Aspirin use and ovarian cancer mortality in a Danish nationwide cohort study
British Journal of Cancer
Aspirin use and ovarian cancer mortality in a Danish nationwide cohort study
Freija Verdoodt 0 3
Susanne K Kjaer 0 1 3
Christian Dehlendorff 3
S?ren Friis 2 3
0 Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center , Strandboulevarden 49, Copenhagen 2100 , Denmark
1 Department of Gynaecology, Rigshospitalet, University of Copenhagen , Blegdamsvej 9, Copenhagen 2100 , Denmark
2 Department of Public Health, University of Copenhagen , ? ster Farimagsgade 5, Copenhagen 1014 , Denmark
3 Statistics and Pharmacoepidemiology, Danish Cancer Society Research Center , Strandboulevarden 49, Copenhagen 2100 , Denmark
Background: Increasing data suggest that aspirin use may improve cancer survival; however, the evidence is sparse for ovarian cancer. Methods: We examined the association between postdiagnosis use of low-dose aspirin and mortality in a nationwide cohort of women with epithelial ovarian cancer between 2000 and 2012. Information on filled prescriptions of low-dose aspirin, dates and causes of death, and potential confounding factors was obtained from nationwide Danish registries. We used Cox regression models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for ovarian cancer-specific or other-cause mortality associated with low-dose aspirin use. Results: Among 4117 patients, postdiagnosis use of low-dose aspirin was associated with HRs of 1.02 (95% CI: 0.87-1.20) for ovarian cancer mortality and 1.06 (95% CI: 0.77-1.47) for other-cause mortality. Hazard ratios remained neutral according to patterns of low-dose aspirin use, including prediagnosis use or established mortality predictors. Conclusions: Low-dose aspirin use did not reduce mortality among ovarian cancer patients.
ovarian neoplasms; aspirin; mortality; prognosis; pharmacoepidemiology
Despite some advances in treatment modalities, the survival of
ovarian cancer has hardly improved for decades and identification
of modifiable factors that can improve the prognosis of ovarian
cancer patients remains a high priority
(Allemani et al, 2015)
Several epidemiologic studies suggest improved cancer
outcomes with regular aspirin use among patients with clinically
manifest cancer, and a number of randomised clinical trials are
currently ongoing to evaluate the role of aspirin in the treatment of
common cancers, notably colorectal cancer
(Coyle et al, 2016;
Elwood et al, 2016)
. The exact mechanisms behind the
antineoplastic effects of aspirin remain to be established
(Thun et al,
2012; Umar et al, 2016)
. For ovarian cancer, some studies in
murine models and human cell lines have demonstrated an
interaction between platelets and proliferation, angiogenesis, and
metastasis of ovarian tumours, suggesting a role for aspirin via the
(Cooke et al, 2015; Cho et al, 2017)
other mechanisms have also been suggested
(Hudson et al, 2008;
Gates et al, 2010)
. Only few epidemiologic studies of ovarian
cancer patients have evaluated outcomes associated with aspirin
use and the results have been too equivocal to allow efficient design
of clinical trials
(Minlikeeva et al, 2015; Nagle et al, 2015; Bar et al,
2016; Dixon et al, 2017; Verdoodt et al, 2017b)
. A pooled analysis
of 12 studies within the Ovarian Cancer Association Consortium
(OCAC) reported a neutral association between aspirin use and
overall survival among ovarian cancer patients; however, aspirin
exposure was self-reported and only prediagnosis use was
evaluated (Dixon et al, 2017). The influence of postdiagnosis
aspirin use, a clinically more relevant exposure, has been explored
in only one small cohort study reporting a statistically significant
50% reduction in overall mortality with aspirin use
(Bar et al,
. This prompted us to conduct a cohort study of
postdiagnosis low-dose aspirin use and mortality among ovarian
cancer patients in Denmark, using the unique Danish nationwide
MATERIALS AND METHODS
From the Danish Cancer Registry, we identified all women aged
30?84 years with incident primary epithelial ovarian cancer
between 2000 and 2012 and no history of cancer (except
nonmelanoma skin cancer). Information on filled prescriptions for
low-dose aspirin and other drugs, tumour and patient
characteristics, comorbid conditions, and mortality outcomes were retrieved
from nationwide demographic, prescription, and patient registries,
using the unique civil registration number assigned to all Danish
residents for linkage. The Supplementary Material provides a
detailed description of the registries, with codes for ovarian cancer,
drug exposure, and covariates.
The study outcomes were ovarian cancer-specific and
othercause mortality. Patients were followed from 1 year after ovarian
cancer diagnosis until death, migration, or end of the study (31
We defined postdiagnosis use of low-dose (75?150 mg) aspirin
as X1 prescription filled after the ovarian cancer diagnosis.
Prediagnosis use of low-dose aspirin was defined as X1
prescription within 5 years before the ovarian cancer diagnosis.
In the primary analysis, we assessed postdiagnosis use of low-dose
aspirin as a time-varying covariate lagged by 1 year
(Chubak et al,
. Thus, postdiagnosis low-dose aspirin users were regarded as
non-users until 1 year after their first prescription.
In secondary analyses, we evaluated the influence of timing of
low-dose aspirin use by developing a supplementary time-varying
exposure matrix: (1) no pre- or postdiagnosis use (reference
group), (2) prediagnosis use only, (3) pre- and postdiagnosis use,
and (4) postdiagnosis use only.
In two sensitivity analyses with fixed exposure periods,
low-dose aspirin use was assessed from time of diagnosis until
the start of follow-up at 1 or 3 years following the ovarian cancer
diagnosis, and was considered invariable thereafter
(Verdoodt et al,
We used Cox proportional hazard regression models to estimate
hazard ratios (HRs) and 95% confidence intervals (CIs) for the
association between postdiagnosis low-dose aspirin use and
ovarian cancer-specific and other-cause mortality. Minimally
adjusted analyses included age at diagnosis, clinical stage, and
year of diagnosis. Fully adjusted models further included tumour
histology, chemotherapy, highest achieved education, disposable
income, marital status, comorbid conditions, and non-aspirin drug
use (Table 1 and Supplementary Material). The proportional
hazards assumption was tested using scaled Schoenfeld residuals.
Finally, we evaluated the influence of competing risks as a result of
death from other causes using the subdistribution hazards model
proposed by Fine and Gray adapted for time-dependent covariates
(Fine and Gray, 1999)
All analyses were performed using the R statistical software
version 3.2.3 and the survival package
(R Foundation for
Statistical Computing, 2015; Therneau, 2015)
guidelines were used to outline this study
(von Elm et al, 2007)
Danish Data Protection Agency and Statistics Denmark?s Scientific
Board approved the study. According to Danish law, ethical
approval is not required for registry-based studies
(Thygesen et al,
Among 5439 eligible women with a primary diagnosis of epithelial
ovarian cancer, 4117 were alive 1 year after the diagnosis and
included in our study. During a mean follow-up of 3.6 years
(maximum 13 years), 2245 (55%) patients died and of these, 1903
(85%) women died from ovarian cancer. Characteristics of the
study population are shown in Table 1.
In the primary, time-varying analysis, we saw no association
between postdiagnosis use of low-dose aspirin and ovarian cancer
(HR: 1.02, 95% CI: 0.87?1.20) or other-cause (HR: 1.06, 95% CI:
0.77?1.47) mortality (Table 2). Further, we observed no substantial
variation in HRs according to estimated dose (tablet size),
cumulative amount of postdiagnosis low-dose aspirin use, or with
timing of use (Table 2). Stratification according to tumour
histology (Table 3), age at diagnosis, clinical stage, or year of
diagnosis (Online Supplementary eTable 2) did not materially
influence the associations.
We also observed overall neutral associations for ovarian
cancer-specific and other-cause mortality in sensitivity analyses,
except for an increased HR with short duration of low-dose aspirin
use in the 3-year analysis; however, these estimates were based on
small numbers (Supplementary eTable 3). Finally, analyses
accounting for competing risks (Fine and Gray) exhibited results
similar to those of the primary analyses (data not shown).
Our finding of a null association between use of low-dose aspirin
and mortality after ovarian cancer is compatible with the results of
the OCAC study based on prediagnosis use, but our results are in
contrast to a previous study reporting a substantial reduction in
overall mortality among ovarian cancer patients with postdiagnosis
(Bar et al, 2016)
. However, besides a small sample size,
the latter cohort study was prone to time-related bias which are
likely to have influenced the estimates
(Chubak et al, 2013)
In our study, we evaluated the influence of low-dose aspirin on
mortality after ovarian cancer, assuming that one tablet was
equivalent to daily use. Higher dosages of aspirin might be required
to obtain a beneficial effect on ovarian cancer prognosis; however,
this is not readily supported by analyses of various patterns of
lowdose aspirin use in our study, or the similar associations for
lowdose (o100 mg) and higher-dose (4100 mg) aspirin in the OCAC
(Dixon et al, 2017)
. Moreover, for cancer in general, there is
no solid evidence that doses of aspirin higher than those used in
cardioprotection (75?150 mg) would provide stronger anticancer
(Coyle et al, 2016; Elwood et al, 2016)
Among the strengths of our study were the nationwide cohort,
large study size, high-quality and continuously updated registry
data, and complete follow-up. The use of the Danish Prescription
Registry ensured complete assessment of prescription drug use.
The study design eliminated recall bias, and minimised selection
bias and time-related biases.
A limitation of our study was the lack of data on
over-thecounter (OTC) purchases of aspirin. However, in Denmark, most
(490%) of the total sales of low-dose aspirin are prescribed
(Schmidt et al, 2014)
, and this proportion may even be higher in
cancer patients who are typically under close medical surveillance.
High-dose (500 mg) aspirin preparations are mainly sold OTC in
Denmark, and thus use of aspirin at this dose may have driven a
possible slight inverse association towards the null given that
highdose aspirin is more likely to be used by non-users of low-dose
aspirin than among users. However, high-dose aspirin is mainly
used for short-term treatment of transient, non-cancer-related pain
and therefore OTC use of high-dose aspirin likely resulted in at
most minor misclassification of long-term aspirin use. Moreover,
the absence of any material differences in associations with
increasing dose and cumulative amount of low-dose aspirin
indicates that OTC sales of high-dose aspirin likely did not have
major impact on our results. Furthermore, in Denmark, regular use
of drugs, including high-dose aspirin, is generally prescribed
because of at least 50% cost reimbursement and the need for
medical surveillance for adverse effects
(Schmidt et al, 2014)
our study population, only five patients filled a minimum of one
prescription for high-dose aspirin, thus suggesting that use of
aspirin at this dose was indeed only sporadical. Still, although we
adjusted for several potential confounding factors, residual
Prediagnosis cumulative amount (tablets)d
Abbreviations: CI ? confidence interval; HR ? hazard ratio.
aAdjusted for age at diagnosis, year of diagnosis, and clinical stage.
bAdjusted for age at diagnosis, year of diagnosis, clinical stage, tumour histology, chemotherapy, highest achieved education, disposable income, marital status, use of non-aspirin drugs, and
cA supplementary exposure matrix including both pre- and postdiagnosis low-dose aspirin use was developed, using four time-varying categories: (1) no pre- or postdiagnosis use (?never use?,
reference), (2) prediagnosis use only, (3) postdiagnosis use only, and (4) both pre- and postdiagnosis use.
dEvaluation according to cumulative number of prediagnosis low-dose aspirin tablets among patients with both pre- and postdiagnosis use, compared with never use.
confounding could have been introduced by lifestyle factors, such
as physical activity, smoking and obesity, or other unmeasured
factors potentially associated with both low-dose aspirin use and
ovarian cancer mortality.
In conclusion, we found no evidence of reduced mortality
among ovarian cancer patients associated with postdiagnosis use of
This project was funded by the Sapere Aude-program of the
Danish Council for Independent Research (Det Frie Forskningsr?d
Sapere Aude-program, project No. 6110-00596B), and the Mermaid
project (Mermaid III).
CONFLICT OF INTEREST
The authors declare no conflict of interest.
This work is published under the standard license to publish
agreement. After 12 months the work will become freely available and
the license terms will switch to a Creative Commons
AttributionNonCommercial-Share Alike 4.0 Unported License.
Supplementary Information accompanies this paper on British Journal of Cancer website (http://www.nature.com/bjc)
Allemani C , Weir HK , Carreira H , Harewood R , Spika D , Wang XS , Bannon F , Ahn JV , Johnson CJ , Bonaventure A , Marcos-Gragera R , Stiller C , Azevedo e Silva G , Chen WQ , Ogunbiyi OJ , Rachet B , Soeberg MJ , You H , Matsuda T , Bielska-Lasota M , Storm H , Tucker TC , Coleman MP ( 2015 ) Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2) . Lancet 385 : 977 - 1010 .
Bar D , Lavie O , Stein N , Feferkorn I , Shai A ( 2016 ) The effect of metabolic comorbidities and commonly used drugs on the prognosis of patients with ovarian cancer . Eur J Obstet Gynecol Reprod Biol 207 : 227 - 231 .
Cho MS , Noh K , Haemmerle M , Li D , Park H , Hu Q , Hisamatsu T , Mitamura T , Mak SLC , Kunapuli S , Ma Q , Sood AK , Afshar-Kharghan V ( 2017 ) Role of ADP receptors on platelets in the growth of ovarian cancer . Blood 30 ( 10 ): 1235 - 1242 .
Chubak J , Boudreau DM , Wirtz HS , McKnight B , Weiss NS ( 2013 ) Threats to validity of nonrandomized studies of postdiagnosis exposures on cancer recurrence and survival . J Natl Cancer Inst 105 : 1456 - 1462 .
Cooke NM , Spillane CD , Sheils O , O'Leary J , Kenny D ( 2015 ) Aspirin and P2Y12 inhibition attenuate platelet-induced ovarian cancer cell invasion . BMC Cancer 15 : 627 .
Coyle C , Cafferty FH , Langley RE ( 2016 ) Aspirin and colorectal cancer prevention and treatment: is it for everyone? Curr Colorectal Cancer Rep 12 : 27 - 34 .
Dixon SC , Nagle CM , Wentzensen N , Trabert B , Beeghly-Fadiel A , Schildkraut JM , Moysich KB , deFazio A , Risch HA , Rossing MA , Doherty JA , Wicklund KG , Goodman MT , Modugno F , Ness RB , Edwards RP , Jensen A , Kjaer SK , Hogdall E , Berchuck A , Cramer DW , Terry KL , Poole EM , Bandera EV , Paddock LE , Anton-Culver H , Ziogas A , Menon U , Gayther SA , Ramus SJ , Gentry-Maharaj A , Pearce CL , Wu AH , Pike MC , Webb PM ( 2017 ) Use of common analgesic medications and ovarian cancer survival: results from a pooled analysis in the Ovarian Cancer Association Consortium . Br J Cancer 116 : 1223 - 1228 .
Elwood PC , Morgan G , Pickering JE , Galante J , Weightman AL , Morris D , Kelson M , Dolwani S ( 2016 ) Aspirin in the treatment of cancer: reductions in metastatic spread and in mortality: a systematic review and metaanalyses of published studies . PLoS One 11 : e0152402 .
Fine JP , Gray RJ ( 1999 ) A proportional hazards model for the subdistribution of a competing risk . J Am Stat Assoc 94 : 496 - 509 .
Gates MA , Tworoger SS , Eliassen AH , Missmer SA , Hankinson SE ( 2010 ) Analgesic use and sex steroid hormone concentrations in postmenopausal women . Cancer Epidemiol Biomarkers Prev 19 : 1033 - 1041 .
Hudson AG , Gierach GL , Modugno F , Simpson J , Wilson JW , Evans RW , Vogel VG , Weissfeld JL ( 2008 ) Nonsteroidal anti-inflammatory drug use and serum total estradiol in postmenopausal women . Cancer Epidemiol Biomarkers Prev 17 : 680 - 687 .
Minlikeeva AN , Freudenheim JL , Lo-Ciganic WH , Eng KH , Friel G , Diergaarde B , Modugno F , Cannioto R , Gower E , Szender JB , Grzankowski K , Odunsi K , Ness RB , Moysich KB ( 2015 ) Use of common analgesics is not associated with ovarian cancer survival . Cancer Epidemiol Biomarkers Prev 24 : 1291 - 1294 .
Nagle CM , Ibiebele TI , DeFazio A , Protani MM , Webb PM ( 2015 ) Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, acetaminophen and ovarian cancer survival . Cancer Epidemiol 39 : 196 - 199 .
R Foundation for Statistical Computing ( 2015 ) R: A Language and Environment for Statistical Computing [Online] . R Core Team: Vienna, Austria. Available at: https://www.r-project.org/. Accessed on 1 January 2017 .
Schmidt M , Hallas J , Friis S ( 2014 ) Potential of prescription registries to capture individual-level use of aspirin and other nonsteroidal antiinflammatory drugs in Denmark: trends in utilization 1999-2012 . Clin Epidemiol 6 : 155 - 168 .
Therneau T ( 2015 ) A Package for Survival Analysis in S, version 2 .38 [Online]. Available at: http://CRAN.R-project.org/package=survival. Accessed on 1 January 2017 .
Thun MJ , Jacobs EJ , Patrono C ( 2012 ) The role of aspirin in cancer prevention . Nat Rev Clin Oncol 9 : 259 - 267 .
Thygesen LC , Daasnes C , Thaulow I , Br?nnum-Hansen H ( 2011 ) Introduction to Danish (nationwide) registers on health and social issues: structure, access, legislation, and archiving . Scand J Public Health 39 : 12 - 16 .
Umar A , Steele VE , Menter DG , Hawk ET ( 2016 ) Mechanisms of nonsteroidal anti-inflammatory drugs in cancer prevention . Semin Oncol 43 : 65 - 77 .
Verdoodt F , Kjaer Hansen M , Kjaer SK , Pottegard A , Friis S , Dehlendorff C ( 2017a ) Statin use and mortality among ovarian cancer patients: a population-based cohort study . Int J Cancer 141 : 279 - 286 .
Verdoodt F , Kjaer SK , Friis S (2017b) Influence of aspirin and non-aspirin NSAID use on ovarian and endometrial cancer: summary of epidemiologic evidence of cancer risk and prognosis . Maturitas 100 : 1 - 7 .
von Elm E , Altman DG , Egger M , Pocock SJ , Gotzsche PC , Vandenbroucke JP ( 2007 ) The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies . Ann Intern Med 147 : 573 - 577 .