Walter ta The genotoxic effects of acetaminophen,a major metabolite esepatients presen ver.acetaminophen inhibits replicative DNA synthe As another argument against d symptom reactive metabolite of acetaminophen,N-acetyl-p-benzoquinone those c as g begun use anc itr ouit remained significantly increased throughout the later par of the follow-up period (%Cl.1.04to e cld,wynee the incne o rcinogenic effects on liver es in useofsr rted acetamin from the time of the cancer of the kidneysor the urothelial system. ated design. wo-fodrisk for use at forat eas usof the ent WHO 4 years.Case-control studies,in vitro studies,a and one long-term nal ex nt support t mmendations about acctaminophen use could be made.Neithe 袋 om regula oic maligna dotaCertaindosepcrd AUTHORS DISCLOSURES O POTENTIAL CONFUCTS rom的ndo b study and ad to attenuation The author(s)indicated no potential conflicts of interest Of some concern is the possibility of reverse causation.that is disease and/or symptoms could lead to exposures (eg,acetaminophen AUTHOR CONTRIBUTIONS use)rather than the ion and desi advanced and aggre Emily Whit B.Wa er,Emily W However,werequired at least 4yearsof nigh user,n and ady m ome cases.two recent studies of patients with lmphoma su the median time from symptoms to diagnosis is about 25 to4 Final approval of manuscript:All authors B.Lin DY.Wei LJ:The robus REFERENCES Ho sk in nort for th unY小Alvaro T.ta Medic sn KE.Jaey CA.eta 2.R roid the risk White F Patte 3 Be s And io's Car ng T.Weir EG. 42007 of Tu e-controlstudy Natl Cancer WHO Press.2008 215200 243002011bAm an Society of Clinicsl Oncoloa 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 under￾stood. However, acetaminophen inhibits replicative DNA synthe￾sis and DNA repair synthesis and increases the frequency of chromosomal damage in cell lines and experimental animals, pos￾sibly 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 acet￾aminophen, 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 re￾ported 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 per￾sonal lifestyle and medical history allowed adjustment for major po￾tential confoundingfactors, including adjustmentfor confounding by indication. On the other hand, some limitations need to be acknowl￾edged. Although we ascertained years of use and days per week for several types of analgesics and separated use of low-dosefrom regular￾strength 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 nondifferen￾tial 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 aggres￾sive 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 atten￾uation 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 de￾creased 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: Cancer￾related 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 malig￾nancies. Leuk Lymphoma 49:1452-1462, 2008 3. Bernatsky S, Lee JL, Rahme E: Non-Hodgkin’s lymphoma–meta-analyses of the effects of corticoste￾roids and non-steroidal anti-inflammatories. Rheuma￾tology (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 north￾ern 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: VITa￾mins And Lifestyle cohort study: Study design and characteristics of supplement users. Am J Epide￾miol 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 anti￾inflammatory drug use with incidence of non￾Hodgkin 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 population￾based 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