USA

Mix

53.5

2873

Gliomas (1339)

7

Ferris et al. (2012)

Case-control

USA

Mix

57.4

917

Gliomas (517)

6

Seliger et al. (2015)

Case-control

United Kingdom

Mix

55.5

22055

Gliomas (2005)

7

Seliger et al. (2016)

Case-control

United Kingdom

Mix

55.3

27159

Gliomas (2469)

7

Friis et al. (2003)

Cohort

Denmark

Mix

70.0

29470

Brain tumours (193)

7

Sørensen et al. (2003)

Cohort

USA

Mix

47.2

172057

Brain tumours (170)

8

Daugherty et al. (2011)

Cohort

USA

Mix

63.4

302767

Gliomas (674)

Glioblastoma (521)

7

Cook et al. (2005)

Randomizedclinical trial

USA

Female

54.6

39876

Brain tumours (31)

6

Table 2: Outcomes and covariates of included studies of nonsteroidal anti-inflammatory drugs using in relation to risk of central nervous system tumor

Author (year)

Endpoints

Data source

Category and relative risk (95% CI)

Covariates in fully adjusted model

Bannon et al. (2013)

Brain tumours (5052)

Gliomas (2313)

Meningiomas (861)

Population-based

Non-aspirin NSAIDs

Gliomas

0 DDDs, 1.0 (reference); > 0- < 28, 1.00 (0.85, 1.16); > 28- < 65, 0.99 (0.85, 1.16); > 65- < 212, 1.21 (1.04, 1.40); > 212, 0.96 (0.82, 1.1.13)

Meningiomas

0 DDDs, 1.0 (reference); > 0- < 28, 1.02 (0.79, 1.31); > 28- < 65,1.40 (1.10, 1.77); > 65- < 212, 1.32 (1.04, 1.67); > 212, 1.35 (1.06, 1.71)

Aspirin

Gliomas

0 DDDs, 1.0 (reference); > 0- < 224, 1.08 (0.85, 1.38); > 224- < 728, 1.09 (0.86, 1.40); > 728- < 1572, 1.01(0.78,1.31); > 1572, 0.85 (0.65, 1.12)

Meningiomas

0 DDDs, 1.0 (reference); > 0- < 224, 1.39 (0.98, 1.97); > 224- < 728, 1.29 (0.88, 1.90); > 728- < 1572, 0.88 (0.58,1.32); > 1572, 0.97 (0.64, 1.47)

Adjusted for age,sex, history of osteoarthritis/arthralgia;history of rheumatoid arthritis, history of allergy, history of hormone replacement therapy use.

Gaist et al. (2013)

Gliomas (2688)

Self-administered

Recent use, years

Non-aspirin NSAIDs

Never use, 1.0 (reference); > 0- < 2, 1.06 (0.95, 1.17); > 2- < 4, 0.97 (0.60, 1.57); > 5, 1.11 (0.57, 2.17)

Aspirin

Never use, 1.0 (reference); > 0- < 2, 0.96 (0.79, 1.16); > 2- < 4, 0.80 (0.60, 1.06); > 5, 0.80 (0.53, 1.21)

Past use, years

Non-aspirin NSAIDs

Never use, 1.0 (reference); > 0- < 2, 1.05 (0.95, 1.17); > 2, 0.91 (0.29, 2.83)

Aspirin

Never use, 1.0 (reference); > 0- < 2, 0.84(0.61, 1.15); > 2, 0.47 (0.14, 1.15)

Adjusted for education, diabetes, stroke, allergy, asthma, use of statins, antihistamines, and anti-asthma medication

Sivak-Sears et al. (2004)

Glioblastoma (236)

Population-based

Recent use, years

Ibuprofen

Never use, 1.0 (reference); > 0- < 5, 0.32 (0.10, 0.70); > 5, 1.04 (0.60, 1.80)

Naproxen

Never use, 1.0 (reference); > 0- < 3, 0.75 (0.30, 1.70); > 3, 0.50 (0.20, 1.20)

Acetaminophen

Never use, 1.0 (reference); > 0- < 10, 0.72 (0.30, 1.50); > 10, 1.08 (0.60, 2.00)

Aspirin

Never use, 1.0 (reference); > 0- < 10, 0.71 (0.40, 1.20); > 10, 0.66 (0.40, 1.10)

Adjustment for gender, ethnicity, income, and education

Scheurer et al. (2011)

Gliomas (1339)

Population-based

NSAIDs

Never use, 1.0 (reference); > 0- < 10, 0.55 (0.35, 0.88); > 10, 0.65 (0.39, 1.07)

Adjusted for age, race, sex, education, study series, family history of brain tumors, and history of chickenpox and controlled for all other covariates in the table.

Ferris et al. (2012)

Gliomas (517)

Self-administered

Recent use, years

Aspirin

< 6 Months, 1.0 (reference); > 7- < 24, 0.57 (0.30, 1.08); > 25- < 60, 0.64 (0.38, 1.06); > 60, 0.80 (0.51, 1.24)

Ibuprofen

< 6 Months, 1.0 (reference); > 7- < 24, 1.49 (0.40, 5.54); > 25- < 60, 1.06 (0.55, 2.06); > 60, 1.08 (0.64, 1.84)

Naproxen

< 6 Months, 1.0 (reference); > 7- < 24, 3.40 (0.68, 17.34); > 25- < 60, 0.85 (0.23, 2.98); > 60, 0.37 (0.13, 1.11)

All NSAIDs

< 6 Months, 1.0 (reference); > 7- < 24, 0.70 (0.35, 1.38); > 25- < 60, 0.75 (0.46,1.23); > 60- < 120, 0.73 (0.49, 1.08); > 120, 0.62 (0.38, 1.00)

Adjusted for individual statins, NSAIDs, age, race, gender and center

Seliger et al. (2015)

Gliomas (2005)

Population-based

Number of prescriptions

NSAIDs

Never use, 1.0 (reference); > 1- < 9, 0.98 (0.89, 1.08); > 10, 1.05 (0.84, 1.33)

Aspirin

Never use, 1.0 (reference); > 1- < 14, 0.78 (0.55, 1.11); > 15, 1.22 (0.76, 1.94)

Adjusted for age, sex, general practice, number of years of active history in the database, and adjusted for BMI and smoking

Seliger et al. (2016)

Gliomas (2469)

Self-administered

Number of prescriptions

Aspirin

Never use, 1.0 (reference); > 1- < 9, 0.83(0.60, 1.15); > 10- < 29, 0.80 (0.43, 1.50); > 30, 1.19 (0.66, 2.13)

COX-2 inhibitors

Never use, 1.0 (reference); > 1- < 9, 1.02 (0.92, 1.13); > 10- < 29, 1.01 (0.80, 1.28); > 30, 1.16 (0.76, 1.55)

Ibuprofen

Never use, 1.0 (reference); > 1- < 9, 0.95 (0.86, 1.05); > 10- < 29, 1.03 (0.77, 1.39); > 30, 0.94 (0.60, 1.48)

Naproxen

Never use, 1.0 (reference); > 1- < 9, 0.91 (0.79, 1.05); > 10- < 29, 0.52 (0.28, 0.96); > 30, 1.45 (0.83, 2.52)

Adjusted for age, sex, general practice, and number of years of active history in the database, body mass index, smoking, diabetes, congestive heart failure, and all other medications in this table

Daugherty et al. (2011)

Gliomas (674)

Glioblastoma (521)

Population-based

Number of prescriptions

Glioma

Aspirin

Never use, 1.0 (reference); > 0- < 2, 1.21(0.91, 1.61); > 2- < 6, 1.07 (0.70, 1.62); > 7, 1.21 (0.88, 1.65)

Non Aspirin NSAID

Never use, 1.0 (reference); > 0- < 2, 1.06(0.84, 1.33); > 2- < 6, 0.87 (0.53, 1.44); > 7, 0.92 (0.62, 1.36)

Glioblastoma

Aspirin

Never use, 1.0 (reference); > 0- < 2, 1.30(0.94, 1.80); > 2- < 6, 1.06 (0.65, 1.72); > 7, 1.21 (0.84, 1.75)

Non Aspirin NSAID

Never use, 1.0 (reference); > 0- < 2, 1.03(0.79, 1.34); > 2- < 6, 0.58 (0.30, 1.15); > 7, 0.96 (0.62, 1.49)

Adjusting for sex, race, and history of heart disease using age as time metric

Abbreviations: DDD: defined daily dose.

NSAIDs use and CNS tumors risk

Thirty-three independent reports from twelve studies investigated the association between NSAIDs use and CNS tumors risk. Compared with no NSAIDs use, NSAIDs use was significantly associated with a lower risk of CNS tumors risk (RR:0.89; 95% CI, 0.81–0.95; P = 0.001) (Table 3). Furthermore, NSAIDs use was associated with significantly a lower risk of glioma (RR:0.92; 95% CI, 0.87–0.98; P = 0.012) (Table 3), glioblastoma (RR:0.86; 95% CI, 0.73–0.98; P < 0.001) (Table 3) but not meningioma (RR:0.73; 95% CI, 0.48–1.12; P = 0.149) (Table 3). That may be because there isn’t enough data in meningioma and CNS tumors risk.

Table 3: Stratified analyses of relative risk of central nervous system tumor risk

Studies groups

No of reports

Relative risk (95% CI)

Heterogeneity

P for test

P value

I2 (%)

Total

33

0.89 (0.81–0.95)

0.000

55.8%

0.001

Subgroup analyses for nonsteroidal anti-inflammatory drugs using

Type of drugs use

Non-aspirin NSAIDs using

22

0.86 (0.78–0.92)

0.001

54.9%

0.002

Aspirin using

11

0.88 (0.79–0.95)

0.014

54.8%

0.006

Tumour subtype

Glioma

18

0.92 (0.87–0.98)

0.000

55.3%

0.012

Meningioma

2

0.73 (0.48–1.12)

0.135

55.3%

0.149

Glioblastoma

7

0.86 (0.73–0.98)

0.177

39.1%

< 0.001

Study design

Case–control

27

0.89 (0.83–0.96)

0.000

60.5%

0.001

Cohort

6

0.93 (0.83–0.99)

0.256

23.7%

0.043

No of participants

≥ 10 000

23

0.94 (0.86–0.99)

0.000

57.6%

0.038

< 10 000

10

0.72 (0.62–0.83)

0.705

0.0%

< 0.001

No of cases

≥1000

21

0.94 (0.87–0.99)

0.000

59.1%

0.041

<1000

12

0.80 (0.68–0.90)

0.051

43.8%

< 0.001

Study quality

Score ≥ 7

30

0.83 (0.73–0.93)

0.000

65.4%

< 0.001

Score < 7

3

0.95 (0.86–1.05)

0.313

0.0%

0.413

Non-aspirin NSAIDs use and CNS tumors risk

Twenty-two independent reports from ten studies investigated the association between non-aspirin NSAIDs use and CNS tumors risk. Non-aspirin NSAIDs use was significantly associated with a lower risk of CNS tumors risk (RR:0.86; 95% CI, 0.78–0.94; P = 0.002) (Table 4). Furthermore, non-aspirin NSAIDs use was associated with significantly a lower risk of glioma (RR:0.94; 95% CI, 0.88–0.99; P = 0.042) (Table 4), glioblastoma (RR:0.78; 95% CI, 0.63–0.95; P = 0.014) (Table 4) but not meningioma (RR:0.97; 95% CI, 0.64–1.47; P = 0.880) (Table 4).

Table 4: Associations between non-aspirin NSAIDs using and central nervous system tumor risk in subgroup meta-analyses

Studies groups

No of reports

Relative risk (95% CI)

Heterogeneity

P for test

P value

I2 (%)

Total

22

0.86 (0.78–0.92)

0.001

54.9%

0.002

Tumour subtype

Glioma

16

0.94 (0.88–0.99)

0.003

57.0%

0.042

Meningioma

1

0.97 (0.64–1.47)

0.880

Glioblastoma

5

0.78 (0.63–0.95)

0.883

0.0%

0.014

Study design

Case–control

19

0.88 (0.78–0.95)

0.000

60.3%

< 0.001

Cohort

3

0.93 (0.85–0.98)

0.686

0.0%

0.013

No of participants

≥ 10 000

17

0.87 (0.78–0.91)

0.000

66.0%

0.003

< 10 000

5

0.91 (0.85–0.97)

0.155

46.3%

< 0.001

No of cases

≥ 1000

11

0.83 (0.73–0.94)

0.162

24.2%

0.005

< 1000

11

0.90 (0.81–0.98)

0.001

65.8%

0.013

Study quality

Score ≥ 7

20

0.88 (0.78–0.98)

0.002

54.6%

0.007

Score < 7

2

0.74 (0.67–0.82)

0.448

0.0%

< 0.001

Aspirin use and CNS tumors risk

Eleven independent reports from seven studies investigated the association between aspirin use and CNS tumors risk. Compared with no aspirin use, aspirin use was significantly associated with a lower risk of CNS tumors risk (RR:0.88; 95% CI, 0.79–0.95; P = 0.006)(Table 5). Furthermore, aspirin use was associated with significantly a lower risk of glioma(RR:0.86; 95% CI, 0.76–0.95; P < 0.001) (Table 5) but not meningioma (RR:0.85; 95% CI, 0.65–1.12; P = 0.253) (Table 5) and glioblastoma (RR:0.91; 95% CI, 0.55–1.50; P = 0.701) (Table 5)

Table 5: Associations between aspirin using and central nervous system tumor risk in subgroup meta-analyses

Studies groups

No of reports

Relative risk (95% CI)

Heterogeneity

P for test

P value

I2 (%)

Total

11

0.88 (0.79–0.95)

0.014

54.8%

0.006

Tumour subtype

Glioma

8

0.86 (0.76–0.95)

0.013

43.8%

< 0.001

Meningioma

1

0.85 (0.65–1.12)

0.253

Glioblastoma

2

0.91 (0.55–1.50)

0.038

76.7%

0.701

Study design

Case–control

8

0.83 (0.72–0.96)

0.032

54.4%

0.001

Cohort

3

0.92 (0.82–0.96)

0.055

65.5%

0.025

No of participants

≥ 10 000

10

0.85 (0.75–0.96)

0.021

54.1%

0.003

< 10 000

1

1.08 (0.64–1.34)

0.651

No of cases

≥ 1000

10

0.85 (0.75–0.96)

0.021

54.1%

0.003

< 1000

1

1.08 (0.64–1.34)

0.651

Study quality

Score ≥ 7

10

0.85 (0.75–0.96)

0.021

54.1%

0.003

Score < 7

1

1.08 (0.64–1.34)

0.651

Dose-response between NSAIDs use and CNS tumors risk

Use restricted cubic spline function, the test for a nonlinear dose-response relationship was significant (likelihood ratio test, P < 0.001), suggesting curvature in the relationship between NSAIDs use and CNS tumors risk. Increasing cumulative 100 defined daily dose of NSAIDs use was associated with a 5% decrement of CNS tumors risk, the summary relative risk of CNS tumors risk for an per cumulative 100 defined daily dose of NSAIDs use was 0.95 (95% CI: 0.92–0.98, P = 0.003) (Figure 2). Furthermore, increasing NSAIDs use (per 3 prescriptions increment) was associated with a 7% decrement of CNS tumors risk, the summary relative risk of CNS tumors risk for an per 3 prescriptions increment of NSAIDs use was 0.93 (95% CI: 0.88–0.97, P < 0.001) (Figure 3). Increasing non-aspirin NSAIDs use (per 3 prescriptions increment) was associated with a 7% decrement of CNS tumors risk, the summary relative risk of CNS tumors risk for an per 3 prescriptions increment of non-aspirin NSAIDs use was 0.93 (95% CI: 0.89–0.97, P < 0.001) (Figure 4). Increasing aspirin use (per 3 prescriptions increment) was associated with a 10% decrement of CNS tumors risk, the summary relative risk of CNS tumors risk for an per 3 prescriptions increment of aspirin use was 0.90 (95% CI: 0.85–0.95, P < 0.001) (Figure 5). Additionally, increasing per 2 year of duration of NSAIDs use was associated with a 6% decrement of CNS tumors risk, the summary relative risk of CNS tumors risk for an per 2 year of duration of NSAIDs use was 0.94 (95% CI: 0.92–0.98, P = 0.001) (Figure 6), increasing per 2 year of duration of non-aspirin NSAIDs use was associated with a 8% decrement of CNS tumors risk, the summary relative risk of CNS tumors risk for an per 2 year of duration of non-aspirin NSAIDs use was 0.92 (95% CI: 0.87–0.97, P = 0.001) (Figure 7), increasing per 2 year of duration of aspirin use was associated with a 6% decrement of CNS tumors risk, the summary relative risk of CNS tumors risk for an per 2 year of duration of aspirin use was 0.94 (95% CI: 0.88–0.98, P = 0.005) (Figure 8).

Dose-response relationship between cumulative daily dose of NSAIDs use in relation to risk of central nervous system tumor.

Figure 2: Dose-response relationship between cumulative daily dose of NSAIDs use in relation to risk of central nervous system tumor.

Dose-response relationship between number of prescriptions of NSAIDs use in relation to risk of central nervous system tumor.

Figure 3: Dose-response relationship between number of prescriptions of NSAIDs use in relation to risk of central nervous system tumor.

Dose-response relationship between number of prescriptions of non-aspirin NSAIDs use in relation to risk of central nervous system tumor.

Figure 4: Dose-response relationship between number of prescriptions of non-aspirin NSAIDs use in relation to risk of central nervous system tumor.

Dose-response relationship between number of prescriptions of aspirin use in relation to risk of central nervous system tumor.

Figure 5: Dose-response relationship between number of prescriptions of aspirin use in relation to risk of central nervous system tumor.

Dose-response relationship between duration of NSAIDs use in relation to risk of central nervous system tumor.

Figure 6: Dose-response relationship between duration of NSAIDs use in relation to risk of central nervous system tumor.

Dose-response relationship between duration of non-aspirin NSAIDs use in relation to risk of central nervous system tumor.

Figure 7: Dose-response relationship between duration of non-aspirin NSAIDs use in relation to risk of central nervous system tumor.

Dose-response relationship between duration of aspirin use in relation to risk of central nervous system tumor.

Figure 8: Dose-response relationship between duration of aspirin use in relation to risk of central nervous system tumor.

Subgroup analyses

Subgroup analysis was performed to check the stability of the primary outcome. Subgroup meta-analyses in study design, study quality, number of participants and number of cases showed consistent findings (Tables 35).

Sensitivity analysis

Sensitivity analysis was conducted to assess the stability of the results. The results show the association between NSAIDs use and CNS tumors risk were stable (Supplementary Figures 1–3).

Publication bias

Publication bias of NSAIDs use was evaluated with both Begg’s and Egger’s tests. Results from Egger’s tests indicated no evidence of publication bias among these studies (Supplementary Table 1). A funnel plot for publication bias assessment is illustrated in Supplementary Figures 4–6.

DISCUSSION

In the current meta-analysis was based on 12 case-control or cohort study, with 667085 participants with 19394 incident cases. Thus, this meta analysis provides the most up-to-date epidemiological evidence supporting NSAIDs use is helpful for CNS tumors. A dose-response analysis revealed that increasing cumulative 100 defined daily dose of NSAIDs use was associated with a 5% decrement of CNS tumors risk, increasing NSAIDs or non-aspirin NSAIDs or aspirin use (per 3 prescriptions increment) was associated with a 7%, 7%, 10% decrement of CNS tumors risk, increasing per 2 year of duration of NSAIDs or non-aspirin NSAIDs or aspirin use was associated with a 6%, 8%, 6% decrement of CNS tumors risk.

Previous meta-analysis reported the association between NSAIDs use and brain tumour risk, and found NSAIDs use did not appear to be associated with brain tumour risk [24]. Though, the result is quite different with ours, it still exist some problems. On the one hand, previous meta-analysis included just ten reports from ten studies, our meta-analysis included thirty-three independent reports from twelve studies, the quantity of reports involving in their meta-analysis was smaller, which weak the persuasive power of their research, and our results become more convincing. On the other hand, previous meta-analysis did not include all NSAIDs in the study, this may be affect the result and all NSAIDs acted as a independent report in our meta-analysis.

Several plausible pathways may reasonable for the relationship between NSAIDs use and CNS tumors risk. Firstly, NSAIDs have been found to inhibit or kill glioma cells, and the nonsteroidal anti-inflammatory drug can suppresses the growth and induces apoptosis of human glioblastoma cells via the NF-kappaB pathway [2527]. Secondly, refractoriness of glioblastoma multiforme (GBM) largely depends on its radioresistance, and celecoxib enhances radiosensitivity of hypoxic glioblastoma cells through endoplasmic reticulum stress [2831]. Third, NSAIDs use can significantly enhance glioblastoma radiosensitivity, reduced clonogenic survival, and prolonged survival of glioblastoma-implanted mice by inhibition of tumor angiogenesis with extensive tumor necrosis and reduce angiogenesis [3234]. Fourth, NSAIDs use is sufficient to render unmodified tumor cells immunogenic in immunotherapy of experimental brain tumors, and stimulate anti-tumour immune reactions in vitro and in established animal models [3537]. However, the potential mechanisms of NSAIDs use and tumor growth still remain unclear and controversial.

To our knowledge, this is the first comprehensive study to identify and quantify the potential dose-response association between NSAIDs use and CNS tumors risk in both men and women. Although, we performed this meta-analysis very carefully, some limitations must be considered in the current meta-analysis. Firstly, despite we searched all studies describing the association between NSAIDs use and CNS tumors risk, there are only 12 studies about NSAIDs use and CNS tumors risk, the number of eligible studies was still limited. On the other hand, 12 studies from only three countries, different ethnic population are warranted to validate the association between NSAIDs use and CNS tumors risk. Thirdly, we only select literature that written by English, which may have resulted in a language or cultural bias, other languages should be chosen in the further. Fourth, in the subgroup analysis in CNS tumors type, there has no insufficient statistical power to check a dose-response in different CNS tumors type, large data in different CNS tumors type is warranted to validate this association.

In conclusion, our findings underscore the notion that NSAIDs use was significantly associated with CNS tumors risk decrement. In the future, large-scale case-control and population based association studies must be performed in the future to validate the risk identified in the current meta-analysis.

MATERIALS AND METHODS

Our meta-analysis was conducted according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) checklist [38].

Search strategy

We included eligible studies investigating the relationship of NSAIDs use and CNS tumors risk. To develop a flexible, non-linear, r meta-regression model, we required that an eligible study should have categorized into 3 or more levels.

Eligible studies were systematically searched of PubMed and Embase update to July 2017 for case control or cohort studies examining the relationship between NSAIDs use and CNS tumors risk, with keywords including “brain cancer” [MeSH] OR “glioma”[MeSH] OR “glioblastoma” [MeSH] OR “meningioma” [MeSH] AND “aspirin” [MeSH] OR “NSAIDs” [MeSH] OR “ibuprofen”[MeSH] OR “naproxen” [MeSH] OR “indomethacin” [MeSH] OR “meloxicam” [MeSH] OR “nimesulide” [MeSH] OR “celecoxib” [MeSH] OR “rofecoxib”[MeSH] OR “acetaminophen” [MeSH] OR “diclofenac”[MeSH]. We refer to the relevant original essays and commentary articles to determine further relevant research.

Study selection

Two independent researchers investigate information the correlation between NSAIDs use and CNS tumors risk: outcome was CNS tumors; the relative risks at least three quantitative categories of NSAIDs use and CNS tumors risk. Moreover, we precluded non-human studies, reviews, editorials and published letters.

Data extraction

Use standardized data collection tables to extract data. We extracted the following information: first author; publication year; age; country; sex; cases and participants; the categories of NSAIDs use; relative risk(RR) or odds ratio (OR). We collect the risk estimates with multivariable-adjusted. According to the Newcastle-Ottawa scale [39], quality assessment was performed for non-randomized studies.

Statistical analysis

We pooled relative risk estimates to measure the association between NSAIDs use and CNS tumors risk; the hazard ratio were considered equivalent to the relative risk [40]. Results in different subgroups of NSAIDs use and CNS tumors risk were treated as two separate reports.

Due to different definitions cut-off points in the included studies for categories, we performed a relative risk estimates by increasing cumulative 100 defined daily dose of NSAIDs use or per 3 prescriptions of NSAIDs use or per 2 year of duration of NSAIDs use the method recommended by Greenland, Longnecker and Orsini and colleagues [41]. In addition, use restricted cubic splines to evaluate the non-linear association between NSAIDs use and CNS tumors risk, with three knots at the 10th, 50th, and 90th percentiles of the distribution. A flexible meta-regression based on restricted cubic spline (RCS) function was used to fit the potential non-linear trend, and generalized least-square method was used to estimate the parameters. This procedure treats NSAIDs use (continuous data) as an independent variable and logRR of diseases as a dependent variable, with both tails of the curve restricted to linear. A P value is calculated for linear or non-linear by testing the null hypothesis that the coefficient of the second spline is equal to zero [42].

We use STATA software 12.0 (STATA Corp, College Station, TX, USA) to evaluate the relationships between NSAIDs use and CNS tumors risk. Heterogeneity among studies used Q test and I2 statistic to assess. If PQ< 0.10 or I2 > 50%, random-effect model was chosen, otherwise, fixed-effect mode was applied. Begg’s and Egger’s tests were to assess the publication bias of each study. P < 0.05 was considered signifcant for all tests.

CONFLICTS OF INTEREST

Authors have disclosed no conflicts of interest.

FUNDING

This study received no specific external funding.

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