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There are few known modifiable risk factors for Hodgkin lymphoma (HL), but the recent finding of an inverse association between routine regular-strength aspirin use and HL risk suggests that aspirin may protect against HL development. To further investigate this association using prospectively collected data, we conducted a population-based case-control study in Northern Denmark. A total of 478 incident HL cases were identified in nationwide health care databases from 1991 through 2008. Ten population controls were matched to each case on age, sex, and county using risk-set sampling. Use of aspirin, selective cyclooxygenase-2 (sCOX-2) inhibitors, and other NSAIDs from 1989 through 2007 was ascertained by linkage to a population-based prescription database. Conditional logistic regression was used to estimate odds ratios (ORs) for associations between medication use and risk of HL. The OR for ever use (>2 prescriptions) compared with never/rare use (≤2 prescriptions) of low-dose aspirin was 0.7 (95% confidence interval [CI]: 0.5–1.2). The association with low-dose aspirin use did not vary appreciably by recentness, duration, or intensity of use. Recent use (>2 prescriptions in the 1–2 years before the index date), short-term use (<7 years), and medium/high-intensity use (≥25% of duration of use covered by prescription) of sCOX-2 inhibitors or other NSAIDs was associated with increased HL risk, possibly due to prodromal symptoms among cases. In conclusion, our results provide some evidence of a protective effect of low-dose aspirin, but not other NSAIDs, against HL development.
Hodgkin lymphoma (HL) is one of the most common cancers of children and young adults in Western countries, and it is the third leading cancer in terms of average years of life lost per patient in the US (1). Few, if any, established HL risk factors are readily modifiable. However, an inverse association between routine regular-strength (325 mg) aspirin use and risk of HL was recently observed in a US population-based case-control study of 565 HL patients and 679 controls (2). Comparing routine users (those who reported using aspirin ≥2 times per week during the last 5 years) with non-routine users, the odds ratio (OR) of HL was 0.60 (95% confidence interval [CI]: 0.42–0.85). This inverse association did not vary by age group, sex, level of education, use of non-aspirin NSAIDs or acetaminophen, or, among HL patients, by presence of B-symptoms, time interval between diagnosis and interview, or tumor Epstein-Barr virus positivity. In the same study, there was no association between routine use of non-aspirin NSAIDs and HL risk.
Distinctive biological properties of aspirin, including irreversible binding to cyclooxygenase-2 (COX-2) (3) and inhibition of pro-inflammatory transcription factor nuclear factor kappa-B (NF-κB) (4, 5), a necessary survival factor for malignant HL cells (6–9), may partially explain the observed inverse association of aspirin but not other NSAIDs with HL risk. To follow up on these findings, we conducted a population-based case-control study with prospectively collected data in Northern Denmark to investigate the association of aspirin and other NSAIDs, including selective COX-2 (sCOX-2) inhibitors, with risk of HL.
This study included residents of the four former Danish counties of North Jutland, Aarhus, Viborg, and Ringkoebing, which have a combined population of approximately 1.7 million inhabitants. The Danish National Health Service provides tax-supported health care to all residents of the country and refunds part of patient expenditures on a wide range of prescribed drugs, including NSAIDs and sCOX-2 inhibitors, the latter of which became available in Denmark in 1999. All health-related services are registered to individual patients by use of their civil personal registration (CPR) number, assigned to all Danish citizens since 1968. This unique CPR number facilitates linkage between population-based registries, including the Danish Cancer Registry (10), the Danish National Registry of Patients (11), and countywide prescription databases.
The methods we used have been described elsewhere (12), with expansion of the study base to the four former counties for which data have been merged into a research database at Aarhus University. Briefly, we used the Cancer Registry to identify all patients (N=403) who had a first diagnosis of HL (International Classification of Diseases, 10th revision (ICD-10) code C81) starting on January 1, 1991, in North Jutland County; January 1, 1998, in Aarhus County; and January 1, 2000, in Viborg and Ringkoebing counties; and continuing through December 31, 2006, in all four former counties (now merged into two regions); and we used the National Registry of Patients (which has more recent data) to ascertain all patients (N=75) who had a first diagnosis of HL within all hospitals in the two regions from January 1, 2007, through December 31, 2008. The Cancer Registry includes the CPR number and detailed individual data on all cancer diagnoses in Denmark since 1943 (10), while the Registry of Patients includes the CPR number and detailed individual data on all non-psychiatric hospital admissions since 1977 and out-patient contacts since 1995 (11). Until 2003, the Cancer Registry was based on mandatory notifications by Danish medical doctors (10); since then, the Cancer Registry has been based on records from the Registry of Patients, with secondary histological confirmation from the National Pathology Registry (13, 14). Within the Danish Civil Registration System database (15, 16), we performed risk-set sampling to select 10 population controls per case among living individuals without a history of HL on the index date (i.e., the date of diagnosis for each case), for a total of 4,780 controls matched on age, sex, and county of residence.
All pharmacies in the four former counties are equipped with computerized accounting systems that record a customer’s CPR number and prescription data, including type and quantity according to the Anatomical Therapeutic Chemical (ATC) Classification System (17), and date of dispensing at the pharmacy. This information is transferred electronically to countywide prescription databases (12, 18). Using these databases (established in North Jutland County in 1989, Aarhus County in 1996, and Viborg and Ringkoebing counties in 1998, thus ensuring a minimum of two years of prescription history in the present study), we identified prescriptions for low-dose aspirin (75, 100, or 150 mg per tablet; ATC codes B01AC06 and N02BA01), high-dose aspirin (500 mg per tablet; ATC codes N02BA51 and N02BA01), sCOX-2 inhibitors (ATC codes M01AH01, M01AH, M01AH03, M01AH05, M01AC05, M01AB05, and M01AC06), and other NSAIDs (remaining ATC codes within group M01A). We excluded prescriptions within 1 year of the index date to reduce any potential effect of subclinical disease on medication use.
We defined “ever users” of a medication as individuals who had >2 prescriptions and “never/rare users” as those who had ≤2 prescriptions. The average length of a prescription was 30 days. Ever users were further divided into recent users (those who had >2 prescriptions during the period 1–2 years before the index date) and former users (>2 prescriptions overall, but ≤2 during the recent period). Duration of use was classified as long-term (≥7 years) or short-term (<7 years), based on the number of days between the first and last prescriptions plus the duration of the last prescription. Intensity of use was defined as low (<25%) or medium/high (≥25%), according to the number of days of prescription coverage divided by duration of use in days (12).
To obtain a nonspecific proxy for chronic NSAID use, we identified subject comorbidities before the index date using inpatient and outpatient data from the Registry of Patients. Comorbidities were summarized using Deyo’s adaptation of the Charlson Index (19, 20). In addition, because connective tissue disorders in particular (e.g., rheumatoid arthritis, which is associated with both greater NSAID use and higher HL risk (21, 22)) may confound the associations of interest, we identified connective tissue disorders before the index date.
We used conditional logistic regression to compute ORs and 95% CIs, matching on age, sex, and former county of residence, and additionally adjusting for Charlson Index (0, 1–2, or ≥3 comorbidities). Further adjustment for connective tissue disorders did not affect the results (data not shown). Because the etiology of HL varies by age (23), we stratified the results by age (<40 years vs. ≥40 years) and performed Wald tests for interactions between medication use and age group. In all analyses, never/rare users (≤2 prescriptions) comprised the reference group. Given the risk set sampling of controls, the ORs are estimates of the incidence rate ratios in the underlying population.
The distribution of HL cases and matched controls is shown in Table 1. Ever use of low-dose aspirin was associated with 30% lower risk of HL (95% CI=−50% to +20%), but the estimate was statistically non-significant, as were the estimates for former and recent use, short-term and long-term use, and low-intensity and medium/high-intensity use, as well as ever use of high-dose aspirin (Table 2). When low-dose aspirin use was classified according to both intensity and duration of use (i.e., short-term, low-intensity; short-term, high-intensity; long-term, low-intensity; or long-term, medium/high-intensity), the lowest ORs were found in association with short-term, low-intensity use (OR=0.5, 95% CI=0.2–1.3) and long-term, medium/high-intensity use (OR=0.7, 95% CI=0.2, 3.5). However, the numbers of cases included in these analyses were small.
HL risk did not vary markedly by overall use or recentness of use of high-dose aspirin or sCOX-2 inhibitors (results not shown for recentness). Although recent use of other NSAIDs was associated with increased HL risk, former use and overall use were not. In addition, HL risk was elevated in association with short-term or medium/high-intensity use of non-aspirin NSAIDs (including sCOX-2 inhibitors), but not long-term or low-intensity use. When use of non-aspirin NSAIDs was categorized according to both duration and intensity of medication use, there was a positive association with short-term, medium/high-intensity use (OR=1.7, 95% CI=1.2–2.6), but not other categories of use.
Adjustment for duration and intensity of use of non-aspirin NSAIDs did not affect the association of HL risk with ever use of low-dose aspirin (OR=0.7, 95% CI=0.5–1.2). However, the inverse association with low-dose aspirin use was apparent only among never/rare users of non-aspirin NSAIDs (OR=0.6, 95% CI=0.3–1.0), and not among ever users of non-aspirin NSAIDs (OR=1.0, 95% CI=0.5–1.9). When the analysis was restricted to individuals with at least 7 years of prescription history, the estimates of association with use of low-dose aspirin and non-aspirin NSAIDs, including duration of use, did not change substantially (data not shown). Likewise, when we limited the analysis to HL patients included in the Danish Cancer Registry (1991–2006; N=403) or when we excluded prescriptions within 2 years of the index date, the results were unchanged (data not shown).
In an exploratory analysis stratified by age group (<40 years vs. ≥40 years), we found that only one control and no HL cases aged <40 years were ever users of low-dose aspirin. Therefore, the association with low-dose aspirin use could be estimated only among subjects aged ≥40 years (OR=0.8, 95% CI=0.5–1.2). The association with ever use of sCOX-2 inhibitors or other NSAIDs did not vary between younger (OR=1.1, 95% CI=0.7–1.8) and older adults (OR=1.3, 95% CI=1.0–1.8; Pheterogeneity=0.58). Likewise, there was no variation by age group in the association with ever use of sCOX-2 inhibitors alone (OR for <40 years=0.9, 95% CI=0.3–2.2; OR for ≥40 years=1.1, 95% CI=0.7, 1.8; Pheterogeneity=0.62) or with ever use of other NSAIDs alone (OR for <40 years=1.4, 95% CI=0.9–2.4; OR for ≥40 years=1.1, 95% CI=0.8–1.6; Pheterogeneity=0.43).
Consistent with earlier observations (2), we found an inverse association between use of low-dose aspirin and risk of HL in this study. Although the association was statistically non-significant, the OR estimate of 0.7 is comparable to the previously reported point estimate of 0.6 for use of ≥2 regular-strength tablets per week, on average, versus <2 tablets per week during the preceding 5 years (2). The inverse association was limited to adults aged ≥40 years, although we could not rule out an association among younger adults. In the earlier study (2), aspirin use was inversely associated with HL risk among both younger and older adults.
We also detected positive associations with recent use of other NSAIDs and short-term, medium/high-intensity use of non-aspirin NSAIDs (including sCOX-2 inhibitors), but no association with long-term or low-intensity use. Although we excluded prescriptions within 1 year of the index date (and, in a secondary analysis, prescriptions within 2 years of the index date), the observed positive associations may nevertheless be due to use of non-aspirin NSAIDs to treat prodromal symptoms (including fever and swollen lymph nodes) among HL cases. It is possible that the inverse association of HL risk with use of low-dose aspirin, particularly among never/rare users of non-aspirin NSAIDs, as well as the positive association with recent or short-term, medium/high-intensity use of non-aspirin NSAIDs, were due to switching from aspirin to other NSAIDs to treat symptoms prior to HL diagnosis. However, we lacked a large enough sample to examine this question in detail. Our previous cohort analysis of prescription data in North Jutland County revealed no association between non-aspirin NSAID use and HL risk (based on 23 cases) (24), but had insufficient case numbers to study the association between low-dose aspirin use and HL risk (25). To our knowledge, no other studies have examined the association between NSAID use and HL risk.
The possible biological mechanisms underlying our findings are not clear, but aspirin inhibits the transcription factor nuclear NF-κB (4, 5), which regulates the expression of genes involved in immune activation, inflammation, cell growth, and apoptosis (4, 26). Constitutively active NF-κB is detected in virtually all malignant HL cells (6), and NF-κB inactivation causes spontaneous apoptosis of those cells (8, 9). Thus, NF-κB appears to play a vital role in HL cell survival (7), and medications that target NF-κB may protect against HL development. In addition, aspirin is unique among the NSAIDs in that it binds irreversibly to the active site of COX-2 (3), the pro-inflammatory enzyme targeted by standard NSAIDs and sCOX-2 inhibitors (27). These differences between aspirin and other NSAIDs may underlie the inverse association of aspirin alone with risk of HL in the current and previous studies (2).
Unique strengths of the present study include the use of prospectively collected, continuously updated, accurate information on drug prescriptions for up to 18 years. In addition, our current findings are strengthened by the population-based study design and valid, complete ascertainment and follow-up of incident HL (10, 28). Our study included a relatively large number of patients with a disease as uncommon as HL; however, the sample size was nevertheless modest, leading to imprecise OR estimates.
Our study is also limited by the lack of information on compliance with prescriptions, indications for prescriptions, and over-the-counter use of aspirin and other NSAIDs. The vast majority of aspirin prescriptions in Denmark are for low-dose aspirin to treat or prevent cardiovascular disease (e.g., thrombosis prevention) (25). Although low-dose aspirin (≤150 mg) and ibuprofen (200 mg) are available without a prescription, the government refunds 50% of costs at the time of prescription, making it likely that we identified most patients using these medications under physician guidance (25). Over-the-counter use of non-aspirin NSAIDs in Denmark accounts for only 14% of total use (29), but over-the-counter use may be more common among individuals without prescriptions than those with prescriptions, leading to an underestimation of any association with HL risk. Over-the-counter use may also be more common among individuals of high socioeconomic status, among whom HL risk is elevated (30), further diminishing any inverse association with risk. Without detailed information on individual characteristics and exposures, we were unable to adjust for potential confounding by socioeconomic status and other risk factors.
In summary, our observation of a statistically non-significant inverse association between aspirin use and HL risk is consistent with, although not entirely confirmatory of, earlier findings. Thus, routine aspirin use remains a theoretically promising means of reducing HL risk. Additional studies with similar prospective, validated data on aspirin use, and ideally with a larger sample size, are needed to establish whether this promise translates into a true protective effect.
This study was supported in part by the Karen Elise Jensen’s Foundation. We thank Sidsel Tonder for her assistance with preliminary statistical analyses.