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Supplementary Table S1. Strings used for the literature search in Pubmed/MEDLINE, Embase, and Cochrane Library.

Pubmed/MEDLINE (aspirin OR acetylsalicylic acid OR Nonsteroidal anti-inflammatory drug OR Nonsteroidal anti-inflammatory drugs) AND (cancer OR cancers OR neoplasm OR neoplasms) AND (risk OR risks OR mortality) AND (case-control OR cohort OR prospective OR meta-analysis OR pooled-analysis)Limits: publ. year January 1, 2011- March 18, 2019

Embase ('aspirin':ti,ab,kw OR 'acetylsalicylic acid':ti,ab,kw OR 'nonsteroid antiinflammatory agent':ti,ab,kw) AND ('cancer':ti,ab,kw OR 'neoplasm':ti,ab,kw OR 'neoplasms':ti,ab,kw) AND ('risk':ti,ab,kw OR 'risks':ti,ab,kw OR 'mortality':ti,ab,kw) AND ('(case-control':ti,ab,kw OR 'cohort':ti,ab,kw OR 'prospective':ti,ab,kw OR 'meta-analysis':ti,ab,kw OR 'pooled-analysis)':ti,ab,kw) AND (2011:py OR 2012:py OR 2013:py OR 2014:py OR 2015:py OR 2016:py OR 2017:py OR 2018:py OR 2019:py) AND ('article'/it OR 'article in press'/it OR 'review'/it)

Cochrane Library (aspirin OR acetylsalicylic acid OR Nonsteroidal anti-inflammatory drug) AND (cancer OR neoplasm) in Title Abstract Keyword with Cochrane Library publication date from January 2011 to March 2019, (Word variations have been searched)

1

Supplementary Table S2. Main characteristics of epidemiological studies on aspirin use and risk of colorectal cancer included in the meta-analysis.

First author, year, reference

Country, study acronym, study characteristics

N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears

Subt

ype

Definition of (regular) exposure

Available information

Mg/

die

Dur

atio

n

Cohort studies

Paganini-Hill et al. 1989 [1] Los Angeles, USA(Incidence) 181 13,987 C ≥1 per day

Thun et al. 1993 [2] USAACS/CPS II (Mortality)

812 C119 R 635,031 C, R 1-15 tablets/month, ≥1 year

≥16 tablets/month, 1 year X

Schreinemachers and Everson 1994a [3]

USANHANES I (Incidence) 169 12,668 CR ≥1 per month

Ratnasinghe et al. 2004 [4]USANHANES I and II (Mortality)

193 22,834 CR Any use in the past 30 days or the past 6 months

Chan et al. 2005b [5] USANHS (Incidence) 962 82,911 CR, C,

R ≥2 per week

Larsson et al. 2006 [6] Sweden SMC (Incidence) 705 74,250 CR, C,

R 2-6 per week X X

Mahipal et al. 2006 [7] Iowa, USAIWHS (Incidence) 637 27,160 C, R 2-5 per week

Jacobs et al. 2007 [8]USAACS/CPS II Nutrition Cohort (Incidence)

1861 184,190 CR ≥1 per day, ≥ 5 years X

Chan et al. 2008b [9] USAHPFS (Incidence) 975 47,363 CR, C,

R ≥2 per week

2



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears

Subt

ype



Mg/

die

Dur

atio

n

Siemes et al. 2008 [10] The NetherlandsRotterdam Study (Incidence) 124 7621 CR, C,

R Any use X

Friis et al. 2009 [11] DenmarkDCHS (Incidence) 615 51,053 CR 1-6 per week

≥7 per week X X

Ruder et al. 2011 [12]USANIH-AARP Diet and Health Study (Incidence)

3894 301,240 CR, C, R ≥1 per day

Coghill et al. 2012c [13] USAWHI (Mortality) 2119 160,143 CR ≥2 per week, ≥ 3 year X

Jacobs et al. 2012c [14]USACPS II Nutrition Cohort (Mortality)

465 100,139 CR Current use, ≥1 per day

Huang et al. 2013 [15]TaiwanLHID (Incidence)Prescription database

143 9925 CR ≥1 per day, ≥ 3.5 year

Brasky et al. 2014 [16] USAWHI (Incidence) 1287 129,013 CR ≥2 per week, ≥3 years X

Wang et al. 2015 [17] USAVITAL (Incidence) 674 73,458 CR ≥1 per week, ≥1 year

Cao et al. 2016 [18] USANHS, HPFS (Incidence) 1458 173,229 CR ≥2 per week X X

Vaughan et al. 2016 [19] USAIWHS (Incidence) 222 14386 C 2-5 per week

≥6 per week X

3



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears

Subt

ype



Mg/

die

Dur

atio

n

Park et al. 2017 [20] California, USAMEC (Incidence) 4882 183,199 CR, C,

R ≥2 per week, ≥1 month X

Tsoi et al. 2018 [21] Hong Kong(Incidence/Mortality) 18,454 612,509 CR, C,

R ≥6 months

Ventura et al. 2018 [22]ItalyTuscany Cancer Registry(Mortality)

787 227,011 CR, C, R

1 year coverage

Nested case-control studies

García Rodríguez and Huerta Alvarez 2001 [23]

UKGPRD (Incidence)Prescription database

2002 943,903 CR Any prescription within one year X X

Rahme et al. 2003 [24]CanadaRAMQ (Incidence)Prescription database

179 2568 CR ≥3 months

Muscat et al. 2005 [25]USAThe Framingham Study(Incidence)

145 433 CR ≥1 per week

Chan et al. 2007c [26] USANHS (Mortality) 433 79,439 CR ≥2 per week

Vinogradova et al. 2007 [27]UKQRESEARCH (Incidence)Prescription database

5686 24,982 CR2-12 prescriptions in 4 years13-24 prescriptions in 4 years≥25 prescriptions in 4 years

4



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears

Subt

ype



Mg/

die

Dur

atio

n

Lewis et al. 2007 [28] UKTHIN (Incidence)Prescription database

7080 21,185 C Any prescription within one year of diagnosis

Friis et al. 2015 [29]

DanishDanish Cancer Registries(Incidence)Prescription database

10,280 102,800 CR, C, R

≥2 prescriptions, >1 year before the index date X X

Nan et al. 2015d [30] Various countriesPooled Analysis (Incidence) 2675 2575 CR Various definitions

García Rodríguez et al. 2017 [31]

UKTHIN (Incidence)Prescription database

3033 10,000 CR, C, R

Current use (use on theindex date or in the previous 90 days)

X X

Kahi et al. 2018 [32]Vermount, USAVA–Medicare administrative database (Mortality)

4964 19,856 CR Ever use X

Kuo et al. 2018 [33]TaiwanLHID (Incidence)Prescription database

65,208 65,208 CRAt least 2 prescriptions13–48 months prior to the index date

X

Rodriguez-Miguel et al. 2018 [34]

SpainBIFAP (Incidence)Prescription database

15,491 60,000 CR Current use (use at least up to 90 days before index date) X X

Sheth et al. 2018 [35]UK and USAUK-CCSG, NIH-CCFR(Incidence)

3325 2262 CR ≥1 per day, ≥3 month

5



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears

Subt

ype



Mg/

die

Dur

atio

n

Case-control studies

Kune et al. 1988 [36]Melbourne, AustraliaMCCSPopulation controls

715 727 CR, C, R

Current use

Suh et al. 1993 [37]

New York, USARPCIPopulation and hospital controls

830 1662

CR, C, R ≥2 per day, ≥1 year

Peleg et al. 1994 [38]Georgia, USAGMHTRHospital controls

97 388 CR >313 g in the 4 previous years X

Reeves et al. 1996 [39]Wisconsin, USAWCRSPopulation controls

184 293 CR ≥2 per week, ≥1 year

La Vecchia et al. 1997 [40] ItalyHospital controls 1357 1891 CR ≥5 per week, ≥7 months X

Friedman et al. 1998 [41]Northern California, USAKPMCPPopulation controls

1993 2410 C ≥3 per week, ≥1 month X

Neugut et al. 1998 [42]New York, USACPMCHospital controls

256 322 CR Current use

Rosenberg et al. 1998 [43] Massachusetts, USAPopulation controls 1201 1201 CR ≥4 per week, ≥3 months X X

6



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears

Subt

ype



Mg/

die

Dur

atio

n

Evans et al. 2002 [44]UKMCCRPopulation controls

512 512 CR ≥7 per week

Slattery et al. 2004b [45]Northern California, USAKPMCPPopulation controls

2298 2749 CR, C, R ≥3 per week, ≥1 month

Sansbury et al. 2005 [46]North Carolina, USANCCCSPopulation controls

643 1048 C Any use

Hoffmeister et al. 2007 [47] GermanyPopulation controls 540 614 CR ≥2 per week, ≥1 year X

Harris et al. 2008 [48]Ohio, USACHRIHospital controls

326 652 C ≥1 per week, ≥1 month X

Kim et al. 2008 [49]North Carolina, USANCCCS IIPopulation controls

1057 1019 CR, C, R ≥3 per week, ≥3 months

Din et al. 2010 [50]ScotlandSCCSPopulation controls

2279 2907 CR ≥5 per week, ≥2 months X X

Rennert et al. 2010 [51]IsraelMECCPopulation controls

2566 2566 CR ≥1 per day, ≥3 years

7



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears

Subt

ype



Mg/

die

Dur

atio

n

Amitay et al. 2018 [52] GermanyDACHS studyPopulation controls

2444 3130 CR ≥2 per week, ≥ 1 year X

Shivappa et al. 2018 [53]

IranCancer Institute of Imam Khomeini Hospital ComplexHospital controls

71 142 CR Any use

ACS: American Cancer Society; BIFAP: Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria; C: Colon; CHRI: Cancer Hospital and Research Institute; CPMC: Columbia-Presbyterian Medical Centre; CPS: Cancer Prevention Study; DACHS: Darmkrebs: Chancen der Verhütung durch Screening - Colorectal Cancer: Chances for Prevention Through Screening; DCHS: Diet Cancer and Health Study; GMHTR: Grady Memorial Hospital Tumor Registry; GPRD: General Practice Research Database; HPFS: Health Professionals Follow-up Study; IWHS: Iowa Women’s Health Study; KPMCP: Kaiser Permanente Medical Care Program; LHID: Longitudinal Health Insurance Database; MCCR: Merseyside and Cheshire Cancer Registry; MCCS: Melbourne Colorectal Cancer Study; MEC: Multiethnic Cohort Study; MECC: Molecular Epidemiology of Colorectal Cancer; NCCCS: North Carolina Colon Cancer Study; NHANES: National Health and Nutrition Examination Survey; NHS: Nurses’ Health Study; NIH-AARP: National Institute of Health-American Association of Retired Persons; NIH-CCRF: National Institute of Health-Colon Cancer Family Registry; R: Rectum; RAMQ: Régie de l’assurance maladie du Québec; RPCI: Roswell Park Cancer Institute; SCCS: Study of Colorectal Cancer in Scotland; SMC: Swedish Mammography Cohort; THIN: The Health Improvement Network; UK-CCSG: United Kinngdom-Colorectal Cancer Study Group; VITAL: VITAmins and Lifestyle; WCRS: Wisconsin Cancer Reporting System; WHI: Women’s Health Initiative. a Excluded from the main analysis, since we considered the study on the same cohort presenting data on mortality.b Contributed only with estimates for subsites.c Excluded from the main analysis, since we considered the study on the same cohort presenting data on incidence.

8

d Contributed with five studies (Colon Cancer Family Registry; Diet, Activity and Lifestyle Study; Ontario Familial Colorectal Cancer Registry; Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; Postmenopausal Hormone Study-Colon Cancer Family Registry).

9

Supplementary Table S3. Main characteristics of epidemiological studies on aspirin use and head and neck cancer risk included in the meta-analysis.

First author, year (Reference)


N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears

Subt

ype



Mg/

die

Dur

atio

n

Cohort studies

Wilson et al. 2013 [54]USAPLCO(Incidence)

316 142,034 HN Regular use


Becker et al. 2015 [55]UKCPRDPrescription database

2745 16,470 HN ≥1 prescription

Mcfarlane et al. 2014 [56]UKPCCIUPrescription database

1195 3580 HN At least 1 prescription more than 1 year before


Bosetti et al. 2003 [57] ItalyHospital controls 740 1779 UADT ≥1 per week, ≥ 6 months X

Rosenquist et al. 2005 [58] SwedenPopulation controls 132 320 OP Ever use

Jayaprakash et al. 2006 [59]USARPCIHospital controls

529 529 HN Ever use X

Ahmadi et al. 2010 [60]

USALombardi Comprehensive Cancer Center, GUMCPopulation controls

71 71 HN Daily use

10



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears

Subt

ype



Mg/

die

Dur

atio

n

Mcfarlane et al. 2012 [61]EuropeARCAGEHospital controls

1779 1993 UADT ≥1 per week, for 1 year X

Di Maso et al. 2015 [62] ItalyHospital controls 198 592 NP ≥1 per week, ≥ 6 months

Xiao et al. 2018 [63]ChinaNPCGEEPopulation controls

23532 2597 NP Use for at least 3 months in 1 year X

ARCAGE: Alcohol-related cancer and genetic susceptibility; CPRD: Clinical Practice Research Datalink; GUMC: Georgetown University Medical School; HN: Head and neck; NPCGEE: Nasopharyngeal carcinoma Genes, Environment, and Epstein-Barr virus study; NP: nasopharyngeal; OP: oral and oropharyngeal; PCCIU: Primary Care Clinical Information Unit; PLCO: Prostate, Lung, Colorectal, and Ovarian cancer screening trial; RPCI: Roswell Park Cancer Institute; UADT: upper aerodigestive tract.

11

Supplementary Table S4. Main characteristics of epidemiological studies on aspirin use and risk of squamous cell carcinoma of the esophagus included in the meta-analysis.



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears

Subt

ype



Mg/

die

Dur

atio

n

Cohort studies

Thun et al. 1993 [2] USAACS/CPS II (Mortality) 157 635,031 E 1-15 tablets/month, ≥1 year

≥16 tablets/month, 1 year X

Funkhouser et al. 1995a [64] USANHANES I (Incidence) 15 14,407 E


37 22,786 E Any use in the past 30 days or the past 6 months

Jacobs et al. 2012 [14]USACPS II Nutrition Cohort (Mortality)

121 100,139 E Current use, ≥1 per day X

Tsoi et al. 2018 [65] Hong Kong(Incidence) 2634 612,509 E Any use for ≥6 months

Nested case-controls

Lindblad et al. 2005 [66]UKGPRD (Incidence)Prescription database

909 10,000 E Any prescription within 1 year X

Macfarlane et al. 2014 [56]Scotland, UKPCCIU (Incidence)Prescription database

1197 7165 E Ever use

12



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears

Subt

ype



Mg/

die

Dur

atio

n


Farrow et al. 1998 [67] USAPopulation controls 221 695 SCC ≥1 per week, ≥6 months X

Sharp et al. 2001 [68] UKPopulation controls 159 159 SCC

Jayaprakash et al. 2006 [69] New York State, USAHospital controls 67 482 SCC ≥1 per week, ≥6 months X

Ranka et al. 2006 [70] Norfolk, EnglandHospital controls 93 1644 SCC ≥4 weeks

Fortuny et al. 2007 [71] USAPopulation controls 114 3996 SCC >7 prescriptions

Sadeghi et al. 2008 [72] AustraliaPopulation controls 309 1580 SCC ≥1 per week

Macfarlane et al. 2012 [61]EuropeARCAGE projectHospital controls

153 2227 ≥1 per week, ≥1 year

ARCAGE: Alcohol-Related CAncers and GEnetic susceptibility; CPS: Cancer Prevention Study; E: esophageal cancer; GPRD: General Practice Research Database; NHANES: National Health and Nutrition Examination Survey; PCCIU: Primary Care Clinical Informatics Unit; SCC: squamous cell carcinoma.a Excluded from the main analysis, since we considered the study on the same cohort presenting data on mortality.

13

Supplementary Table S5. Main characteristics of epidemiological studies on aspirin use and risk of adenocarcinoma of the esophagus and gastric cardia included in the meta-analysis.



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears

Subt

ype



Mg/

die

Dur

atio

n

Cohort studies

Abnet et al. 2009 [73]USANIH-AARP Diet and Health Study (Incidence)

228178 311,115 EA

GCA ≥1 per week

Epplein et al. 2009 [74] California, USAMEC (Incidence) 93 269,292 GCA ≥2 per week, ≥1 month X


Farrow et al. 1998 [67] USAPopulation controls

293261 695 EA

GCA≥1 per week, ≥6 months. Current use X

Akre et al. 2001 [75] SwedenPopulation controls 90 1165 GCA ≥1 per month

Anderson et al. 2006 [76] IrelandPopulation controls 227 260 EA ≥1 per week, ≥6 months

Jayaprakash et al. 2006 [69] New York State, USAHospital controls 87 482 EA ≥1 per week, ≥6 months

Ranka et al. 2006 [70] Norfolk, EnglandHospital controls 318 1644 EA ≥4 weeks

Fortuny et al. 2007 [71] USAPopulation controls

163176 3996 EA

GCA >7 prescriptions

Duan et al. 2008 [77] California, USAPopulation controls

220277 1356 EA

GCA2-6 per week ≥7 per week

14



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears

Subt

ype



Mg/

die

Dur

atio

n

Sadeghi et al. 2008 [72] AustraliaPopulation controls

367426 1580 EA

GCA ≥1 per week X

EA: esophageal adenocarcinoma; GCA: gastric cardia adenocarcinoma; MEC: Multiethnic Cohort Study; NIH-AARP: National Institute of Health-American Association of Retired Persons.

15

Supplementary Table S6. Main characteristics of epidemiological studies on aspirin use and risk of stomach cancer included in the meta-analysis.



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears



Mg/

die

Dur

atio

n

Cohort studies

Thun et al. 1993 [2] USAACS/CPS II (Mortality) 266 635,031 1-15 tablets/month, ≥1 year

≥ 16 tablets/month, ≥1 year X

Schreinemachers and Everson 1994a [3]

USANHANES I (Incidence) 39 12,668 ≥1 per month


48 22,786 Any use in the past 30 days or the past 6 months

Abnet et al. 2009 [73]USANIH-AARP Diet and Health Study (Incidence)

182 311,115 ≥1 per week

Epplein et al. 2009 [74] California, USAMEC (Incidence) 550 193,000 ≥2 per week, ≥1 month X


91 100,139 Current use, ≥1 per day X

Tsoi et al. 2018 [65] Hong Kong(Incidence) 5827 612,509 Any use for ≥6 months

Nested case-controls

16



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears



Mg/

die

Dur

atio

n

Lindblad et al. 2005 [66]UKGPRD (Incidence)Prescription database

1023 10,000 Any prescription within 1 year X


Farrow et al. 1998 [67] USAPopulation controls 232 695 ≥1 per week, ≥6 months X

Zaridze et al. 1999 [78] Moscow, RussiaHospitals controls 356 610 ≥2 per week, ≥6 months

Akre et al. 2001 [75] Sweden Population controls 477 1165 ≥1 per month

Fortuny et al. 2007 [71] USAPopulation controls 320 3996 >7 prescriptions

Duan et al. 2008 [77] California, USAPopulation controls 441 1356 2-6 per week

≥7 per week X

Bertuccio et al. 2010 [79] ItalyHospitals controls 229 543 ≥1 per week, ≥6 months X

Wang et al. 2015 [80] ChinaHospitals controls 175 350 ≥1 per week, ≥1 year X

ACS: American Cancer Society; CPS: Cancer Prevention Study; GPRD: General Practice Research Database; MEC: Multiethnic Cohort Study; NHANES: National Health and Nutrition Examination Survey; NIH-AARP: National Institute of Health-American Association of Retired Persons.a Excluded from the main analysis, since we considered the study on the same cohort presenting data on mortality.

17

Supplementary Table S7. Main characteristics of epidemiological studies on aspirin use and hepato-biliary cancer risk included in the meta-analysis.



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears

Subt

ype



Mg/

die

Dur

atio

n

Cohort studies

Jacobs et al. 2012a [14]USACPS II Nutrition Cohort (Mortality)

118 100,139 L Current use, ≥1 per day X

Petrick et al. 2015b [81]

Various countriesPooled analysisLiver Cancer Pooling Project(Incidence)

679225 1,084,133 HCC

ICC Various definitions X X

Tsoi et al. 2018 [65] Hong Kong(Incidence) 9370 612,509 L ≥6 months


Yang et al. 2016 [82]UKCPRDPrescription database

1195 4640 L ≥2 prescriptions


Burr et al. 2014 [83] UKHospital controls 81 275 CC Any use

Choi et al. 2016 [84]USAMayo ClinicHospital controls

2395 4769 CC ≥1 per week X X

CC: cholangiocarcinoma; CPRD: Clinical Practice Research Datalink; CPS: Cancer Prevention Study; HCC: hepatocellular carcinoma; HPFS: Health Professionals Follow-up Study; ICC: intrahepatic cholangiocarcinoma; L: liver; NHIS-NSC: National Health Insurance Service National Sample Cohort; NHS: Nurses’ Health Study.

18

a Excluded from the main analysis, since we considered the study on the same cohort presenting data on incidence.b Contributed with 10 cohort studies (Agriculture Health Study; Breast Cancer Detection Demonstration Project; Black Women’s Health Study; CPS II; National Institute of Health-American Association of Retired Persons, Health Professionals Follow-up Study; HPFS; NHS; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; United State Radiologic Technologist Study; Women’s Health Initiative).

19

Supplementary Table S8. Main characteristics of epidemiological studies on aspirin use and pancreatic cancer risk included in the meta-analysis.



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears



Mg/

die

Dur

atio

n

Cohort studiesSchreinemachers and Everson 1994a [3]

USA NHANES I (Incidence) 30 12,668 ≥1 per month

Anderson et al. 2002 [85] Iowa, USAIWHS (Incidence) 80 28,283 Any use

Jacobs et al. 2004 [86] USAACS/CPS II (Mortality) 4577 12,668 ≥1 per day

Ratnasinghe et al. 2004 [4]USA NHANES I and II (Mortality)

78 22,834 Any use in the past 30 days/past 6 months

Jacobs et al. 2007a [8]USAACS/CPS II Nutrition Cohort (Incidence)

404 146,113 ≥1 per day, <5 years≥1 per day, ≥5 years X

Brasky et al. 2014 [16] USAWHI (Incidence) 378 129,013 ≥2 per week X

Lad et al. 2017 [87]USANIH-AARP Diet and Health Study (Incidence)

1048 297,525 ≥1 per day

Khalaf et al. 2018 [88] USANHS, HPFS (Incidence) 1122 141,940 ≥2 per week

20



N. c

ases

N. c

ontr

ols/

Coh

ort s

ize

or

pers

on-y

ears



Mg/

die

Dur

atio

n

Tsoi et al. 2018 [65] Hong Kong (Incidence) 2759 612,509 Any use, ≥6 months

Nested case-control

Bradley et al. 2010 [89]UKGPRD (Incidence)Prescription database

1141 7954 Any prescription within one year of diagnosis


Menezes et al. 2002 [90] New York State, USAHospital controls 194 582 ≥1 per week, ≥6 months X

Bonifazi et al. 2010 [91] ItalyHospital controls 308 477 ≥1 per week, >6 months X

Tan et al. 2011 [92] Minnesota, USAHospital controls 904 1224 ≥1 day per month

Streicher et al. 2014 [93] Connecticut, USAPopulation controls 362 690 ≥1 per week, ≥3 months X

Kho et al. 2016 [94] AustraliaPopulation controls 522 653 Ever use

Archibugi et al. 2017 [95] ItalyHospital controls 408 816 Ever use, ≥3 months X

Rish et al. 2017 [96] Shanghai, ChinaPopulation controls 761 794 ≥1 tablet per week, ≥3 months X

21

ACS: American Cancer Society; CPS: Cancer Prevention Study; HPFS: Health Professionals Follow-up Study; IWHS: Iowa Women’s Health Study; NHANES: National Health and Nutrition Examination Survey; NHS: Nurses’ Health Study; GPRD: General Practice Research Database; NIH-AARP: National Institute of Health-American Association of Retired Persons; WHI: Women’s Health Initiative.a Excluded from the main analysis, since we considered the study on the same cohort presenting data on mortality.

22

Supplementary Table S9. List of epidemiological studies on aspirin use and risk of colorectal cancer excluded from the meta-analysis since included in more recent and complete studies.

First author, year, Reference


Reason of exclusion

Cohort studies

Giovannucci et al. 1994 [97] USAMHPS (Incidence)

Data presented in Cao et al. 2016 [18]

Giovannucci et al. 1995 [98] USANHS (Incidence)


Allison et al. 2006 [99] USAWHI (Incidence)

Data presented in Brasky et al. 2014 [16]

Brasky et al. 2012 [100] USAVITAL (Incidence)

Data presented in Wang et al. 2015 [17]

Nishihara et al. 2013 [101] USANHS, HPFS (Incidence)


Cao et al. 2016 [102] USANHS, HPFS (Incidence)


Tsoi et al. 2018 [65] Hong Kong(Incidence)

Data presented in Tsoi et al. 2018 [21]


Zhan et al. 2011 [103] USANHS, HPFS (Incidence)


Nan et al. 2013 [104] USANHS, HPFS (Incidence)


Cea Soriano et al. 2016 [105]UKTHIN (Incidence)Prescription database

Data presented in García Rodríguez et al. 2017 [31]


Kune et al. 2007 [106]Melbourne, AustraliaMCCSPopulation controls

Same study as Kune et al. 1988 [36]

Slattery et al. 2009 [107]

Northern California, USAKPMCPPopulation controls

Data presented in Slattery et al. 2004 [45] and Friedman et al. 1998 [41]

Rennert et al. 2009 [108]IsraelMECCPopulation controls

Data presented in Rennert et al. 2010 [51]

HPFS: Health Professionals Follow-up Study; KPMCP: Kaiser Permanente Medical Care Program; MCCS: Melbourne Colorectal Cancer Study; MHPS: Male Health Professionals Study; MECC: Molecular Epidemiology of Colorectal Cancer; NHS: Nurses’ Health Study; THIN: Health Improvement Network; VITAL: VITAmins and Lifestyle; WHI: Women’s Health Initiative.

23

Supplementary Table S10. List of epidemiological studies on aspirin use and risk of squamous cell carcinoma of the esophagus excluded from the meta-analysis since included in more recent and complete studies.

First author, year, referenceCountry, study acronym, study characteristics

Reason of exclusion


Figueroa et al. 2009 [109] USAPopulation controls

Data presented in Farrow et al. 1998 [67]

24

Supplementary Table S11. List of epidemiological studies on aspirin use and risk of adenocarcinoma of the esophagus and gastric cardia excluded from the meta-analysis since included in more recent and complete studies.

First author, year, referenceCountry, study acronym, study characteristics

Reason of exclusion

Cohort studies

Liao et al. 2012 [110]

Various countriesPooled analysis (Incidence)

Individual level data included in Sadeghi et al. 2008 [72], Farrow et al. 1998 [67], Duan et al. 2008 [77], Anderson et al. 2006 [76], and Abnet et al. 2009 [73]




25

Supplementary Table S12. List of epidemiological studies on aspirin use and risk of stomach cancer excluded from the meta-analysis since included in more recent and complete studies.



Reason of exclusion




26

Supplementary Table S13. List of epidemiological studies on aspirin use and hepato-biliary cancer risk excluded from the meta-analysis since included in more recent and complete studies.



Reason of exclusion

Cohort studies

Sahasrabuddhe et al. 2012 [111]

USANIH-AARP Diet and Health Study (Incidence)

Data included in Petrick et al. 2015 [81]

Simon et al. 2018 [112] USANHS, HPFS (Incidence)

Data included in Petrick et al. 2015 [81]

HPFS: Health Professionals Follow-up Study; NHS: Nurses’ Health Study; NIH-AARP: National Institute of Health-American Association of Retired Persons, Health Professionals Follow-up Study.

27

Supplementary Table S14. List of epidemiological studies on aspirin use and risk of pancreatic cancer excluded from the meta-analysis since included in more recent and complete studies.



Reason of exclusion

Cohort studiesSchernhammer et al. 2004 [113]

USA NHS (Incidence)

Data presented in Khalaf et al. 2018 [88]


Data presented in Jacobs et al. 2004 [86]

Cao et al. 2016 [102] USANHS, HPFS (Incidence)

Data presented in Khalaf et al. 2018 [88]

CPS: Cancer Prevention Study; HPFS: Health Professionals Follow-up Study; NHS: Nurses’ Health Study.

28

Supplementary Table S15. Pooled relative risks (RR) and corresponding 95% confidence intervals (CI) of colorectal cancer for regular aspirin use versus non-use and across strata of selected study characteristics.

Strata N. of studies

Pooled RR(95% CI)

Heterogeneity within strata

(P-value)

Heterogeneity across strata

(P-value)

Geographic areaa

USA 22 0.71 (0.65-0.78) <0.001 0.587Europe 14 0.76 (0.68-0.85) <0.001Other 8 0.70 (0.60-0.81) <0.001

Type of controlsb

Hospital 4 0.54 (0.33- 0.89) 0.078 0.534Population 14 0.64 (0.57-0.71) <0.001

Endpointc

Incidence 13 0.77 (0.72-0.83) <0.001 0.455Mortality 6 0.72 (0.61-0.85) 0.001

Year of publication<2000 8 0.59 (0.50-0.71) 0.042 0.0382000-2009 14 0.77 (0.68-0.86) <0.0012010-2018 24 0.75 (0.69-0.81) <0.001

SexMen 6 0.71 (0.63-0.79) 0.111 0.429Women 9 0.77 (0.65-0.91) <0.001

a Studies conducted in multiple countries from different geographic areas were not included. b For case-control studies only. Pooled analyses considering both studies with hospital and with population controls were not included. c For cohort studies and nested case-control studies only. Studies providing RRs for both incidence and mortality were considered in both categories.

29

Supplementary Table S16. Pooled relative risks (RR) and corresponding 95% confidence intervals (CI) of head and neck cancer risk for regular aspirin users versus no users, overall and across strata of selected study characteristics.


Pooled RR(95% CI)


(P-value)


(P-value)

Geographic areaa

USA 4 0.84 (0.63-1.13) 0.002 <0.001Europe 5 0.89 (0.76-1.04) 0.330Other 1 1.91 (1.52-2.41) -

Type of controlsb

Hospital 3 0.72 (0.49-1.07) 0.161 0.329Population 3 1.12 (0.51-2.42) 0.006

Year of publication2000-2009 3 0.81 (0.66-1.00) 0.537 0.2932010-2018 7 0.97 (0.75-1.26) <0.001

a Studies conducted in multiple countries from different geographic areas were not included. b For case-control studies only. Pooled analyses considering both studies with hospital and with population controls were not included.

30

Supplementary Table S17. Pooled relative risks (RR) and corresponding 95% confidence intervals (CI) of squamous cell carcinoma of the esophageal for regular aspirin use versus non-use, overall and across strata of selected study characteristics.


Pooled RR(95% CI)


(P-value)


(P-value)

Geographic areaa

USA 6 0.65 (0.53-0.80) 0.441 0.151Europe 5 0.77 (0.61-0.97) 0.104Other 2 0.59 (0.52-0.67) 0.782

Type of controlsb


Endpointe

Incidence 2 0.34 (0.07-1.70) 0.109 0.340Mortality 3 0.76 (0.58-0.99) 0.449

Year of publication<2000 2 0.64 (0.45-0.91) 0.254 0.8252000-2009 7 0.64 (0.48-0.84) 0.0882010-2018 4 0.71 (0.53-0.95) 0.003


31

Supplementary Table S18. Pooled relative risks (RR) and corresponding 95% confidence intervals (CI) of adenocarcinoma of the esophagus and gastric cardia for regular aspirin use versus non-use, overall and across strata of selected study characteristics.


Pooled RR(95% CI)


(P-value)


(P-value)

Geographic areaa

USA 6 0.66 (0.49-0.87) <0.001 0.581Europe 3 0.50 (0.33-0.76) 0.001Other 1 0.59 (0.41-0.85) <0.001

Type of controlsb

Hospital 3 0.49 (0.36-0.68) 0.079 0.394Population 5 0.60 (0.43-0.84) <0.001

Year of publication<2000 1 0.55 (0.26-1.17) - 0.7422000-2009 9 0.63 (0.49-0.79) <0.001

a Studies conducted in multiple countries from different geographic areas were not included. b For case-control studies only. Pooled analyses considering both studies with hospital and with population controls were not included.

32

Supplementary Table S19. Pooled relative risks (RR) and corresponding 95% confidence intervals (CI) of stomach cancer for regular aspirin use versus non-use, overall and across strata of selected study characteristics.


Pooled RR(95% CI)


(P-value)


(P-value)

Geographic areaa

USA 8 0.58 (0.48-0.71) 0.014 0.034Europe 4 0.89 (0.65-1.23) 0.005Other 2 0.49 (0.34-0.72) 0.023

Type of controlsb

Hospital 3 0.67 (0.46-0.97) 0.109 0.729Population 4 0.60 (0.40-0.92) <0.001

Endpointc


Year of publication<2000 3 0.52 (0.43-0.64) 0.665 0.1452000-2009 7 0.74 (0.56-0.97) <0.0012010-2018 4 0.60 (0.41-0.88) 0.001


33

Supplementary Table S20. Pooled relative risks (RR) and corresponding 95% confidence intervals (CI) of hepato-biliary cancer risk for regular aspirin users versus no users, overall and across geographic area.


Pooled RR (95% CI)


(P-value)


(P-value)

Geographic areaa

USA 1 0.34 (0.30-0.39) - <0.001Europe 2 0.75 (0.31-1.81) 0.020Other 1 0.49 (0.45-0.53) -

a Studies conducted in multiple countries from different geographic areas were not included.

34

Supplementary Table S21. Pooled relative risks (RR) and corresponding 95% confidence intervals (CI) of pancreatic cancer for regular aspirin use versus non-use, overall and across strata of selected study characteristics.


Pooled RR (95% CI)


(P-value)


(P-value)

Geographic areaa

USA 9 0.82 (0.72-0.94) <0.001 0.11Europe 3 0.92 (0.79-1.06) 0.586Other 3 0.64 (0.47-0.88) 0.003

Type of controlsb


Endpointc


Year of publication2000-2009 4 0.89 (0.73-1.08) 0.182 0.2082010-2018 11 0.75 (0.64-0.89) <0.001


35

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