Tracey G. Simon, MD, MPH

Mollie E. Barnard, ScD

Data from two large U.S. prospective cohort studies indicate the benefits of regular aspirin use in preventing hepatocellular carcinoma and epithelial ovarian cancer. As reported by Tracey G. Simon, MD, MPH, of Massachusetts General Hospital, Harvard Medical School, and colleagues, in JAMA Oncology,¹ use of at least two standard-dose aspirin tablets per week was associated with a significant reduction in the risk for hepatocellular carcinoma. As reported by Mollie E. Barnard, ScD, of the Department of Epidemiology, Harvard T.H. Chan School of Public Health, and colleagues, also in JAMA Oncology,² regular use of low-dose aspirin—but not standard-dose aspirin—was associated with a reduced risk of epithelial ovarian cancer. The latter study found trends toward an increased risk with the use of standard-dose aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs).

Aspirin and Hepatocellular Carcinoma

Study Details: The study involved data from 133,371 participants, including 87,507 women and 45,864 men, in the Nurses’ Health Study and Health Professional Follow-up Study. The investigators reported on aspirin use, frequency, dosage, and duration of use biennially since 1980 in women and 1986 in men.¹ Participants with a cancer diagnosis at baseline other than nonmelanoma skin cancer were excluded from the analysis.

The mean age was 62 years for women and 64 years for men. The results are from a multivariate model that was conditioned on age (continuous years) and year of questionnaire return; the findings were adjusted for sex, race/ethnicity, body mass index, alcohol intake, smoking status, physical activity, diabetes, hypertension, dyslipidemia, regular multivitamin use, regular use of oral antidiabetic medications, and regular use of statins, as well as regular use of NSAIDs assessed as a time-varying covariate.

Regular, long-term aspirin use is associated with a dose-dependent reduction in [hepatocellular carcinoma] risk, which is apparent after 5 or more years of use.

— Tracey G. Simon, MD, MPH, and colleagues

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Aspirin Use and Hepatocellular Carcinoma Risk: With more than 26 years of follow-up representing 4,232,188 person-years, 108 participants were diagnosed with hepatocellular carcinoma, including 65 women and 43 men. Compared with nonregular use (no use or up to two standard-dose 325-mg tablets/wk), regular aspirin use, defined as at least two standard-dose tablets/wk, was associated with a significantly reduced risk of hepatocellular carcinoma (adjusted hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.34–0.77). Compared with nonuse of aspirin, adjusted hazard ratios for hepatocellular carcinoma were 0.87 (95% CI = 0.51–1.48) for up to 1.5 standard-dose tablets/week, 0.51 (95% CI = 0.30–0.86) for between 1.5 and 5 tablets/week, and 0.49 (95% CI = 0.28–0.96) for more than 5 tablets/week (P for trend = .006).

The association between aspirin dose and hepatocellular carcinoma risk remained significant (P for trend = .005) after additional adjustment for the duration of aspirin use. No significant reduction in hepatocellular carcinoma risk was observed with less than 5 years of regular aspirin use vs nonregular use; adjusted hazard ratios were 0.62 (95% CI = 0.34–1.13) for between 5 and 10 years of use and 0.55 (95% CI = 0.32–0.93) for 10 years or more of use (P for trend = .03). Analysis of dose and duration indicated that the benefit of aspirin in reducing hepatocellular carcinoma risk was apparent with use of 1.5 or more standard-dose aspirin tablets/week for at least 5 years (adjusted HR = 0.41, 95% CI = 0.21–0.77). Compared with current aspirin users, an increasing number of years since discontinuation of aspirin use was associated with an increased hepatocellular carcinoma risk (P for trend = .006); the hazard ratio for discontinuation of aspiring use at least 8 years ago vs current aspirin use was 1.77 (95% CI = 1.06–2.97).

Use of nonaspirin NSAIDs was not associated with hepatocellular carcinoma risk (adjusted HR = 1.09, 95% CI = 0.78–1.51).

The investigators concluded: “This study suggests that regular, long-term aspirin use is associated with a dose-dependent reduction in [hepatocellular carcinoma] risk, which is apparent after 5 or more years of use. Similar associations were not found with nonaspirin NSAIDs. Further research appears to be needed to clarify whether aspirin use represents a feasible strategy for primary prevention against [hepatocellular carcinoma].”

Analgesic Use and Risk of Ovarian Cancer

Study Details: The study involved data from 93, 664 women in the Nurses’ Health Study I (NHSI) followed from 1980 to 2014 (mean age at baseline = 45.9 years) and 111,834 from the Nurses’ Health Study II (NHSII) followed from 1989 to 2015 (mean age at baseline = 34.2 years).² Data on the use of aspirin, low-dose aspirin, nonaspirin NSAIDs, and acetaminophen,

These results appear to be consistent with case-control studies that show a reduced risk of ovarian cancer among regular users of low-dose aspirin.

— Mollie E. Barnard, ScD, and colleagues

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including timing, duration, frequency, and number of tablets, were evaluated, with updates performed every 2 to 4 years. Regular use of these analgesics was defined as at least two times/week. Models accounted for variation in baseline hazards by cohort, age in months (continuous), and calendar years (continuous), with multivariate analysis also adjusting for menopausal status, parity, duration of oral contraceptive use, duration of postmenopausal hormone therapy by type, history of tubal ligation, history of hysterectomy, family history of breast or ovarian cancer, and body mass index.

Associations With Analgesic Use: Among the 205,498 women, representing 1,779, 572 person-years in the NHSI and 1,884,999 person-years in the NHSII, there were 1,054 incident cases of epithelial ovarian cancer. No significant association for current vs nonuse of any aspirin dose was observed for the risk for ovarian cancer regardless of the dose (HR = 0.99, 95% CI = 0.83–1.19).

In a separate analysis, use of low-dose aspirin (≤ 100 mg) was associated with a reduced risk of disease (HR = 0.77, 95% CI = 0.61–0.96), whereas standard-dose aspirin was associated with a nonsignificant increase in risk (HR = 1.17, 95% CI = 0.92–1.49). No difference in risk with low-dose aspirin was observed for a longer duration of use (≥ 5 vs < 1 year, HR = 0.92, 95% CI = 0.57–1.48; P = .41 for trend), with a positive trend of higher risk with longer use being observed for standard-dose aspirin (≥ 5 vs < 1 year, HR = 1.77, 95% CI = 1.13–2.77; P = .004 for trend).

Current use of nonaspirin NSAIDs was associated with a risk for ovarian cancer compared with nonuse (HR = 1.19, 95% CI = 1.00–1.41), with significant positive trends for the duration of use (P = .02 for trend; eg, HR = 1.34, 95% CI = 1.06–1.70, for ≥ 10 years vs no regular use) and cumulative average tablets/week (P = .03 for trend; eg, HR = 1.35, 95% CI = 1.02–1.79, for average of ≥ 10 vs < 1 tablets/week).

No clear associations between acetaminophen use and risk of cancer were identified.

The investigators concluded: “These results appear to be consistent with case-control studies that show a reduced risk of ovarian cancer among regular users of low-dose aspirin. An increased risk of ovarian cancer with long-term high-quantity use of other analgesics, particularly nonaspirin NSAIDs, was observed, although this finding requires confirmation.” ■

DISCLOSURE: Both studies were supported by grants from the National Cancer Institute and the National Institutes of Health. For full disclosures of the authors of both studies, visit www.jama.network.com.

REFERENCES

1. Simon TG, Ma Y, Ludvigsson JF, et al: Association between aspirin use and risk of hepatocellular carcinoma. JAMA Oncol 4:1683-1690, 2018.

2. Barnard ME, Poole EM, Curhan GC, et al: Association of analgesic use with risk of ovarian cancer in the Nurses’ Health Studies. JAMA Oncol 4:1675-1682, 2018.