Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, acetaminophen and ovarian cancer survival

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Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, acetaminophen and ovarian cancer survival Christina M. Nagle a,*, Torukiri I. Ibiebele a, Anna DeFazio b, Melinda M. Protani a, Penelope M. Webb a on behalf of the Australian Ovarian Cancer Study Group a

Gynaecological Cancers Group, QIMR Berghofer Medical Research Institute, Herston, Queensland 4029, Australia Department of Gynaecological Oncology, Westmead Hospital and Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead, New South Wales 2145, Australia

b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 16 July 2014 Received in revised form 21 December 2014 Accepted 24 December 2014 Available online xxx

Aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to decrease tumor progression in pre-clinical models of ovarian cancer, however the influence of these drugs on survival in women following a diagnosis of ovarian cancer is unknown. We included 1305 Australian women diagnosed with incident invasive epithelial ovarian cancer, recruited into a population-based case–control study. Use of aspirin, nonaspirin NSAIDs and acetaminophen in the 5 years preceding ovarian cancer diagnosis was assessed from self-reports. Deaths were ascertained up to October 2011 via linkage with the Australian National Death Index. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CI). During a mean followup time of 4.9 years (SD 2.8 years), there were 834 deaths, of which 779 (93% of deaths) were from ovarian cancer. We found uniformly inverse, but non-significant, HRs for ever use in the last five years of aspirin, nonaspirin NSAIDs and acetaminophen compared with no use (adjusted HRs 0.92 [95% CI 0.81– 1.06], 0.91 [95% CI 0.80–1.05] and 0.91 [95% CI 0.69–1.20], respectively). There was no evidence of any dose response trends. The results remained unchanged when we limited the outcome to ovarian cancer mortality. Associations did not differ by histologic subtype, age at diagnosis or stage. Given current interest in the role of aspirin and nonaspirin NSAIDs in cancer survival these results are noteworthy given they are the first to investigate these associations in women with ovarian cancer. Our results provide no strong evidence that pre-diagnostic use of aspirin or nonaspirin NSAIDs are associated with improved survival in women with ovarian cancer. ß 2015 Elsevier Ltd. All rights reserved.

Keywords: Ovarian cancer Survival Mortality Aspirin NSAIDs

1. Introduction Ovarian cancer represents the leading cause of death among women with gynecological malignancies, with only approximately 40–45% of women alive 5 years after diagnosis [1]. About 75% of ovarian cancers are diagnosed at an advanced stage, acquired chemoresistance is common and there is a lack of new effective agents [2]. Most of the strongest known prognostic factors, such as stage of disease, tumor grade and age at diagnosis, are not modifiable. The search for ways to improve survival has lead to

* Corresponding author at: Gynaecological Cancers Group, QIMR Berghofer Medical Research Institute, Locked Bag 2000, Royal Brisbane Hospital, Herston, QLD 4029, Australia. Tel.: +61 733623265; fax: +61 738453502. E-mail address: [email protected] (C.M. Nagle).

interest in identifying potentially modifiable factors that might improve prognosis. Several lines of evidence suggest that ovarian cancer may be related to chronic inflammation [3]. Increasing evidence from the basic sciences, epidemiological studies and randomized controlled trials supports the effectiveness of aspirin, as well as other nonaspirin nonsteriodal anti-inflammatory drugs (NSAIDs) in reducing risk of cancer at several sites [4–7]. A recent analysis of pooled data from 12 population-based, case–control studies has suggested that aspirin and nonaspirin NSAIDs may reduce the risk of ovarian cancer [8]. There is also some evidence from laboratory studies [9–12] and animal models [13] suggesting that aspirin and NSAIDs can decrease the progression of ovarian cancer by inducing apoptosis and inhibiting angiogenesis. We have followed a large cohort of women to report for the first time the association between the use of aspirin, nonaspirin NSAIDs,

http://dx.doi.org/10.1016/j.canep.2014.12.010 1877-7821/ß 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Nagle CM, et al. Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, acetaminophen and ovarian cancer survival. Cancer Epidemiology (2015), http://dx.doi.org/10.1016/j.canep.2014.12.010

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acetaminophen and mortality overall, and by histologic subtype and FIGO (International Federation of Gynecology and Obstetrics) stage. 2. Materials and methods This study included 1305 women diagnosed with incident, primary, invasive epithelial ovarian cancer (including primary peritoneal and fallopian tube cancer) who originally participated in a national population-based case–control study: the Australian Ovarian Cancer Study (AOCS). Full details of the study have been provided elsewhere [14]. Briefly, information about socio-demographic, hormonal, reproductive and lifestyle factors was obtained via self-administered questionnaire at study enrollment. Women were asked how often, in the five years preceding their cancer diagnosis, they had taken aspirin, nonaspirin NSAIDs and acetaminophen medications. For this analysis frequency of use was categorized as never use, use 1/week and use >1/week. Vital status was determined through data abstracted from medical records every 6–12 months, and linkage to the Australian National Death Index (NDI). Survival time was calculated from the date of histologic diagnosis to study exit due to death or censoring (31st October 2011). We also repeated analyses using age, rather than time, as the time metric. All-cause mortality was the endpoint for follow-up; however we repeated the analyses using ovarian cancer mortality as the endpoint. Associations between aspirin, nonaspirin NSAIDs and acetaminophen use, overall and ovarian cancer specific mortality were estimated using Cox proportional hazards regression; multivariate hazard ratios (HR) and 95% confidence intervals (CIs) were generated using SAS (SAS, version 9.2; SAS Institute, Cary, NC). Multivariate models were adjusted for age at diagnosis (continuous), FIGO stage at diagnosis (I, II, III, IV) and grade (well, moderately, poorly/undifferentiated, unknown), residual disease after surgery (nil, 1 cm, >1 cm/not resected, unknown) and the presence of other major co-morbidities (yes/no) (based on comorbidities included in the Charlson Index [15], with the exception of peptic ulcers and the inclusion of other major co-morbidities which may impact survival e.g. multiple sclerosis). Survival models were left-truncated at the date of study co\nsent as women had to survive to this point to be eligible for inclusion. Test for proportional hazard between each of these variables and survival was assessed using univariate proportional hazards regression. Where the proportional hazards assumption was violated a timevariable interaction term was included in the multivariate model. We also conducted subgroup analyses to examine whether the associations between aspirin, non aspirin NSAIDs or acetaminophen and survival were modified by histologic subtype (serous vs. non-serous), age at diagnosis (<60 and 60 years) or stage (I/II and III/IV). The statistical significance of any observed stratum differences was assessed by including a cross-product term in survival models. Ethics approval and informed consent were obtained prior to study enrollment.

Table 1 Baseline characteristics and 5-year survival in women with ovarian cancer. Baseline (n)

Crude 5-year survival % (% survived)

Age group (at diagnosis, years) <50 50 to <60 60 to <70 70+

236 412 411 246

59 50 46 35

FIGO stage I II III IV

245 121 801 131

87 74 35 25

Histologic subtype Serous Mucinous Endometrioid Clear cell Other

911 51 140 87 116

41 74 77 64 40

<0.0001

<0.0001

<0.0001

Tumor grade Well differentiated Moderately differentiated Poorly/undifferentiated Unknown

121

71

247 851 86

48 43 60

Residual disease No residual disease 1 cm >1 cm/not resected Unknown

563 295 319 128

73 33 22 35

888 355

50 43

Co-morbidities (Charlston)b No co-morbidity One or more co-morbidities

P valuea

<0.0001

<0.0001

0.0048

a

P value = Log-rank test of equality over strata. Based on co-morbidities included in the Charlson Index [14] with the exception of peptic ulcers and the inclusion of other major co-morbidities which may impact survival e.g. multiple sclerosis. b

Multivariate analyses identified no significant associations between use or increasing frequency of use of aspirin, nonaspirin NSAIDs or acetaminophen and mortality (Table 2). The HRs were uniformly inverse and non-significant for users vs. never users of aspirin (HR = 0.92), nonaspirin NSAIDs (HR = 0.91) and acetaminophen (HR = 0.91). Results were not appreciably different for users of both aspirin and nonaspirin NSAIDs or a combined group of users of either aspirin or nonaspirin NSAIDs (compared to women who used neither aspirin nor nonaspirin NSAIDs). These results were unchanged when we used age as the time metric, ovarian cancer mortality as the end point and did not vary appreciably across the different histologic subtypes of ovarian cancer (serous, non-serous), age at diagnosis (<60 and 60 years) or by cancer stage (I/II vs. III/IV) (results not shown). 4. Discussion

3. Results The descriptive characteristics of the women are shown in Table 1. Briefly, 834 (64%) women died during the follow-up period, of which 779 (93%) died due to ovarian cancer. For women who were alive at the end of follow-up, the mean time of follow-up from date of diagnosis was 4.9 years (interquartile range 2.3–7.3 years) and the 5-year survival of the entire cohort was 48%. As expected, women who were older, had late stage, higher grade disease, serous histology, residual disease or co-morbidities experienced worse survival in crude analyses.

Despite promising pre-clinical results, in this study of just over 1300 women with invasive ovarian cancer we found no evidence that use of aspirin or nonaspirin NSAIDs during the 5-years prediagnosis was associated with better survival outcomes. To our knowledge, no prior study has examined the association between aspirin, non aspirin NSAIDs and ovarian cancer mortality, however some epidemiologic evidence from other cancers, notably breast and colon, suggests that post-diagnostic use of aspirin/nonaspirin NSAIDs may be important in terms of survival [16,17]. The fact that our study was limited to pre-diagnostic use might explain our null

Please cite this article in press as: Nagle CM, et al. Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, acetaminophen and ovarian cancer survival. Cancer Epidemiology (2015), http://dx.doi.org/10.1016/j.canep.2014.12.010

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Table 2 Association between use of aspirin, nonaspirin NSAIDs and acetaminophen in the 5 years prior to study enrollment and overall survival among women with ovarian cancer. n dead

5-year survival %

Crude HR (95% CI)

Adjustedb HR (95% CI)

664 641

429 405

47 48

1.00 0.97 (0.85–1.11)

1.00 0.92 (0.81–1.06)

411 112 118

261 66 78

47 53 45

0.99 (0.85–1.16) 0.83 (0.64–1.07) 1.04 (0.82–1.33) 0.70

0.95 (0.81–1.11) 0.86 (0.67–1.11) 0.91 (0.71–1.16) 0.23

604 690

399 428

46 49

1.00 0.88 (0.77–1.01)

1.00 0.91 (0.80–1.05)

376 123 191

236 72 120

50 51 46

0.89 (0.76–1.05) 0.80 (0.62–1.02) 0.91 (0.74–1.12) 0.15

0.97 (0.83–1.14) 0.78 (0.61–1.00) 0.90 (0.73–1.11) 0.12

82 1223

56 778

43 48

1.00 0.87 (0.67–1.15)

1.00 0.91 (0.69–1.20)

671 336 216

433 211 134

49 47 46

0.88 (0.67–1.17) 0.86 (0.64–1.16) 0.86 (0.63–1.18) 0.46

0.91 (0.69–1.20) 0.92 (0.68–1.24) 0.91 (0.67–1.26) 0.87

n Aspirin Never usea Ever use Frequency of use Occasionally 1/week >1/week P-trend Nonaspirin NSAIDc Never usea Ever use Frequency of use Occasionally 1/week >1/week P-trend Acetaminophen Never usea Ever use Frequency of use Occasionally 1/week >1/week P-trend a

Referent group – never use aspirin; or never use NSAID; or never use acetaminophen. Adjusted for age at diagnosis (continuous); FIGO stage (I, II, III, IV); grade (well differentiated, all other grades); residual disease (nil, 1 cm, >1 cm/not resected, unknown); co-morbidity. c NSAIDs = non steroidal anti-inflammatory drugs. b

findings; however there remains uncertainty about the most appropriate timing of aspirin or nonaspirin NSAID use to improve cancer survival. Although assessment of aspirin and nonaspirin NSAID use was unbiased with respect to outcome, it will have been subject to random error, potentially biasing the results toward null. Our study also has several strengths. Firstly, women were drawn from a population-based study and were unselected with regard to aspirin/nonaspirin NSAID use. Follow-up and outcome ascertainment through medical records and the NDI were complete and standardized. Baseline clinical and pathologic measures were made independently of aspirin or nonaspirin NSAID use and are likely to be accurate. 5. Conclusion In conclusion, our findings do not support the hypothesis that pre-diagnostic use of aspirin or nonaspirin NSAIDs are associated with better survival after a diagnosis of ovarian cancer. There is a need for further study of the timing of use (pre-diagnostic and post-diagnostic) with regard ovarian cancer mortality. Sources of support The Australian Ovarian Cancer Study was supported by the U.S. Army Medical Research and Materiel Command (DAMD17-01-10729), the National Health and Medical Research Council (NHMRC) of Australia (Grants 400281, 400413, 199600), the Cancer Councils of Victoria, Queensland, New South Wales, South Australia and Tasmania and the Cancer Foundation of Western Australia. CMN and TII are supported by NHMRC Program Grant 552429, PMW by a fellowship from the NHMRC and AdeF is supported by the University of Sydney Cancer Research Fund and the Cancer Institute NSW through the Sydney-West Translational Cancer Research Centre.

Authorship contribution Christina M. Nagle substantially contributed to conception and design; analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published. Torukiri I. Ibiebele substantially contributed to analysis and interpretation of data; revising the articlecritically for important intellectual content; final approval of the version to be published. Anna DeFazio substantially contributed to conception and design; acquisition of data; revising the article critically for important intellectual content; final approval of the version to be published. Melinda M Protani substantially contributed to acquisition of data; interpretation of data; revising the article critically for important intellectual content; final approval of the version to be published. Penelope M. Webb substantially contributed to conception and design; acquisition of data; interpretation of data; revising the article critically for important intellectual content; final approval of the version to be published. Acknowledgements We gratefully acknowledge the members of the Australian Ovarian Cancer Study Group including all the clinical and scientific collaborators, participating institutions, study nurses and research assistants (see http://www.aocstudy.org/ for a complete listing), and thank all of the women who participated in the study. References [1] Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, et al. SEER cancer statistics review 1975–2011; 2014, Based on November 2013 SEER data submission, posted to the SEER website, April 2014. Available from: http://seer.cancer.gov/csr/1975_2011/ [accessed 02.11.14]. [2] Hunn J, Rodriguez GC. Ovarian cancer: etiology, risk factors, and epidemiology. Clin Obstet Gynecol 2012;55(1):3–23.

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Please cite this article in press as: Nagle CM, et al. Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, acetaminophen and ovarian cancer survival. Cancer Epidemiology (2015), http://dx.doi.org/10.1016/j.canep.2014.12.010