title: NSAID Use and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: The Liver Cancer Pooling Project.
abstract: Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC = 679, ICC = 225) from 10 U.S.-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted HRs and 95% confidence intervals (CI). Current aspirin use, versus nonuse, was inversely associated with HCC (HR, 0.68; 95% CI, 0.57-0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5- and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR, 0.64; 95% CI, 0.42-0.98) but not women (HR, 1.34; 95% CI, 0.89-2.01; P(interaction) = 0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggests the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. jessica.petrick@nih.gov.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Petrick
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Vikrant V
authors.initials: VV
authors.lastname: Sahasrabuddhe
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Alavanja
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Beane-Freeman
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Department of Epidemiology, Harvard School of Public Health, Boston, MA.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Buring
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
authors.forename: Dawn Q
authors.initials: DQ
authors.lastname: Chong
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Freedman
authors.affiliation: Department of Medicine, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. VA Boston Healthcare System, Brockton, Massachusetts.
authors.forename: John Michael
authors.initials: JM
authors.lastname: Gaziano
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA.
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Graubard
authors.affiliation: AARP, Washington, District of Columbia (retired).
authors.forename: Albert R
authors.initials: AR
authors.lastname: Hollenbeck
authors.affiliation: Department of Preventive Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Lifang
authors.initials: L
authors.lastname: Hou
authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Jacobs
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Lindsay Y
authors.initials: LY
authors.lastname: King
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Jill
authors.initials: J
authors.lastname: Koshiol
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Department of Epidemiology, Harvard School of Public Health, Boston, MA.
authors.forename: I-Min
authors.initials: IM
authors.lastname: Lee
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Martha S
authors.initials: MS
authors.lastname: Linet
authors.affiliation: Slone Epidemiology Center at Boston University, Boston, Massachusetts.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Palmer
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Purdue
authors.affiliation: Slone Epidemiology Center at Boston University, Boston, Massachusetts.
authors.forename: Lynn
authors.initials: L
authors.lastname: Rosenberg
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Schairer
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Department of Epidemiology, Harvard School of Public Health, Boston, MA.
authors.forename: Howard D
authors.initials: HD
authors.lastname: Sesso
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Alice J
authors.initials: AJ
authors.lastname: Sigurdson
authors.affiliation: Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, New York.
authors.forename: Jean
authors.initials: J
authors.lastname: Wactawski-Wende
authors.affiliation: Department of Population Health, New York University School of Medicine, New York.
authors.forename: Anne
authors.initials: A
authors.lastname: Zeleniuch-Jacquotte
authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Campbell
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: McGlynn
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001650:Bile Duct Neoplasms / Q000453:epidemiology*; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology*; D018281:Cholangiocarcinoma / Q000453:epidemiology*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012307:Risk Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal