复旦大学：《循证医学》课程教学资源（参考教材）Unit 06 病因及危险因素的分析评价（主讲教师：王小钦、陈波斌）.pdf

Long-Term Use of Acetaminophen, Aspirin, and Other Nonsteroidal Anti-Inflammatory Drugs and Risk of Hematologic Malignancies: Results From the Prospective Vitamins and Lifestyle (VITAL) Study Roland B. Walter, Filippo Milano, Theodore M. Brasky, and Emily White Roland B. Walter, Filippo Milano, Theodore M. Brasky, and Emily White, Fred Hutchinson Cancer Research Center; Roland B. Walter, Theodore M. Brasky, and Emily White, University of Washington, Seattle, WA. Submitted January 4, 2011; accepted March 16, 2011; published online ahead of print at www.jco.org on May 9, 2011. Supported by Grants No. P30-CA15704- 35S6 (R.B.W.), K05-CA154337 (E.W.), and R25-CA094880 (T.M.B.) from the National Cancer Institute, National Institutes of Health. Presented in part at the 52nd Annual Meeting of the American Society of Hematology, Orlando, FL, December 4-7, 2010. Authors’ disclosures of potential con- flicts of interest and author contributions are found at the end of this article. Corresponding author: Roland B. Walter, MD, PhD, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D2-190, Seattle, WA 98109-1024; e-mail: rwalter@fhcrc.org. © 2011 by American Society of Clinical Oncology 0732-183X/11/2917-2424/$20.00 DOI: 10.1200/JCO.2011.34.6346 ABSTRACT Purpose Among previous studies examining the associations of over-the-counter analgesics or nonsteroidal anti-inflammatory drugs (NSAIDs) and incident hematologic malignancies, results were inconsistent for NSAIDs but suggested an increased risk with acetaminophen (paracetamol). Herein, we used a large prospective cohort study to examine these associations. Patients and Methods In total, 64,839 men and women age 50 to 76 years were recruited from 2000 to 2002 to the Vitamins and Lifestyle (VITAL) study. Incident hematologic malignancies (n 577) were identified through December 2008 by linkage to the Surveillance, Epidemiology and End Results cancer registry. Hazard ratios (HRs) associated with use of analgesics for total incident hematologic malignancies and cancer subcategories were estimated by Cox proportional hazards models. Models were adjusted for age, sex, race/ethnicity, education, smoking, self-rated health, arthritis, chronic musculoskeletal pain, migraines, headaches, fatigue, and family history of leukemia/lymphoma. Results After adjustment, there was an increased risk of incident hematologic malignancies associated with high use ( 4 days/week for 4 years) of acetaminophen (HR, 1.84; 95% CI, 1.35 to 2.50 for high use; P trend .004). This association was seen for myeloid neoplasms (HR, 2.26; 95% CI, 1.24 to 4.12), non-Hodgkin’s lymphomas (HR, 1.81; 95% CI, 1.12 to 2.93), and plasma cell disorders (HR, 2.42; 95% CI, 1.08 to 5.41), but not chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; HR, 0.84; 95% CI, 0.31 to 2.28). By comparison, there was no association with risk of incident hematologic malignancies for increasing use of aspirin, nonaspirin NSAIDs, or ibuprofen. Conclusion High use of acetaminophen was associated with an almost two-fold increased risk of incident hematologic malignancies other than CLL/SLL. Neither aspirin nor nonaspirin NSAIDs are likely useful for prevention of hematologic malignancies. J Clin Oncol 29:2424-2431. © 2011 by American Society of Clinical Oncology INTRODUCTION Increasing evidence from experimental studies links inflammation to the development, survival, and progression of tumors.1 This notion is corroborated by epidemiologic studies showing that chronic in- flammation predisposes to various types of cancer.1 Accordingly, regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with decreased risk of, and mortality from, several tumor types.1 However, although compelling in some neoplasms such as colorectal cancers, the chemopreventive role of these drugs in other cancers remains unclear. This is particularly true for hematologic malignancies, for which previous studies2,3 yielded inconsistent results. For example, several case-control studies examined the association between NSAIDs and development of nonHodgkin’s lymphoma (NHL) and found either an increased risk, a decreased risk, or no association, whereas the only prospective study2,3 reported an increased risk. Findings from a limited number of JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT VOLUME 29 NUMBER 17 JUNE 10 2011 2424 © 2011 by American Society of Clinical Oncology

studies conducted in Hodgkin’s lymphoma suggested a reduced risk with use of aspirin but not with use of other NSAIDs.2,4 Similarly, a small number of studies2 suggested a reduced risk of acuteleukemiawith use of aspirin but yielded conflicting findings for use of nonaspirin NSAIDs. By comparison, a relatively small number of studies have examined the association between risk of hematologicmalignancies and use of acetaminophen (paracetamol), one of the most widely used analgesics. Nevertheless, these results have raised concerns that acetaminophen may increase the risk of several types of these malignancies.2 Specifically, use of acetaminophen has been found to be associated with an increased risk of some hematologic malignancies in some but not all case-control studies2,5; however, no prior prospective studies have examined this association. Given these conflicting findings and the relative lack of cohort studies on this topic, we examined the association of aspirin, nonaspirin NSAIDs, and acetaminophen use with incident hematologic malignancies in the prospective Vitamins and Lifestyle (VITAL) study.6 PATIENTS AND METHODS Study Cohort Details of the VITAL study, which was approved by the institutional review board of the Fred Hutchinson Cancer Research Center, have been published previously.6 Briefly, we mailed questionnaires to 364,418 men and women age 50 to 76 years who lived in the 13-county area in western Washington State covered by the Surveillance, Epidemiology and End Results (SEER) cancer registry. Between October 2000 and December 2002, 79,300 questionnaires were returned, of which 77,719 were deemed eligible. To avoid treatment for an earlier cancer as a cause of blood cancer, we excluded 11,487 participants with prior history of any cancer other than nonmelanoma skin cancer reported at baseline (n 11,273) and those with missing cancerinformation at baseline (n214).We additionally excluded 1,388 participants with missing information regarding use of all medications and five cases with postbaseline blood cancer on death certificate only without a diagnosis date, leaving 64,839 men and women available for study. Data Collection Participants completed a 24-page self-administered, sex-specific, optically scanned questionnaire at baseline that covered three content areas: medication and supplement use, health history and risk factors, and diet. Participants were asked about their regular use ( 1 days/week for 1 years) of any of the following NSAIDs and other analgesics, including frequency (days/week) and duration of use over the previous 10 years: low-dose aspirin (81 mg), regular or extra-strength aspirin, ibuprofen, naproxen, celecoxib or rofecoxib, other pain relievers (piroxicam or indomethacin), and acetaminophen. For each drug type, the most common brand names were given as examples, including both over-the-counter and prescription brands. Ten-year average use (continuous) was computed by multiplying the reported frequency of use by years of use and dividing the product by 10. These data were also categorized as “no use,” “low use” ( 4 days/week or 4 years), and “high use” ( 4 days/week and 4 years). Two summary NSAID variables were created by combining all NSAIDs except low-dose aspirin and all nonaspirin NSAIDs. We also ascertained information on age, race/ethnicity, education, smoking, self-rated health, medical history, family history of leukemia or lymphoma, and other lifestyle characteristics. Medical conditions that may be associated with analgesic use were ascertained as self-report of health complaints over the prior year, including chronic neck, back, or joint pain; fatigue or lack of energy; frequent headaches; or self-report of ever having a physician diagnosis of selected conditions, including rheumatoid arthritis, arthritis other than rheumatoid, coronary artery disease defined as history of heart attack, coronary bypass surgery, angioplasty and/or angina, stroke, and migraine headaches. Diabetes was defined as current insulin use or drug treatment for diabetes. Case Ascertainment Incident cases of hematologic and other malignancies were identified through December 2008 by annual linkage to the western Washington SEER cancer registry by using matching algorithms described previously.6 Cases were categorized by using the 2008 WHO classification system.7 Follow-Up for Censoring The end date offollow-upwas the earliest date of thefollowing: diagnosis of hematologic malignancy (0.9%), withdrawal from study (0.03%), emigration from the SEER region (5.3%), cancer diagnosis other than hematologic malignancy or nonmelanoma skin cancer (9.4%), death (3.1%), or last linkage to the SEER registry (December 31, 2008; 81.3%). Moves out of the SEER region were identified via linkage to the US Post Office National Change of Address file, follow-up letters, and phone calls. Deaths were ascertained via linkage to the Washington State death file. Statistical Analysis Sex- and multivariable-adjusted Cox proportional hazards models that used robust standard errors8 were used to estimate hazard ratios (HRs) and 95% CIs for the associations between medication use and risk of hematologic malignancies. Age was the time metric in regression models, with participants entering at the age of completing the baseline questionnaire and exiting at their age at end of follow-up. We selected a priori potential confounders, including known and suspected risk factors, for hematologic malignancies and medical conditions that may be indications for use of NSAIDs for adjustment in multivariable regression models. Specifically, for all models except low-dose aspirin, we adjusted for sex, race/ethnicity (white, Hispanic, other), education (high school graduate or less, some college, college, or advanced degree), smoking (pack-years), self-rated health (excellent, very good, good,fair, poor), history of rheumatoid arthritis, history of nonrheumatoid arthritis or chronic neck/back/joint pain, history of fatigue or lack of energy, history of migraines or frequent headaches, and number of first-degree relatives with a history of leukemia or lymphoma (none, one, two ormore). For low-dose aspirin,which is primarily used for cardiovascular disease prevention rather than pain, we used the same covariates except a history of rheumatoid or nonrheumatoid arthritis or chronic pain but additionally included a history of coronary artery Table 1. Classification of Incident Hematologic Malignancies Disease Patients No. % Myeloid neoplasms 136 23.6 MDS 54 9.4 AML 36 6.2 Myeloproliferative neoplasms 46 8.0 Mature B-cell neoplasms 389 67.4 CLL/SLL 88 15.3 Plasma cell disorders 66 11.4 Other mature B-cell neoplasm entities 235 40.7 Hodgkin’s lymphoma 22 3.8 Mature natural killer/T-cell neoplasms 17 3.0 Others† 13 2.3 Total 577 100 Abbreviations: AML, acute myeloid leukemia; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; MDS, myelodysplastic syndrome. Includes the diagnostic category of myelodysplastic/myeloproliferative neoplasms. †Includes cases of malignant lymphoma, not otherwise specified (NOS); leukemia, NOS; acute biphenotypic leukemia; and precursor B-cell lymphoblastic leukemia. Analgesics and Incident Hematologic Cancers www.jco.org © 2011 by American Society of Clinical Oncology 2425

Table 2. Associations Between Baseline Characteristics and Risk of Hematologic Malignancies Characteristic Cases (n 577) Noncases (n 64,262) HR Adjusted for No. % No. % Age and Sex 95% CI P Demographic factors Age at baseline, years N/A 55 47 8.2 16,126 25.09 55 to 60 110 19.1 15,232 23.7 60 to 65 95 16.5 11,694 18.2 65 to 70 116 20.1 10,131 15.8 70 209 36.2 11,079 17.2 Sex Women 231 40.0 33,061 51.5 Ref. Men 346 60.0 31,201 48.6 1.67 1.41 to 1.97 .001 Race/ethnicity White 534 92.6 58,885 91.6 Ref. Hispanic 8 1.4 568 0.9 1.86 0.92 to 3.74 .083 Other 26 4.5 3,757 5.9 0.81 0.54 to 1.20 .287 Missing information 9 1.6 1,052 1.6 Education High school graduate or less 125 21.7 12,219 19.0 Ref. Some college 196 34.0 24,226 37.7 0.95 0.76 to 1.19 .665 College or advanced degree 247 42.8 26,780 41.7 1.07 0.85 to 1.33 .574 Missing information 9 1.6 1,037 1.6 Lifestyle Smoking status (cigarettes) Never smoker 254 44.0 30,728 47.8 Ref. Current or former smoker 317 54.9 33,130 51.6 Pack-years† 1.00 1.00 to 1.00 .625 Mean 28.1 25.7 SD 24.1 23.2 Missing information 6 1.0 404 0.6 Medical history Self-reported health Excellent 66 11.4 10,009 15.6 Ref. Very good 216 37.4 24,971 38.9 1.23 0.93 to 1.62 .145 Good 203 35.2 21,175 33.0 1.30 0.99 to 1.72 .063 Fair 66 11.4 6,148 9.6 1.46 1.04 to 2.06 .028 Poor 14 2.4 1,006 1.6 2.18 1.23 to 3.86 .008 Missing information 12 2.1 953 1.5 History of rheumatoid arthritis No 540 93.6 61,868 96.3 Ref. Yes 37 6.4 2,383 3.7 1.63 1.17 to 2.28 .004 Missing information 0 0 11 0.02 History of nonrheumatoid arthritis/chronic joint pain No 267 46.3 33,259 51.8 Ref. Yes 310 53.7 30,992 48.2 1.23 1.04 to 1.45 .016 Missing information 0 0 11 0.02 History of migraines/frequent headaches No 489 84.7 54,192 84.3 Ref. Yes 88 15.3 10,059 15.7 1.25 1.00 to 1.58 .054 Missing information 0 0 11 0.02 History of fatigue/lack of energy No 471 81.6 52,695 82.0 Ref. Yes 106 18.4 11,556 18.0 1.15 0.93 to 1.42 .203 Missing information 0 0 11 0.02 Family history of leukemia/lymphoma None 528 91.5 60,308 93.9 Ref. One first-degree relative 34 5.9 3,300 5.1 1.16 0.82 to 1.64 .410 Two or more first-degree relatives 6 1.0 147 0.2 4.09 1.82 to 9.16 .001 Missing information 9 1.6 507 0.8 Abbreviations: HR, hazard ratio; N/A, not applicable; Ref., reference; SD, standard deviation. Reference value of 1.00. †Among smokers and former smokers. Walter et al 2426 © 2011 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

disease, stroke, diabetes, and use of antihypertensive or lipid-lowering medications. P values for trend were computed by using the continuous 10-year average use variable in the model. Finally, we examined whether the associations between medication use and incident hematologic malignancies differed by tumor morphology by treating various disease entities as separate outcomes. In these analyses, patients with the other morphologies were censored at the time of cancer diagnosis. All reportedPvalues are two-sided, andP.05 was considered statistically significant. All analyses were performed by using STATA 11 (StataCorp, College Station, TX). RESULTS Overall, 64,839 men and women, age 61.5 7.4 years (mean standard deviation), were included in this study. After a mean follow-up of 6.5 1.8 years, 577 (0.89%) developed a hematologic malignancy (Table 1). Participants who developed a hematologic malignancy were older at baseline (65.6 7.2 v 61.4 7.3 years; P .001), were more likely male (P .001), and more often had at least two first-degree relatives with a family history of leukemia or lymphoma (P .001; Table 2). Cases also more often rated their health in the lower three of five categories (P .0124) and more often had a history of rheumatoid arthritis (P .001) or osteoarthritis and/or chronic joint pain (P .0097) than did noncases. The associations between acetaminophen, aspirin, and nonaspirin NSAIDs and incidence of hematologic malignancies are summarized in Table 3. After adjustment, there was an increased risk of hematologic malignancies associated with high use ( 4 days/week for 4 years) of acetaminophen (HR, 1.84; 95% CI, 1.35 to 2.50; P trend .004). There was no association with risk of hematologic malignancies for increasing use of low-dose aspirin, total NSAID use excluding low-dose aspirin, regular-dose aspirin, nonaspirin NSAIDs, or ibuprofen. To address the possibility of reverse causation (ie, the possibility that these analgesics and antipyretics were used to treat symptoms of a yet undiagnosed hematologic malignancy), we repeated these analyses after exclusion of the 146 incident cases that occurred within 2 years of baseline. After multivariate adjustment, there was an increased risk of incident hematologic malignancies associated with high use of acetaminophen (HR, 1.50; 95% CI, 1.04 to 2.18; data not shown). When we stratified malignancies by WHO disease classification (Table 4), we found that high use of acetaminophen was associated with increased risk of myeloid neoplasms (HR, 2.26; 95% CI, 1.24 to 4.12); restriction ofmyeloid neoplasms to patientswithmyelodysplastic syndrome or acute myeloid leukemia yielded similar findings (HR, 2.30; 95% CI, 1.12 to 4.73 for high use). High use of acetaminophen Table 3. Associations Between 10-Year Acetaminophen, Aspirin, and Nonaspirin NSAID Use and Risk of Hematologic Malignancies Use in 10 Years Prior to Baseline Cases (n 577) Noncases (n 64,262) Adjusted for Age and Sex Multivariable Adjusted† No. % No. % HR 95% CI P P Trend HR 95 CI P P Trend Acetaminophen .001 .004 Nonuser 405 73.2 48,523 77.9 Ref.‡ Ref.‡ Low 96 17.4 10,552 16.9 1.22 0.97 to 1.52 .086 1.16 0.92 to 1.47 .201 High 52 9.4 3,206 5.2 2.04 1.53 to 2.72 .001 1.84 1.35 to 2.50 .001 Low-dose aspirin .759 .840 Nonuser 371 68.0 43,717 71.8 Ref.‡ Ref.‡ Low 89 16.3 9,895 16.3 0.97 0.77 to 1.22 .791 0.97 0.77 to 1.23 .795 High 86 15.8 7,270 11.9 1.05 0.83 to 1.34 .664 1.04 0.82 to 1.33 .739 Total NSAID excluding low-dose aspirin .852 .642 Nonuser 271 49.8 31,613 52.0 Ref.‡ Ref.‡ Low 160 29.4 17,879 29.4 1.13 0.93 to 1.37 .215 1.08 0.88 to 1.32 .466 High 113 20.8 11,319 18.6 1.03 0.83 to 1.29 .768 0.96 0.77 to 1.21 .737 Regular-dose aspirin .474 .324 Nonuser 404 72.3 47,018 75.4 Ref.‡ Ref.‡ Low 82 14.7 8,090 13.0 1.14 0.90 to 1.45 .272 1.13 0.89 to 1.44 .312 High 73 13.1 7,281 11.7 0.89 0.69 to 1.15 .368 0.86 0.66 to 1.11 .251 Total nonaspirin NSAID .357 .976 Nonuser 393 70.7 41,923 67.9 Ref.‡ Ref.‡ Low 118 21.2 15,095 24.5 0.98 0.80 to 1.20 .849 0.91 0.73 to 1.13 .387 High 45 8.1 4,696 7.6 1.20 0.88 to 1.64 .247 1.06 0.77 to 1.45 .742 Ibuprofen .607 .988 Nonuser 447 79.3 46,858 75.2 Ref.‡ Ref.‡ Low 87 15.4 12,009 19.3 0.92 0.73 to 1.16 .472 0.89 0.70 to 1.13 .343 High 30 5.3 3,420 5.5 1.10 0.76 to 1.60 .599 0.99 0.68 to 1.44 .972 Abbreviations: HR, hazard ratio; NSAID, nonsteroidal anti-inflammatory drug. Low use, less than 4 days/week or less than 4 years; high use, at least 4 days/week and at least 4 years. †All models except for low-dose aspirin adjusted for age, sex, race/ethnicity, education, smoking, self-reported health, history of rheumatoid arthritis, history of nonrheumatoid arthritis or chronic neck/back/joint pain, history of migraines or frequent headaches, history of fatigue/lack of energy, and family history of leukemia/lymphoma. Model for low-dose aspirin adjusted for age, sex, race/ethnicity, education, smoking, self-reported health, history of coronary artery disease, diabetes, stroke, use of antihypertensive or cholesterol-lowering medications, history of fatigue/lack of energy, and family history of leukemia/lymphoma. ‡Reference value of 1.00. Analgesics and Incident Hematologic Cancers www.jco.org © 2011 by American Society of Clinical Oncology 2427