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_大学文库

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

was also associated with increased risk of mature B-cell neoplasms other than chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or plasma cell disorders (HR, 1.81; 95% CI, 1.14 to 2.93);furthermore, therewas anincreased risk of plasma cell disorders (HR, 2.42; 95% CI, 1.08 to 5.41). There was no association between acetaminophen use and risk of CLL/SLL (HR, 0.84; 95% CI, 0.31 to 2.28for high use). Furthermore,in these stratified analyses, high use of low-dose aspirin was associated with an increased risk of CLL/SLL (HR, 2.26; 95% CI, 1.35 to 3.79; P .004 for trend) and a trend toward decreased risk of plasma cell disorders (P .069 for high use; P .024 for trend); however, there was no clear association of these conditions with use of regular-dose aspirin. We observed no associations between use of nonaspirin NSAIDs or ibuprofen and any individual hematologic malignancy category. When the entire cohort was stratified by sex (Table 5), the association between acetaminophen use and total incident hematologic malignancies was stronger for females (HR for high use, 2.15; 95% CI, 1.41 to 3.28) than for males, in whom statistical significance was not reached (HR for high use, 1.55; 95% CI, 0.97 to 2.50). Low use but not high use of total NSAIDs excluding lowdose aspirin was associated with an increased risk in females (HR, 1.53; 95% CI, 1.12 to 2.09); otherwise, there was no association with risk of incident hematologic malignancies for use of the other medications studied when we stratified the analysis by sex. We also examined the associations of medication use with mature B cell neoplasms (excluding CLL/SLL and plasma cell disorders), the largest disease category, stratified by sex.High use of regular-strength aspirinwas associated with a nonsignificantly increased risk of such neoplasms in women (HR, 1.62; 95% CI, 0.86 to 3.04), whereas no such effect was seen in men (HR, 0.96; 95% CI, 0.61 to 1.53). In contrast, high use of total nonaspirin NSAIDs was not associated with increased risk of these B-cell neoplasms in either women (HR, 0.76; 95% CI, 0.37 to 1.57) or men (HR, 0.83; 95% CI, 0.39 to 1.78). DISCUSSION Previous results of the role of aspirin or nonaspirin NSAIDs on incident hematologic malignancies have been inconsistent across several case-control studies.2,3 In the only other prospective study among the 27,290 postmenopausal women who were followed for 7 years as part of the Iowa Women’s Health Study, use of nonaspirin NSAIDs (HR, 2.39; 95%CI, 1.18 to 4.83) and aspirin (HR, 1.71; 95%CI, 0.94 to 3.13) were associated with increased risk of NHL.9 In our large, prospective cohort study, we found no evidence that long-term use of regularstrength aspirin or nonaspirinNSAIDswas associatedwith risk of total hematologic malignancies or most subtypes classified by using the WHO system. In sex-stratified analyses, however, high use of regularstrength aspirin was associated with a nonsignificantly increased risk Table 4. Multivariable-Adjusted HRs of 10-Year Acetaminophen, Aspirin, and Nonaspirin NSAID Use and Risk of Individual Hematologic Malignancies Use in 10 Years Prior to Baseline Myeloid Neoplasms (n 136) CLL/SLL (n 88) Plasma Cell Disorders (n 66) Mature B-Cell Neoplasms Other Than CLL/ SLL or Plasma Cell Disorders (n 235) No. % HR 95% CI P P Trend No. % HR 95% CI P P Trend No. % HR 95% CI P P Trend No. % HR 95% CI P P Trend Acetaminophen .102 .261 .007 .055 Nonuser 88 67.7 Ref.† 70 80.5 Ref.† 44 67.7 Ref.† 169 76.1 Ref.† Low 28 21.5 1.55 0.98 to 2.43 .060 13 14.9 0.93 0.50 to 1.73 .820 14 21.5 1.63 0.88 to 3.04 .120 30 13.5 0.84 0.56 to 1.26 .403 High 14 10.8 2.26 1.24 to 4.12 .008 4 4.6 0.84 0.31 to 2.28 .732 7 10.8 2.42 1.08 to 5.41 .031 23 10.4 1.81 1.12 to 2.93 .016 Low-dose aspirin .113 .004 .024 .159 Nonuser 77 60.2 Ref.† 47 56.0 Ref.† 49 76.6 Ref.† 163 73.1 Ref.† Low 25 19.5 1.24 0.78 to 1.97 .357 13 15.5 1.13 0.60 to 2.10 .708 11 17.2 0.93 0.48 to 1.80 .832 33 14.8 0.83 0.57 to 1.22 .338 High 26 20.3 1.40 0.88 to 2.22 .157 24 28.6 2.26 1.35 to 3.79 .002 4 6.3 0.39 0.14 to 1.08 .069 27 12.1 0.75 0.49 to 1.15 .184 Total NSAID excluding low-dose aspirin .931 .195 .196 .460 Nonuser 57 46.3 Ref.† 70 80.5 Ref.† 44 67.7 Ref.† 156 68.7 Ref.† Low 37 30.1 1.23 0.81 to 1.89 .334 9 10.3 1.18 0.72 to 1.91 .510 9 13.9 1.48 0.84 to 2.61 .180 35 15.4 0.93 0.67 to 1.30 .675 High 29 23.6 1.08 0.68 to 1.71 .753 8 9.2 0.76 0.42 to 1.35 .346 12 18.5 1.38 0.73 to 2.58 .319 36 15.9 1.11 0.78 to 1.57 .559 Regular-dose aspirin .366 .057 .308 .341 Nonuser 93 72.7 Ref.† 45 51.7 Ref.† 28 43.1 Ref.† 107 49.1 Ref.† Low 18 14.1 1.07 0.64 to 1.77 .808 28 32.2 0.71 0.35 to 1.42 .334 21 32.3 1.18 0.57 to 2.43 .663 59 27.1 1.25 0.86 to 1.81 .235 High 17 13.3 0.76 0.45 to 1.29 .314 14 16.1 0.55 0.27 to 1.14 .108 16 24.6 1.31 0.67 to 2.58 .433 52 23.9 1.17 0.80 to 1.71 .423 Total Nonaspirin NSAID .188 .516 .617 .325 Nonuser 85 66.4 Ref.† 59 67.8 Ref.† 44 66.7 Ref.† 165 73.7 Ref.† Low 28 21.9 1.08 0.69 to 1.68 .740 21 24.1 1.14 0.67 to 1.92 .634 17 25.8 1.27 0.73 to 2.21 .392 43 19.2 0.70 0.49 to 1.01 .054 High 15 11.7 1.69 0.95 to 3.02 .075 7 8.1 1.17 0.54 to 2.54 .687 5 7.6 1.19 0.40 to 3.13 .831 16 7.1 0.79 0.47 to 1.33 .382 Ibuprofen .605 .607 .154 .456 Nonuser 101 77.7 Ref.† 67 76.1 Ref.† 48 72.7 Ref.† 187 81.3 Ref.† Low 20 15.4 0.96 0.59 to 1.57 .867 17 19.3 1.18 0.68 to 2.03 .555 13 19.7 1.31 0.71 to 2.41 .387 32 13.9 0.74 0.50 to 1.09 .129 High 9 6.9 1.31 0.65 to 2.63 .450 4 4.6 0.93 0.34 to 2.50 .880 5 7.6 1.67 0.62 to 4.52 .310 11 4.8 0.81 0.44 to 1.49 .503 NOTE. 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. Abbreviations: CLL, chronic lymphocytic leukemia; HR, hazard ratio; NSAID, nonsteroidal anti-inflammatory drug; Ref., reference; SLL, small lymphocytic lymphoma. Low use, less than 4 days/week or less than 4 years; high use, at least 4 days/week and at least 4 years. †Reference value of 1.00. Walter et al 2428 © 2011 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

of mature B-cell neoplasms (excluding CLL/SLL and plasma cell disorders) of magnitude similar to that in the results from the Iowa Women’s Health Study. In contrast, no such effect was seen in men in our study, nor was high use of total nonaspirin NSAIDs associated with increased risk of mature B-cell neoplasm in either women or men. Thus, our findings provide some support to the earlier prospective study showingapositiveassociationbetweenuseofaspirinand riskof some B-cell neoplasms in women, although the mechanism underlying this observation remains unclear. We also found low-dose aspirin use to be associated with an increased risk of CLL/SLL and a reduced risk of plasma cell disorders among men and women combined. Given the relatively small number of incident cases in these two disease subgroups, we cannot exclude the possibility of chance findings, and further studies will be necessary to confirm these observations. Similarly, we found low use of total NSAIDs excluding low-dose aspirin to be associated with an increased risk of total hematologic malignancies in females; this finding should be interpreted cautiously because the scientific basis for such a sex-specific negative effect of low but not high drug use is unclear. The strongest and most consistent finding from our study was that high use of acetaminophen is associated with an almost two-fold increased risk of total hematologic malignancies and of myeloid neoplasms, plasma cell disorders, and other mature B-cell neoplasms except CLL/SLL. The association of acetaminophen use with total hematologic malignancies was greater among women than among men; the reason for this modifying effect of sex is currently unclear and will require further study. Several casecontrol studies have examined the association between acetaminophen use and risk of hematologic malignancies. Studying 169 cases and 676 controls, Weiss et al10 found an increased risk of acute leukemia for ever-use of acetaminophen (odds ratio [OR], 1.53; 95% CI, 1.03 to 2.26). In a large study of 2,362 lymphoma cases and 2,458 controls,5 an increased risk was found for intake of acetaminophen (OR, 2.29; 95% CI, 1.49 to 3.51). Regular use of acetaminophen was also associated with increased risk of Hodgkin’s lymphoma in a study of 525 cases and 679 controls (OR, 1.72; 95% CI, 1.29 to 2.31)11 as well as with NHL among women (OR, 1.71; 95% CI, 1.18 to 2.50) but not men (OR, 0.75; 95% CI, 0.48 to 1.17) in another study12 comprising 625 cases and 2,512 controls. In contrast, two studies13,14 reported no association of use of acetaminophen with NHL. Finally, Moysich et al15 found an increased risk among regular users of acetaminophen for development of multiple myeloma in a study comprising 117 cases and 483 controls (OR, 2.95; 95% CI, 1.72 to 5.08). To the best of our knowledge, ours is the first prospective study of acetaminophen use and hematologic malignances, and our results support the majority of prior case-control studies. Table 5. Associations Between 10-Year Acetaminophen, Aspirin, and Nonaspirin NSAID Use and Risk of Hematologic Malignancies, Stratified by Sex Use in 10 Years Prior to Baseline Men Women Cases (n 346) Noncases (n 31,201) MultivariableAdjusted HR 95% CI P P Trend Cases (n 231) Noncases (n 33,061) MultivariableAdjusted HR 95% CI P P No. % No. % No. % No. % Trend Acetaminophen .549 .001 Nonuser 265 79.8 25,308 83.1 Ref.† 140 63.4 23,215 72.9 Ref.† Low 48 14.5 4,077 13.4 1.12 0.81 to 1.54 .490 48 21.7 6,475 20.3 1.22 0.87 to 1.73 .250 High 19 5.7 1,065 3.5 1.55 0.97 to 2.50 .070 33 14.9 2,141 6.7 2.15 1.41 to 3.28 .001 Low-dose aspirin .490 .216 Nonuser 231 70.9 20,673 70.0 Ref.† 140 63.6 23,044 73.5 Ref.† Low 44 13.5 4,649 15.7 0.79 0.57 to 1.10 .156 45 20.5 5,246 16.7 1.21 0.86 to 1.72 .273 High 51 15.6 4,207 14.3 0.88 0.65 to 1.20 .419 35 15.9 3,063 9.8 1.35 0.91 to 2.00 .141 Total NSAID excluding low-dose aspirin .163 .209 Nonuser 181 55.2 15,793 53.1 Ref.† 90 41.7 15,820 50.9 Ref.† Low 75 22.9 7,847 26.4 0.83 0.63 to 1.10 .202 85 39.4 10,032 32.3 1.53 1.12 to 2.09 .007 High 72 22.0 6,099 20.5 0.83 0.63 to 1.09 .181 41 19.0 5,220 16.8 1.29 0.87 to 1.90 .206 Regular-dose aspirin .122 .524 Nonuser 235 70.8 21,246 70.3 Ref.† 169 74.5 25,772 80.1 Ref.† Low 46 13.9 4,203 13.9 1.01 0.73 to 1.39 .946 36 15.9 3,887 12.1 1.35 0.94 to 1.94 .099 High 51 15.4 4,778 15.8 0.77 0.57 to 1.05 .094 22 9.7 2,503 7.8 1.10 0.70 to 1.74 .679 Total nonaspirin NSAID .669 .604 Nonuser 263 77.4 22,470 74.1 Ref.† 130 60.2 19,453 62.0 Ref.† Low 53 15.6 6,209 20.5 0.73 0.54 to 1.00 .048 65 30.1 8,886 28.3 1.15 0.83 to 1.59 .406 High 24 7.1 1,658 5.5 1.12 0.74 to 1.71 .596 21 9.7 3,038 9.7 1.03 0.63 to 1.68 .904 Ibuprofen .487 .476 Nonuser 288 84.2 24,030 78.9 Ref.† 159 71.6 22,828 71.8 Ref.† Low 39 11.4 5,129 16.8 0.70 0.50 to 0.98 .037 48 21.6 6,880 21.6 1.15 0.82 to 1.62 .421 High 15 4.4 1,313 4.3 0.91 0.54 to 1.53 .719 15 6.8 2,107 6.6 1.10 0.64 to 1.87 .740 NOTE. 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. Abbreviations: HR, hazard ratio; NSAID, nonsteroidal anti-inflammatory drug; Ref., reference. Low use, less than 4 days/week or less than 4 years; high use, at least 4 days/week and at least 4 years. †Reference value of 1.00. Analgesics and Incident Hematologic Cancers www.jco.org © 2011 by American Society of Clinical Oncology 2429

The genotoxic effects of acetaminophen, a major metabolite of phenacetin, which has been linked to the development of cancer of the upper and lower urinary tract,16,17 remain poorly understood. However, acetaminophen inhibits replicative DNA synthesis and DNA repair synthesis and increases the frequency of chromosomal damage in cell lines and experimental animals, possibly due to inhibition of ribonucleotide reductase.18 The major reactive metabolite of acetaminophen, N-acetyl-p-benzoquinone imine, has been shown to cause extensive DNA single-strand breaks and to strongly enhance DNA cleavage by topoisomerase II in vitro.18,19 Similarly, p-aminophenol, another metabolite of acetaminophen, has been reported to be mutagenic in the L5178Y mouse lymphoma assay and may induce single-strand breaks and chromosome aberrations.20,21 Studies in experimental animals suggest that acetaminophen is genotoxic in vivo in bone marrow cells and, with long-term exposure, may increase the incidence of mononuclear cell leukemia and have carcinogenic effects on liver and bladder.18 Moreover, some epidemiologic studies have reported acetaminophen use to be associated with several types of cancer of the kidneys or the urothelial system.18,22 This study has several strengths, including its prospective design, the large cohort size, case ascertainment through the SEER cancer registry, and the use of the most recent WHO disease classification system. Furthermore, the availability of baseline information on personal lifestyle and medical history allowed adjustment for major potential confoundingfactors, including adjustmentfor confounding by indication. On the other hand, some limitations need to be acknowledged. Although we ascertained years of use and days per week for several types of analgesics and separated use of low-dosefrom regularstrength and extra-strength aspirin, we did not ascertain dose per day; moreover, medication use was self-reported. However, measurement error from these sources and from poor recall would be nondifferential in a prospective study and therefore would lead to attenuation of results. Of some concern is the possibility of reverse causation, that is, disease and/or symptoms could lead to exposures (eg, acetaminophen use) rather than the reverse. For example, fever and night sweats, as part of constitutional (“B”) symptoms, may precede the diagnosis of a hematologic malignancy, particularly in some advanced and aggressive lymphoid neoplasms.23,24However, we required at least 4 years of drug use for categorization as “high user,” and although a prolonged period of B symptoms preceding a cancer diagnosis may occur in some cases, two recent studies of patients with lymphoma suggest that the median time from symptoms to diagnosis is about 2.5 to 4 months.25,26 In contrast, fevers are a rare presenting symptom in multiple myeloma ( 1%); however, many of these patients present with bone pain, although the vast majority of patients are diagnosed within 1 year of onset of symptoms.27 As another argument against reverse causality, one might expect that disease-associated symptoms would lead to use of any type of NSAID or acetaminophen rather than acetaminophen alone. Nonetheless, we additionally excluded cases arising in the first 2 years offollow-up in an analysis of acetaminophen use; this ensures that those classified as high users had begun use at least 6 years before diagnosis. In this analysis, the HR was attenuated although it remained significantly increased throughout the later part of the follow-up period (HR for high use, 1.50; 95% CI, 1.04 to 2.18). Thus, it is possible that reverse causation explains part but not all of the increased risk of hematologic malignancies found in this study (and other studies) of acetaminophen use. Alternatively, the attenuation of risk in our study after removing the first 2 years of follow-up could be due to increased exposure measurement error caused by changes in use of specific analgesics as one moves farther from the time of the questionnaire. In conclusion, high use of acetaminophen was associated with increased risk of incident hematologic malignancies other than CLL/ SLL,with an almost two-fold riskfor use atleast4 days/weekfor atleast 4 years. Case-control studies, in vitro studies, and one long-term animal experiment support these results. Nonetheless, supporting evidence from other prospective studies would be needed before any recommendations about acetaminophen use could be made. Neither regular aspirin nor nonaspirin NSAIDs were associated with decreased risk, implying that these drugs are unlikely to be useful for prevention of hematologic malignancies. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Roland B. Walter, Emily White Financial support: Roland B. Walter, Emily White Provision of study materials or patients: Emily White Collection and assembly of data: Emily White Data analysis and interpretation: Roland B. Walter, Filippo Milano, Theodore M. Brasky, Emily White Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Mantovani A, Allavena P, Sica A, et al: Cancerrelated inflammation. Nature 454:436-444, 2008 2. Robak P, Smolewski P, Robak T: The role of non-steroidal anti-inflammatory drugs in the risk of development and treatment of hematologic malignancies. Leuk Lymphoma 49:1452-1462, 2008 3. Bernatsky S, Lee JL, Rahme E: Non-Hodgkin’s lymphoma–meta-analyses of the effects of corticosteroids and non-steroidal anti-inflammatories. Rheumatology (Oxford) 46:690-694, 2007 4. Chang ET, Cronin-Fenton DP, Friis S, et al: Aspirin and other nonsteroidal anti-inflammatory drugs in relation to Hodgkin lymphoma risk in northern Denmark. Cancer Epidemiol Biomarkers Prev 19:59-64, 2010 5. Becker N, Fortuny J, Alvaro T, et al: Medical history and risk of lymphoma: Results of a European case-control study (EPILYMPH). J Cancer Res Clin Oncol 135:1099-1107, 2009 6. White E, Patterson RE, Kristal AR, et al: VITamins And Lifestyle cohort study: Study design and characteristics of supplement users. Am J Epidemiol 159:83-93, 2004 7. Swerdlow SH, Campo E, Harris NL, et al: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (ed 4). Geneva, Switzerland, WHO Press, 2008 8. Lin DY, Wei LJ: The robust interference for the Cox proportional hazards model. J Am Stat Assoc 84:1074-1078, 1989 9. Cerhan JR, Anderson KE, Janney CA, et al: Association of aspirin and other non-steroidal antiinflammatory drug use with incidence of nonHodgkin lymphoma. Int J Cancer 106:784-788, 2003 10. Weiss JR, Baker JA, Baer MR, et al: Opposing effects of aspirin and acetaminophen use on risk of adult acute leukemia. Leuk Res 30:164-169, 2006 11. Chang ET, Zheng T, Weir EG, et al: Aspirin and the risk of Hodgkin’s lymphoma in a populationbased case-control study. J Natl Cancer Inst 96:305- 315, 2004 Walter et al 2430 © 2011 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

12. Baker JA, Weiss JR, Czuczman MS, et al: Regular use of aspirin or acetaminophen and risk of non-Hodgkin lymphoma. Cancer Causes Control 16: 301-308, 2005 13. Holly EA, Lele C, Bracci PM, et al: Casecontrol study of non-Hodgkin’s lymphoma among women and heterosexual men in the San Francisco Bay Area, California. Am J Epidemiol 150:375-389, 1999 14. Kato I, Koenig KL, Shore RE, et al: Use of anti-inflammatory and non-narcotic analgesic drugs and risk of non-Hodgkin’s lymphoma (NHL) (United States). Cancer Causes Control 13:965-974, 2002 15. Moysich KB, Bonner MR, Beehler GP, et al: Regular analgesic use and risk of multiple myeloma. Leuk Res 31:547-551, 2007 16. McCredie M, Stewart JH, Ford JM, et al: Phenacetin-containing analgesics and cancer of the bladder or renal pelvis in women. Br J Urol 55:220- 224, 1983 17. Piper JM, Tonascia J, Matanoski GM: Heavy phenacetin use and bladder cancer in women aged 20 to 49 years. N Engl J Med 313:292-295, 1985 18. Bergman K, Mu¨ller L, Teigen SW: Series: Current issues in mutagenesis and carcinogenesis, No. 65. The genotoxicity and carcinogenicity of paracetamol: A regulatory (re)view. Mutat Res 349: 263-288, 1996 19. Bender RP, Lindsey RH Jr, Burden DA, et al: N-acetyl-p-benzoquinone imine, the toxic metabolite of acetaminophen, is a topoisomerase II poison. Biochemistry 43:3731-3739, 2004 20. Oberly TJ, Bewsey BJ, Probst GS: An evaluation of the L5178Y TK/ mouse lymphoma forward mutation assay using 42 chemicals. Mutat Res 125:291-306, 1984 21. Majeska JB, Holden HE: Genotoxic effects of p-aminophenol in Chinese hamster ovary and mouse lymphoma cells: Results of a multiple endpoint test. Environ Mol Mutagen 26:163-170, 1995 22. Pommer W, Bronder E, Klimpel A, et al: Urothelial cancer at different tumour sites: Role of smoking and habitual intake of analgesics and laxatives— Results of the Berlin Urothelial Cancer Study. Nephrol Dial Transplant 14:2892-2897, 1999 23. Armitage JO, Weisenburger DD: New approach to classifying non-Hodgkin’s lymphomas: Clinical features of the major histologic subtypes— Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol 16:2780-2795, 1998 24. Ng AK, Bernardo MP, Weller E, et al: Longterm survival and competing causes of death in patients with early-stage Hodgkin’s disease treated at age 50 or younger. J Clin Oncol 20:2101-2108, 2002 25. Allgar VL, Neal RD: Delays in the diagnosis of six cancers: Analysis of data from the National Survey of NHS Patients—Cancer. Br J Cancer 92: 1959-1970, 2005 26. Molassiotis A, Wilson B, Brunton L, et al: Mapping patients’ experiences from initial change in health to cancer diagnosis: A qualitative exploration of patient and system factors mediating this process. Eur J Cancer Care (Engl) 19:98-109, 2010 27. Kyle RA, Gertz MA, Witzig TE, et al: Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 78:21-33, 2003 ■■■ Simplify Your Search With JCO Subject Collecons Subject Collecons are topic-specific archives of arcles published on JCO.org that make it easy for you to find the research you need. Instead of random, me-consuming keyword searches, JCO Subject Collecons allow you to quickly browse your interest areas for arcles on specific diseases and treatments. Best of all, by signing up for Collecon Alerts, you’ll receive e-mail noficaon whenever JCO publishes an arcle in your interest area. Sign up today at www.jco.org/collecons. Analgesics and Incident Hematologic Cancers www.jco.org © 2011 by American Society of Clinical Oncology 2431

AMERICAN JOURNAL OF INDUSTRIAL MEDICINE (2008) Risk of Leukemia and Multiple Myeloma Associated With Exposure to Benzene and Other Organic Solvents: Evidence From the Italian Multicenter Case–Control Study Adele Seniori Costantini, MD, 1 Alessandra Benvenuti, DSc, 1 Paolo Vineis, MD, 2,3 David Kriebel, DSc, 4 Rosario Tumino, MD, 5 Valerio Ramazzotti, MD, 6 Stefania Rodella, MD, 7,8 Emanuele Stagnaro, MD, 9 Paolo Crosignani, MD, 10 Dino Amadori, MD, 11 Dario Mirabelli, MD, 12 Letizia Sommani, MD, 13 Isabella Belletti, DSc, 10 Loredana Troschel, DSC, 10 Luciano Romeo, MD, 14 Giuseppe Miceli, MD, 15 Giulio Andrea Tozzi, DSc, 16 Igino Mendico, MD, 17 Simona Alberghini Maltoni,1 and Lucia Miligi, DSc1 Background While there is a general consensus about the ability of benzene to induce acute myeloid leukemia (AML), its effects on chronic lymphoid leukemia and multiple myeloma (MM) are still under debate. We conducted a population-based case–control study to evaluate the association between exposure to organic solvents and risk of myeloid and lymphoid leukemia and MM. Methods Five hundred eighty-six cases of leukemia (and 1,278 population controls), 263 cases of MM (and 1,100 population controls) were collected. Experts assessed exposure at individual level to a range of chemicals. Results We found no association between exposure to any solvent and AML. There were elevated point estimates for the associations between medium/high benzene exposure and chronic lymphatic leukemia (OR ¼ 1.8, 95% CI ¼ 0.9–3.9) and MM (OR ¼ 1.9, 95% CI ¼ 0.9–3.9). Risks of chronic lymphatic leukemia were somewhat elevated, albeit with wide confidence intervals, from medium/high exposure to xylene and toluene as well. Conclusions We did not confirm the known association between benzene and AML, though this is likely explained by the strict regulation of benzene in Italy nearly three decades prior to study initiation. Our results support the association between benzene, 2008 Wiley-Liss,Inc. 14Occupational Medicine, Department of Medicine and Public Health, University of Verona, Verona, Italy 15Occupational Health and Safety Local Unit, S.Pre.S.A.L, Az. Unita' Sanitaria Locale 7, Ragusa, Italy 16Occupational Health and Safety Local Unit, S.Pre.S.A.L, Az. Unita' Sanitaria Locale 3 Genoa, Italy 17Health Prevention Department, Az. Unita' Sanitaria Locale, Latina, Italy Contract grant sponsor: U.S. National Cancer Institute; Contract grant number: NCI CA51086; Contract grant sponsor: European Community (Europe against Cancer Programme); Contract grant sponsor: Italian Alliance against Cancer (Lega Italiana per la Lotta contro i Tumori). *Correspondence to: Dr. Adele. Seniori Costantini, Unit of Environmental and Occupational Epidemiology, Center for Study and Prevention of Cancer,Via di S. Salvi12, 50135 Florence, Italy. E-mail: a.seniori@cspo.it Accepted 4 April 2008 DOI10.1002/ajim.20592. Published online in Wiley InterScience (www.interscience.wiley.com) 1 Unit of Environmental and Occupational Epidemiology,Center for Study and Prevention of Cancer, Florence, Italy 2 University of Turin,Turin, Italy 3 Imperial College London, London, UK 4 Department of Work Environment, University of Massachusetts, Lowell, Massachusetts 5 RegistroTumori Azienda Ospedaliera ‘‘CivileM.P. Arezzo’’ Ragusa, Italy 6 Servizio Integrato di Epidemiologia e Sistemi Informativi, National Cancer Institute, Istituto Regina Elena, Rome, Italy 7 Agenzia Regionale di Sanita' Florence, Italy 8 Az. Ospedaliera,Verona, Italy 9 Environmental Epidemiology Unit, National Cancer Research Institute, Genoa, Italy 10Epidemiology Unit, National Cancer Institute, Milan, Italy 11Medical Oncology Department,Pierantoni Hospital, Istituto Oncologico Romagnolo, Forl|', Italy12Unit of Cancer Epidemiology, CPO San Giovanni Battista Hospital of Turin, University of Turin,Turin, Italy 13Preventive Medicine Service, Local Health Unit, Florence, Italy