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  • Research article
  • Open Access
  • Open Peer Review

Associations between aspirin use and the risk of cancers: a meta-analysis of observational studies

Contributed equally
BMC Cancer201818:288

https://doi.org/10.1186/s12885-018-4156-5

  • Received: 28 September 2017
  • Accepted: 20 February 2018
  • Published:
Open Peer Review reports

Abstract

Background

Epidemiological studies have clarified the potential associations between regular aspirin use and cancers. However, it remains controversial on whether aspirin use decreases the risk of cancers risks. Therefore, we conducted an updated meta-analysis to assess the associations between aspirin use and cancers.

Methods

The PubMed, Embase, and Web of Science databases were systematically searched up to March 2017 to identify relevant studies. Relative risks (RRs) with 95% confidence intervals (CIs) were used to assess the strength of associations.

Results

A total of 218 studies with 309 reports were eligible for this meta-analysis. Aspirin use was associated with a significant decrease in the risk of overall cancer (RR = 0.89, 95% CI: 0.87–0.91), and gastric (RR = 0.75, 95% CI: 0.65–0.86), esophageal (RR = 0.75, 95% CI: 0.62–0.89), colorectal (RR = 0.79, 95% CI: 0.74–0.85), pancreatic (RR = 0.80, 95% CI: 0.68–0.93), ovarian (RR = 0.89, 95% CI: 0.83–0.95), endometrial (RR = 0.92, 95% CI: 0.85–0.99), breast (RR = 0.92, 95% CI: 0.88–0.96), and prostate (RR = 0.94, 95% CI: 0.90–0.99) cancers, as well as small intestine neuroendocrine tumors (RR = 0.17, 95% CI: 0.05–0.58).

Conclusions

These findings suggest that aspirin use is associated with a reduced risk of gastric, esophageal, colorectal, pancreatic, ovarian, endometrial, breast, and prostate cancers, and small intestine neuroendocrine tumors.

Keywords

  • Aspirin
  • Cancers
  • Meta-analysis
  • Observational studies

Background

Aspirin has been used as an analgesic and in the prevention of cardiovascular diseases events in the past decades and is one of the most commonly used drugs worldwide [1, 2]. Clinical and epidemiological studies reported that the rates of aspirin usage in different populations across different countries ranging from 11% to 54% [35]. Since the 1970s, many researchers started to focus on the effects of aspirin on cancers [6, 7]. However, these original studies were not comprehensive, and the effects on some cancers were controversial [8, 9].

Although several meta-analyses have been conducted to assess the associations between aspirin use and the risk of cancers(e.g., gastric, esophageal, pancreatic, lung, squamous cell carcinoma, breast, ovarian, and prostate cancers) [1018], most of these studies were restricted to certain types of cancers, and some types such as hepatobiliary and cervical cancer could not be investigated. In addition, 70 new studies have been published since 2012. Therefore, this comprehensive systematic review and updated meta-analysis was conducted to explore the reliability of risk estimates between aspirin usage and most types of cancers and provide a landscape of aspirin use and cancer incidence.

Methods

Search strategy

This systematic review was conducted in accordance with the checklist proposed by the Meta-analysis of Observational Studies in Epidemiology group [19]. We searched multiple electronic bibliographic databases to identify studies published from database inception till March 2017, including PubMed, Embase, and Web of Science databases, with the following search terms: (“cancer” OR “neoplasm” OR “carcinoma”) AND (“aspirin” OR “acetylsalicylic acid” OR “non-steroidal anti-inflammatory drugs” OR “NSAIDs”). We restricted our search to human studies and published in English. In addition, reference lists from relevant reviews and retrieved articles were searched for qualifying studies.

Inclusion criteria

The inclusion criteria were: 1) case-control or cohort studies; 2) studies that evaluated the relationships between the use of aspirin and the risk of cancers; 3) studies that reported risk estimates with 95% confidence interval (CI) or provided information that enabled us to calculate them. The exclusion criteria were: 1) studies that used other combinations of NSAIDs, which prevented the determination of the specific effect of aspirin, and 2) studies involving patients with specific diseases (e.g., Barrett’s esophagus, Crohn’s disease, or ulcerative colitis). Only the latest or the most informative study was included when multiple studies were published on the same study population.

Data extraction

The following information was obtained from each study: first author name, year of publication, study period, study location, study design, number of cases, number of participants, gender, definition of aspirin exposure, as curtained methods of exposure, odds ratios (ORs), hazard ratios (HRs) or relative risks (RRs) with their corresponding 95% CIs, and confounding factors adjusted in the analysis. The most fully-adjusted risk estimates with its corresponding 95% CIs (when available) were preferentially extracted. Data extraction was conducted independently by two authors (Y.Q. and T.T.Y.), and discrepancies were resolved by discussion with a third investigator (Z.X.L.).

Quality assessment

Quality assessment of eligible studies was performed independently by two reviewers (Y.Q. and T.T.Y.) according to the Newcastle-Ottawa Quality Assessment Scale [20]. This scale allocates a maximum of nine points based on the selection (0–4 points), comparability (0–2 points), and exposure/outcome of the study participants (0–3 points). Scores of 0–3, 4–6, and 7–9 were classified as low, moderate, and high-quality studies respectively.

Statistical analysis

RRs were used as the common measurement of the associations between aspirin use and the risk of cancer. Because cancer is a rare event in general, we could generally ignore the distinctions among the various measures of relative risk (e.g., odds ratios, rate ratios, and risk ratios) [21], and considered that ORs and HRs were similar to RRs. When risk estimates for different durations of aspirin use or different levels of aspirin utilization were available, the study-specific RRs were subsequently recalculated in the primary analysis by pooling the risk estimates compared with the reference group. A random effects model was selected to estimate the pooled RRs (95% CI) for the associations between aspirin use and the risk of cancer if the risk estimates for different subtypes of cancer were available. Summary estimates were derived from meta-analyses using random effects models. Studies involving different populations or different types of cancers were treated as independent studies.

To assess the heterogeneity in results of individual studies, I2 statistic (values of 25%, 50%, and 75% represented cutoff points for low, moderate, and high degrees of heterogeneity, respectively) were used [22]. Publication bias was assessed with Funnel plots, the Begg’s rank correlations and Egger’s regression model. Subgroup analyses for study design, study location, gender, exposure assessment, quality assessment, duration of aspirin use (years), and frequency of aspirin use (tablets/week) were conducted to explore the potential heterogeneity among studies. Subgroup analysis was not conducted for strata with less than five studies. Because time-related biases are common in observational studies of medications and are often responsible for apparent protective effects of drugs, we conducted analyses both including and excluding studies with immortal time bias (bias because of the inclusion of follow-up time during which events cannot occur) [23]. Statistical analyses were performed with Stata version 12.0. (College Station, TX, USA). All reported probabilities (P values) were two-tailed with a significance level of 0.05.

Results

Literature search and study characteristic

Figure 1 shows the process for the identification of eligible studies. A total of 28,683 studies were identified and 298 studies remained in the analysis after assessing the titles and abstracts according to the criteria mentioned above. In total, 307 potentially relevant articles were reviewed in their entirety. Among them, 89 articles were further excluded due to the following reasons: 26 articles were not observational design, 11 articles defined exposure combined with other NSAIDs, 8 articles evaluated cancer mortality, 39 articles were duplicate publications on the same subject population, and 5 articles (1 for Crohn’s disease [24], 1 for ulcerative colitis [25], 3 for Barrett’s esophagus [2628]) included patients with specific diseases. Ultimately, 218 studies with 309 independent reports were included in the present meta-analysis.
Fig. 1
Fig. 1

Flow chart of study selection

The main characteristics of the 218 eligible articles published between 1985 and 2016 are summarized in Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 and 21. Results were presented according to study design. This study altogether included 161 cohort studies and 148 case-control studies. Among them, 135 studies were conducted in North America, 12 in Asia, 61 in Europe, 8 in Oceania, and 2 were multi-country studies. Overall, the summarized RR was 0.89(95%CI: 0.87–0.91), indicating a decreased risk of cancer associated with the use of aspirin. The combined RRs were 0.82 (95% CI: 0.79–0.85) for the case-control studies and 0.94 (95% CI: 0.92–0.97) for the cohort studies. We also observed a apparent beneficial effect of aspirin use when excluding 41 studies deemed to be prone to immortal time bias (RR = 0.87, 95%CI:0.85–0.89) in the meta-analysis.
Table 1

Characteristics of included studies- gastric cancer

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Iqbal U [47], 2017, China

M/F

2001–2011

The Taiwan NHI database

22,574

90,296

Gastric cancer

Prescription

Use at least for 2 months during the 3-year period before the initial cancer diagnosis

1,2,13,14,15,16,17

7

 Wang Y [48], 2015, China

M/F

2005–2010

Population from China

175

350

Gastric cancer

Structured questionnaire

Use at least once a week for one year (regular)

2,3,5,6,7,10,18,19,20

7

 Gong EJ [49], 2014, Korea

M/F

2000–2010

Asian Medical Center

327

327

Gastric cancer

Self-administered questionnaire

Use of aspirin - not further defined

1,2,3,4,6,8,10,11,12,18,21,22,23,

6

 Bertuccio P [50], 2010, Italy

M/F

1997–2007

Population from Italy

229

543

Gastric cancer

Structured questionnaire

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

1,2,4,5,6,10,24

7

 Figueroa JD [51], 2009, US

M/F

1993–1995

Population from Connecticut, New Jersey, and western Washington state

367

695

Gastric adenocarcinomas

Structured interviews

Use at least once per week for 6 months or more

1,2,3,10,25,26

7

 Duan L [52], 2008, US

M/F

1992–1997

Los Angeles County Cencer Surveillance Program

718

1356

Gastric adenocarcinoas

Structured questionnaire

Use of aspirin - not further defined

1,2,3,5,10,20,25,27,28

7

 Fortuny J [53], 2007, US

M/F

1980–2002 1993–2004

GHC and HFHS

496

3996

Gastric cancer

Outpatient pharmacy records

No prescription for aspirin (never users)

1,2,25,29,30

7

 Akre K [54], 2001, Sweden

M/F

1989–1995

Population from Swedish counties

567

1165

Gastric cancer

Interviews

Ever use of aspirin (ever users)

1,2,9

7

 Coogan PF [55], 2000, US

M/F

1977–1998

Population from Baltimore, Boston, New York, and Philadelphia

254

5952

Stomach cancer

Administered questionnaires

Use at least 4 days/week for at least 3 months (regular)

1,2,3,4,5,6,25,32,33,34

8

 Zaridze D [56], 1999, Russia

M/F

1993–1997

Moscow City Oncology Hospital and Cancer Research Center and were Moscow City residents

448

610

Stomach cancer

Self-administered questionnaire

Use at least 2 days a week for 6 months or more (regular)

1,5

6

Cohort studies

 Kim YI [57], 2016, Koreaa

M/F

2004–2010

KNHI database

117

11,598

Gastric cancer

Prescription database

Never make claims for aspirin prescription or less than 6 months of aspirin prescriptions (non-users)

1,2,20, 35

7

 Lee J [58], 2012, Korea

M/F

1999–2008

Samsung Medical Center

184

347

Gastric cancer

Prescription

Have aspirin fill prescriptions for at least 6 months

1,2,14

6

 Abnet CC [59], 2009, US

M/F

1995–2003

AARP

360

311,115

Gastric cancer

Questionnaire

Any use in the past 12 months

1,2,3,5,6,10,34,36,37

7

 Epplein M [60], 2009, US

M/F

1993–2004

Multiethnic Cohort (Hawaii and Los Angeles, California)

643

169,292

Gastric cancer

Self-administered questionnaire

Use any aspirin at least 2 times a week (for 1 month or longer)

1,2,3,6,10,25

7

 Lindblad M [61], 2005, UKa

M/F

1994–2001

General Practitioners Research Database

1023

1000

Gastric Cancer

Prescription database

Any recorded use of aspirin (ever use)

1,2,3,6,10,28, 31

8

 Friis S [62], 2003, Denmarka

M/F

1989–1997

Population from North Jutland County

68

29,470

Stomach cancer

Prescription database

75–150 mg once daily(low-dose aspirin)

1,2

8

 Schreinemachers DM [63], 1994, US

M/F

1971–1987

The National Health and Examination Survey Ι

39

12,668

Stomach cancer

Self-reported

Use aspirin during the 30-day period before the interview

1,2

6

1 = age, 2 = sex, 3 = smoking, 4 = family history, 5 = educational level, 6 = alcohol intake, 7 = marriage, 8 = fat distribution, 9 = social status, 10 = BMI, 11 = total cholesterol, 12 = triglyceride, 13 = charlson comorbidity index, 14 = statin, 15 = metformin, 16 = ACE inhibitors, 17 = angiotensin II receptor blockers, 18 = helicobacter pylori, 19 = history of diabetes, 20 = resident district, 21 = percent body fat, 22 = HDL cholesterol, 23 = LDL cholesterol, 24 = period of interview, 25 = race, 26 = gastro-esopageal refiux disease, 27 = antacid use, 28 = upper gastrointestinal tract history, 29 = health plan, 30 = duration of continuous, 31 = calendar year enrollment in the health plan at the date of diagnosis, 32 = interview year, 33 = center, 34 = religion, 35 = comorbidity, 36 = total calorie, fibre and calcium intake, 37 = fruit, vegetable and/or vitamin intake, 38 = physical activity, 39 = processed meat intake

AARP AARP diet and health study, GHC Group Health Cooperative, HFHS Henry Ford health system’s health alliance plan, KNHI Korean National Health Insurance database

aStudy deemed to be prone to immortal time bias

Table 2

Characteristics of included studies- esophagus cancer

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Figueroa JD [51], 2009, US

M/F

1993–1995

Population from Connecticut, New Jersey, and western Washington state

282

695

Oesophageal cancer

Structured interviews

Use at least once per week for 6 months or more

1,2,3,10,11,12

7

 Sadeghi S [64], 2008, Australia

M/F

2001–2005

Population from Australia

1102

1580

Oesophageal cancer

Questionnaire

Use at least once a week for duration of 6 months or more(regular)

1,2,4,6,10,16,28,29

6

 Duan L [52], 2008, US

M/F

1992–1997

Los Angeles County Cencer Surveillance Program

220

1356

Esophageal adenocarcinoma

Structured questionnaire

Use of aspirin - not further defined

1,2,3,5,10,11,14,15,16,

7

 Fortuny J [53], 2007, US

M/F

1980–2002 1993–2004

GHC and HFHS

277

3996

Oesophageal cancer

Outpatient pharmacy records

No prescription for aspirin (never users)

1,2,11,17,18

7

 Ranka S [65], 2006, UK

M/F

1999–2004

Population from Norfolk

411

1644

Oesophageal cancer

Self-reported,medical admission notes and nursing records

Use of aspirin - not further defined

3,6

8

 Anderson LA [66], 2006, Ireland

M/F

2002–2004

The FINBAR study

224

260

Esophageal adenocarcinoma

Interview

Use aspirin at least once weekly for ≥ 6 months

1,2,3,5, 6,10,30,31,

6

 Jayaprakash V [67], 2006, US

M/F

1982–1998

RPCI

163

482

Oesophageal cancer

Questionnaire

Use at least once a week for 6 months (regular)

1,2,3,6,10,32,

6

 Sharp L [68], 2001, UK

F

1993–1996

Population in England and Scotland

159

159

Oesophagus squamous cell carcinoma

Interview

Daily use of aspirin for at least a month

1,33

7

Cohort sutdies

 Macfarlane TV [69], 2014, UKa

M/F

1996–2010

PCCIU database

1197

3585

Oesophageal cancer

Prescription database

Had at least one Prescription (users)

1,2,13,23,24,25,26,27

7

 Abnet CC [59], 2009, US

M/F

1995–2003

AARP

228

311,115

Oesophageal adenocarcinoma

Questionnaire

Any use in the past 12 months

1,2,3,5,6,10,20,21,22

7

 Lindblad M [61], 2005, UKa

M/F

1994–2001

GPRD database

909

1000

Esophageal cancer

Prescription database

Any recorded use of aspirin (ever use)

1,2,3,6, 10,14, 19

8

 Friis S [62], 2003, Denmarka

M/F

1989–1997

Population of North Jutland County

26

29,470

Oesophagus cancer

Prescription database

75–150 mg once daily (low-dose aspirin)

1,2

8

1 = age, 2 = sex, 3 = smoking, 4 = family history, 5 = educational level, 6 = alcohol intake, 7 = marriage, 8 = Fat distribution, 9 = social status, 10 = BMI, 11 = race 12 = gastroesopageal refiux disease, 13 = other NSAID 14 = upper gastrointestinal tract history, 15 = antacid use, 16 = birthplace,17 = health plan, 18 = duration of continuous enrollment in the health plan at the date of diagnosis, 19 = calendar year, 20 = total calorie, fibre and calcium intake, 21 = fruit, vegetable and/or vitamin intake, 22 = physical activity, 23 = CHD, 24 = stroke, 25 = COX-2 inhibitors, 26 = duration of observation in the database, 27 = deprivation, 28 = household income, 29 = cumulative and frequency of gastroesophageal reflux symptoms 10 y before diagnosis, 30 = location, 31 = job type, 32 = year of completing the questionnaire, 33 = general practice

AARP AARP diet and health study, FINBAR the factors influencing the Barrett’s adenocarcinoma relationship study, GHC Group Health Cooperative, GPRD General Practitioners research database, HFHS Henry Ford health system’s health alliance plan, PCCIU primary care clinical informatics unit database, RPCI the Roswell park cancer Institute

aStudy deemed to be prone to immortal time bias

Table 3

Characteristics of included studies- colorectal cancer

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Iqbal U [47], 2017, China

M/F

2001–2011

The Taiwan NHI database

86,597

346,388

Colorectal cancer

Prescription

Patients had aspirin prescribed at least for 2 months during the 3-year period before the initial cancer diagnosis

1,2,13,14,15,16,17

7

 Friis S [70], 2015, Dermark

M/F

1994–2011

Danish Cancer Registry, Aarhus University Prescription Database, Danish National Patient Registry, Danish Civil Registration

System

10,280

10,280

Colorectal cancer

Prescription database

Have 2 or more prescriptions for aspirin(ever use)

1,2,14,26,27,28,29,30,31,32,33.

8

 Rennert G [71], 2010, Israel

M/F

1988–2006

The MECC

2648

2566

Colorectal cancer

Interviewed

Daily aspirin use for at least 3 years

1,2,7,26

5

 Din FV [72], 2010, UK

M/F

2001–2008

SCCS

2279

2907

Colorectal cancer

Questionnaire

Use > 4 tablets/week for > 1 month

1,2,3,6,8,18,19,34,35

4

 Harris RE [73], 2008, US

M/F

2003–2004

The CHRI

326

652

Colon cancer

Questionnaire

Use at least once per week for more than 1 year

1,3,4,6,7,8,26,36

5

 Kim S [74], 2008, US

M/F

2001–2006

North Carolina Colon Cancer Study II

1057

1019

Colorectal cancer

Questionnaire

Any use of aspirin in the past 5 years (ever users)

1,2,7, 8,18,37, 38,39,40

6

 Hoffmeister M [75], 2007, Germany

M/F

2003–2004

The Rhine–Neckar–Odenwald region in the South-West of Germany

477

517

Colorectal cancer

Questionnaire

Use at least 2 times per week for at least 1 year(current regular use)

1,2,3,4,5,6,8,22,27,30,41,42,43

8

 Slattery ML [76], 2006, US

M/F

1991–1994

KPMCP

2351

2972

Colorectal cancer

Questionnaire

Use at least three times a week for 1 month(regular)

1,2,7

7

 Macarthur M [77], 2005, UK

M/F

1998–2000

Grampian Health

Board residents

264

408

Colorectal cancer

Questionnaire

Use aspirin every day for a month or more(regular)

1,2

6

 Juarranz M [78], 2002, Spain

M/F

1995–1996

The Research Unit of the Council of Health and Social Services of the Community ofMadrid

196

228

Colon cancer

Questionnaire

Consider aspirin use as a continuous numeric variable in milligrams/week -not further defined

1,2

8

 Evans RC [79], 2002, UK

M/F

Merseyside and Cheshire Cancer Registry

512

512

Colorectal cancer

Questionnaire

Use at least once per day(regular)

1,2,26,38

8

 Neugut AI [80], 1998, US

M/F

1989–1992

Columbia-Prebyterian Medical Center

256

322

Colon cancer

Medical record

Use aspirin-not further defined

1,4,5

6

 Rosenberg L [81], 1998, US

M/F

1992–1994

Hospital in Massachusetts

942

935

Large bowel carcinoma

Questionnaire

Use at least 4 days a week for at least 3 months

1,2

9

 La VC [82], 1997, Italy

M/F

1992–1996

Population from Italian areas

1357

1891

Colorectal adenoma

Questionnaire

Use more than four times per week for > 6 months

1,2,5,6,8,18,26,34, 43

7

 Reeves MJ [83], 1996, US

F

1991–1992

Wisconsin Cancer Reporting system

21

22

Colorectal cancer

Self-reported

Use at least one table twice weekly or more than at least 12 months

1,4,8,30

8

 Suh O [84], 1993, US

M/F

1982–1991

Roswell Park Tumor Registry and Diagnostic Index

830

1662

Colorectal adenoma

Questionnaire

Use aspirins for at least 1 year(users)

1,2,5,26

9

 Kune GA [85], 1988, Australia

M/F

1980–1981

Population in Melbourne

715

727

Colorectal adenoma

Questionnaire, hospital records, and interview

Use aspirin “daily” “weekly” or “don’t know- not further defined”

1,2

8

Cohort studies

 Park SY [86], 2017, US

M/F

1993–2012

The MEC Study

3879

183,199

Colorectal cancer

Questionnaire

Had ever use of aspirin

1,3,4,6,8,18,19,27,30,34,37,43, 48,49

8

 Kim C [87], 2016, US

M

1982–2000

Physicians Health Study

268

446

Colorectal cancer

Questionnaire

Use of aspirin- not further defined

6,8,18,19, 20

9

 Soriano LC [88], 2016, UK(STUDY 1)

M/F

2000–2011

THIN

3033

10,000

Colorectal cancer

Prescription

No recorded use at any time(non user)

1,2,3,8,21, 22,24,25

9

 Soriano LC [88], 2016, UK(STUDY 2)

M/F

2001–2012

THIN

3174

10,000

Colorectal cancer

Prescription

No recorded use at any time(non user)

1,2,3,8,21,22,23

9

 Soriano LC [88], 2016, UK(STUDY 3)

M/F

2001–2012

THIN

12,333

20,000

Colorectal cancer

Prescription

No recorded use at any time(non user)

1,2,3,8,21,22

9

 Vaughan LE [89], 2016, US

F

2004–2011

IWHS

218

14,386

Colon cancer

Questionnaire

Never use aspirin (non-user)

1,3,8,22

8

 Cao Y [8], 2016, US

M/F

1980–2010

1986–2012

NHS and HPFS

2895

135,965

Colorectal cancer

Questionnaire

Use at least 2 times per week(regular)

3,4,6,7,8,18,19,27,30,34,37,42,43,49,50,51,52,53

9

 Lin CC [90], 2015, Chinaa

M/F

2000–2009

The Longitudinal Health Insurance Database

467

60,828

Colorectal cancer

Prescription database

Use any low-dose aspirin (75–165 mg)

1,2,54,55

8

 Hollestein LM [91], 2014, Netherlandsa

M/F

1998–2010

PHARMO and the Eindhoven Cancer Registry

972

109,276

Colorectal cancer

Prescription database

Low dose aspirin (≤100 mg daily)- not further defined

1,2,56,72

8

 Brasky TM [92], 2014, US

F

1998–2010

WHI

1397

140,933

Colorectal cancer

Self-administered questionnaires

Use at both baseline and year 3 visits (consistent)

1,3,4,5,6,7,8,37,18,19,22,26,27,33,43,50,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71

9

 Brasky TM [93], 2012, US

M/F

2002–2008.12.30

The VITAL

451

64,847

Colorectal cancer

Questionnaire

Use ≥1 day/week for ≥ 1 year(regular)

1,3,4,5,6,7,8,9,10,18,19,22,28,30,33,42,43, 50,67,68,69,71

8

 Ruder EH [94], 2011, US

M/F

1996–2006

National Institutes of Health-AARP Diet and Health Study

3894

301,240

Colorectal cancer

Self-administered questionnaire

Use aspirin during the previous 12 months

1,2,3,4,5, 6,7,8,18,27

7

 Friis S [95], 2009, Denmark

M/F

1995–2006

Danish Diet, Cancer, and Health Study

615

51,053

Colorectal cancer

Questionnaire

Use fewer than 2 pills per month (nonuse)

1,2,6,8,14,22,27,30,

7

 Siemes C [96], 2008, Netherlands

M/F

1992–2004

The Rotterdam Study

195

7621

Colorectal cancer

Questionnaire and prescriptions

The absence of a prescription for any non-aspirin or aspirin NSAID(no use)

1,2,3,8,18, 27,34,70,73,74

8

 Vinogradova Y [97], 2007, UKa

M/F

1995–2005

QRESEARCH database

1226

5369

Colorectal cancer

Prescription database

Receive ≥1 prescription for aspirin in the 13 to 48 months before index date

3, 8,22,41

8

 Jacobs EJ [98], 2007, US

M/F

1992–2003

Cancer Prevention Study II Nutrition Cohort

1861

146,113

Colorectal cancer

Questionnaire

Use at least 30 “times” per month(daily use of adult-strength)

1,2,3,5,7,18,22,27,28,30,36,68,52,53

8

 Larsson SC [99], 2006, Sweden

M/F

1998–2005

Swedish Mammography Cohort and Cohort of Swedish Men

705

74,250

Colorectal cancer

Questionnaire

Aspirin use- not further defined

1,2,3,4,5,8,18

28

9

 Muscat JE [100], 2005, US

M/F

1983–1999

The Framingham Heart study

145

433

Colorectal cancer

Questionnaire

Never/< 1/week, 1–3/week, > 3/week

1,2,3,44

9

 Rahme E [101], 2003, Canada

M/F

1997–2001

RAMQ

179

2568

Colorectal adenoma

Prescription

Use at least 1 year

45,46,47

7

 Rodríguez LAG [102], 2001, UKa

M/F

1994–1997

The GPRD

2002

943,903

Colorectal cancer

Prescription database

Never received a single prescription(non-user)

1,2

8

 Schreinemachers DM [63], 1994, US

M/F

1971–1987

The National Health and Examination Survey Ι

169

12,668

Colorectal cancer

Self reported

Use aspirin during the 30-day period before the interview

1,2

6

 Paganini-Hill A [103], 1989, US

M/F

1981–1988

Population from Leisure World, Laguna Hills, US

181

13,870

Colon cancer

Questionnaire

Aspirin use: none,<daily, daily

2

4

1 = age, 2 = sex, 3 = smoking, 4 = family history, 5 = educational level, 6 = alcohol intake, 7 = race, 8 = BMI, 9 = marital status, 10 = self-rated health, 11==C-reactive protein level, 12 = cholesterol, 13 = Charlson comorbidity index, 14 = statin, 15 = metformin, 16 = ACE inhibitors, 17 = angiotensin II receptor blockers, 18 = physical activity 19 = fruit, vegetable and/or vitamin intake, 20 = seafood and dairy foods intake, 21 = number of PCP visits in the year before the index date, 22 = other NSAIDs, 23 = paracetamol, 24 = insulin, 25 = oral steroids, 26 = area (county/region), 27 = hormone replacement therapy, 28 = history of diabetes mellitus, 29 = history of cholecystectomy, 30 = history of colonoscopy, 31 = chronic obstructive pulmonary disease or asthma,32 = antidepressants, 33 = migraine,34 = total energy intake, 35 = deprivation index, 36 = hypertension ampling probability, 37 = ever use of calcium supplements in the past 5 years, 38 = primary care practitioner, 39 = dietary fat intake, 40 = sampling probability, 41 = morbidity (diabetes, ischemic heart disease, hypertension, stroke, colitis, rheumatoid arthritis, and osteoarthritis), 42 = former health checkup, 43 = red meat, 44 = Nitro-vasodilator use, 45 = number of drugs, 46 = number of physician encounters, 47 = all-cause hospitalization in prior year, 48 = dietary fiber, 49 = folate, 50 = height, 51 = Alternate Healthy Eating Index-2010, 52 = PSA test in past 2 y, 53 = mammogram in past 2 y, 54 = duration of diabetes, 55 = propensity score at baseline, 56 = unique number of hospitalizations in the year prior to start of follow up, 57 = observational study enrollment, 58 = diet modification trial enrollment, 59 = screening for cancer, 60 = age at menarche, 61 = age at menopause, 62 = gravidity, 63 = age atfirst birth, 64 = duration of estrogen therapy, 65 = duration of combined postmenopausal hormone therapy, 66 = hysterectomy status, 67 = use of antihypertensive medication, 68 = history of coronary heart disease, 69 = use of cholesterol-lowering medication, 70 = history of arthritis, 71 = history of Ulcer, 72 = unique number of dispensing

AARP AARP diet and health study, CHRI Cancer Hospital and Richard J. Solove Research Institute, GPRD General Practitioners Research Database, HPFS Health Professionals follow-up study, IWHS Iowa Women’s Health Study, KPMCP Kaiser Permanente Medical Care Program of Northern California, MEC Multiethnic Cohort Study, MECC the molecular epidemiology of colorectal cancer, NHS nurses’ health study, RAMQ Re′gie de l’Assurance Maladie du Que’bec, SCCS study of colorectal cancer in Scotland, THIN the health improvement Network, VITAL the vitamins and lifestyle, WHI women’s health initiative

aStudy deemed to be prone to immortal time bias

Table 4

Characteristics of included studies- hepato-biliary cancer

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Choi J [104], 2016, US

M/F

2000–2014

Patients seen at the Mayo Clinic

2395

4769

Cholangiocarcinoma

Electronic medical record

Use at least once per week at the index date

1,2,3,11,12,13,14,15

9

 Yang B [105], 2016, UK

M/F

1988–2011

CPRD

814

3180

Primary liver cancer

Medical records database

Had two or more aspirin prescriptions recorded prior to the index date(ever use)

3,6,10,15,16,17,18

7

 Burr NE [106], 2014, UK

M/F

2004–2010

NNUH and LGH

81

275

Cholangiocarcinoma

Letters from general practitioners (GPs), hospital clerkings, surgical records, nursing notes and radiological reports

Drug was recorded in any of the data sources

1,2,3,15

7

Cohort studies

 Kim G [107], 2017, Korea

M/F

2003–2012

NHIS-NSC

229

1145

Hepatocellular carcinoma

Prescription

At least one prescription of aspirin between the cohort entry and the index date

1,2,19,20,

6

 Petrick JL [108], 2015, US

M/F

from 1993

AARP,AHS, USRT,BCDDP, PLCO,HPFS, CPSII, BWHS WHI,NHS

904

1,084,133

Hepatocellular carcinoma and intrahepatic cholangiocarcinoma

Questionnaire

Any reported aspirin use in the 12 months prior to baseline

1,2,3,6,10,11,15, 21

7

 Liu E [109], 2005, China

M/F

1997–2001

Population from Shanghai

368

1013

Gallbladder Cancer

Questionnaire

Use at least twice a week for longer than a month 1 year before interview

1,2,5, 22

6

 S Friis [62], 2003, Denmarka

M/F

1989–1997

Population from North Jutland County

21

29,470

Liver cancer

Prescription database

75–150 mg once daily(low-dose aspirin)

1,2

8

1 = age, 2 = sex, 3 = smoking, 4 = family history, 5 = educational level, 6 = alcohol intake, 7 = marriage, 8 = Fat distribution, 9 = social status, 10 = BMI, 11 = race,12 = primary sclerosing cholangitis (PSC), 13 = non-PSC-related cirrhosis, 14 = biliary tract diseases, 15 = diabetes, 16 = hepatitis B or C virus infection, 17 = rare metabolic disorders, 18 = use of paracetamol, antidiabetic medications, and statins,19 = follow–up duration, 20 = the date of the diabetes diagnosis, 21 = cohort (AARP, AHS, USRT, PLCO, HPFS, CPSII, IWHS, BWHS, WHI, NHS), 22 = biliary stone status

AARP AARP diet and health study, AHS Agriculture Health Study, BCDDP the breast cancer detection demonstration project, BWHS black women’s health study, CPRD clinical practice research datalink, CPSII cancer prevention study II, HPFS Health Professionals follow-up study, IWHS Iowa Women’s Health Study, LGH Leicester General Hospital NHS Trust, NHIS-NSC National Health Insurance Service National Sample Cohort, NHS nurses’ health study, NNUH Norfolk and Norwich University Hospital, PLCO prostate, lung, colorectal and ovarian cancer screening trial, USRT United State Radiologic Technologist Study, WHI women’s health initiative

aStudy deemed to be prone to immortal time bias

Table 5

Characteristics of included studies- pancreatic cancer

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Risch HA [110], 2017, China

M/F

2006–2011

Our Shanghai study

761

794

Pancreatic cancer

In-person questionnaire interviews

Use at least one tablet per week for 3 months or longer(regular)

1,2,3,5,7,10,50,51

7

 Kho PF [111], 2016, Australia

M/F

2007–2011

The QPCS

522

652

Pancreatic cancer

Questionnaire

Long-term use of aspirin ((> 2 years)

1,2,3,6,10

8

 Streicher SA [112], 2014, US

M/F

2005–2009

Population from Connecticut

360

682

Pancreatic cancer

Questionnaire

Use at least once a week on average, for 3 months or more

1,2,3,5,7,10,11,52

8

 Tan XL [113], 2011, US

M/F

2004–2010

Patients from the Mayo Clinic

740

1043

Pancreatic cancer

Questionnaire

Use aspirin ≥1 day per month

1,2,3,7,10

6

 Pugh TFG [114], 2011, UK

M/F

2004–2007

Clinical management databases in Norfolk and Leicestershire

206

251

Pancreatic cancer

Medical records

Use of aspirin - not further defined

1,2,3,7

6

 Bonifazi M [115], 2010, Italy

M/F

1991–2008

Patients in in the province of Pordenone and in the greater Milan area, northern Italy

308

477

Pancreatic cancer

Questionnaire

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

1,2,3,5,7,10,53,54

8

 Menezes RJ [116], 2002, US

M/F

1982–1998

The RPCI

194

585

Pancreatic cancer

Patient Epidemiology Data System (PEDS) and questionnaire

Use at least once a week for six consecutive months(regular)

1,3,4

5

Cohort studies

 Cao Y [8], 2016, US

M/F

1980–2010

1986–2012

NHS and HPFS

607

135,965

Pancreatic cancer

Questionnaire

Use at least 2 times per week(regular)

3,4,6,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24

9

 Brasky TM [92], 2014, US

F

1998–2010

WHI

397

142,330

Pancreatic cancer

Self-administered questionnaires

Use at both baseline and year 3 visits (consistent)

1,3,4,5, 6,10,11,17,18,19,25,26,28,29,30,31,32,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48

9

 Bradley MC [117], 2010, UKa

M/F

1995–2006

GPRD

564

3984

Pancreatic cancer

Prescription Database

Use 300 mg or more a day (high-dose)

3,6,7,10, 25,27,47,55,

8

 Jacobs EJ [98], 2007, US

M/F

1992–2003

Cancer Prevention Study II Nutrition Cohort

404

146,113

Pancreatic cancer

Questionnaire

Use at least 30 “times” per month(daily use of adult-strength)

1,2,3,5,7,10,11, 15,16,17,18,20,25, 45, 49

8

 Friis S [62], 2003, Denmarka

M/F

1989–1997

Population from North Jutland County

62

29,470

Pancreatic cancer

Prescription Database

75–150 mg once daily(low-dose aspirin)

1,2

8

 Anderson KE [118], 2002, US

F

1992–1999

IWHS

80

28,283

Pancreatic cancer

Questionnaire

Never use any type of medication (never use)

1,3,7,19

7

 Schreinemachers DM [63], 1994, US

M/F

1971–1987

The National Health and Examination Survey Ι

30

12,668

Pancreatic cancer

Self reported

Use aspirin during the 30-day period before the interview

1,2

6

1 = age, 2 = sex, 3 = smoking, 4 = family history, 5 = educational level, 6 = alcohol intake, 7 = diabetes, 8 = Fat distribution, 9 = social status, 10 = BMI, 11 = race, 12 = folate, 13 = height, 14 = Alternate Healthy Eating Index-2010, 15 = PSA test in past 2 y, 16 = mammogram in past 2 y, 17 = hormone replacement therapy, 18 = physical activity, 19 = fruit, vegetable and/or vitamin intake, 20 = history of colonoscopy, 21 = total energy intake, 22 = ever use of calcium supplements in the past 5 years, 23 = former health checkup, 24 = red meat, 25 = other NSAIDs, 26 = area (county/region), 27 = prior cancer, 28 = migraine, 29 = ever use of calcium supplements in the past 5 years, 30 = red meat, 31 = Nitro-vasodilator use, 32 = height, 33 = unique number of hospitalizations in the year prior to start of follow up, 34 = observational study enrollment, 35 = diet modification trial enrollment, 36 = screening for cancer, 37 = age at menarche, 38 = age at menopause, 39 = gravidity, 40 = age atfirst birth, 41 = duration of estrogen therapy, 42 = duration of combined postmenopausal hormone therapy, 43 = hysterectomy status, 44 = use of antihypertensive medication, 45 = history of coronary heart disease, 46 = use of cholesterol-lowering medication, 47 = history of arthritis, 48 = history of ulcer, 49 = hypertension, 50 = H. pylori CagA seropositivity, 51 = ABO blood group A vs. non-A, 52 = ABO blood group O vs. non-O, 53 = center, 54 = year of interview, 55 = history of chronic pancreatitis

GPRD General Practitioners Research Database, HPFS Health Professionals follow-up study, IWHS Iowa Women’s Health Study, NHS nurses’ health study, QPCS the Queensland Pancreatic Cancer Study, RPCI the Roswell Park Cancer Institute, WHI women’s health initiative

aStudy deemed to be prone to immortal time bias

Table 6

Characteristics of included studies- lung cancer

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Iqbal U [47], 2017, China

M/F

2001–2011

The Taiwan NHI database

68,409

273,636

Lung cancer

Prescription

Patients had aspirin prescribed at least for 2 months during the 3-year period before the initial cancer diagnosis

1,2,13,14,15,16,17

7

 Lim WY [119], 2012, Singapore

F

2005–2008

Population from Chinese

252

556

Lung cancer

Questionnaire

Use twice a week or more, for a month or more(regular)

1, 3,4,5,19,34

7

 McCormack VA [120], 2011, US

M/F

AHFTS

977

683

Lung cancer

Interview

1,3,5,11

7

 McCormack VA [120], 2011, US

M/F

Population from Boston

768

123

Lung cancer

1,3,5,11

7

 McCormack VA [120], 2011, US

M/F

Population from Florida

467

889

Lung cancer

1,3,5,11

7

 McCormack VA [120], 2011, US

M/F

Population from Hawaii

629

588

Lung cancer

1,3,5,11

7

 McCormack VA [120], 2011, US

M/F

MSKCC

102

101

Lung cancer

1,3,5,11

7

 McCormack VA [120], 2011, US

M/F

NELCS

276

251

Lung cancer

1,3,5,11

7

 McCormack VA [120], 201, Israel

M/F

NICCC

280

270

Lung cancer

1,3,5,11

7

 Kelly JP [121], 2008, US

M/F

1976–2007

Patients in Boston Baltimore New York and Philadelphia

1884

6251

Lung cancer

In-person interview

Use at least 4 days per week for at least three continuous months(regular)

1,2,3,4,6,29, 30,36

6

 Van Dyke AL [122], 2008, US

F

2001–2005

Metropolitan Detroit Cancer Surveillance System, a participant in the National Cancer Institute’s Surveillance

580

541

Lung Cancer

Questionnaire

Had taken any aspirin

1,3,4,5,10,11, 3135,37

7

 Harris RE [123], 2007, US

M/F

2002–2004

The Ohio State University Medical Center, Columbus, Ohio

375

654

Lung Cancer

Interview

Use no more than one pill per week for less than 1 year(nonuser)

1,2,3,5,6,10,11,35

7

 Muscat JE [124], 2003, US

M/F

1992–2000

Hospitals in New York and Washington, D.C

997

918

Lung Cancer

Questionnaire

Use three tablets per week for 1 or more years(regular)

1,2,3,4

7

 Moysich KB [125], 2002, US

M/F

1982–1998

RPCI

868

935

Lung Cancer

Epidemiological questionnaire

Use at least once a week for one year(regular)

1,3,4

8

Cohort studies

 Cao Y [8], 2016, US

M/F

1980–2010

1986–2012

NHS and HPFS

2430

135,965

Lung cancer

Questionnaire

Use at least 2 times per week(regular)

3,5,6,7,8,9,10,11,12,18,19,20,21,22,23,24,25,28

9

Baik CS [126], 2015, US

F

1993–2010

WHI

1902

143,841

Lung cancer

Questionnaire

Use at least twice a week in each of the two weeks preceding the interview(regular)

1,3,5,6,10,11,19,25,31,50,51,52

8

 Hollestein LM [91], 2014, Netherlandsa

M/F

1998–2010

PHARMO and the Eindhoven Cancer Registry

915

109,276

Lung cancer

Prescription database

Low dose aspirin (≤ 100 mg daily)- not further defined

1,2,26,27

8

 Brasky TM [127], 2012, US

M/F

2000–2007

The VITAL cohort

100

69,919

Lung cancer

The baseline questionnaire

Use aspirin ≥1 day/week for ≥ 1 year(regular)

1,2,3,4,5,10,11, 29,35,46,53,54

8

 McCormack VA [120], 2011, US

M/F

DDCHS

812

55,396

Lung cancer

Questionnaire

1,3,5,11,

7

 Siemes C [96], 2008, Netherland

M/F

1992–2004

The Rotterdam Study

134

7621

Lung cancer

Questionnaire and prescriptions.

The absence of a prescription for any non-aspirin or aspirin NSAID(no use)

1,2,10,18,21,25, 35,55,56,57

8

 Olse JH [128], 2008, Dermarka

M/F

2002–2005

Danish Diet, Cancer and Health prospective cohort study

282

390

Lung cancer

Questionnaire and prescription database

Any use of aspirin or 1 year or more before the index date

1,2,3,4,38,39

7

 Hernández-Díaz S [129], 2007, UKa

M/F

1995–2004

THIN database

4336

10,000

Lung cancer

THIN database

Had recorded prescription at any time before the index date

1,2,3,6,10, 14,33,35,40,41,42,43,44,45,46,47,48

8

 Jacobs EJ [98], 2007, US

M/F

1992–2003

Cancer Prevention Study II Nutrition Cohort

1815

146,113

Lung cancer

Questionnaire

Use at least 30 “times” per month(daily use of adult-strength)

1,2,3,4,9,10,11, 18,25,28,29, 31,32,33

8

 Hayes JH [130], 2006, US

F

1992–2002

IWHS

403

27,162

Lung cancer

Questionnaire

Never, less than one weekly, once weekly, two to five times weekly, and six or more times weekly

1,3,4,6,10,19, 29,58

7

 Akhmedkhanov A [131], 2002, US

F

1994–1996

NYU and Women’s Health Study cohort.

81

808

Lung cancer

Questionnaire

Use three or more times per week for a period of 6 months or longer

1,3,4,49

7

 Schreinemachers DM [63], 1994, US

M/F

1971–1987

The National Health and Examination Survey Ι

163

12,668

Lung cancer

Self reported

Use aspirin during the 30-day period before the interview

1,2

6

 Paganini-Hill A [103], 1989, US

M/F

1981–1988

Population in Leisure World, Laguna Hills, US

111

13,870

Lung cancer

Questionnaire

Aspirin use: none,<daily, daily

2

4

1 = age, 2 = sex, 3 = smoking, 4 = education level, 5 = family history, 6 = alcohol intake, 7 = height, 8 = Alternate Healthy Eating Index-2010, 9 = PSA test in past 2 y, 10 = BMI, 11 = race, 12 = folate, 13 = Charlson comorbidity index, 14 = statin, 15 = metformin, 16 = ACE inhibitors, 17 = Angiotensin II receptor blockers, 18 = physical activity, 19 = fruit, vegetable and/or vitamin intake, 20 = history of colonoscopy, 21 = total energy intake, 22 = ever use of calcium supplements in the past 5 years, 23 = former health checkup, 24 = red meat, 25 = hormone replacement therapy, 26 = unique number of dispensing, 27 = unique number of hospitalizations in the year prior to start of follow up, 28 = mammogram in past 2 y, 29 = other NSAIDs, 30 = area (county/region), 31 = history of coronary heart disease, 32 = diabetes, 33 = hypertension, 34 = housing type, 35 = history of arthritis, 36 = interview year, 37 = history of COLD, 38 = study, 39 = use of acetaminophen, 40 = smoking cessation advice by general practitioner, 41 = smoking cessation treatment, 42 = number of visits to general practitioner, 43 = number of referrals, 44 = use of oral corticosteroids, 45 = antihypertensives and other lipid-lowering drugs, 46 = chronic obstructive pulmonary disease, 47 = cerebrovascular disease, 48 = ischemic heart disease, 49 = menopausal status, 50 = age started and years since quitting smoking, 51 = emphysema, 52 = randomization arm of the DM trial, 53 = history of ulcer, migraine or chronic headache, osteoarthritis or chronic joint pain, 54 = coronary artery disease, 55 = C-reactive protein level, 56 = pack years of smoking, 57 = cholesterol, 58 = any heart disease/heart attack

AHFTS American Health Foundation Tobacco Study, DDCHS Danish Diet Cancer and Health Study, HPFS Health Professionals follow-up study, IWHS Iowa Women’s Health Study, MSKCC Memorial Sloan-Kettering Cancer Center, NELCS New England Lung Cancer study, NHS nurses’ health study, NICCC National Israel Cancer Control Center, NYU New York University, RPCI the Roswell Park Cancer Institute, THIN the Health Improvement Network, VITAL the vitamins and lifestyle, WHI women’s health initiative

aStudy deemed to be prone to immortal time bias

Table 7

Characteristics of included studies- breast cancer

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Iqbal U [47], 2017, China

F

2001–2011

The Taiwan NHI database

65,491

435,364

Breast cancer

Prescription

Patients had aspirin prescribed at least for 2 months during the 3-year period before the initial cancer diagnosis

1,2,13,14, 15,16,17

7

 Dierssen-Sotos T [132], 2016, Spain

F

2008–2013

The MCC study

1736

1909

Breast cancer

Questionnaire

Use of aspirin- not further defined

1,3,4,5,10,30,36,40,50,51

8

 Cui Y [133], 2014, US

F

2001–2011

Nashville Breast Health Study

2154

1831

Breast cancer

Telephone interview

Use aspirin three or more times a week for a minimum duration of 1 year(regular)

1,3,4,5,6,11,18,25,40,50,51,52,53

7

 Brasky TM [134], 2010, US

F

1996–2001

WEB Study

1057

2094

Breast cancer

Self-reported

Use 0 days/month (non-users)

1,4,5,11,25,29,36,37,38,53,

6

 Cronin-Fenton DP [135], 2010, Denmark

F

1991–2006

Population from North Jutland and Aarhus counties, Denmark

8195

81,950

Breast cancer

Danish healthcare databases

Use at least 2 prescriptions within 2 years of diagnosis(recent use)

25,31,39

8

 Slattery ML [136], 2007, US

F

1999–2004

Population from the southwestern United States (4-Corner’s Breast Cancer Study)

2325

2525

Breast cancer

Questionnaire

Use at least thrice weekly for at least 1 month(regular)

1,10,18,38,54,55,56

7

 Harris RE [137], 2006, US

F

2003–2004

CHRI

277

493

Breast cancer

Questionnaire

Use at least two times per week for 2 years or more

1,3,5,6,10,38,51

7

 Swede H [138], 2005, US

F

1982–1998

The Roswell Park Cancer Institute

1478

3383

Breast cancer

Questionnaire

Use aspirin at least once a week for at least 1 year(regular)

5,10,36,40,53

6

 Zhang YQ [139], 2005, US

F

1976–2002

The Case-Control Surveillance Study Revisited

2406

1554

Breast cancer

Questionnaire

Use at least four times per week for 3 or more continuous months(regular)

1,4,5,6,10,11, 36,37,38,40,41,53,54,61,62,63,64

5

 Terry MB [140], 2004, US

F

1996–1997

The Long Island Breast Cancer Study Project

1442

1420

Breast cancer

Questionnaire

Use at least once a week for 6 months or longer(ever use)

1,10,29,31

6

 Moorman PG [141], 2003, US

F

1996–2000

Phase II of the Carolina Breast Cancer and Carcinoma In Situ Study

500

2631

Breast cancer

Questionnaire

Use at least 8 days a month for three or more months(regular)

1

6

 Cotterchio M [142], 2001, Canada

F

1996–1998

Population in Canada

2696

2600

Breast cancer

Questionnaire

Daily use for≥ 2 months(any use)

1,39,53

6

 Neugut AI [80], 1998, US

F

1989–1992

Columbia-Prebyterian Medical Center

252

176

Breast cancer

Medical record

Use aspirin-not further defined

1,4,5

6

Cohort studies

 Cao Y [8], 2016, US

F

1980–2010

1986–2012

NHS and HPFS

7424

135,965

Breast cancer

Questionnaire

Use at least 2 times per week(regular)

3,5,6,7,8,9,10,11,12,18,19,20,21,22,23,24,25,28

9

 Kim S [143], 2015, US

F

2003–2013

Sister Study

2118

50,884

Breast cancer

Questionnaire

Use at least once a week(current user)

4,5,10,11,40,51,53, 67

8

 Hollestein LM [91], 2014, Netherlandsa

F

1998–2010

PHARMO and the Eindhoven Cancer Registry

585

55,597

Breast cancer

Prescription database

Low dose aspirin (≤ 100 mg daily)- not further defined

1,2,26,27

8

 Brasky TM [92], 2014, US

F

1998–2010

WHI

5401

142,330

Breast cancer

Self-administered questionnaires

Use at both baseline and year 3 visits (consistent)

1,3,4,5, 6,7,10,11,18,19,22,24,25,29,30,31,,32,33,34,35,36,37,38,39,40,4142,43,44,45,46,47

9

 Bardia A [144], 2011, US

F

1986–2005

The IWHS

1581

26,580

Breast cancer

Questionnaire

Ever use aspirin- not further defined

1,3,4,5,6,10, 18,25,36,37,38,39,40,68,69

8

 Bosco JL [145], 2011, US

F

1995–2007

BWHS

1275

59,000

Breast cancer

Questionnaire

Use aspirin ≥ 3 days per week (regular)

1,3,4,10,18,25,29,70

9

 Eliassen AH [146], 2009, US

F

1989–2003

NHS II

1229

112,292

Breast cancer

Questionnaire

Use aspirin ≥2 times per week(regular)

5,6,7,10,36,38,40,53, 68,71

9

 Friisa S [147], 2008, Denmark

F

1993–2003

The prospective Diet, Cancer and Health cohort study

396

28,695

Breast cancer

Questionnaire

Use more than one pill per month

1,4,25,38,50,53

7

 Gierach GL [148], 2008, US

F

1995–2003

AARP

4451

126,124

Breast cancer

Questionnaire

Ever use aspirin- not further defined

1,5,6,11,25,29,40,49, 72

7

 Ready A [149], 2008, US

F

2000–2004

VITAL cohort

479

35,323

Breast cancer

Questionnaire

Use at least once a week for a year during the last 10 years(any use)

1,5,6,10,11,19,28,29,36,37,40,72, 73,74

7

 Siemes C [96], 2008, Netherland

F

1992–2004

The Rotterdam Study

175

7621

Breast cancer

Questionnaire and prescriptions.

The absence of a prescription for any non-aspirin or aspirin NSAID(no use)

1,3,10,25,36,37,50, 75

8

 Jacobs EJ [98], 2007, US

F

1992–2003

Cancer Prevention Study II Nutrition Cohort

3121

76,303

Breast cancer

Questionnaire

Use at least 30 “times” per month(daily use of adult-strength)

1,3,4,10,11,18,20,25, 28,29,45,48,49

8

 Gill JK [150], 2007, US

F

1993–2002

Multiethnic Cohort

1457

98,920

Breast cancer

Questionnaire

Use at least two times per week for 1 month or longer

1,4,5,6,10,11, 25,28,36,37,40,50,51,76

7

 Gallicchio L [151], 2007, US

F

1989–2006

CLUE II (“Give us a Clue to Cancer and Heart Disease”)

418

15,651

Breast cancer

Questionnaire

Use aspirin in the last 48 h(current user)

1

7

 Marshall SF [152], 2005, US

F

1995–2001

The California Teachers Study

2391

114,640

Breast cancer

Questionnaire

Use at least once a Week(regular)

1,3,5,6,10,11,18, 25,28,51,53,59,77

9

 Rahme E [153], 2005, Canadaa

F

1998–2202

RAMQ

664

23,573

Breast cancer

Prescription database

Ever use aspirin during the year prior to the index date

1,25,28,53,57,58,60

7

 Rodríguez LA [154], 2004, UKa

F

1995–2001

GPRD

3708

23,708

Breast cancer

Prescription database

No recorded use at any time before the index date(nonuser)

1,3,6,10,25,29,53, 62,65,66

8

 Harris RE [155], 1999, US

F

1991–1996

Population from The Ohio State University Comprehensive Cancer Center in Columbus, Ohio

316

32,505

Breast cancer

Questionnaire

Use aspirin ≥1 pill per week

1

5

 Schreinemachers DM [63], 1994, US

F

1971–1987

The National Health and Examination Survey Ι

147

12,668

Breast cancer

Self reported

Use aspirin during the 30-day period before the interview

1,2

6

 Paganini-Hill A [103], 1989, US

F

1981–1988

Population from Leisure World, Laguna Hills, US

214

13,870

Breast cancer

Questionnaire

Aspirin use: none,<daily, daily

2

4

1 = age, 2 = sex, 3 = smoking, 4 = education level, 5 = family history, 6 = alcohol intake, 7 = height, 8 = Alternate Healthy Eating Index-2010, 9 = PSA test in past 2 y, 10 = BMI, 11 = race, 12 = folate, 13 = Charlson comorbidity index, 14 = statin, 15 = metformin, 16 = ACE inhibitors, 17 = Angiotensin II receptor blockers, 18 = physical activity, 19 = fruit, vegetable and/or vitamin intake, 20 = history of colonoscopy, 21 = total energy intake, 22 = ever use of calcium supplements in the past 5 years, 23 = former health checkup, 24 = red meat, 25 = hormone replacement therapy, 26 = unique number of dispensing, 27 = unique number of hospitalizations in the year prior to start of follow up, 28 = mammogram in past 2 y, 29 = other NSAIDs, 30 = area (county/region), 31 = migraine, 32 = Nitro-vasodilator use, 33 = observational study enrollment, 34 = diet modification trial enrollment, 35 = screening for cancer, 36 = age at menarche, 37 = age at menopause, 38 = gravidity, 39 = history of arthritis, 40 = age at first birth, 41 = duration of estrogen therapy, 42 = duration of combined postmenopausal hormone therapy, 43 = hysterectomy status, 44 = use of antihypertensive medication, 45 = history of coronary heart disease, 46 = use of cholesterol-lowering medication, 47 = history of ulcer, 48 = diabetes, 49 = hypertension, 50 = number of deliveries, 51 = menopausal status, 52 = household income, 53 = personal history of benign breast disease, 54 = study center, 55 = referent year, 56 = percentage Native American ancestry, 57 = breast procedure in the prior 3 years, 58 = other breast disease in the prior 3 years, 59 = neighborhood socioeconomic status, 60 = visit to a gynecologist in the prior year, 61 = practice of breast selfexamination, 62 = year of interview, 63 = number of physician visits 2 years before hospitalization, 64 = duration of oral contraceptive use, 65 = paracetamol, 66 = steroid, 67 = time since the last mammogram and duration and frequency of use, 68 = use of oral contraceptives, 69 = relative weight at age 12, 70 = questionnaire cycle, 71 = weight change since age 18 years, 72 = number of breast biopsies, 73 = history of surgical menopause, 74 = years of combined estrogen and progesterone hormone therapy, 75 = C-reactive protein level, 76 = all pain medication use, 77 = parity status before age 30

AARP AARP diet and health study, BWHS Black Women’s Health Study, CHRI Cancer Hospital and Richard J. Solove Research Institute, GPRD General Practitioners Research Database, HPFS Health Professionals follow-up study, IWHS Iowa Women’s Health Study, MCC the Spanish Multi-Case-control study, NHS nurses’ health study, RAMQ Re′gie de l’Assurance Maladie du Que’bec, VITAL the vitamins and lifestyle, WEB Western New York exposures and breast cancer study, WHI women’s health initiative

aStudy deemed to be prone to immortal time bias

Table 8

Characteristics of included studies- ovarian cancer

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Peres LC [156], 2016, US

F

2010–2015

AACES

541

731

Epithelial ovarian cancer

Questionnaire

Use at least once a week or at least 5 days out of the month, at any point in their lifetime(regular)

1,4,5,10,18, 29,48,49,50,51,52,53,54,55

7

 Baandrup L [157], 2015, Denmark

F

2000–2011

The Danish Cancer Registry

4103

58,706

Epithelial ovarian cancer

The Danish Prescription Registry

Use < 2 prescriptions (non-users)

1,5,7,25,29,43,50,52,55, 56,57,58,

8

 Lo-Ciganic WH [158], 2012, US

F

2003–2008

HOPE study

625

1210

Ovarian cancer

Questionnaire

Use at least 2 tablets per week for 6 months or more(regular)

1, 5,7,10,11,30,39,42,49,50,55,59,60

7

 Ammundsen HB [159], 2012, Denmark

F

1995–1999

Danish MALOVA study

756

1564

Ovarian cancer

Questionnaire

Use two times or more per week for more than 1 month

1,38,50,55,61

6

 Pinheiro SP [160], 2010, US

F

1992–2003

New England Case-Control Study

1120

1160

Ovarian cancer

Questionnaire

Use at least twice aweek(regular)

1, 54

7

 Wu AH [161], 2009, US

F

1998–2002

Population from Los Angeles County

582

668

Ovarian cancer

Questionnaire

Use aspirin medication 2 or more times a week for 1 month or longer

1,4,5,11,49, 50,51,55, 62

8

 Wernli KJ [162], 2008, US

F

1998–2001

Population from Wisconsin and Massachusetts

400

2107

Ovarian cancer

Telephone interview

Use aspirin for more than 6 months and more than twice per week(ever use)

1,4,30, 43,49,51

7

 Merritt MA [163], 2008, Australia

F

2002–2005

Australian Ovarian Cancer Study

1564

1502

Ovarian cancer

Self-administered questionnaires

Ever use of aspirin-not further defined

1,5,50,55

6

 Schildkraut JM [164], 2006, US

F

1999–2003

North carolina ovarian cancer study

586

627

Ovarian cancer

In-person questionnaires

Use at least 3 month of use during the 5-year period(regular)

1,4,5,11,43,49, 50,53,60,63,64

7

 Moysich KB [165], 2001, US

F

1982–1998

RPCI buffalo

547

1094

Ovarian cancer

Self-administered questionnaires

Use at least once a week for 6 consecutive months(regular)

1,4, 40,49,55, 65

6

 Rosenberg L [166], 2000, US

F

1976–1998

Patients from hospital in Baltimore, Boston, New York, and Philadelphia

780

4623

Ovarian cancer

Questionnaire

Use at least 1 day per week for at least 6 months(regular)

1,30,59

7

 Tavani A [167], 2000, US

F

1992–1999

Population from Italy

749

898

Ovarian cancer

Questionnaires

Use at least once a week for more than six consecutive months(regular)

1,5,10,37,50,54, 55,59

6

 Cramer DW [168], 1998, US

F

1992–1997

Patients from hospital in eastern Massachusetts and all of New Hampshire

563

523

Ovarian cancer

In-person interviews

Use at least once a week for at least 6 months

1,5,9,46,54,55,66,67,68

8

Cohort studies

 Brasky TM [92], 2014, US

F

1998–2010

WHI

445

116,248

Ovarian cancer

Questionnaire

Use at both baseline and year 3 visits (consistent)

1,3,4,5, 6, 10,11,18,19,22,24,25,29,30,31,,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47

9

 SetiawanVW [169], 2012, Multinational

F

1993–2008

MEC

275

64,000

Ovarian cancer

Questionnaire

Use at least 2 times a week for 1 month or longer

1,11,25,36,50, 55

7

 Murphy MA [170], 2012, US

F

1995–2006

AARP

438

96,710

Ovarian cancer

Mailed questionnaires

Use one or more pills per week(regular)

1,4,11,25,36,37,43,50,55,

7

 Prizment AE [171], 2010, US

F

1992–2006

IWHS

157

21,694

Ovarian cancer

Questionnaire

Had ever taken aspirin- not further defined

1,10,25,45,55,69

9

 Pinheiro SP [160], 2010, US

F

1992–2003

NHS and NHS-II cohorts

217

628

Ovarian cancer

Questionnaire

Use at least twice a week(regular)

1,25,51

7

 Lacey JV [172], 2004, US

F

1979–1998

BCDDP

116

31,364

Ovarian cancer

Telephone interview and mailed questionnaires

Use at least once a week for 1 year(regular)

1,4,10,11,42,50,51,55

7

 Friis S [62], 2003, Denmarka

F

1989–1997

Population from North Jutland County

34

29,470

Ovarian cancer

Prescription database

75–150 mg once daily(low-dose aspirin)

1,2

8

 Akhmedkhanov A [173], 2001, US

F

1994–1996

The NYU Women’s Health Study

68

680

Epithelial ovarian cancer

Self-administered questionnaires

Use three or more times per week for at least 6 months

4,36,50, 55

8

1 = age, 2 = sex, 3 = smoking, 4 = family history, 5 = educational level, 6 = alcohol intake, 7 = chronic obstructive pulmonary disease or asthma, 8 = Fat distribution, 9 = religion, 10 = BMI, 11 = race, 12 = folate, 13 = Charlson comorbidity index, 14 = statin, 15 = metformin, 16 = ACE inhibitors, 17 = Angiotensin II receptor blockers, 18 = physical activity, 19 = fruit, vegetable and/or vitamin intake, 20 = history of colonoscopy, 21 = total energy intake, 22 = ever use of calcium supplements in the past 5 years, 23 = former health checkup, 24 = red meat, 25 = hormone replacement therapy, 26 = unique number of dispensing, 27 = unique number of hospitalizations in the year prior to start of follow up, 28 = mammogram in past 2 y, 29 = other NSAIDs, 30 = area (county/region), 31 = migraine, 32 = Nitro-vasodilator use, 33 = observational study enrollment, 34 = diet modification trial enrollment, 35 = screening for cancer, 36 = age at menarche, 37 = age at menopause, 38 = gravidity, 39 = history of arthritis, 40 = age at first birth, 41 = duration of estrogen therapy, 42 = duration of combined postmenopausal hormone therapy, 43 = hysterectomy status, 44 = use of antihypertensive medication, 45 = history of coronary heart disease, 46 = use of cholesterol-lowering medication, 47 = history of ulcer, 48 = income, 49 = tubal ligation, 50 = oral contraceptive use, 51 = menopausal status, 52 = endometriosis, 53 = pelvic inflammatory disease, 54 = study site, 55 = parity, 56 = infertility, 57 = diabetes mellitus, 58 = tubal sterilization, 59 = interview year, 60 = breastfeeding, 61 = duration of oral contraceptive use, 62 = talc use, 63 = months of pregnancy, 64 = severe menstrual cramping, 65 = presence of irregular menses, 66 = menstrual, headache, or arthritic pain, 67 = ibuprofen, 68 = paracetamol, 69 = partial oophorectomy

AACES the African American Cancer Epidemiology Study, AARP AARP Diet and Health Study, BCDDP the Breast Cancer Detection Demonstration Project, HOPE hormones and Ovarian cancer prediction study, IWHS Iowa Women’s Health Study, MALOVA Danish MALignant Ovarian cancer study, MEC multiethnic cohort study, NHS nurses’ health study, NYU New York University, RPCI the Roswell Park Cancer Institute, WHI women’s health initiative

aStudy deemed to be prone to immortal time bias

Table 9

Characteristics of included studies- endometrial cancer

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Brons N [174], 2015, Denmark

F

2000–2009

Patients from Civil Registration System

5382

72,127

endometrial cancer

Prescription

Use ≥2 prescriptions on separate dates over the entire study period(ever users)

1,5,25,29,48,49,50,51

8

 Neill AS [175], 2013, Australia

F

2005–2007

ANECS

1360

712

endometrial cancer

Telephone interview

Had ever taken aspirin- not further defined

1,3,10,25,36,48,50,52

7

 Bosetti C [176], 2010, Italy

F

1992–2006

Population from Italy

442

676

Endometrial Cancer

Questionnaire

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

1,5,10,25,36,48, 52,53,54,55

5

 Fortuny J [177], 2009, US

F

2001–2005

The EDGE Study

469

467

endometrial cancer

Interview

Use aspirin for 6 months or longer

1,10

7

 Bodelon C [178], 2009, US

F

2003–2005

Population from King, Pierce, and Snohomish counties

330

286

Endometrial Cancer

In-person interview

Use for more than 5 days per month for at least 6 months

1,7,10,25,30

6

 Moysich KB [179], 2005, US

F

1982–1998

RPCI Institute

427

427

Endometrial Cancer

Questionnaire

Use at least once a week for 6 months (regular)

1,5,10,36,37,48

6

Cohort studies

 Brasky TM [92], 2014, US

F

1998–2010

WHI

865

85,351

Endometrial cancer

Questionnaire

Use at both baseline and year 3 visits (consistent)

1,3,4,5, 6, 10,11,18,19,22,24,25,29,30,31, 32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47

9

 Brasky TM [180], 2013, US

F

2000–2010

VITAL Cohort

248

22,268

Endometrial Cancer

Mailed baseline questionnaire

Use≥4 days/week and ≥ 4 years(high use)

1,3,4,5,6,10,11,18,25,29,31,36.37,39,45,47,48, 50,57,58,59

7

 SetiawanVW [169], 2012, Multinational

F

1993–2008

MEC

620

64,000

Endometrial cancer

Questionnaire

Use at least 2 times a week for 1 month or longer

1,3,10,11,25,36,48,52,.

7

 Prizment AE [171], 2010, US

F

1992–2006

IWHS

311

21,694

Endometrial cancer

Questionnaire

Had ever taken aspirin- not further defined

1,6,10,25,36,37,50,52, 56

9

 Danforth KN [181], 2009, US

F

1995–2003

AARP

576

72,524

Endometrial cancer

Mailed questionnaire

Had ever taken aspirin- not further defined

3,4,10,11,18,36,37,45,48,50,52,56

7

 Viswanathan AN [182], 2008, USa

F

1980–2004

The NHS

436

82,971

Endometrial cancer

Medical record

Use at least 1 tablet per week or 1 day per week(current user)

4,10,18,25,37,40,60,61,62

6

 Friis S [62], 2003, Denmarka

F

1989–1997

Population of North Jutland County

45

29,470

Endometrial cancer

Prescription database

75–150 mg once daily(low-dose aspirin)

1,2

8

 Schreinemachers DM [63], 1994, US

F

1971–1987

The National Health and Examination Survey Ι

26

12,668

Endometrial cancer

Self reported

Use aspirin during the 30-day period before the interview

1,2

6

1 = age, 2 = sex, 3 = smoking, 4 = family history, 5 = educational level, 6 = alcohol intake, 7 = calendar year, 8 = Fat distribution, 9 = social status, 10 = BMI, 11 = race, 12 = folate, 13 = Charlson comorbidity index, 14 = statin, 15 = metformin, 16 = ACE inhibitors, 17 = Angiotensin II receptor blockers, 18 = physical activity, 19 = fruit, vegetable and/or vitamin intake, 20 = history of colonoscopy, 21 = total energy intake, 22 = ever use of calcium supplements in the past 5 years, 23 = former health checkup, 24 = red meat, 25 = hormone replacement therapy, 26 = unique number of dispensing, 27 = unique number of hospitalizations in the year prior to start of follow up, 28 = mammogram in past 2 y, 29 = other NSAIDs, 30 = area (county/region), 31 = migraine, 32 = Nitro-vasodilator use, 33 = observational study enrollment, 34 = diet modification trial enrollment, 35 = screening for cancer, 36 = age at menarche, 37 = age at menopause, 38 = gravidity, 39 = history of arthritis, 40 = age at first birth, 41 = duration of estrogen therapy, 42 = duration of combined postmenopausal hormone therapy, 43 = hysterectomy status, 44 = use of antihypertensive medication, 45 = history of coronary heart disease, 46 = use of cholesterol-lowering medication, 47 = history of ulcer, 48 = parity, 49 = obesity, 50 = diabetes, 51 = chronic obstructive pulmonary disease, 52 = oral contraceptive use, 53 = study center, 54 = period of interview, 55 = menopausal status, 56 = hypertension, 57 = years of oral contraceptive use, 58 = oophoerectomy, 59 = history of stroke, 60 = waist-hip ratio, 61 = intrauterine device use, 62 = height

AARP AARP diet and health study, ANECS Australian National Endometrial Cancer Study, EDGE Study estrogen, diet, genetics, and endometrial cancer, IWHS Iowa Women’s Health Study, MEC multiethnic cohort study, NHS nurses’ health study, RPCI the Roswell Park Cancer Institute, VITAL the vitamins and lifestyle, WHI women’s health initiative

aStudy deemed to be prone to immortal time bias

Table 10

Characteristics of included studies- cervix uterus

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Friel G [183], 2015, US

F

1982–1998

RPCI

272

1072

Cervical Cancer

Questionnaire

Use at least once a week for 6 months(regular)

1,3,4,5, 6,7,8,9,10,11,12,13

7

Cohort studies

 Wilson JC [184], 2013, UKa

F

1995–2010

CPRD

724

3479

Cervical Cancer

Prescription database

Use of aspirin - not further defined

3,14,15,16,17,18,19,20,21

7

 Friis S [62], 2003, Denmarka

F

1989–1997

Population from North Jutland County

15

29,470

Cervix uterus cancer

Prescription database

75–150 mg once daily(low-dose aspirin)

1,2

8

 Schreinemachers DM [63], 1994, US

F

1971–1987

The National Health and Examination Survey Ι

29

12,668

Cervix uterus cancer

Self reported

Use aspirin during the 30-day period before the interview

1,2

6

1 = age, 2 = sex, 3 = smoking, 4 = spermicide contraceptive use, 5 = circulatory system disease, 6 = education, 7 = age at first pregnancy, 8 = menopausal status, 9 = genital tract disease, 10 = year survey completed,11 = blood and blood-forming organs disease, 12 = oral, 13 = barrier, 14 = HRT use, 15 = hormone contraceptive use, 16 = systemic steroids, 17 = DMARD use, 18 = history of cancer, 19 = years of follow-up, 20 = sexually transmitted infections, 21 = use of antiviral drugs

CPRD clinical practice research datalink, RPCI the Roswell Park Cancer Institute

aStudy deemed to be prone to immortal time bias

Table 11

Characteristics of included studies- prostate cancer

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Iqbal U [47], 2017, China

M

2001–2011

The Taiwan NHI database

32,419

129,676

Prostate cancer

Prescription

Patients had aspirin prescribed at least for 2 months during the 3-year period before the initial cancer diagnosis

1,2,13,14, 15,16,17

7

 Skriver C [185], 2016, Denmark

M

2000–2012

Danish nationwide registries

35,600

177,992

Prostate cancer

Prescription

Use aspirin ≥ 2 prescriptions redeemed on separate dates(ever use)

1, 4,14,28,30,36,37,38,,40,

8

 Veitonmäki T [186], 2013, Finland

M

1995–2002

Finnish Cancer Registry

13,478

24,657

Prostate cancer

Prescription database

Ever use aspirin- not further defined

1,32

8

 Murad AS [187], 2011, UK

M

2001–2008

ProtecT

1016

5043

Prostate cancer

Questionnaire

Ever use aspirin- not further defined

1,28,33,35

8

 Salinas CA [188], 2010, US

M

2002–2005

SEER cancer registry

1000

942

Prostate cancer

Questionnaire

Use at least once per week for 3 months(ever use)

1,11,42

7

 Harris RE [189], 2007, US

M

1999–2005

CHRI

24

39

Prostate cancer

Medical-record

At least two times per week for 2 years or more

1,3,5,6,10

5

 Bosetti C [190], 2006, Italy

M

1991–2002

Population from the greater Milan area, the provinces of Pordenone, Gorizia, Latina and the urban area of Naples

1261

1131

Prostate cancer

Standard questionnaire

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

1,4,5,34

5

 Dasgupta K [191], 2006, Canada

M

1999–2002

RAMQ

2025

2150

Prostate cancer

Prescription database

Did not receive any prescription for aspirin (nonuser)

1,43

6

 Liu X [192], 2006, US

M

2001–2004

Population from Cleveland, Ohio

471

468

Prostate cancer

Personal interview

Use at least twice a week for more than a month(any use)

1,11,44

5

 Menezes RJ [193], 2006, US

M

1982–1998

RPCI

1029

1029

Prostate cancer

Questionnaire

Use at least once a week for at least 6 months (regular)

1,5,10

5

 Perron L [194], 2003, Canada

M

1993–1995

RAMQ

2221

11,105

Prostate cancer

Prescription database

Ever use aspirin- not further defined

1,50

6

 Norrish AE [195], 1998, New Zealand

M

1996–1997

Auckland Prostate Study

317

480

Prostate cancer

Questionnaire

At least once per week(regular)

1,50,51,52,53

7

 Neugut AI [80], 1998, US

M

1989–1992

Columbia-Prebyterian Medical Center

319

189

Prostate cancer

Medical record

Use aspirin-not further defined

1,4,5

6

Cohort studies

 Cao Y [8], 2016, US

M

1980–2010

1986–2012

NHS and HPFS

1019

135,965

Prostate cancer

Questionnaire

Use at least 2 times per week(regular)

3,5,6,7,8,9,10,11,12,18,19,20,21,22,23,24,25,70

9

 Lapi F [196], 2016, Italya

M

2002–2013

HSD

187

13,453

Prostate Cancer

Prescription database

Use low-dose aspirin-not further defined

1,3,6,9,13,14,16,28,38,54,55,56,57

8

 Nordström T [197], 2015, Swedena

M

2007–2012

Population from Stockholm County, Sweden

8430

204,241

Prostate cancer

Swedish Prescribed Drug Register

Any dispensed prescription of the drug within 2 years before biopsy

1,4,13,14, 58,59,60

5

 Hollestein LM [91], 2014, Netherlandsa

M

1998–2010

PHARMO and the Eindhoven Cancer Registry

882

53,679

Prostate cancer

Prescription database

Low dose aspirin (≤ 100 mg daily)- not further defined

1,2,26,27

8

 Shebl FM [198], 2012, US

M

1993–2001

PLCO

3573

29,450

Prostate cancer

Questionnaire

Regular use aspirin-not further defined

5,11,34, 42,62

7

 Mahmud SM [199], 2011, Canadaa

M

1985–2000

Saskatchewan Ministry of Health (SH) databases and the Saskatchewan Cancer Registry (SCR).

9007

35,891

Prostate cancer

Prescription database

Had a participant ever filled a prescription of aspirin in the index class at any time during his exposure history

28,41,42

6

 Brasky TM [200], 2010, US

M

2000–2007

VITAL Cohort

1547

34,132

Prostate cancer

Questionnaire

Use aspirin ≥1 day/ week for ≥ 1 year(regular)

1,4,5,9,10,11,19,30,55, 65,66,67

5

 Siemes C [96], 2008, Netherland

M

1992–2004

The Rotterdam Study

216

7621

Prostate cancer

Questionnaire and prescriptions

The absence of a prescription for any non-aspirin or aspirin NSAID(no use)

1,3,10,61

8

 Jacobs EJ [98], 2007, US

M

1992–2003

Cancer Prevention Study II Nutrition Cohort

5539

69,810

Prostate cancer

Questionnaire

Use at least 30 “times” per month(daily use of adult-strength)

1,3,4,9,10,11,18, 20,28,29,30,31

8

 Platz EA [201], 2005, US

M

1980–2004

BLSA

141

9748

Prostate cancer

Self-reported

Had ever taken aspirin-not further defined

1,28,45,68

7

 García Rodríguez LA [44], 2004, UKa

M

1995–2001

GPRD

2096

9579

Prostate cancer

Prescription database

No use of aspirin at any time before the index date(nonuser)

1,45,46,47,48,49

8

 Friis S [62], 2003, Denmarka

M

1989–1997

Population of North Jutland County

196

29,470

Prostate cancer

Prescription database

75–150 mg once daily(low-dose aspirin)

1,2

8

 Habel LA [202], 2002, US

M

1964–1973

The Kaiser Permanente Medical Care Program in Northern California

2574

90,100

Prostate cancer

Questionnaire

Use more than six aspirin per days

1,4,11,69

6

 Schreinemachers DM [63], 1994, US

M

1971–1987

The National Health and Examination Survey Ι

123

12,668

Prostate cancer

Self reported

Use aspirin during the 30-day period before the interview

1,2

6

 Paganini-Hill A [103], 1989, US

M

1981–1988

Population from Leisure World, Laguna Hills, US

149

13,870

Prostate cancer

Questionnaire

Aspirin use: none,<daily, daily

2

4

1 = age, 2 = sex, 3 = smoking, 4 = education level, 5 = family history, 6 = alcohol intake, 7 = height, 8 = Alternate Healthy Eating Index-2010, 9 = PSA test in past 2 y, 10 = BMI, 11 = race, 12 = folate, 13 = Charlson comorbidity index, 14 = statin, 15 = metformin, 16 = ACE inhibitors, 17 = Angiotensin II receptor blockers, 18 = physical activity, 19 = fruit, vegetable and/or vitamin intake, 20 = history of colonoscopy, 21 = total energy intake, 22 = ever use of calcium supplements in the past 5 years, 23 = former health checkup, 24 = mammogram in past 2 y, 25 = hormone replacement therapy, 26 = unique number of dispensing, 27 = unique number of hospitalizations in the year prior to start of follow up, 28 = other NSAIDs, 29 = history of heart attack, 30 = diabetes, 31 = hypertension, 32 = simultaneous use of other medications (cholesterol lowering drugs, anti-diabetic drugs, antihypertensive drugs and benign prostatic hyperplasia medication), 33 = the primary care centres from which they were recruited, 34 = study center, 35 = any paracetamol use, 36 = residence (by design), 37 = use of high-dose aspirin, 38 = 5-alpha reductase inhibitors, 39 = income, 40 = selected cardiovascular drugs, and antidepressants or neuroleptics, 41 = ever visited a urologist 1–11 years prior, 42 = SCREENED and volume of family physician visits in the 5 years prior to the index date, 43 = finasteride, 44 = medical institution, 45 = calendar year, 46 = prior BPH history, 47 = number of visits to general practitioners, 48 = referrals, 49 = hospitalizations, 50 = recent medical contacts, 51 = socio-economic status, 52 = total polyunsaturated fat consumption, 53 = a-linolenic acid and ratio of dietary n-6:long-chain n-3 polyunsaturated fatty acids, 54 = presence of obesity, 55 = benign prostatic hypertrophy, 56 = alpha-adrenoreceptor antagonists, 57 = immunosuppressive drugs, 58 = natural log-transformed prostate specific antigen (PSA) concentration, 59 = PSA quotient, 60 = use of antidiabetic medication, 61 = C-reactive protein level, 62 = ibuprofen use, 63 = osteoarthritis, 64 = rheumatoid arthritis,65 = enlarged prostate, 66 = coronary artery disease, 67 = chronic joint pain, chronic headaches, and migraines, 68 = acetaminophen, 69 = and number of health checkups, 70 = red meat

BLSA Baltimore Longitudinal study of Aging, CHRI Cancer Hospital and Richard J. Solove Research Institute, GPRD general practitioners research database, HPFS Health Professionals follow-up study, HSD health search IMS health longitudinal patient database, NHS nurses’ health study, PLCO prostate, lung, colorectal and ovarian cancer screening trial, ProtecT prostate testing for cancer and Treatment, RAMQ Re′gie de l’Assurance Maladie du Que’bec, RPCI the Roswell Park Cancer Institute, SEER surveillance, epidemiology and end results, VITAL the vitamins and lifestyle

aStudy deemed to be prone to immortal time bias

Table 12

Characteristics of included studies- renal cancer

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Karami S [203], 2016, US

M/F

2002–2007

US Kidney Cancer Study

1187

1204

Renal-cell cancer

Questionnaires

Use at least once a week for 3 months or longer, at least 2 years prior to the interview

1,2,3,4,5,10,11, 27,51,52

8

 Tavani A [204], 2010, Italy

M/F

1992–2004

Population from Italian areas

755

1297

Renal-cell cancer

Questionnaires

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

1,2,3,5,6,7,27,55,56

7

 Gago-Dominguez M [205], 1999, US

M/F

1986–1994

Patients from Los Angeles County

1204

1204

Renal-cell cancer

Questionnaires

Had ever taken the drug 20 or more times

3,5,10,27,57

6

 Chow WH [206], 1994, US

M/F

1988–1990

Population from Minnesota

440

691

Renal-cell cancer

Interviewer

Use at least 2 or more times per week for 1 month or longer (regular)

1,3,10

6

 McCredie M [207], 1993, Austrilia

M/F

1989–1990

The NSW Central Cancer Registry

489

523

Renal-cell cancer

Questionnaires

Had ever taken the drug 20 or more times

1,2,3,50,58,

7

 McCredie M [208], 1988, Austrilia

M/F

1977–1982

New South Wales Central Cancer Registry

360

985

Kidney cancer

Questionnaires

Had taken a total of more than 0.1 kg

1,2,3,44,59,60,61

6

Cohort studies

 Karami S [203], 2016, US

M/F

2002–2007

Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial

135

98,807

Renal cell carcinoma

Questionnaires

Use at least once per week

1,3,5,10,11,27,51

7

 Brasky TM [92], 2014, US

F

1998–2010

WHI

329

141,880

Kidney cancer

Questionnaires

Use at both baseline and year 3 visits (consistent)

1,3,4,5, 6,10,11,17,18,19,25,26,28,29,30,31,32,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48

9

 Liu W [209], 2013, US

M/F

1996–2006

AARP

884

298,468

Renal cell carcinoma

Questionnaires

Any use of aspirin

1,2,3,4,5,6,7,10,11,18,27,53,54

7

 Cho E [210], 2011, US

F

1986–2006

NHS

153

77,525

Renal cell carcinoma

Questionnaires

Use aspirin ≥2 times/week(regular)

1,3,6,10,18,19,27,39

7

 

M

1990–2006

HPFS

180

49,403

Renal cell carcinoma

Questionnaires

Use aspirin ≥2 times/week(regular)

1,3,6,10,18,19,27

9

 Jacobs EJ [98], 2007, US

M/F

1992–2003

Cancer Prevention Study II Nutrition Cohort

365

146,113

Kidney cancer

Questionnaires

Use at least 30 “times” per month(daily use of adult-strength)

1,2,3,5,7,10,11, 15,16,17,18,20,25, 27,45

8

 Friis S [62], 2003, Denmarka

M/F

1989–1997

Population from North Jutland County

67

29,470

Kidney cancer

Prescription database

75–150 mg once daily(low-dose aspirin)

1,2

8

 Schreinemachers DM [63], 1994, US

M/F

1971–1987

The National Health and Examination Survey Ι

32

12,668

Kidney cancer

Self reported

Use aspirin during the 30-day period before the interview

1,2

6

 Paganini-Hill A [103], 1989, US

M/F

1981–1988

Population from Leisure World, Laguna Hills, US

25

13,870

Kidney cancer

Questionnaires

Aspirin use: none,<daily, daily

2

4

1 = age, 2 = sex, 3 = smoking, 4 = family history, 5 = educational level, 6 = alcohol intake, 7 = diabetes, 8 = fat distribution, 9 = social status, 10 = BMI,11 = race, 12 = folate, 13 = height, 14 = Alternate Healthy Eating Index-2010, 15 = PSA test in past 2 y, 16 = mammogram in past 2 y, 17 = hormone replacement therapy, 18 = physical activity, 19 = fruit, vegetable and/or vitamin intake, 20 = history of colonoscopy, 21 = total energy intake, 22 = ever use of calcium supplements in the past 5 years, 23 = former health checkup, 24 = red meat, 25 = other NSAIDs, 26 = area (county/region), 27 = hypertension, 28 = migraine, 29 = ever use of calcium supplements in the past 5 years, 30 = red meat, 31 = Nitro-vasodilator use, 32 = height, 33 = unique number of hospitalizations in the year prior to start of follow up, 34 = observational study enrollment, 35 = diet modification trial enrollment, 36 = screening for cancer, 37 = age at menarche, 38 = age at menopause, 39 = gravidity, 40 = age atfirst birth, 41 = duration of estrogen therapy, 42 = duration of combined postmenopausal hormone therapy, 43 = hysterectomy status, 44 = use of antihypertensive medication, 45 = history of coronary heart disease, 46 = use of cholesterol-lowering medication, 47 = history of arthritis, 48 = history of ulcer, 49 = method of interview, 50 = obesity, 51 = center, 52 = dialysis treatment, 53 = marital status, 54 = total dietary fiber, 55 = study center, 56 = year of interview, 57 = regular use of amphetamines, 58 = method of interview, 59 = phenacetin, 60 = paracetamol, 61 = urological disease

AARP AARP diet and health study, HPFS Health Professionals follow-up study, NHS nurses’ health study, WHI women’s health initiative

aStudy deemed to be prone to immortal time bias

Table 13

Characteristics of included studies- renal pelvis and ureter

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Linet MS [211], 1995, US

M/F

1983–1986

Cancer registries in New Jersey,Iowa and Los Angeles

418

405

Renal pelvis and ureter cancer

Questionnaire

Use 2 or more doses per week for at least 1 month or longer(regular)

1,2,3,7

8

 Mccredie M [207], 1993, Australia

M/F

1989–1990

The NSW Central Cancer Registry

147

523

Renal pelvis cancer

Questionnaire

Had ever taken the drug 20 or more times

1,2,3,5,8

7

 Ross RK [212], 1989, US

M/F

1978–1982

The Cancer Surveillance Program in Los Angeles County

187

187

Renal pelvis and ureter cancer

Telephone interviews

Use aspirin for more than 30 days in a single year

1,2,6

8

 Jensen OM [213], 1989, Denmark

M/F

1979–1982

Patients in hospitals of Copenhagen

90

251

Renal pelvis and ureter cancer

Face-to-face interviews

Use of aspirin - not further defined

1,2,4

7

1 = age, 2 = sex, 3 = smoking, 4 = hospital, 5 = educational level, 6 = race, 7 = geographic site, 8 = method of interview

Table 14

Characteristics of included studies- bladder cancer

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Baris D [214], 2013, US

M/F

2001–2004

Population from Maine, Vermont and New Hampshire

783

890

Bladder cancer

Self-reported

Use at least 20 times(any)

1,2,3,11,26,51

6

 Fortuny J [215], 2007, US

M/F

1998–2001

The New Hampshire State Department of Health and Human Services’ rapid reporting Cancer Registry

456

369

Bladder cancer

Interview

Use at least four times a week for 1 month or longer prior to the reference date

1,2,3,25

7

 Fortuny J [216], 2006,Spain

M/F

1997–2000

Patients from five regions in Spain (Barcelona, Valle’s/Bages, Alacant, Tenerife, and Asturias)

907

965

Bladder cancer

Self-reported

Use twice or more weekly for ≥ 1 month (regular)

1,2,3,25,26,52,53

8

 Castelao JE [217], 2000, US

M/F

1987–1996

SEER cancer registry

1514

1514

Bladder cancer

Questionnaire

Use at least 20 times(any)

3,5,53,54,55,56, 57,58,59,60

7

 Steineck G [218], 1995, Sweden

M/F

1985–1987

Population from the County of Stockholm

325

393

Bladder cancer

Questionnaire

Had ever taken aspirin-not further defined

1,2,3,55,56,61,62,63

5

Cohort studies

 Brasky TM [92], 2014, US

F

1998–2010

WHI

175

142,330

Bladder cancer

Questionnaire

Use at both baseline and year 3 visits (consistent)

1,3,4,5,6,10,11,17,18,19,25,26,,28,29,30,31,32,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48

9

 Shih C [219], 2013, US

M/F

2000–2010

The VITAL cohort

344

77,048

Bladder cancer

Questionnaire

Use at least once per week, for at least 1 year

1,2,3,4,5,11,49

8

 Daugherty SE [220], 2011, US

M/F

1995–1996

AARP

1660

334,908

Bladder cancer

Questionnaire

Use aspirin ≥ 2times/week (regular)

3,10,11,25,27

7

  

1993–2001

PLCO Cancer Screening

704

154,952

Bladder cancer

Questionnaire

Use aspirin ≥ 2times/week (regular)

3,10,11,25,27

7

  

1994–1998

The USRT Study

97

90,972

Bladder cancer

Questionnaire

Use aspirin ≥ 2times/week (regular)

3,10,11,25,27

7

 Genkinger JM [221], 2007, US

M

1986–2004

HPFS

392

49,448

Bladder cancer

Questionnaire

Use 2 or more times per week(regular)

1,3,26,50

9

 Jacobs EJ [98], 2007, US

M/F

1992–2003

Cancer Prevention Study II Nutrition Cohort

867

146,113

Bladder cancer

Questionnaire

Use at least 30 “times” per month(daily use of adult-strength)

1,2,3,5,7,10,11, 15,16,17,18,22, 25,45, 63

8

 Friis S [62], 2003, Denmarka

M/F

1989–1997

Population of North Jutland County

161

29,470

Bladder cancer

Prescription database

75–150 mg once daily(low-dose aspirin)

1,2

8

 Schreinemachers DM [63], 1994, US

M/F

1971–1987

The National Health and Examination Survey Ι

35

12,668

Bladder cancer

Self reported

Use aspirin during the 30-day period before the interview

1,2

6

 Paganini-Hill A [103], 1989, US

M/F

1981–1988

Population from Leisure World, Laguna Hills, US

96

13,870

Bladder cancer

Questionnaire

Aspirin use: none,<daily, daily

2

4

1 = age, 2 = sex, 3 = smoking, 4 = family history, 5 = educational level, 6 = alcohol intake, 7 = history of colorectal endoscopy, 8 = Fat distribution, 9 = social status, 10 = BMI,11 = race, 12 = folate, 13 = height, 14 = Alternate Healthy Eating Index-2010, 15 = PSA test in past 2 y, 16 = mammogram in past 2 y, 17 = hormone replacement therapy, 18 = physical activity, 19 = fruit, vegetable and/or vitamin intake, 20 = history of colonoscopy, 21 = total energy intake, 22 = diabetes, 23 = former health checkup, 24 = red meat, 25 = other NSAIDs, 26 = area (county/region), 27 = study, 28 = migraine, 29 = ever use of calcium supplements in the past 5 years, 30 = red meat, 31 = Nitro-vasodilator use, 32 = height, 33 = unique number of hospitalizations in the year prior to start of follow up, 34 = observational study enrollment, 35 = diet modification trial enrollment, 36 = screening for cancer, 37 = age at menarche, 38 = age at menopause, 39 = gravidity, 40 = age atfirst birth, 41 = duration of estrogen therapy, 42 = duration of combined postmenopausal hormone therapy, 43 = hysterectomy status, 44 = use of antihypertensive medication, 45 = history of coronary heart disease, 46 = use of cholesterol-lowering medication, 47 = history of arthritis, 48 = history of ulcer, 49 = indications for NSAID use, 50 = fluid intake, 51 = hispanic status, 52 = Metamizol, 53 = Acetic acids, 54 = number of years employed as hairdresser/barber, 55 = use of phenacetin, 56 = acetaminophen, 57 = Other salicylic acids, 58 = Propionic acids, 59 = Oxicam,60 = Pyrazolon derivatives, 61 = Dextropropoxyphene, 62 = Phenazon, 63 = Other analgesics (codeine, chlormezanone, caffeine), 63 = hypertension

AARP AARP diet and health study, HPFS Health Professionals follow-up study, PLCO prostate, lung, colorectal and ovarian cancer screening trial, SEER surveillance, epidemiology and end results, USRT United State Radiologic Technologist Study, VITAL the vitamins and lifestyle, WHI women’s health initiative

aStudy deemed to be prone to immortal time bias

Table 15

Characteristics of included studies- brain tumor

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Egan KM [41], 2016, US

M/F

2004–2012

Population in Southeastern US

1433

1296

Brain tumor

Interview

Use at least twice a week for 12 consecutive months (regular)

1,2,5,7,8

6

 Gaist D [222], 2013, Denmark

M/F

2000–2009

Danish Cancer Registry, Civil Registration System, National Prescription Registry, Danish National Registry of Patients, and Danisheducation and fertility registries within Statistics Denmark

2688

18,848

Glioma

National Prescription Registry

Use aspirin as a ‘low’ (≤ 100 mg) or ‘high’ (150 mg) daily dose of low-dose aspirin

5,10,13,14,15,16,17,18

7

 Ferris J [223], 2012, US

M/F

2007–2010

CUMC

236

230

Glioma

Questionnaire

Use at least twice a weekfor 6 months or longer(ever use)

1,2,7,9,11,12,13

7

   

The UCSF

281

170

Glioma

Questionnaire

Use at leasttwice a week for 6 months or longer(ever use)

1,2,7,9,11,12,13

 

Cohort studies

 Bannon FJ [224], 2013, UKa

M/F

1987–2009

UK Clinical Practice Research Datalink(CPRD)

5052

42,678

Brain tumor

Prescription database

Had ever taken aspirin- not further defined

1,2,8

7

 Daugherty SE [225], 2011, US

M/F

1996–2006

AARP

605

302,767

Glioma

Questionnaire

Use aspirin ≥ 2 times/wk.(regular)

1,2,7,19

7

 Friis S [62], 2003, Denmarka

M/F

1989–1997

Population from North Jutland County

70

29,470

Brain tumor

Prescription database

75–150 mg once daily(low-dose aspirin)

1,2

8

1 = age, 2 = sex, 3 = smoking, 4 = family history, 5 = educational level, 6 = alcohol intake, 7 = race, 8 = state of residence, 9 = center, 10 = anti-asthma medications, 11 = individual NSAIDs, 12 = acetaminophen, 13 = statins, 14 = diabetes, 15 = stroke, 16 = allergy, 17 = asthma, 18 = antihistamines, 19 = history of heart disease using age as time metric

AARP AARP diet and health study, CPRD clinical practice research datalink, CUMC Columbia University Medical Center, UCSF University of California San Francisco

aStudy deemed to be prone to immortal time bias

Table 16

Characteristics of included studies- head and neck cancers

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Di Maso M [226], 2015, Italy

M/F

1992–2008

Population from Aviano, Pordenone and the greater Milan area in northern Italy

198

596

Nasopharyngeal cancer

Questionnaire

Use at least one aspirin a week for at least 6 months(regular)

1,2,3,5,11,12,13

6

 Becker C [227], 2015, UK

M/F

1995–2013

CPRD

2745

16,470

Head and neck cancer

Prescription database

Use aspirin ≥1 Prescription

3,6,8,10

7

 Macfarlane TV [228], 2012, Europe

M/F

 

ARCAGE

1779

1993

Head and neck cancer

Questionnaire

Use at least once a weekfor a year(regular)

1,2,3,5,6,10,18

7

 Ahmadi N [229], 2010, US

M/F

2003–2007

Patients from the Lombardi Comprehensive Cancer Center, at GUMC

25

25

Head and neck cancer

Questionnaire

Daily use of aspirin

5,19

5

 Jayaprakash V [230], 2006, US

M/F

1982–1998

RPCI

529

529

Head and neck cancer

Questionnaire

Had ever taken aspirin before the onset of the present illness

1,2,3,6

7

 Rosenquist K [231], 2005, Sweden

M/F

2000–2004

Population from the Southern healthcare region of Sweden

132

320

Oral and oropharyngeal squamous cell carcinoma

Interview

Had ever taken aspirin-not further defined

3,6

6

 Bosetti C [232], 2003, Italy

M/F

1992–2000

Population from Italy

740

1779

Oral and pharyngeal, laryngeal cancer

Questionnaire

Use at least once a week for more than 6 months

1,2,3,5,6,11

6

Cohort studies

 Macfarlane TV [69], 2014, UKa

M/F

1996–2010

PCCIU database

1195

3580

Head and neck cancer

Prescription database

Had at least one Prescription (users)

1,2,8,14,15,16,17

7

 Wilson JC [233], 2013, US

M/F

1993–2001

PLCO

316

142,034

Head and neck cancer

Questionnaire

Use aspirin regularly -not further defined

1,2,3,10

7

 Friis S [62], 2003, Denmarka

M/F

1989–1997

Population from North Jutland County

68

29,470

Head and neck cancer

Prescription database

75–150 mg once daily(low-dose aspirin)

1,2

8

1 = age, 2 = sex, 3 = smoking, 4 = family history, 5 = educational level, 6 = alcohol intake, 7 = race, 8 = other NSAIDs, 9 = social status, 10 = BMI, 11 = area of residence, 12 = period of interview, 13 = occupation, 14 = deprivation, 15 = CHD, 16 = stroke, 17 = COX-2 inhibitors, 18 = fruit consumption, 19 = marital status

ARCAGE the alcohol-related cancers and genetic susceptibility, CPRD clinical practice research datalink, GUMC Georgetown University Medical School, PCCIU primary care clinical informatics unit database, PLCO prostate, lung, colorectal and ovarian cancer screening trial, RPCI the Roswell Park Cancer Institute

aStudy deemed to be prone to immortal time bias

Table 17

Characteristics of included studies- thyroid cancer

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Cohort studies

 Patel D [234], 2015, US

M/F

1993–2001

AARP

292

269,553

Thyroid cancer

Questionnaires

Use aspirin ≤ 2 times/Week(no regular use)

2,3,6,8,11

7

   

PLCO

56

58,433

Thyroid cancer

Questionnaires

Use aspirin ≤ 2 times/Week(no regular use)

2,3,6,8,11

6

   

U.S. Radiologic Technologists Study

133

60,591

Thyroid cancer

Questionnaires

Use aspirin ≤ 2 times/Week(no regular use)

2,3,6,8,11

6

 Brasky TM [92], 2014, US

F

1998–2010

WHI

229

142,330

Thyroid cancer

Questionnaires

Use at both baseline and year 3 visits (consistent)

1,3,4,5,6,7,9,10,11,12,13,14,15,16,17,18,19,22,24,25,26,27,28,29,30,31,32,33,34,35,36,37

9

1 = age, 2 = sex, 3 = smoking, 4 = education level, 5 = family history, 6 = alcohol intake, 7 = height, 8 = weight, 9 = history of ulcer, 10 = BMI, 11 = race, 12 = duration of estrogen therapy, 13 = duration of combined postmenopausal hormone therapy, 14 = hysterectomy status, 15 = use of antihypertensive medication, 16 = history of coronary heart disease, 17 = use of cholesterol-lowering medication, 18 = physical activity, 19 = fruit, vegetable and/or vitamin intake, 20 = history of colonoscopy, 21 = total energy intake, 22 = ever use of calcium supplements in the past 5 years, 23 = former health checkup, 24 = red meat, 25 = hormone replacement therapy, 26 = gravidity, 27 = history of arthritis, 28 = age at first birth, 29 = other NSAIDs, 30 = area (county/region), 31 = migraine, 32 = Nitro-vasodilator use, 33 = observational study enrollment, 34 = diet modification trial enrollment, 35 = screening for cancer, 36 = age at menarche, 37 = age at menopause

AARP AARP diet and health study, PLCO prostate, lung, colorectal and ovarian cancer screening trial, WHI women’s health initiative

Table 18

Characteristics of included studies- skin cancer

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Reinau D [235], 2015, UK

M/F

1995–2013

GPRD

73,262

96,854

Skin cancer

Prescription database

Last prescription ≤ 1 year before the index date(current user)

3,6,10, 29,43,47,48,49,50,51,52

8

 Johannesdottir SA [236], 2012, Denmark

M/F

1991–2009

Population from northern Denmark

18,532

178,655

Skin cancer

Prescription records

Redeemed > 2 prescriptions during the entire study period

1,2,20,44,45,46

8

 Torti DC [237], 2011, US

M/F

1997–2000

Population from New Hampshire and bordering regions

1022

1484

Skin cancer

Interview

Use at least four times a week for at least 1 month

1,2,3,53,54,55

8

 Curiel-Lewandrowski C [238], 2011, US

M/F

2004–2007

Dana Farber Harvard Cancer Center Institutions and Dermatology Associates of Concord, Boston(USA)

400

600

Cutaneous melanoma

Telephone interview

Use at least once weekly within a year preceding the interview (current user)

56

8

 Jeter JM [239], 2011, US

M/F

2000–2003

The GEM study

327

119

Melanoma

Self-reported

Daily basis for at least 3 months

1,2,4,53,57

6

 Asgari MM [240], 2010, US

M/F

1994–2004

KPNC

415

415

Cutaneous squamous sell sarcinoma

Questionnaire

Use at least once a week for at least 1 year(regular)

3,4,5,30,53,56,58,59,60,61,62,63,64,65,66,67,68

8

Cohort studies

 Hollestein LM [91], 2014, Netherlandsa

M/F

1998–2010

PHARMO and the Eindhoven Cancer Registry

2363

109,276

Skin cancer

Prescription database

Low dose aspirin (≤ 100 mg daily)- not further defined

1,2,11,12

8

 Wysong A [241], 2014, US

F

1993–1998

WHI

7652

54,728

Non-melanoma skin cancer

Questionnaire

Use ≥ 2 times/week for at least 2 weeks(regular)

1,3,5,7,10,14,15,19,21,29,43,69,70,71,72,73,74

6

 Brasky TM [92], 2014, US

F

1998–2010

WHI

585

142,330

Melanoma

Self-administered questionnaires

Use at both baseline and year 3 visits (consistent)

1,3,4,5,6,10,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37

9

 Jeter JM [242], 2012, US

F

1980–2008

NHS

17,074

92,125

Skin cancer

Questionnaire

Use at least 1–2 tablets/week or 1 day/week of regular use at any lifetime(current user)

1,3,4,7,10,14,15,54,57,75,76,77,78,79

7

 Cahoon EK [243], 2012, US

M/F

1994–1998 2003–2005

United States Radiologic Technologists study

2215

58,213

Basal cell carcinoma

Questionnaire

Use at least 1 days per month in the past year

1,2,80

8

 Asgari MM [244], 2008, US

M/F

2000–2005

The VITAL cohort

216

39,909

Melanoma

Questionnaire

Use at least once a week for a year in the 10-year period before baseline(ever use)

1,2,4,5,7,15,29, 30,56,59,69,73,81,82,83

8

 Jacobs EJ [98], 2007, US

M/F

1992–2003

Cancer Prevention Study II Nutrition Cohort

1049

146,113

Melanoma

Questionnaire

Use at least 30 “times” per month(daily use of adult-strength)

1,2,3,5,10,13,14,18,19,36,38,39,40,41,42

8

 Schreinemachers DM [63], 1994, US

M/F

1971–1987

The National Health and Examination Survey Ι

69

12,668

Melanoma

Self reported

Use aspirin during the 30-day period before the interview

1,2

6

1 = age, 2 = sex, 3 = smoking, 4 = family history, 5 = educational level, 6 = alcohol intake, 7 = skin reaction to the sun, 8 = Fat distribution, 9 = social status, 10 = BMI, 11 = unique number of dispensing, 12 = unique number of hospitalizations in the year prior to start of follow up, 13 = race, 14 = physical activity, 15 = fruit, vegetable and/or vitamin intake, 16 = ever use of calcium supplements in the past 5 years, 17 = red meat, 18 = hormone replacement therapy, 19 = other NSAIDs, 20 = area (county/region), 21 = migraine, 22 = Nitro-vasodilator use, 23 = observational study enrollment, 24 = diet modification trial enrollment, 25 = screening for cancer, 26 = age at menarche, 27 = age at menopause, 28 = gravidity, 29 = history of arthritis, 30 = history of ulcer, 31 = age at first birth, 32 = duration of estrogen therapy, 33 = duration of combined postmenopausal hormone therapy, 34 = hysterectomy status, 35 = use of antihypertensive medication, 36 = history of coronary heart disease, 37 = use of cholesterol-lowering medication, 38 = mammography, 39 = history of colorectal endoscopy, 40 = history of PSA testing, 41 = diabetes, 42 = hypertension,43 = the number of general practitioner visits in the year before the index date, 44 = use of systemic glucocorticoids, cytostatic or immunosuppressive medication, 45 = drugs with pigmenting adverse effects, 46 = Charlson comorbidity index, 47 = photosensitising or phototoxic drugs,48 = inflammatory bowel disease, 49 = ischemic stroke/ transient ischemic attack, 50 = ischemic heart disease, 51 = psoriasis, 52 = systemic glucocorticoids and other immunosuppressants, 53 = skin type, 54 = lifelong number of painful sunburns, 55 = lifelong cumulative number of hours of sun exposure, 56 = number of sunburns of children, 57 = number of moles, 58 = eye color, 59 = natural hair color, 60 = exposure to industrial chemicals, 61 = history of freckling, 62 = outdoor sun exposure, 63 = occupational sun exposure, 64 = tanning bed use, 65 = history of high-risk exposures such as UV light, 66 = burn scar, 67 = radiation treatment, 68 = arsenic exposure, 69 = personal history of nonmelanoma skin cancer, 70 = personal history of melanoma, 71 = current and childhood summer sun exposure, 72 = sunscreen use, 73 = history of cardiovascular disease, 74 = regional solar radiation (Langleys), 75 = menopausal status and use of postmenopausal hormones, 76 = questionnaire cycle, 77 = ability to tan, 78 = UV-B availability at state of residence, 79 = height, 80 = solar UV exposure quartile calculated from summer erythemal UV values weighted by time outdoors, 81 = ever had moles removed, 82 = chronic pain in last year, 83 = kidney disease or ulcer

GEM the genes, environment, and melanoma study, GPRD general practitioners research database, KPNC Kaiser Permanente Northern California population, NHS nurses’ health study, VITAL the vitamins and lifestyle, WHI women’s health initiative

aStudy deemed to be prone to immortal time bias

Table 19

Characteristics of included studies- lymphoma

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Baecklund E [245], 2006, Swedish

M/F

196–1995

From the Swedish Inpatient Register

269

225

Lymphoma

Hospital records

Use aspirin for 4 consecutive weeks

15,16

5

 Zhang YQ [246], 2006, US

M/F

197–2002

Subjects were recruited from patients admitted to hospitals in New York, Philadelphia, Boston and Baltimore

412

1524

Non-Hodgkin lymphoma

Nurse-interviewers administered standard questionnaires

Use at least four times per week for at least three or more continuous months(regular)

1,2,7,8

7

 Flick ED [247], 2006, US+

M/F

200–2004

Population from the California counties of San Francisco, Alameda, Marin, Contra Costa, San Mateo, and Santa Clara

604

638

Non-Hodgkin lymphoma

Interview

Use at least 2 days per week for 3 months or longer during the past 20 years

1,2,17

7

 Baker JA [248], 2005, US

M/F

198–1998

RPCI

628

2512

Non-Hodgkin lymphoma

Questionnaire

Use at least once per week for 6 months

1

5

 Chang ET [249], 2004, US

M/F

1997–2000

population from the greater Boston, Massachusetts, metropolitan area and in the state of Connecticut

565

679

Hodgkin’s lymphoma

Telephone interview

Use two or more tablets per Week(regular)

1,2,3,9,17

6

 Zhang YW [250], 2004, US

M/F

1996–2000

Patients in Yale Cancer Center’s Rapid Case Ascertainment Shared Resource(RCA)

601

717

Non-Hodgkin lymphoma

Iinterview

Use at least once a day for a period of 6 months or longer previous to 1 year ago

1,4,10,18

7

Cohort studies

 Hollestein LM [91], 2014, Netherlands a

M/F

1998–2010

PHARMO and the Eindhoven Cancer Registry

256

109,276

Lymphoma

Prescription database

Low dose aspirin (≤100 mg daily)- not further defined

1,2,11,12

8

 Birmann BM [251], 2014, US

F

1976–2008

NHS

196

85,942

Multiple myeloma

Questionnaire

81-mg “baby” and 325-mg “adult” strength

1,10

8

 

M

1986–2008

HPFS

132

47,029

Multiple myeloma

Questionnaire

81-mg “baby” and 325-mg “adult” strength

1,10

8

 Teras LR [252], 2013, US

M/F

1992–2007

The CPS-II Nutrition Cohort Cancer Prevention Study-II (CPS-II) Nutrition Cohort

1709

149,570

Lymphoma

Questionnaire

Use aspirin ≥30 aspirin pills/Month(regular)

1,3,4,5,6,10,19,20, 21,22,23,24,25

7

 Chang ET [253], 2011, Denmarka

M/F

1995–2008

Population from Denmark

1659

8089

Hodgkin lymphoma

Prescription database

Use aspirin ≥ 2 times per week

1,2,13,14

8

 Walter RB [254], 2011, US

M/F

2000–2002

VITAL Study

224

64,839

Lymphoma

Questionnaire

Had ever taken low dose aspirin(81 mg)

4,21,23,26,27,28,29,33

6

 Erber E [255], 2009, US

M/F

199–1996

MEC Study

896

193,050

Non-Hodgkin Lymphoma

Self-completed questionnaire

Use at least two times per week for 1 month or longer

5,6,10

8

 Cerhan JR [256], 2003, US

M/F

199–1999

IWHS

130

27,290

Non-Hodgkin Lymphoma

Self-completed questionnaire

Had ever taken aspirin- not further defined

1,3,6,17,21,25, 29,30,31,32

7

 Friis S [62], 2003, Denmarka

M/F

1989–1997

Population from North Jutland County

57

29,470

Non-Hodgkin’s lymphoma

Prescription database

75–150 mg once daily(low-dose aspirin)

1,2

8

 Schreinemachers DM [63], 1994, US

M/F

1971–1987

The National Health and Examination Survey Ι

48

12,668

Lymphoma

Self reported

Use aspirin during the 30-day period before the interview

1,2

6

1=age, 2=sex, 3=smoking, 4=family history, 5=educational level, 6=alcohol intake, 7=year of interview, 8=study center, 9=use of other analgesics, 10=BMI, 11=unique number of dispensing, 12=unique number of hospitalizations in the year prior to start of follow up, 13=Charlson comorbidity index, 14= history of connective tissue disorder, 15=auranofin, chlorambucil, cyclophosphamide, cyclosporine, D-penicillamine, and podophyllotoxin, 16=disease activity, 17=residence, 18=menopausal status, 19=race, 20=sitting time, 21=diabetes status, 22=rheumatoid arthritis status, 23=cholesterol-lowering drug use, 24=acetaminophen use, 25=postmenopausal hormone use, 26=self-reported health, 27=history of coronary artery disease, 28=stroke, 29=marital status, 30=transfusion history,31= red meat and fruit intake,32= replacement therapy, 33=history of fatigue/lack of energy

HPFS Health Professionals follow-up study, IWHS Iowa Women’s Health Study, MEC multiethnic cohort study, NHS nurses’ health study, RPCI the Roswell Park Cancer Institute, VITAL the vitamins and lifestyle

aStudy deemed to be prone to immortal time bias

Table 20

Characteristics of included studies- leukemia

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Ross JA [257], 2011, US

M/F

2005–2009

The MCSS

734

697

Leukemia

Questionnaire

Use at least once per week for at least 1 year

1,7,10

9

 Weiss JR [258], 2006, US

M/F

1981–1998

RPCI

169

676

Leukemia

Questionnaire

Use at least once per week for 6 months(regular)

1,2

6

 Oleske D [7], 1985, US

M/F

1975–1981

Hairy Cell Tumor Registry and Treatment Center

45

134

Leukemia

Questionnaire

Use three times a week or more for more than 2 months

1,2,6,11

6

Cohort studies

 Jacobs EJ [98], 2007, US

M/F

1992–2003

Cancer Prevention Study II Nutrition Cohort

465

146,113

Leukemia

Questionnaire

Use at least 30 “times” per month(daily use of adult-strength)

1,2,3,5,10,11,12,13,14,15,16,17,18,19

8

 Kasum CM [259], 2003, US

F

1992–2000

IWHS

81

28,224

Leukemia

Questionnaire

Had ever taken aspirin- not further defined

1,3,5

8

 Friis S [62], 2003, Denmarka

M/F

1989–1997

Population from North Jutland County

69

29,470

Leukemia

Prescription database

75–150 mg once daily(low-dose aspirin)

1,2

8

 Schreinemachers DM [63], 1994, US

M/F

1971–1987

The National Health and Examination Survey Ι

39

12,668

Leukemia

Self reported

Use aspirin during the 30-day period before the interview

1,2

6

1=age, 2=sex, 3=smoking, 4=family history, 5=educational level, 6=residence, 7=other analgesic use, 8=fat distribution, 9=social status, 10=BMI, 11=race, 12=physical activity level, 13=use of hormone replacement therapy, 14=history of mammography, 15=history of colorectal endoscopy, 16=use of non-aspirin NSAIDs, 17= history of heart attack, 18=diabetes, 19=hypertension

IWHS Iowa Women’s Health Study, MCSS the Minnesota Cancer Surveillance System, RPCI the Roswell Park Cancer Institute

aStudy deemed to be prone to immortal time bias

Table 21

Characteristics of included studies- small intestine neuroendocrine tumors

Study source

Sex

Study period

Source of subjects

No of case

No of control/cohort size

Cancer site

Exposure assessment

Exposure Definition

Adjustment for covariates

Study quality

Case-control studies

 Rinzivillo M [260], 2016, Italy

M/F

2009–2012

Population from Universities of Rome and Bologna and at the European Institute of Oncology

215

860

Small Intestine Neuroendocrine Tumors

Questionnaire

Use at any dose at least twice a week for more than one consecutive year

1,2,

7

1= age, 2=sex

Aspirin use and the risk of cancers

Figures 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18 and Additional file 1: Table S1 shows the RRs for the 21 separate cancer sites that we assessed and that of the total cancers. The use of aspirin was associated with a reduced cancer risk for ten specific sites: gastric cancer (RR =0.75, 95%CI:0.65–0.86), esophagus cancer (RR = 0.75, 95%CI:0.62–0.89), colorectal cancer(RR = 0.79, 95%CI:0.74–0.85), pancreatic cancer (RR = 0.80, 95%CI:0.68–0.93), breast cancer (RR = 0.92, 95%CI:0.88–0.96), ovarian cancer (RR = 0.89, 95%CI:0.83–0.95), endometrial cancer (RR = 0.92, 95%CI:0.85–0.99), prostate cancer (RR = 0.94, 95%CI:0.90–0.99), and small intestine neuroendocrine tumors (RR = 0.17, 95%CI:0.05–0.58). However, there was no significant association between aspirin use and the risk of some cancers, including hepato-biliary, lung, cervical uterus, renal, renal pelvis and ureter, bladder, brain, head and neck, thyroid, and skin cancers, as well as lymphoma and leukemia.
Fig. 2
Fig. 2

Forest plot of aspirin use and the risk of gastric cancer

Fig. 3
Fig. 3

Forest plot of aspirin use and the risk of esophagus cancer

Fig. 4
Fig. 4

Forest plot of aspirin use and the risk of colorectal cancer

Fig. 5
Fig. 5

Forest plot of aspirin use and the risk of hepato-biliary cancer

Fig. 6
Fig. 6

Forest plot of aspirin use and the risk of pancreatic cancer

Fig. 7
Fig. 7

Forest plot of aspirin use and the risk of lung cancer

Fig. 8
Fig. 8

Forest plot of aspirin use and the risk of breast cancer

Fig. 9
Fig. 9

Forest plot of aspirin use and the risk of ovarian cancer

Fig. 10
Fig. 10

Forest plot of aspirin use and the risk of endometrial cancer

Fig. 11
Fig. 11

Forest plot of aspirin use and the risk of prostate cancer

Fig. 12
Fig. 12

Forest plot of aspirin use and the risk of renal cancer

Fig. 13
Fig. 13

Forest plot of aspirin use and the risk of bladder cancer

Fig. 14
Fig. 14

Forest plot of aspirin use and the risk of brain tumors

Fig. 15
Fig. 15

Forest plot of aspirin use and the risk of head and neck cancers

Fig. 16
Fig. 16

Forest plot of aspirin use and the risk of skin cancer

Fig. 17
Fig. 17

Forest plot of aspirin use and the risk of lymphoma

Fig. 18
Fig. 18

Forest plot of aspirin use and the risk of leukemia

Additional file 1: Tables S1–S18 shows the RRs for cancers at 17 sites, in subgroups of studies defined by their design, study location, gender, exposure assessment, quality assessment, duration of aspirin use, and frequency of aspirin use.

We conducted a subgroup analysis stratified by questionnaires and medical records, and found a lower risk in medical records with most cancers (gastric, esophageal, colorectal, hepato-biliary, and pancreatic cancers), however, significant heterogeneity of effects was noted for those subgroups (Additional file 1: Tables S2–S18). As we expected, the decreased risk of colorectal cancer (RRs = 0.76, 95%CI: 0.66–0.87 for ≥5 years), pancreatic cancer (RRs = 0.75, 95%CI: 0.57–0.99 for ≥5 years), ovarian cancer (RRs = 0.77, 95%CI: 0.63–0.93 for ≥5 years), and brain cancer (RRs = 0.65, 95%CI: 0.43–0.97 for ≥5 years) were more pronounced with longer duration of aspirin use. However, the aspirin-associated RR for 21 specific cancers did not vary significantly by other characteristics (gender, quality assessment and frequency of aspirin use).

Publication bias

The funnel plot showed asymmetry (Fig. 19). In addition, the Begg’s test and Egger’s test provided evidence of publication bias among the included studies (Begg’s test Z = 4.34, P < 0.001; Egger’s test Z = − 5.27, P < 0.001).
Fig. 19
Fig. 19

Funnel plot of aspirin use and cancer

Discussion

The results of our meta-analysis supported the presence of inverse associations between aspirin use and the risk of overall cancer, gastric, esophageal, colorectal, pancreatic, breast, ovarian, endometrial, and prostate cancers, as well as small intestine neuroendocrine tumors. However, no significant associations were observed between the use of aspirin and the risk of other cancers, including hepato-biliary, lung, cervical uterus, renal, renal pelvis and ureter, bladder, brain, head and neck, thyroid, and skin cancers, as well as lymphoma, and leukemia.

There are several potential biological mechanisms through which aspirin could reduce the risk of cancer. First, aspirin and other NSAIDs have been proven to inhibit the activity of the enzyme cyclooxygenase 2 (COX-2), which is responsible for the synthesis of prostaglandins [29]. COX-2 has been reported to be overexpressed in many cancers and participates in key cellular activities, including cell proliferation, apoptosis, angiogenesis, and metastasis [3032]. Second, aspirin could activate the NF-kappa B (NF-κB) signaling pathway, which triggers apoptosis in neoplasia [33, 34]. In addition, some studies showed that aspirin might induce gene selection and modulate mitochondrial voltage dependent anion channels (VDACs) to reduce the risk of cancer progression and metastasis [35, 36].

The results of this meta-analysis indicated that utilization of aspirin had different protective effects on the development of cancer. This difference may be attributed to the different expression levels of COX in various cancers [37]. Furthermore, Zumwalt et al. [38] reported that the effectiveness of aspirin was primarily determined by specific genetic variants. Aspirin inhibited cell growth in all cancer cell lines regardless of mutational background, however, the effects were exacerbated in cells with PIK3CA mutations, which might explain the different effects of aspirin on cancers.

The decreased risk of gastric, esophageal, pancreatic, lung, breast, and ovarian cancers was observed in the case-control studies but not in the cohort studies. One possible explanation for the difference might be that cases in the case-control studies might have a recall bias and tended to overestimate the risk of cancer by aspirin use. Another possible explanation is that misclassification or measurement errors for aspirin use in the cohort studies might have distorted the association because most of our analyses were based on baseline data, and there might be a discrepancy between initial recruitment and subsequent aspirin consumption.

The longer those who had used aspirin, the lower their risk of cancer was, with longer duration of use associated with an RR of 0.90 (95% CI 0.89–0.74), based on 118 studies that reported associations with longer (≥5 years) duration of aspirin use and 105 studies that reported associations with shorter (< 5 years) duration of aspirin use. For most cancers (colorectal, pancreatic, ovarian, and brain cancers), risk reductions were more pronounced with longer duration of use, and these results agree with those of previous studies [3941]. In addition, the United States Preventive Services Task Force (USPSTF) indicated that cancer prevention was a significant aspect in the overall health benefit of aspirin, but this benefit was not apparent until several years after the initiation of aspirin therapy [42, 43]. It is of note that a significant inverse association with prostate cancer was observed in the patients who took aspirin for less than 5 years. Indeed, after the study that relied on the General Practice Research Database [44] was excluded, the discrepancy disappeared. Considering that aspirin use was off-prescription in the United Kingdom, misclassification was likely to occur in this study because many commonly used aspirins do not require a prescription. Therefore, it can be deduced that the patients who used aspirin for at least 5 years were more likely to realize the potential cancer prevention benefit.

There was no statistically significant difference between the pooled RRs for the frequency of aspirin in most studies. Given that a few studies were included in the subgroup analysis on the basis of the frequency of aspirin use and most studies lacked information on this variable, the results on the risks associated with the frequency of aspirin use should be interpreted with caution. Further studies that explore the associations between the frequency of aspirin use and cancer risk are necessary to elucidate the effects of aspirin.

In addition, our results indicated that the strongest reduction in the risk of most cancers associated with aspirin was found in North American countries. However, two-thirds of the included studies were performed in North America and a few studies were performed in Asian and European countries, which might distort the accuracy of the results. Therefore, more studies are necessary to examine the discrepancies among the different countries and regions.

Comparison with other studies

Bosetti et al. (2011) [45] conducted a meta-analysis on aspirin and 12 selected cancer sites based on 139 observational studies and 187,167 cases. Our study included 218 studies involving 737,409 cases and examined the correlation between aspirin use and the risk of skin, head and neck, hepatobiliary, thyroid, cervical uterus, renal pelvis, ureter, and brain cancers, lymphoma, small intestine neuroendocrine tumors, and leukemia, thereby providing more comprehensive and reliable evidence for this correlation. More importantly, this study was the first meta-analysis to evaluate the association between aspirin use and the risk of hepatobiliary cancer and we found a non-significant effect of aspirin on the risk of hepatobiliary cancer (OR = 0.64, 95% CI: 0.40–1.02).

Algra and Rothwell (2012) [46] conducted a meta-analysis on the association between aspirin use and the risk of cancer based on 195 studies and 215,211 cases. Compared with their review, our meta-analysis have added approximately 70 new articles published since 2012, with a total of 737,409 cases, which significantly enhanced the statistical power to determine this potential association. In addition, the exposure in the previous review was inconsistent, which may mislead the estimation. Many studies defined aspirin as the exposure but only a few studies defined NSAIDs as the exposure, and thus the specific effect of aspirin on cancers was not defined. The exposure to aspirin in our meta-analysis was consistent and ensured the reliability of the findings.

Strengths and limitations

This study is the most up-to-date comprehensive review of the effect of aspirin use on the risk of all types of cancers, and the large sample size provides reliable results with greater precision and power. The potential limitations of this study should be noted. First, there was substantial heterogeneity across the included studies, which was likely due to differences in the definitions of exposure, units, assessment methods, and the adjusted variables across different studies. Second, misclassification or measurement errors for aspirin use might distort the association because our analyses were based on baseline data, and changes in the exposure to aspirin were not updated during the follow-up period. Third, the visual inspection of a funnel plot showed asymmetry, and the Begg’s test and Egger’s test also identified evidence of publication bias among the studies included in our meta-analysis.

Our meta-analysis indicated a beneficial role for aspirin for overall cancers; however, the results should be interpreted with caution. Considering that most evaluated studies were based on secondary prevention rather than on primary prevention, the totality of evidence for the high-risk population was incomplete, and it is appropriate to let the beneficial role remain uncertain. At present, we should accept the uncertainties, and future chemoprevention trials should clarify the extent to which aspirin decreases cancers incidence.

Conclusions and implications

Evidence from observational studies indicates that utilization of aspirin is associated with reduced risk of gastric, colorectal, esophageal, pancreatic, ovarian, endometrial, breast, and prostate cancers, in addition to small intestine neuroendocrine tumors. A stronger protective effect was observed in the North American populations and patients who used aspirin for at least 5 years. It is important to address immortal time bias not only to ensure the integrity of the meta-analysis, but also to ensure the integrity of pharmacoepidemiological studies. Moreover, given the confidence limits of the evaluated studies, adequately powered mechanistic studies should help elucidate the mechanisms underlying this correlation.

Abbreviations

CI: 

Confidence interval

COX-2: 

Cyclooxygenase 2

HRs: 

Hazard ratios

NF-κB: 

NF-kappa B

NSAIDs: 

Non-steroidal anti-inflammatory drugs

ORs: 

Odds ratios

RRs: 

Relative risks

USPSTF: 

United States Preventive Services Task Force

VDACs: 

Voltage dependent anion channels

Declarations

Acknowledgements

We would like to thank Xiaoxv Yin and Shiyi Cao for critical review of this manuscript. We are grateful to the members of the Professor Lu for their support and helpful discussions.

Funding

This study was supported by the Fundamental Research Funds for the Central Universities, Huazhong University of Science and Technology, China(2016YXMS215). The funding body contributed to the design of the study and put forward some constructive suggestions for collection, analysis, and interpretation of data and the review and revision of the manuscript.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Authors’ contributions

YQ, YT, and ZL designed the study and were responsible for writing, analysis, interpretation and revision. YQ and YT carried out the data collection. YQ, YG and CW performed the statistical analyses. YQ, YT, and WL drafted the manuscript. ZL and YHG supervised the study and revised the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Social Medicine and Health Management, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
(2)
Department of Nutriology, The People’s Hospital of Henan Province, Zhengzhou, Henan, 450003, People’s Republic of China

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