Real-world Studies Link NSAID Use to Improved Overall Lung Cancer Survival

Inflammation is a cancer hallmark. NSAIDs improve overall survival (OS) in certain cancers. Real-world studies explored here whether NSAIDs improve non–small cell lung cancer (NSCLC) OS. Analyses independently interrogated clinical databases from The University of Texas MD Anderson Cancer Center (MDACC cohort, 1987 to 2015; 33,162 NSCLCs and 3,033 NSAID users) and Georgetown-MedStar health system (Georgetown cohort, 2000 to 2019; 4,497 NSCLCs and 1,993 NSAID users). Structured and unstructured clinical data were extracted from electronic health records using natural language processing (NLP). Associations were made between NSAID use and NSCLC prognostic features (tobacco use, gender, race, and body mass index, BMI). NSAIDs were statistically significantly (P < 0.0001) associated with increased NSCLC survival (5-year OS 29.7% for NSAID users vs. 13.1% for nonusers) in the MDACC cohort. NSAID users gained 11.6 months over nonusers in 5-year restricted mean survival time. Stratified analysis by stage, histopathology, and multicovariable assessment substantiated benefits. NSAID users were pooled independent of NSAID type and by NSAID type. Landmark analysis excluded immortal time bias. Survival improvements (P < 0.0001) were confirmed in the Georgetown cohort. Thus, real-world NSAID usage was independently associated with increased NSCLC survival in the MDACC and Georgetown cohorts. Findings were confirmed by landmark analyses and NSAID type. The OS benefits persisted despite tobacco use and did not depend on gender, race, or BMI (MDACC cohort, P < 0.0001). These real-world findings could guide future NSAID lung cancer randomized trials. Significance: NLP and real-world studies conducted in large cohorts explored whether NSAIDs improved survival across NSCLC stages, histopathology, gender, smoking history, or demographic groups. A statistically significant association between NSAID use and NSCLC survival was found. This provides a rationale for future NSAID randomized NSCLC trials.

[1]  Louise Bowman,et al.  The Magic of Randomization versus the Myth of Real-World Evidence. , 2020, The New England journal of medicine.

[2]  S. Friis,et al.  Use of nonaspirin nonsteroidal anti‐inflammatory drugs and risk of head and neck cancer: A nationwide case–control study , 2020, International journal of cancer.

[3]  Georgia Tourassi,et al.  Use of Natural Language Processing to Extract Clinical Cancer Phenotypes from Electronic Medical Records. , 2019, Cancer research.

[4]  D. Whiteman,et al.  Aspirin and nonsteroidal anti‐inflammatory drug use and keratinocyte cancers: a large population‐based cohort study of skin cancer in Australia , 2019, The British journal of dermatology.

[5]  Rebecca D. Kehm,et al.  Regular use of aspirin and other non-steroidal anti-inflammatory drugs and breast cancer risk for women at familial or genetic risk: a cohort study , 2019, Breast Cancer Research.

[6]  Alind Gupta,et al.  Bayesian Networks for Risk Prediction Using Real-World Data: A Tool for Precision Medicine. , 2019, Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research.

[7]  Simion I. Chiosea,et al.  Use of nonsteroidal anti-inflammatory drugs predicts improved patient survival for PIK3CA-altered head and neck cancer , 2019, The Journal of experimental medicine.

[8]  Kamlesh Khunti,et al.  Interpretation and Impact of Real-World Clinical Data for the Practicing Clinician , 2018, Advances in Therapy.

[9]  R. Weinberg,et al.  The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy , 2018, Science Translational Medicine.

[10]  Hongfang Liu,et al.  CLAMP – a toolkit for efficiently building customized clinical natural language processing pipelines , 2017, J. Am. Medical Informatics Assoc..

[11]  H. Weir,et al.  Liver cancer survival in the United States by race and stage (2001‐2009): Findings from the CONCORD‐2 study , 2017, Cancer.

[12]  S. J. Henley,et al.  Lung cancer survival in the United States by race and stage (2001‐2009): Findings from the CONCORD‐2 study , 2017, Cancer.

[13]  E. Dmitrovsky,et al.  Reply to "Influence of Body Mass Index on Overall Survival Following Surgical Resection of Non-Small Cell Lung Cancer: Methodological Issues". , 2017, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[14]  E. Dmitrovsky,et al.  The Influence of Body Mass Index on Overall Survival Following Surgical Resection of Non–Small Cell Lung Cancer , 2017, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[15]  D. Carbone,et al.  Ibuprofen and fatal lung cancer: A brief report of the prospective results from the Third National Health and Nutrition Examination Survey (NHANES III). , 2017, Molecular and clinical oncology.

[16]  Richard G. Moore,et al.  Nonsteroidal Anti-inflammatory Drugs and Endometrial Carcinoma Mortality and Recurrence , 2017, Journal of the National Cancer Institute.

[17]  R. Fowler,et al.  Immortal time bias in observational studies of time-to-event outcomes. , 2016, Journal of critical care.

[18]  Kirsten Bibbins-Domingo,et al.  Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. , 2016, Annals of internal medicine.

[19]  D. Buist,et al.  Aspirin for the Prevention of Cancer Incidence and Mortality: Systematic Evidence Reviews for the U.S. Preventive Services Task Force , 2016, Annals of Internal Medicine.

[20]  R. Demicheli,et al.  The recurrence pattern following delayed breast reconstruction after mastectomy for breast cancer suggests a systemic effect of surgery on occult dormant micrometastases , 2016, Breast Cancer Research and Treatment.

[21]  David M Jablons,et al.  Lung Cancer Staging and Prognosis. , 2016, Cancer treatment and research.

[22]  A. Dreher Modeling Survival Data Extending The Cox Model , 2016 .

[23]  C. Cardwell,et al.  Low-dose aspirin and survival from lung cancer: a population-based cohort study , 2015, BMC Cancer.

[24]  Bing Liu,et al.  Cyclooxygenase-2 promotes tumor growth and suppresses tumor immunity , 2015, Cancer Cell International.

[25]  F. Balkwill,et al.  Inflammation and cancer: advances and new agents , 2015, Nature Reviews Clinical Oncology.

[26]  B. Rigas,et al.  NSAIDs and Colorectal Cancer Control: Promise and Challenges , 2015, Current Pharmacology Reports.

[27]  Yan Wu,et al.  Aspirin Use and Lung Cancer Risk: A Possible Relationship? Evidence from an Updated Meta-Analysis , 2015, PloS one.

[28]  S. Clarke,et al.  Cancer-related inflammation and treatment effectiveness. , 2014, The Lancet. Oncology.

[29]  G. Piazza,et al.  NSAIDs Inhibit Tumorigenesis, but How? , 2013, Clinical Cancer Research.

[30]  F. Giancotti Mechanisms Governing Metastatic Dormancy and Reactivation , 2013, Cell.

[31]  R. Demicheli,et al.  Reduction of Breast Cancer Relapses with Perioperative Non-Steroidal Anti-Inflammatory Drugs: New Findings and a Review , 2013, Current medicinal chemistry.

[32]  P. Rothwell,et al.  Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. , 2012, The Lancet. Oncology.

[33]  P. Rothwell,et al.  Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials , 2011, The Lancet.

[34]  Özlem Uzuner,et al.  Extracting medication information from clinical text , 2010, J. Am. Medical Informatics Assoc..

[35]  Edward S. Kim,et al.  Biological Activity of Celecoxib in the Bronchial Epithelium of Current and Former Smokers , 2010, Cancer Prevention Research.

[36]  Samy Suissa,et al.  Immortal time bias in pharmaco-epidemiology. , 2008, American journal of epidemiology.

[37]  Michael Baum,et al.  Tumor dormancy and surgery-driven interruption of dormancy in breast cancer: learning from failures , 2007, Nature Clinical Practice Oncology.

[38]  J. Aguirre-Ghiso,et al.  Models, mechanisms and clinical evidence for cancer dormancy , 2007, Nature Reviews Cancer.

[39]  Shuji Ogino,et al.  Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. , 2007, The New England journal of medicine.

[40]  S. Solomon,et al.  Celecoxib for the prevention of sporadic colorectal adenomas. , 2006, The New England journal of medicine.

[41]  S. Solomon,et al.  Celecoxib for the prevention of colorectal adenomatous polyps. , 2006, The New England journal of medicine.

[42]  J. Lafitte,et al.  Has Cox-2 a prognostic role in non-small-cell lung cancer? A systematic review of the literature with meta-analysis of the survival results , 2006, British Journal of Cancer.

[43]  Ping Yang,et al.  Gender differences in non-small-cell lung cancer survival: an analysis of 4,618 patients diagnosed between 1997 and 2002. , 2004, The Annals of thoracic surgery.

[44]  P. Kvale,et al.  Smoking and lung cancer survival: the role of comorbidity and treatment. , 2004, Chest.

[45]  Wei Hong Wang,et al.  Non-steroidal anti-inflammatory drug use and the risk of gastric cancer: a systematic review and meta-analysis. , 2003, Journal of the National Cancer Institute.

[46]  Susan Halabi,et al.  A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. , 2003, The New England journal of medicine.

[47]  S. Piantadosi,et al.  Primary chemoprevention of familial adenomatous polyposis with sulindac , 2002 .

[48]  P. Grambsch,et al.  A Package for Survival Analysis in S , 1994 .

[49]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.

[50]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.