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Figure.
Adjusted Survival Curves Among Postdiagnosis Aspirin Users and Nonusers by Cancer Site
Adjusted Survival Curves Among Postdiagnosis Aspirin Users and Nonusers by Cancer Site

Survival curves were weighted by age and sex distributions of the cohort with aspirin use modeled as time dependent. In patients with gallbladder cancer, the survival probabilities were for aspirin users vs nonusers were 59% (95 CI, 31%-100%) vs 27% (95% CI, 16%-47%). The survival probabilities in aspirin users vs nonusers with cholangiocarcinoma were 62% (95% CI, 42%-98%) 26% (95% CI, 19%-35%). In patients with ampulla of Vater cancer, the survival probabilities were 85% (95% CI, 33%-83%) vs 52% (95% CI, 18%-43%) in aspirin users vs nonusers, respectively. Survival probabilities in aspirin users vs nonusers with overlapping lesions of the biliary tract were 57% (95% CI, 34%-100%) vs 27% (95% CI, 16%-46%). Estimated survival at 1 year after diagnosis (dotted line) was calculated with 95% CIs computed based on the quantiles of the corresponding bootstrap distribution function with 1,000 replications. The numbers at risk represent individuals at the beginning of each time point.

Table.  
Time-Dependent Associations Between Postdiagnosis Aspirin Use and Overall Survival for Each Biliary Tract Cancer Sitea
Time-Dependent Associations Between Postdiagnosis Aspirin Use and Overall Survival for Each Biliary Tract Cancer Sitea
1.
Hundal  R, Shaffer  EA.  Gallbladder cancer: epidemiology and outcome.  Clin Epidemiol. 2014;6:99-109.PubMedGoogle Scholar
2.
Valle  JW, Lamarca  A, Goyal  L, Barriuso  J, Zhu  AX.  New horizons for precision medicine in biliary tract cancers.  Cancer Discov. 2017;7(9):943-962. doi:10.1158/2159-8290.CD-17-0245PubMedGoogle ScholarCrossref
3.
Langley  RE, Burdett  S, Tierney  JF, Cafferty  F, Parmar  MK, Venning  G.  Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy?  Br J Cancer. 2011;105(8):1107-1113. doi:10.1038/bjc.2011.289PubMedGoogle ScholarCrossref
4.
Gasic  GJ.  Role of plasma, platelets, and endothelial cells in tumor metastasis.  Cancer Metastasis Rev. 1984;3(2):99-114. doi:10.1007/BF00047657PubMedGoogle ScholarCrossref
5.
Therneau  TM, Crowson  CS, Atkinson  EJ. Adjusted survival curves. 2015; https://cran.r-project.org/web/packages/survival/vignettes/adjcurve.pdf. Accessed April 8, 2019.
6.
Gay  LJ, Felding-Habermann  B.  Contribution of platelets to tumour metastasis.  Nat Rev Cancer. 2011;11(2):123-134. doi:10.1038/nrc3004PubMedGoogle ScholarCrossref
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    1 Comment for this article
    EXPAND ALL
    liver Fluke Exposure in Southeast Asia
    James James, MD, DrPH, MHA | Editor -in-Chief, Journal of Disaster Medicine and Public Health Preparedness
    As noted by the authors, Biliary Tract Cancers (BTCs) are indeed rare with a worldwide prevalence of 2 per 100,000. What is not noted is the significant variance by geographic region, especially for Southeast Asia (SEA), where the incidence rates may be as much as 10 times higher and are strongly associated with liver fluke infestation from the ingestion of contaminated water and raw fish.(1) These observations have special significance for the large number of servicemen who served in SEA during the Vietnam War. To date over 700 cases of (BTC ) have been identified by the Veterans Administration (VA) from among this population and, on a case by case basis with proper documentation the VA has recognized cases as service connected with significant implication to the service member and family(https://www.hillandponton.com/cholangiocarcinoma-veterans-south-east-asia/).
    I believe these observations are important and should be considered in the design of studies looking at the epidemiological and clinical aspects of BTCs. At a minimum such studies should include, where possible, a history of SEA exposure along with basic demographics. And given the extent of global travel and tourism combined with the popularity of sushi there is no reason to limit the collection of these data to US Military populations.
    (1) Gut Liver. 2018 May; 12(3): 236–245.
    (1)
    CONFLICT OF INTEREST: None Reported
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    Research Letter
    October 17, 2019

    Association Between Aspirin Use and Biliary Tract Cancer Survival

    Author Affiliations
    • 1Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
    • 2Centre for Public Health, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, United Kingdom
    • 3Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research US Food and Drug Administration, Silver Spring, Maryland
    • 4Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Georgetown University, Washington, DC
    JAMA Oncol. Published online October 17, 2019. doi:https://doi.org/10.1001/jamaoncol.2019.4328

    Biliary tract cancers (BTCs) are rare, with a worldwide incidence of less than 2 per 100 000 individuals.1 The 5-year survival rate ranges from 5% to 15%, with a median survival of less than 1 year.1 Between 60% and 70% of patients present with late-stage disease (eg, inoperable or metastatic tumors) owing to the lack of symptoms.2 Consequently, there is a critical need for treatments that improve BTC survival. Aspirin has been proposed as a treatment to reduce cancer mortality because it may slow cancer growth through the inhibition of both cyclooxygenase 2, which promotes inflammation and cell proliferation,3 and platelet aggregation, which may slow the metastatic spread of cancer.4 We investigated the association between postdiagnosis aspirin use and BTC survival.

    Methods

    This study was approved by the National Institutes of Health Human Research Protection Program and the Independent Scientific Advisory Committee of the Clinical Practice Research Datalink ([CPRD] Protocol 17_160.R), and it was deemed exempt from patient written consent requirements because it was conducted using deidentified data. We obtained data, including all-cause deaths, on adult patients diagnosed with BTC from 1990 through 2017 from the United Kingdom’s CPRD, an electronic medical record database. We identified cancers using Read codes for gallbladder cancer (GBC), cholangiocarcinoma, ampulla of Vater cancer (AVC), and overlapping lesions of the biliary tract. We excluded patients with previous cancer, except for nonmelanoma skin cancer.

    Ever use of postdiagnosis aspirin was defined as 1 prescription or more recorded in the CPRD on or after the BTC diagnosis date. We used Cox proportional hazards regression models to estimate the cancer site-specific hazard ratios (HRs) and 95% CIs for the association between time–dependent postdiagnosis aspirin use and overall survival. Patients who received an aspirin prescription within 30 days of diagnosis entered the model as users. The time scale began at diagnosis until death, exit from the study, or the end of follow-up (truncated at 10 years). We adjusted for the following covariates a priori: age at diagnosis, sex, comorbidities, statin use at diagnosis, indicators of a healthy lifestyle, and year of diagnosis. We fit separate models for each BTC type and stratified the baseline hazard by prediagnosis aspirin use (yes/no). We estimated adjusted survival curves using a marginal approach to remove the sex and age effects on aspirin use, accounting for the time-dependent exposure.5 We conducted analyses from April to May 2019 using SAS (version 9.4; SAS Institute) and survival curves in R Studio (version 1.1.453).

    Results

    Among the eligible 2934 patients with BTC, 667 (23%) had GBC; 1559 (53%) cholangiocarcinoma; 224 (8%) AVC; and 484 (16%) overlapping. There were 2415 deaths (82%), with a median survival of 5.8 (interquartile range, 2-15) months. Two-hundred and fifty-six (9%) patients were aspirin users at baseline, with an additional 349 (12%) patients initiating aspirin use after diagnosis. Ninety-six percent of aspirin users (n = 2817) were prescribed a 75-mg dose. Compared with nonusers, aspirin users were more likely to be older, current statin users, and prediagnosis aspirin users and were more likely to have heart disease and comorbidities.

    Aspirin use was associated with decreased risk of death in patients with GBC (HR, 0.63; 95% CI, 0.48-0.83), cholangiocarcinoma (HR, 0.71; 95% CI, 0.60-0.85), AVC (HR, 0.44; 95% CI, 0.26-0.76), and overlapping BTC (HR, 0.68; 95% CI, 0.50-0.92) (Table). The survival probabilities are shown in the Figure. Incident users with no history of aspirin use had a larger benefit from postdiagnosis aspirin use than prevalent users, although all users had a reduction in risk of death.

    Discussion

    We observed a reduced risk of death for postdiagnosis aspirin users across all BTC types. Platelet activation protects tumor cells from elimination, enhances metastatic cell growth, and enables cancerous cells to spread via the bloodstream.4,6 Aspirin may slow the metastatic spread of cancer cells through inhibition of platelet aggregation, improving BTC survival.1 A limitation of our analysis is the lack of data on cancer stage and chemotherapy regimens received (if any). However, most BTCs are diagnosed at late stage2 with less than 10% of patients presenting with resectable tumors and 50% of tumors metastasizing to the lymph nodes.1 The survival benefit of aspirin observed in our study is on par with the current standard of care.2

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    Article Information

    Accepted for Publication: August 8, 2019.

    Published Online: October 17, 2019. doi:10.1001/jamaoncol.2019.4328

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Jackson SS et al. JAMA Oncology.

    Corresponding Author: Sarah S. Jackson, PhD, Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr, Rockville, MD 20892 (sarah.jackson@nih.gov).

    Author Contributions: Drs Jackson and Koshiol had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Study concept and design: Liu, Koshiol.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Jackson, Pfeiffer.

    Critical revision of the manuscript for important intellectual content: Liu, Anderson, Gadalla, Koshiol.

    Statistical analysis: Jackson, Pfeiffer.

    Obtained funding: Koshiol.

    Administrative, technical, or material support: Jackson, Liu, Gadalla, Koshiol.

    Study supervision: Koshiol.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute.

    Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: This article reflects the views of the authors and does not necessarily represent US Food and Drug Administration’s views or policies.

    Additional Contributions: We thank Bin Zhu, PhD, from the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, for his statistical support in an earlier version of this article. He did not receive compensation for his contributions.

    References
    1.
    Hundal  R, Shaffer  EA.  Gallbladder cancer: epidemiology and outcome.  Clin Epidemiol. 2014;6:99-109.PubMedGoogle Scholar
    2.
    Valle  JW, Lamarca  A, Goyal  L, Barriuso  J, Zhu  AX.  New horizons for precision medicine in biliary tract cancers.  Cancer Discov. 2017;7(9):943-962. doi:10.1158/2159-8290.CD-17-0245PubMedGoogle ScholarCrossref
    3.
    Langley  RE, Burdett  S, Tierney  JF, Cafferty  F, Parmar  MK, Venning  G.  Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy?  Br J Cancer. 2011;105(8):1107-1113. doi:10.1038/bjc.2011.289PubMedGoogle ScholarCrossref
    4.
    Gasic  GJ.  Role of plasma, platelets, and endothelial cells in tumor metastasis.  Cancer Metastasis Rev. 1984;3(2):99-114. doi:10.1007/BF00047657PubMedGoogle ScholarCrossref
    5.
    Therneau  TM, Crowson  CS, Atkinson  EJ. Adjusted survival curves. 2015; https://cran.r-project.org/web/packages/survival/vignettes/adjcurve.pdf. Accessed April 8, 2019.
    6.
    Gay  LJ, Felding-Habermann  B.  Contribution of platelets to tumour metastasis.  Nat Rev Cancer. 2011;11(2):123-134. doi:10.1038/nrc3004PubMedGoogle ScholarCrossref
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