Prescription Use of Paracetamol and Risk for Ovarian Cancer in Denmark

JNCI Journal of the National Cancer Institute, Jun 2014

It has been suggested that paracetamol reduces the risk for ovarian cancer. We examined the association between prescription use of paracetamol and ovarian cancer risk in a nationwide case–control study nested within the Danish female population. Case patients (n = 3471) were all women with a first diagnosis of epithelial ovarian cancer during the period from 2000 to 2009. Population control subjects (n = 50576) were selected by risk set sampling. Data were derived from prescription and other nationwide registries. Conditional logistic regression was used to estimate odds ratios (ORs) and two-sided 95% confidence intervals (CIs) for ovarian cancer associated with use of paracetamol or nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs). All statistical tests were two-sided. Use of paracetamol was associated with a reduced odds ratio for ovarian cancer (OR = 0.82; 95% CI = 0.74 to 0.92; P < .001) compared with nonuse, and the odds ratio decreased further with long-term (≥10 years), high-intensity paracetamol use (OR = 0.45; 95% CI = 0.24 to 0.86; P = .02). Use of nonaspirin NSAIDs was not associated with ovarian cancer risk.

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Prescription Use of Paracetamol and Risk for Ovarian Cancer in Denmark

JNCI J Natl Cancer Inst ( Prescription Use of Paracetamol and Risk for Ovarian Cancer in Denmark BRief C OmmUni Cati On 0 Louise Baandrup 0 Søren Friis 0 Christian Dehlendorff 0 Klaus K. Andersen 0 Jørgen H. Olsen 0 Susanne K. Kjaer ) 0 0 Center , Strandboulevarden 49, Copenhagen DK-2100 , Denmark ( It has been suggested that paracetamol reduces the risk for ovarian cancer.We examined the association between prescription use of paracetamol and ovarian cancer risk in a nationwide case-control study nested within the Danish female population. Case patients (n = 3471) were all women with a first diagnosis of epithelial ovarian cancer during the period from 2000 to 2009. Population control subjects (n = 50 576) were selected by risk set sampling. Data were derived from prescription and other nationwide registries. Conditional logistic regression was used to estimate odds ratios (ORs) and two-sided 95% confidence intervals (CIs) for ovarian cancer associated with use of paracetamol or nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs). All statistical tests were two-sided. Use of paracetamol was associated with a reduced odds ratio for ovarian cancer (OR = 0.82; 95% CI = 0.74 to 0.92; P < .001) compared with nonuse, and the odds ratio decreased further with long-term (≥10 years), high-intensity paracetamol use (OR = 0.45; 95% CI = 0.24 to 0.86; P = .02). Use of nonaspirin NSAIDs was not associated with ovarian cancer risk. - In 1998, Cramer et al. reported an inverse association between use of paracetamol and ovarian cancer ( 1 ). The largest reduction was found among women who had used paracetamol daily for more than 10  years. Subsequent observational studies of the association between paracetamol and ovarian cancer have yielded inconclusive results ( 2–14 ); however, most studies have been small, based on self-report, or have had limited follow-up. The aim of this study was to evaluate the association between prescription use of paracetamol and risk for ovarian cancer. For comparison, we included analyses of prescription use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs), which have similar indications for pain relief as paracetamol. We conducted a case–control study nested in the entire Danish female population (2.7 million) using data from seven nationwide registries holding information on cancer diagnoses ( 15 ), prescription use ( 16 ), hospital contacts ( 17 ), reproductive factors ( 18 ), and education ( 19 ). Linkage between the registries was performed by means of the unique civil registration number assigned to all Danish citizens ( 20 ). Case patients were all women aged 30 to 84  years recorded in the Danish Cancer Registry ( 15 ) with a first diagnosis of histologically verified ovarian cancer during the period from 2000 to 2009 and with no prior history of cancer (except nonmelanoma skin cancer). For each case, we randomly selected 15 female age-matched population control subjects (n = 50 576) by risk set sampling among women with no history of cancer or bilateral oophorectomy before the index date (ie, date of case diagnosis and corresponding date for control subjects). From the Danish Prescription Registry, which holds detailed information on prescription drugs dispensed at Danish pharmacies since 1995 ( 16 ), we identified all prescriptions for paracetamol and nonaspirin NSAIDs redeemed by case patients and control subjects between 1995 and 2009. We disregarded use within 1  year of the index date to reduce possible reverse causation ( 21,22 ). Ever use of paracetamol was defined as 2 or more prescriptions on separate dates, whereas less than 2 prescriptions (nonuse) served as reference. Duration of use was defined as the period between the first and last prescription plus 60  days and categorized as less than 5  years, 5 to 10 years, and more than 10 years. Intensity of use was defined as the cumulative number of defined daily doses (23) divided by the duration of use in days and classified into approximate tertiles of low, medium, and high intensity. Conditional logistic regression was used to estimate age- and multivariableadjusted odds ratios (ORs) and two-sided 95% confidence intervals (CIs) for ovarian cancer associated with use of paracetamol or nonaspirin NSAIDs. All statistical tests were two-sided (significance level  =  .05). Analyses were performed with the statistical software R versions 2.15.3 ( 24 ). Further details of the methods, including codes used in the analysis, are presented in the Supplementary Methods and Supplementary Table 1 (available online). We identified 3471 epithelial ovarian cancer case patients (n = 2262 with serous cancer; n = 577 with endometrioid cancer; n = 411 with mucinous cancer; and n = 221 with clear-cell cancer). The characteristics of case patients and age-matched control subjects are presented in Table  1. The prevalence of paracetamol prescription use was 13.2% among case patients and 15.1% among control subjects. Among all 8084 paracetamol users, the median number of prescriptions was eight (range  =  2–551 prescriptions). Ever use of paracetamol was associated with a statistically significant reduced odds ratio for epithelial ovarian cancer (OR  =  0.82; 95% CI  =  0.74 to 0.92; P < .001) and serous ovarian cancer (OR = 0.82; 95% CI = 0.72 to 0.94; P = .003) compared with nonuse (Table  2). Similar risk reductions were observed for the remaining histologic subtypes of epithelial ovarian cancer, albeit with lower statistical precision (Supplementary Table  2, available online). The odds ratios for overall epithelial and serous ovarian cancer decreased Characteristic with increasing duration and estimated daily dose of paracetamol (Table  2). For long-term (≥10  years), high-intensity paracetamol use, the odds ratios were 0.45 (95% CI = 0.24 to 0.86; P = .02) for epithelial ovarian cancer and 0.37 (95% CI = 0.16 to 0.84; P  =  .02) for serous ovarian cancer (Table  2). Similar risk estimates were obtained when the analyses were restricted to recent use of paracetamol (data not shown). The association between ever use of nonaspirin NSAIDs and epithelial ovarian cancer was close to unity. Results did not differ by histologic subtype of epithelial ovarian cancer or by duration and intensity of nonaspirin NSAID use (Supplementary Table 3, available online). Similar results to those of the main analyses were found after additional adjustment for family history of ovarian and breast cancer (information only available for women born after 1953) and in a sensitivity analysis applying a new-user design ( 25 ) (for details, see the Supplementary Methods, available online). Finally, although use of 2 of 5 Brief Communication | JNCI paracetamol and nonaspirin NSAIDs were correlated (correlation coefficient = .26; P < .001), nonaspirin NSAID use did not influence the associations between paracetamol use and ovarian cancer risk among longterm, high-intensity paracetamol users (P = .85). The inverse association between paracetamol use and ovarian cancer risk observed in our study is consistent with a previous meta-analysis in which an overall inverse association was reported, with an indication of a dose–response relationship between paracetamol use and ovarian cancer risk ( 26 ). Overall, most studies of paracetamol use and ovarian cancer risk have reported slightly reduced relative risk estimates ( 4,5,7,8,10,12,14 ), and two studies found strong inverse associations similar to that in our study ( 1,9 ). We included analyses of nonaspirin NSAIDs because paracetamol and nonaspirin NSAIDs have mutual indications. In line with our recent meta-analysis ( 27 ), we observed no association between nonaspirin NSAID use and ovarian cancer. Because of the heterogeneity within the therapeutic group of nonaspirin NSAID agents, our results do not rule out risk variation according to specific types of nonaspirin NSAIDs. However, the fact that we observed substantially reduced risk estimates for paracetamol but not for nonaspirin NSAIDs suggests that our case patient group was not systematically biased with respect to use of analgesics. Some biological explanations for a potential antineoplastic effect of paracetamol against ovarian cancer have been offered. Paracetamol has been suggested to possess antigonadotropic properties due to chemical similarities with the sex steroids estradiol and progesterone ( 1,26,28,29 ). Further, the metabolism of paracetamol requires glutathione, which is also required for both the release and receptor binding of follicle-stimulating hormone. Glutathione depletion from paracetamol metabolism may thus reduce the effective concentration of follicle-stimulating hormone ( 1,26 ). 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Our study had several strengths, including its size, nested case–control design within the entire female Danish population, and virtually complete and accurate cancer ascertainment from the Cancer Registry. Additional strengths include the setting with free access to health services and continuously updated, accurate data on prescriptions, medical conditions, reproductive factors, and education, thus covering most ovarian cancer risk factors. Use of nationwide registries eliminated recall bias and minimized selection bias. Cancer diagnoses were restricted to histologically verified cases, further enhancing validity ( 15 ). If paracetamol does possess antineoplastic effects against ovarian cancer, careful risk– benefit considerations are needed before any chemopreventive measures can be introduced because of the potential adverse effects of long-term paracetamol use. The main limitation of our study was the lack of information of over-the-counter use of paracetamol, which may have introduced residual confounding and misclassification bias. During the study period, approximately 40% to 45% of purchased paracetamol and 80% to 85% of nonaspirin NSAIDs were prescribed ( 31 ). If women receiving paracetamol by prescription differed from other women with respect to ovarian cancer risk factors, confounding might result. However, we were able to adjust for most established ovarian cancer risk factors. Moreover, additional analyses comparing the prescription users of paracetamol with women with no recorded use of analgesic drugs yielded risk estimates for ovarian cancer similar to those of the main analysis. Finally, the prevalence of overthe-counter use of paracetamol was likely lower among chronic users because 50% of the cost of these agents is reimbursed when they are prescribed by a physician. Still, some residual confounding might have resulted from the lack of information on over-the-counter use. Another limitation was potential noncompliance. However, additional analyses restricted to continuous use (≥2 prescriptions per year) of paracetamol yielded results similar to the main analyses, indicating that noncompliance among long-term paracetamol users was not a 4 of 5 Brief Communication | JNCI major issue in this study. Furthermore, we reduced potential misclassification due to use of paracetamol and nonaspirin NSAIDs for symptoms of a yet-undiagnosed ovarian cancer by applying a 1-year lag period and evaluated the influence of use before the start of the Prescription Registry by applying a new-user design. Finally, we only had information on use of oral contraceptives from 1995. However, similar risk estimates were found among users and nonusers of oral contraceptives in additional subanalyses, indicating that residual confounding by use of oral contraceptives was not a major limitation in our study. In conclusion, we found an inverse association between prescription paracetamol use and ovarian cancer risk, which was strongest for long-term, high-intensity use. Additional large studies with long followup and comprehensive information on paracetamol use and ovarian cancer risk factors are needed to confirm our results. n ote 1. Cramer DW , Harlow BL , Titus-Ernstoff L , Bohlke K , Welch WR , Greenberg ER . Overthe-counter analgesics and risk of ovarian cancer . Lancet . 1998 ; 351 ( 9096 ): 104 - 107 . 2. Fairfield KM , Hunter DJ , Fuchs CS , Colditz GA , Hankinson SE . Aspirin, other NSAIDs, and ovarian cancer risk (United States) . Cancer Causes Control . 2002 ; 13 ( 6 ): 535 - 542 . 3. Pinheiro SP , Tworoger SS , Cramer DW , Rosner BA , Hankinson SE . 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Louise Baandrup, Søren Friis, Christian Dehlendorff, Klaus K. Andersen, Jørgen H. Olsen, Susanne K. Kjaer. Prescription Use of Paracetamol and Risk for Ovarian Cancer in Denmark, JNCI Journal of the National Cancer Institute, 2014, DOI: 10.1093/jnci/dju111