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

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. 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. 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 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. 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, I 2 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.

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 [ 26 – 28 ]) included patients with specific diseases. Ultimately, 218 studies with 309 independent reports were included in the present meta-analysis. Fig. 1 Flow chart of study selection 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, Korea a 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, UK a 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, Denmark a 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 a Study 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, UK a 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, UK a 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, Denmark a 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 a Study 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, China a 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, Netherlands a 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, UK a 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/ 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, UK a 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 a Study 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, Denmark a 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 a Study 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, UK a 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, Denmark a 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 a Study 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, Netherlands a 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, Dermark a 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, UK a 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 a Study 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, Netherlands a 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, Canada a 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, UK a 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 a Study 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, Denmark a 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 a Study 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, US a 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, Denmark a 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 a Study 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, UK a 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, Denmark a 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 a Study 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, Italy a 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, Sweden a 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, Netherlands a 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, Canada a 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, UK a 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, Denmark a 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 a Study 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, Denmark a 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 a Study 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, Denmark a 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 a Study 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, UK a 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, Denmark a 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 a Study 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, UK a 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, Denmark a 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 a Study 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, Netherlands a 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 a Study 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, Denmark a 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, Denmark a 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 a Study 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, Denmark a 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 a Study 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 Characteristics of included studies- gastric cancer 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- esophagus cancer 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- colorectal cancer 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- hepato-biliary cancer 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- pancreatic cancer 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- lung cancer 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- breast cancer 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- ovarian cancer 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- endometrial cancer 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- cervix uterus 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- prostate cancer 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- renal cancer 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- renal pelvis and ureter 1 = age, 2 = sex, 3 = smoking, 4 = hospital, 5 = educational level, 6 = race, 7 = geographic site, 8 = method of interview Characteristics of included studies- bladder cancer 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- brain tumor 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- head and neck cancers 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- thyroid cancer 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 Characteristics of included studies- skin cancer 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- lymphoma 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- leukemia 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 a Study deemed to be prone to immortal time bias Characteristics of included studies- small intestine neuroendocrine tumors 1= age, 2=sex 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 Forest plot of aspirin use and the risk of gastric cancer Fig. 3 Forest plot of aspirin use and the risk of esophagus cancer Fig. 4 Forest plot of aspirin use and the risk of colorectal cancer Fig. 5 Forest plot of aspirin use and the risk of hepato-biliary cancer Fig. 6 Forest plot of aspirin use and the risk of pancreatic cancer Fig. 7 Forest plot of aspirin use and the risk of lung cancer Fig. 8 Forest plot of aspirin use and the risk of breast cancer Fig. 9 Forest plot of aspirin use and the risk of ovarian cancer Fig. 10 Forest plot of aspirin use and the risk of endometrial cancer Fig. 11 Forest plot of aspirin use and the risk of prostate cancer Fig. 12 Forest plot of aspirin use and the risk of renal cancer Fig. 13 Forest plot of aspirin use and the risk of bladder cancer Fig. 14 Forest plot of aspirin use and the risk of brain tumors Fig. 15 Forest plot of aspirin use and the risk of head and neck cancers Fig. 16 Forest plot of aspirin use and the risk of skin cancer Fig. 17 Forest plot of aspirin use and the risk of lymphoma Fig. 18 Forest plot of aspirin use and the risk of leukemia Forest plot of aspirin use and the risk of gastric cancer Forest plot of aspirin use and the risk of esophagus cancer Forest plot of aspirin use and the risk of colorectal cancer Forest plot of aspirin use and the risk of hepato-biliary cancer Forest plot of aspirin use and the risk of pancreatic cancer Forest plot of aspirin use and the risk of lung cancer Forest plot of aspirin use and the risk of breast cancer Forest plot of aspirin use and the risk of ovarian cancer Forest plot of aspirin use and the risk of endometrial cancer Forest plot of aspirin use and the risk of prostate cancer Forest plot of aspirin use and the risk of renal cancer Forest plot of aspirin use and the risk of bladder cancer Forest plot of aspirin use and the risk of brain tumors Forest plot of aspirin use and the risk of head and neck cancers Forest plot of aspirin use and the risk of skin cancer Forest plot of aspirin use and the risk of lymphoma 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). 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 Funnel plot of aspirin use and cancer Funnel plot of aspirin use and cancer

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% [ 3 – 5 ]. 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) [ 10 – 18 ], 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.

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 [ 30 – 32 ]. 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 [ 39 – 41 ]. 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. 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. 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.

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.

Additional file 1: Table S1. Summary table. Table S2. Subgroup analysis of relative risk of gastric cancer. Table S3. Subgroup analysis of relative risk of esophagus cancer. Table S4. Subgroup analysis of relative risk of colorectal cancer. Table S5. Subgroup analysis of relative risk of hepato-biliary cancer. Table S6. Subgroup analysis of relative risk of pancreatic cancer. Table S7. Subgroup analysis of relative risk of lung cancer. Table S8. Subgroup analysis of relative risk of breast cancer. Table S9. Subgroup analysis of relative risk of ovarian cancer. Table S10. Subgroup analysis of relative risk of endometrial cancer. Table S11. Subgroup analysis of relative risk of prostate cancer. Table S12. Subgroup analysis of relative risk of renal cancer. Table S13. Subgroup analysis of relative risk of bladder cancer. Table S14. Subgroup analysis of relative risk of brain tumor. Table S15. Subgroup analysis of relative risk of head and neck cancers. Table S16. Subgroup analysis of relative risk of skin cancer. Table S17. Subgroup analysis of relative risk of lymphoma. Table S18. Subgroup analysis of relative risk of leukemia. (DOC 549 kb) Table S1. Summary table. Table S2. Subgroup analysis of relative risk of gastric cancer. Table S3. Subgroup analysis of relative risk of esophagus cancer. Table S4. Subgroup analysis of relative risk of colorectal cancer. Table S5. Subgroup analysis of relative risk of hepato-biliary cancer. Table S6. Subgroup analysis of relative risk of pancreatic cancer. Table S7. Subgroup analysis of relative risk of lung cancer. Table S8. Subgroup analysis of relative risk of breast cancer. Table S9. Subgroup analysis of relative risk of ovarian cancer. Table S10. Subgroup analysis of relative risk of endometrial cancer. Table S11. Subgroup analysis of relative risk of prostate cancer. Table S12. Subgroup analysis of relative risk of renal cancer. Table S13. Subgroup analysis of relative risk of bladder cancer. Table S14. Subgroup analysis of relative risk of brain tumor. Table S15. Subgroup analysis of relative risk of head and neck cancers. Table S16. Subgroup analysis of relative risk of skin cancer. Table S17. Subgroup analysis of relative risk of lymphoma. Table S18. Subgroup analysis of relative risk of leukemia. (DOC 549 kb)