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Nonsteroidal Anti-inflammatory Drugs and Clinical Outcomes among Men with Prostate Cancer: A Systematic Review and Meta-analysis

CC BY-NC-ND 4.0 ? Indian J Med Paediatr Oncol 2018; 39(02): 127-141

DOI: DOI: 10.4103/ijmpo.ijmpo_61_17

Abstract

Background:?Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown properties of inhibiting the progression of prostate cancer (PCa) in preclinical studies. However, epidemiological studies yield mixed results on the effectiveness of NSAIDs in PCa.?Objective:?The objective of this study was to determine the effect of NSAID use on clinical outcomes in PCa using systematic review and meta-analysis.?Methods:?Original articles published until the 1st week of October, 2016, were searched in electronic databases (Medline-Ovid, PubMed, Scopus, The Cochrane Library, and Web of Science) for studies on NSAID use in PCa. The main clinical outcomes for the review were: PCa-specific (PCM) and all-cause mortality (ACM), biochemical recurrence (BCR), and metastases. Meta-analysis was performed to calculate the pooled hazard ratio (pHR) and their 95% confidence interval (95% CI). Heterogeneity between the studies was examined using I2?statistics. Appropriate subgroup analyses were conducted to explore the reasons for heterogeneity.?Results:?Out of 4216 retrieved citations, 24 observational studies and two randomized controlled studies with a total of 89,436 men with PCa met the inclusion criteria. Overall, any NSAID use was not associated with PCM, ACM, and BCR, with significant heterogeneity. Neither precancer treatment aspirin use (pHR: 1.00, 95% CI: 0.83, 1.19,?P?= 0.97, 5 studies, I2: 51%) nor postcancer treatment aspirin use (pHR: 0.94, 95% CI: 0.72, 1.23,?P?= 0.67, 8 studies, I2: 86%) was associated with PCM. Similar findings, that is, no significant association was observed for NSAID use and ACM or BCR overall, and in subgroup by types of NSAID use, and NSAID use following radiation or surgery.?Conclusion:?Although NSAID use was not associated with ACM, PCM, or BCR among men with PCa, significant heterogeneity remained in the included studies even after subgroup analyses.

Publication History

Article published online:
23 June 2021

? 2018. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

Abstract

Background:?Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown properties of inhibiting the progression of prostate cancer (PCa) in preclinical studies. However, epidemiological studies yield mixed results on the effectiveness of NSAIDs in PCa.?Objective:?The objective of this study was to determine the effect of NSAID use on clinical outcomes in PCa using systematic review and meta-analysis.?Methods:?Original articles published until the 1st week of October, 2016, were searched in electronic databases (Medline-Ovid, PubMed, Scopus, The Cochrane Library, and Web of Science) for studies on NSAID use in PCa. The main clinical outcomes for the review were: PCa-specific (PCM) and all-cause mortality (ACM), biochemical recurrence (BCR), and metastases. Meta-analysis was performed to calculate the pooled hazard ratio (pHR) and their 95% confidence interval (95% CI). Heterogeneity between the studies was examined using I2?statistics. Appropriate subgroup analyses were conducted to explore the reasons for heterogeneity.?Results:?Out of 4216 retrieved citations, 24 observational studies and two randomized controlled studies with a total of 89,436 men with PCa met the inclusion criteria. Overall, any NSAID use was not associated with PCM, ACM, and BCR, with significant heterogeneity. Neither precancer treatment aspirin use (pHR: 1.00, 95% CI: 0.83, 1.19,?P?= 0.97, 5 studies, I2: 51%) nor postcancer treatment aspirin use (pHR: 0.94, 95% CI: 0.72, 1.23,?P?= 0.67, 8 studies, I2: 86%) was associated with PCM. Similar findings, that is, no significant association was observed for NSAID use and ACM or BCR overall, and in subgroup by types of NSAID use, and NSAID use following radiation or surgery.?Conclusion:?Although NSAID use was not associated with ACM, PCM, or BCR among men with PCa, significant heterogeneity remained in the included studies even after subgroup analyses.

Introduction

Prostate cancer (PCa) is the second most common nonskin cancer with an estimated 508,345,355 survivors and 1,392,727 incident cases by 2020 as per the World Health Organization's report of 184 countries. PCa accounts for 15% of incident cancer cases diagnosed in men as of 2012 and is the fifth leading cause of death due to cancer in men.[1] Along the global disease burden, the worldwide cost of cancer medications is expected to increase by 11.5% from $107 billion in 2015 to 150 billion by 2020, attributed mainly to newly approved cancer chemotherapy.[2] With advance in the health-care management and focus on the value-based incentive payment models, there are needs to find potentially effective and affordable care among men with PCa.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been the first line of treatment to relieve pain and fever ? two common indicators of majority of diseases. With aspirin being the first NSAID, NSAIDs have seven chemical classes: salicylates, fenamates, para-aminophenol, acetic acid, enolic acid and propionic acid derivatives, and diaryl heterocyclic.[3] Biologically, NSAIDs inhibit development prostanoids by blocking the activity of the cyclooxygenase (COX) enzymes. Blockage of COX enzyme activity leads to a cascade of beneficial reactions inhibiting inflammatory response in cancer. For example, preclinical studies have found that NSAIDs inhibit platelet activation which in turn inhibits the development of aggressive cancers and metastases. Such studies have demonstrated that activated platelet could lead to carcinogenesis via releasing angiogenic factors, forming platelet?tumor cell aggregates, and evading immune surveillance in the blood.[4],[5] In addition, NSAIDs could also play a role by inhibiting cancer-related inflammation such as the infiltration of white blood cells; tumor-associated macrophages (TAMs); cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-?; chemokines such as (C-C motif) ligand 2 (CCL2) and CXCL8; acceleration of cell cycle progression and cell proliferation; evasion from apoptosis; and stimulation of tumor angiogenesis.[6],[7] Therefore, the NSAID may serve as a novel therapeutic option to manage PCa.

Epidemiological studies on NSAIDs yielded mixed results on the association between NSAIDs and clinical outcomes among men with PCa. Previously Liu?et al. conducted a systematic review of eight observational studies and found beneficial association of NSAID and PCa-specific mortality (PCM) for certain subgroups using published literature until 2013.[8] However, there still remains the need for future research to explore significant heterogeneity in the pooled study estimates with limited subgroup analyses. In addition, Liu?et al. did neither examine association between the NSAID use and biochemical recurrence (BCR), metastases, or all-cause mortality (ACM) among men with PCa, nor examine the effect of primary cancer treatment in men with PCa. With available recent publications, there is a need to re-evaluate the impact of NSAIDs and PCa-related outcomes. There have been publications of many studies since the date of search of previous two systematic reviews. Therefore, we carried out a systematic review and meta-analysis to examine the effect of NSAID on the clinical outcomes such as PCM, ACM, BCR, and metastases among men with PCa.

Methods

We followed the standard guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [9] and the Strengthening the Reporting of Observational studies in Epidemiology statement [10] to conduct and report the current systematic review and meta-analysis.

Criteria for study selection

Our systematic review included both prospective randomized controlled trials (RCTs), as well as prospective and retrospective nonrandomized a.k.a observational studies examining the effects of NSAIDs among men with PCa. However, we excluded experimental studies a. k. a cell lines,in vitro?and animal studies, and studies with shorter duration (?6 months) of follow-up. The main outcomes of interest for our review were PCM, ACM, BCR, and development of metastases.

Data sources and searches

We searched electronic databases (Medline [Ovid], Scopus, and the Cochrane library) to identify published articles on topic of our interest from the inception of each database to the 2nd week of March 2016. In addition, we also searched the Web of Science (WOS) to identify gray literature related to conference abstracts from the inception of WOS to the 3rd week of July 2016. We searched these databases using keywords such as ?Non-steroidal anti-inflammatory drugs,? ?Aspirin,? ?prostate neoplasm,? and ?prostate cancer.? We reported the details of search strategy for each database in Appendix 1 with keywords and number of retrieved citations per string. Further, we created a weekly alter for new citations' electronic databases. As of now, we included articles available in weekly search until October 10, 2016. Furthermore, we also scanned through the reference lists of identified studies for additional relevant studies.

Data extraction and quality assessment

Two authors (NR and DT) independently assessed the retrieved articles and gray literature for inclusion of articles in the review. We also checked the agreement for inclusion and exclusion of studies between two authors using the kappa statistic. In case of discrepancies about the inclusion or exclusion between two authors, a third author (ADR) resolved the issues with consensus. Three authors (ADR, NR, and DT) independently extracted information from the included studies using a data extraction template. The data extraction template has information on study design, country of participants, year of publication, sample size, inclusion and exclusion criteria of individual studies, PCa stage and severity-related variables, duration of NSAID use, and type and other baseline characteristics. In addition, we also extracted reported outcomes from each study on BCR, metastases, ACM, and PCM with details on statistical parameters such as number of events, median time to outcomes, unadjusted rates of outcomes, and unadjusted and adjusted hazard ratios (HRs).

We utilized the Newcastle Ottawa scale (NOS) tool to examine the risk of bias in included observational studies. The NOS allots up to nine points for the least risk of bias in three domains: (1) selection of study groups (four points); (2) comparability of groups (two points); and (3) ascertainment of exposure and outcomes (three points) for cohort studies. The risk of bias or poor quality was considered as ?high? with one or four score total scores, ?fair? with a total score of 4?6, and ?good? with a total score 7 or more.[11] In addition, we used the Cochrane Risk of Bias assessment tool to evaluate the risk of bias for performance, selection, reporting, and detecting bias domain for RCTs.[12]

Data synthesis and analysis

We computed a pooled hazard ratio (pHR) with 95% confidence interval (CI) for all clinical outcomes reported in the included studies using random-effects models. We used the Cochrane Chi-square (Cochran Q) statistic and the I2?test to analyze heterogeneity across included studies.[13] In the presence of heterogeneity of pooled estimates, we performed subgroup analyses by study design, countries of studies, cancer stage, primary cancer treatment, types of NSAIDs, timing of NSAID exposures, and potential adjusted confounders. We also determined the presence of publication bias for observational studies using Egger's method (Kendall's Tau)[14] and using a contour-enhanced funnel plot to determine other causes of publication bias by examining the symmetry of the plot.[15] All the analyses were performed using Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Results

We identified 4219 citations through electronic databases and other resources. Out of the 4219 citations, we removed 875 duplicates with 3344 citations eligible for first-level screening. We excluded 3068 citations in the first pass based on title and abstract and 237 citations in the second level screening based on full-text information. We excluded the following studies: animal models,in vitro studies, reviews, RCTs on interventions other than NSAIDs, RCTs or observational studies on NSAID use in noncancer population, and studies assessing the risk of PCa with the use of NSAIDs. Finally, a total of 26 studies (39 references) met inclusion criteria for our review. [Figure 1] depicts the study selection process as per the PRISMA framework from the retrieved citations.

|?Figure.1Systematic review and meta-analyses flow chart for study selection for the systematic review on nonsteroidal anti-inflammatory drugs and clinical outcomes in men with prostate cancer. RCT: Randomized Controlled Trials

Characteristics of included studies

[Table 1] describes the general characteristics of included studies published between 2001 and 2016. We identified 24 observational studies and two randomized controlled studies with a total pooled cohort of 89,436 men with PCa. The included studies had a total of 69,247 men from 20 retrospective cohort studies,[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[40],[41] 13,855 men from two prospective cohort studies,[34],[35] 1619 men from one case cohort study [36] and 4715 men from one nested case?control study,[37] and 300 men from two prospective randomized controlled studies.[38],[39] Seventeen studies were carried out in the United States,[16],[17],[18],[20],[21],[26],[27],[28],[31],[32],[33],[34],[35],[38],[39],[40],[41] three in the United Kingdom (UK),[22],[29],[37] two in Canada,[24],[36] one each in Belgium,[19] Greece,[30] Finland,[41] and Norway.[25] The sample size of the study cohort ranged between 74[27] and 11,779.[29] With respect to types of NSAID use, 23 of the included studies reported aspirin as the NSAID, one of the each studies reported Exisulind and Ketorolac, and two studies did not specify the type of NSAIDs. The proportion of men with NSAID use ranged from 9.7%[30] to 66%.[18] All the included studies had at least 1 year of median follow-up period with a maximum median duration of 9.25 years in a study.[32]

Table 1

Study characteristics of included studies

Seven of the included studies restricted their study cohort to localized PCa [18],[20],[24],[28],[29],[31],[32] and one study included men with advance PCa,[27] whereas the rest of studies did not restrict their cohort based on PCa stage. Six studies included men with PCa treated with radiation therapy (RT),[16],[23],[24],[27],[31],[33] five studies restricted the study cohort to men with PCa treated with radical prostatectomy (RP),[18],[19],[20],[26],[38] one study had men with active surveillance,[32] and the rest of the included men were diagnosed with PCa without restricting them to any primary PCa treatment such as RP/RT.

Characteristics of men with prostate cancer

[Table 2] describes the demographic, comorbidity, and lifestyle characteristics of men among the included studies by NSAID use. Majority of the included studies had 60?66 years of median or mean age of men with PCa. Five of the included studies had 1%?2% of cohort with African-American race distributed evenly between NSAID users and nonusers,[18],[26],[27],[29],[38] whereas one study [33] included only African-American men with PCa. Eleven studies reported the status of chronic conditions.[17],[20],[22],[23],[24],[28],[29],[30],[33],[37],[39] Five studies reported significant greater rate scores of Charlson Comorbidity Index or Adult Comorbidity Score-27 among NSAID users as compared to nonusers,[20],[22],[24],[30],[39] whereas six studies reported greater rates of difference in types of chronic conditions, specifically diabetes, heart disease, and hypertension among NSAID users as compared to nonusers.[17],[23],[24],[27],[29],[37] With regard to lifestyle characteristics, eight studies reported body mass index of the study cohort and majority of the studies had greater proportions of overweight or obese men in both NSAID users and nonusers.[17],[18],[26],[27],[29],[35],[36],[37] Six studies reported had the smoking status of study cohort and out of those all the studies had more than one-third of past or current smokers across NSAID users and nonusers.[17],[18],[22],[27],[36],[37]

Study name

Study design

Time frame

Study sample

Types of NSAID

Number of NSAID users

Percentage of NSAID users

Follow-up (median, IQR), in years

Stage of cancer

aCardwell et al. had a total of 453 cases and 1619 men in the subcohort, bStock et al. had 1184 cases and 3531 controls of which 617 cases and 1365 controls used any NSAID, cOther NSAID use includes the use of diclofenac, naproxen, indomethacin, and ibuprofen. IQR -?Interquartile range; NCCS -?Nested case-control study; NSAIDs -?Nonsteroidal anti-inflammatory drugs; PCa -?Prostate cancer; PCS -?Prospective cohort study; RCS -?Retrospective cohort study; RCT -?Randomized controlled trial; ASA -?Aspirin

Radical prostatectomy

Goluboff, 2001, US

RCT

2000-2001

94

Exisulind

47

50

1

Any PCa

Forget, 2011, Belgium

RCS

1993-2006

1111

Ketorolac

278

25

3.16 (1.33-5.75)

Any PCa

Mondul, 2011, US

RCS

1993-2006

2399

ASA

1584

66

7

Localized PCa

Kontraros, 2013, Greece

RCS

1999-2010

588

ASA

74

13

p: 3.4 (SD: 2.6)

Any PCa

Ishak-Howard, 2014, US

RCS

1999-2009

539

ASA

270

50

p: 7.9 (SD: 4.7)

Any PCa

Zaorsky, 2015, US

RCS

1991-2008

189

ASA

60

32

4.17 (0.28, 17.8)

Localized PCa

Radiation therapy

Zaorsky, 2011, US

RCS

1989-2006

2051

ASA

743

36

6.3 (1.5-19.9)

Localized PCa

Caon, 2014, Canada

RCS

2000-2007

3851

ASA

917

24

8.0

Localized PCa

Jacobs, 2014b, US

RCS

2005-2008

74

ASA

41

55

4.63

Advanced PCa

Choe, 2010, US

RCS

1988-2005

662

ASA

196

30

4.08

Any PCa

Osborn, 2016, US

RCS

2003-2010

469

ASA

147

31

5.08 (2.42-6.83)

Any PCa

Active surveillance

Agarwal, 2015, US

RCS

1994-2000

102

NSAIDs

51

50

9.25 (6.1-12.2)

Localized PCa

Any prostate cancer treatment

Ratansinghe, 2004, US

PCS

1971-1992

9,869

ASA

3934

40

Any PCa

D?Amico, 2008, US

RCT

1995-2001

206

ASA

86

42

8.2 (7.0-9.5)

Any PCa

Choe, 2012, US

RCS

-

5955

ASA

1817

31

5.83

Any PCa

Dhillon, 2012, US

PCS

1990-2005

3986

ASA

1586

40

p: 8.4

Any PCa

Cardwell, 2013a, UK

NCCS

1998-2006

4715

ASA

1982

42

p: 6.0

Any PCa

Daugherty, 2013, US

RCS

1993-2009

3857

ASA

-

-

5

Any PCa

Flahavan, 2013, UK

RCS

2001-2006

2936

ASA

1131

39

5.5

Any PCa

Grytli, 2014, Norway

RCS

2004-2009

3561

ASA

1149

32

3.25

Any PCa

Stock, 2008b, Canada

Case-Cohort

1990-1999

1619

ASA + others

419

26

-

Any PCa

NSAIDs

Veitonmaki, 2015,

RCS

1996-2012

6537

ASA + others

NSAID:

NSAID:

7.5

Any PCa

Finland

NSAIDs

5,591;

86%; ASA:

ASA: 637

10

Katz, 2010, US

RCS

1990-2003

7042

NSAIDs

1830

26

4(0-16)

Any PCa

Jacob, 2014C-1, US

RCS

1992-2010

8427

ASA

4827

57

p: 9.3

Localized PCa

Jacobs, 2014-C2, US

RCS

1992-2010

7118

ASA

4151

58

p: 8.4

Localized PCa

Assayag, 2015, UK

RCS

1996-2012

11,779

ASA

4147

35

p: 5.4 (SD: 2.9)

Localized PCa

Table 2

Demographic, comorbidity, and lifestyle characteristics of study population by nonsteroidal anti-inflammatory drugs use among the included studies

[Table 3] describes PCa-related clinical and cancer-related treatment characteristics by NSAID use. Fourteen studies reported the status of prostate-specific antigen (PSA) levels [16],[18],[19],[20],[23],[25],[26],[28],[29],[31],[35],[36],[38],[39] and those studies did not find significant difference in PSA levels between NSAID users and nonusers. Sixteen studies reported Gleason score,[16],[18],[19],[20],[22],[25],[26],[28],[29],[30],[31],[35],[37],[38],[21],[29],[39] of which two studies included >50% of men with Gleason score >7. Thirteen studies reported tumor stage,[16],[18],[19],[20],[22],[25],[26],[27],[28],[30],[35],[36],[39] of which two studies [20],[36] had significant differences in the proportion of men with T2/3 stages among NSAID users and nonusers. Nine studies [16],[20],[21],[24],[25],[31],[33],[38],[39] reported the National Comprehensive Cancer Network scores of which one study [20] had significant difference in medium- and high-risk PCa among NSAID users and nonusers. Fifteen studies reported androgen deprivation therapy (ADT)[16],[17],[18],[21],[22],[24],[25],[27],[28],[29],[30],[31],[35],[36],[37] of which two studies [18],[31] did not have any men with ADT users among NSAIDs users and no users.

Study name

Study groups

Age (years)

Race/ ethnicity (%)

Comorbidities (%)

BMI (kg/m2)

Smoking (%)

? - mean; M - median; AA -?African-American; ASA -?Aspirin; BMI -?Body mass index; CCI -?Charlson Comorbidity Score; COPD -?Chronic obstructive pulmonary disease; CVD -?Cardiovascular disease; DM -?Diabetes mellitus; HF -?Heart failure; HTN -?Hypertension; LT -?Less than; MI -?Myocardial infarction; NSAID -?Nonsteroidal anti-inflammatory drugs; OD -?Once daily; UK -?United kingdom; US -?United states; W -?Whites; ACS -?Adult Comorbidity Score-27; C/P -?Current smoker or past smoker

Radical prostatectomy

Mondul, 2011, US

Overall

|?Figure.1Systematic review and meta-analyses flow chart for study selection for the systematic review on nonsteroidal anti-inflammatory drugs and clinical outcomes in men with prostate cancer. RCT: Randomized Controlled Trials

|?Figure.2Forest plot of comparison: Nonsteroidal anti-inflammatory drug users versus nonusers for prostate cancer-specific mortality

|?Figure.3Forest plot of comparison: Nonsteroidal anti-inflammatory drug users versus nonusers for all-cause mortality

|?Figure.4Forest plot of comparison: Nonsteroidal anti-inflammatory drug users versus nonusers for biochemical recurrence

References

  1. lobocan 2012 ? Home. Available from: http://www.globocan.iarc.fr/Default.aspx. [Last accessed on 2016 Jun 04].
  2. lobal Oncology Trend Report a Review of 2015 and Outlook to 2020.IMS Health; 2016. Available from: http://www.imshealth.com/en/thought-leadership/ims-institute/reports/global-oncology-trend-report-a-review-of-2015-and-outlook-to-2020 [Last accessed on 2016 Jun 04]
  3. hun MJ, Blackard B.?Pharmacologic effects of NSAIDs and implications for the risks and benefits of long-term prophylactic use of aspirin to prevent cancer. Recent Results Cancer Res 2009; 181: 215-21
  4. oubran HA, Burnouf T, Radosevic M, El-Ekiaby M.?The platelet-cancer loop. Eur J Intern Med 2013; 24: 393-400
  5. ay LJ, Felding-Habermann B.?Contribution of platelets to tumour metastasis. Nat Rev Cancer 2011; 11: 123-34
  6. olotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability?Carcinogenesis?2009; 30:?1073-81
  7. undu JK, Surh YJ.?Inflammation: Gearing the Journey to Cancer. Vol.659. Proceedings 5th International Conference Environmental Mutagens Humam Population ICEMHP 2008; p: 15-30
  8. iu Y, Chen JQ, Xie L, Wang J, Li T, He Y.?et al.?Effect of aspirin and other non-steroidal anti-inflammatory drugs on prostate cancer incidence and mortality: A systematic review and meta-analysis. BMC Med 2014; 12: 55
  9. oher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group.?Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009; 6: e1000097
  10. von ElmE, Altman DG, Egger M, Pocock SJ, G?tzsche PC.?et al?Strengthening the reporting of observational studies in epidemiology (STROBE) statement: Guidelines for reporting observational studies. BMJ 2007; 335: 806-8
  11. Ottawa Hospital Research Institute. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. [Last accessed on 2016 Jun 04].
  12. Cochrane Handbook for Systematic Reviews of Interventions. Available from: http://www.handbook.cochrane.org/. [Last accessed on 2016 Apr 30].
  13. van HouwelingenHC, Arends LR, Stijnen T.?Advanced methods in meta-analysis: Multivariate approach and meta-regression. Stat Med 2002; 21: 589-624
  14. Deeks JJ, Macaskill P, Irwig L.?The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol 2005; 58: 882-93
  15. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L.?Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol 2008; 61: 991-6
  16. Choe KS, Cowan JE, Chan JM, Carroll PR, D'Amico AV, Liauw SL.?et al.?Aspirin use and the risk of prostate cancer mortality in men treated with prostatectomy or radiotherapy. J Clin Oncol 2012; 30: 3540-4
  17. Katz MS, Carroll PR, Cowan JE, Chan JM, D'Amico AV.?Association of statin and nonsteroidal anti-inflammatory drug use with prostate cancer outcomes: Results from caPSURE. BJU Int 2010; 106: 627-32
  18. Mondul AM, Han M, Humphreys EB, Meinhold CL, Walsh PC, Platz EA.?et al.?Association of statin use with pathological tumor characteristics and prostate cancer recurrence after surgery. J Urol 2011; 185: 1268-73
  19. Forget P, Tombal B, Scholt?s JL, Nzimbala J, Meulders C, Legrand C.?et al.?Do intraoperative analgesics influence oncological outcomes after radical prostatectomy for prostate cancer?. Eur J Anaesthesiol 2011; 28: 830-5
  20. Zaorsky NG, Li T, Cohen RJ, Horwitz EM, Uzzo RG, Viterbo R.?et al.?Aspirin use decreases the risk of prostate cancer recurrence after post-prostatectomy radiotherapy. J Radiat Oncol 2015; 4: 193-201
  21. Choe KS, Correa D, Jani AB, Liauw SL.?The use of anticoagulants improves biochemical control of localized prostate cancer treated with radiotherapy. Cancer 2010; 116: 1820-6
  22. Flahavan EM, Bennett K, Sharp L, Barron TI.?A cohort study investigating aspirin use and survival in men with prostate cancer. Ann Oncol 2014; 25: 154-9
  23. Kontraros M, Varkarakis I, Ntoumas K, Deliveliotis C.?Pathological characteristics, biochemical recurrence and functional outcome in radical prostatectomy patients on statin therapy. Urol Int 2013; 90: 263-9
  24. Caon J, Paquette M, Hamm J, Pickles T.?Does statin or ASA affect survival when prostate cancer is treated with external beam radiation therapy?. Prostate Cancer 2014; 2014: 184297
  25. Grytli HH, Fagerland MW, Foss? SD, Task?n KA.?Association between use of ?-blockers and prostate cancer-specific survival: A cohort study of 3561 prostate cancer patients with high-risk or metastatic disease. Eur Urol 2013; 65: 635-41
  26. Ishak-Howard MB, Okoth LA, Cooney KA.?et al.?Neonatal. Neonat 2013; 2: 4-7
  27. Jacobs CD, Chun SG, Yan J, Xie XJ, Pistenmaa DA, Hannan R.?et al.?Aspirin improves outcome in high risk prostate cancer patients treated with radiation therapy. Cancer Biol Ther 2014; 15: 699-706
  28. Jacobs EJ, Newton CC, Stevens VL, Campbell PT, Freedland SJ, Gapstur SM.?et al.?Daily aspirin use and prostate cancer-specific mortality in a large cohort of men with nonmetastatic prostate cancer. J Clin Oncol 2014; 32: 3716-22
  29. Assayag J, Pollak MN, Azoulay L.?The use of aspirin and the risk of mortality in patients with prostate cancer. J Urol 2015; 193: 1220-5
  30. Veitonm?ki T, Murtola TJ, M??tt?nen L, Taari K, Stenman UH, Tammela TL.?Use of non-steroidal anti-inflammatory drugs and prostate cancer survival in the Finnish prostate cancer screening trial. Prostate 2015; 75: 1394-402
  31. Zaorsky NG, Buyyounouski MK, Li T, Horwitz EM.?Aspirin and statin nonuse associated with early biochemical failure after prostate radiation therapy. Int J Radiat Oncol Biol Phys 2012; 84: e13-7
  32. Agarwal G, Spuches J, Luchey A, Patel T, Pow-Sang J.?The effect of NSAID use on disease progression in patients on active surveillance for prostate cancer. Ann Rheum Dis 2015; 193: e756
  33. Osborn VW, Chen SC, Weiner J, Schwartz D.?Impact of aspirin on clinical outcomes for African American men with prostate cancer undergoing radiation. Tumori 2016; 102: 65-70
  34. Ratnasinghe LD, Graubard BI, Kahle L, Tangrea JA, Taylor PR, Hawk E.?et al.?Aspirin use and mortality from cancer in a prospective cohort study. Anticancer Res 2004; 24: 3177-84
  35. Dhillon PK, Kenfield SA, Stampfer MJ, Giovannucci EL, Chan JM.?Aspirin use after a prostate cancer diagnosis and cancer survival in a prospective cohort. Cancer Prev Res (Phila) 2012; 5: 1223-8
  36. Stock DC, Groome PA, Siemens DR, Rohland SL, Sinha S.?Effects of non-selective non-steroidal anti-inflammatory drugs on the aggressiveness of prostate cancer. Prostate 2008; 68: 1655-65
  37. Cardwell CR, Flahavan EM, Hughes CM, Coleman HG, O'Sullivan JM, Powe DG.?et al?Low-dose aspirin and survival in men with prostate cancer: A study using the UK Clinical Practice Research Datalink. Cancer Causes Control 2014; 25: 33-43
  38. Goluboff ET, Prager D, Rukstalis D, Giantonio B, Giantonio D, Madorsky M, Barken I.?et al.?Safety and efficacy of exisulind for treatment of recurrent prostate cancer after radical prostatectomy. J Urol 2001; 166: 882-6
  39. D'Amico AV, Chen MH, Renshaw AA, Loffredo B, Kantoff PW.?Risk of prostate cancer recurrence in men treated with radiation alone or in conjunction with combined or less than combined androgen suppression therapy. J Clin Oncol 2008; 26: 2979-83
  40. Daugherty S, Pfeiffer R, Ghazarian A, Izmirlian G, Prorok P, McGlynn K.?Frequency of aspirin use and prostate cancer mortality among prostate cancer cases in the control arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial. Cancer Res 2013; 73: LB-15
  41. Veitonm?ki T, Murtola TJ, Talala K, Taari K, Tammela T, Auvinen A.?et al?Non-steroidal anti-inflammatory drugs and cancer death in the Finnish prostate cancer screening trial. PLoS One 2016; 11: e0153413
  42. D'Amico AV, Kantoff PW, Chen MH.?Aspirin and hormone therapy for prostate cancer. N Engl J Med 2007; 357: 2737-8