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 regular-strength aspirin or nonaspirin NSAIDs was associated with risk of total hematologic malignancies or most subtypes classified by using the WHO system. In sex-stratified analyses, however, high use of regular-strength aspirin was associated with a nonsignificantly increased risk 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 showing a positive association between use of aspirin and risk of 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 case-control 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.
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
-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
-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 confounding factors, including adjustment for 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-dose from 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 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.23,24
However, 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 of follow-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 risk for use at least 4 days/week for at least 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.