# Nonsteroidal anti-inflammatory drugs (NSAIDs) and prostate cancer risk: results from the EPICAP study

Solène Doat, Sylvie Cenée, Brigitte Tretarre, Xavier Rébillard, Pierre-Jean Lamy, Jean-Pierre Bringer, François Iborra, Thibaut Murez, Marie Sanchez, Florence Menegaux

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Solène Doat, Sylvie Cenée, Brigitte Tretarre, Xavier Rébillard, Pierre-Jean Lamy, et al.. Nonsteroidal anti-inflammatory drugs (NSAIDs) and prostate cancer risk: results from the EPICAP study. Cancer Medicine, 2017, 6 (10), pp.2461 - 2470. 10.1002/cam4.1186. hal-01622150

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# Nonsteroidal anti-inflammatory drugs (NSAIDs) and prostate cancer risk: results from the EPICAP study

Solene Doat<fnref n="1" />,<fnref n="2" />, Sylvie Cénée<fnref n="1" />, Brigitte Trétarre<fnref n="3" />, Xavier Rebillard<fnref n="4" />, Pierre-Jean Lamy<fnref n="4" />,<fnref n="5" />, Jean-Pierre Bringer<fnref n="6" />, François Iborra<fnref n="7" />, Thibaut Murez<fnref n="8" />, Marie Sanchez<fnref n="1" />, Florence Menegaux<fnref n="1" />,<fnref n="9" />

<figure><img src="image_2.png" /></figure>

**Keywords**

Cyclooxygenase, inflammation, NSAIDs, prostate cancer

**Correspondence**

Florence Menegaux, INSERM U1018, CESP, Team Cancer & Environment, 16 av. Paul Vaillant Couturier, 94807 Villejuif Cedex, France. Tel: +33 1 45 59 51 53; Fax: +33 1 47 26 94 54; Email: florence.menegaux@inserm.fr

**Funding Information**

This study was supported by Ligue nationale contre le cancer, Ligue contre le cancer du Val de Marne, Fondation de France, and Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES).

Received: 9 May 2017; Revised: 6 July 2017; Accepted: 7 August 2017

**Cancer Medicine 2017; 6(10):2461-2470**

doi: 10.1002/cam4.1186

The members of the EPICAP study group are listed in the Acknowledgment section.

**Abstract**

Chronic inflammation may play a role in prostate cancer carcinogenesis. In that context, our objective was to investigate the role of nonsteroidal anti-inflammatory drugs (NSAIDs) in prostate cancer risk based on the EPICAP data. EPICAP is a population-based case-control study carried out in 2012-2013 (département of Hérault, France) that enrolled 819 men aged less than 75 years old newly diagnosed for prostate cancer and 879 controls frequency matched to the cases on age. Face to face interviews gathered information on several potential risk factors including NSAIDs use. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated using unconditional logistic regression models. All-NSAIDs use was inversely associated with prostate cancer: OR 0.77, 95% CI 0.61-0.98, especially in men using NSAIDs that preferentially inhibit COX-2 activity (OR 0.48, 95% CI 0.28-0.79). Nonaspirin NSAIDs users had a decreased risk of prostate cancer (OR 0.72, 95% CI 0.53-0.99), particularly among men with an aggressive prostate cancer (OR 0.49, 95% CI 0.27-0.89) and in men with a personal history of prostatitis (OR 0.21, 95% CI 0.07-0.59). Our results are in favor of a decreased risk of prostate cancer in men using NSAIDs, particularly for men using preferential anti-COX-2 activity. The protective effect of NSAIDs seems to be more pronounced in aggressive prostate cancer and in men with a personal history of prostatitis, but this needs further investigations to be confirmed.

**Introduction**

Prostate cancer is the most common male cancer in westernized countries with an estimated 1.1 million men diagnosed with prostate cancer in 2012 worldwide [1]. In France, more than 50,000 cases of prostate cancer were diagnosed

in 2011, with almost 9000 related deaths that same year making it the third cause of cancer-related mortality [2].

Except age, ethnic origin, and family history of prostate cancer that are well-established nonmodifiable risk factors, the etiology of prostate cancer remains largely unknown. Accumulating epidemiological, biological, genetic, and

<footnote n="1">¹CESP (Center for Research in Epidemiology and Population Health), Inserm, Team Cancer and Environment, Université Paris-Saclay, Université Paris-Sud, Villejuif, France</footnote>

<footnote n="2">²Hepato-gastroenterology Department, Unit of Gastrointestinal Tumor Screening and Treatment, Pitié-Salpêtrière Hospital, Paris Public Hospital Authority (AP-HP), Paris, France</footnote>

<footnote n="3">³Registre des Tumeurs de l'Hérault, Montpellier, France</footnote>

<footnote n="4">⁴Service Urologie, Clinique Beau Soleil, Montpellier, France</footnote>

<footnote n="5">⁵Institut médical d'Analyse Génomique-Imagenome, Labosud, Montpellier, France</footnote>

<footnote n="6">⁶Polyclinique Saint Privat, Béziers, France</footnote>

<footnote n="7">⁷Cabinet Urologie du Polygone, Montpellier, France</footnote>

<footnote n="8">⁸Hôpital Lapeyronie, Centre Hospitalo-Universitaire, Montpellier, France</footnote>

<footnote n="9">⁹Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina</footnote>
experimental evidence suggested that chronic inflammation
may be associated either with initiation or progression
of several cancers, including prostate cancer [3–6]. Indeed,
inflammatory cells as well as the chemokines and cytokines
they produce confer a microenvironment favorable to
tumor growth, by increasing the production of reactive
oxygen species leading to oxidative DNA damage and
reduce DNA repair, and tumor progression by promoting
angiogenesis [3–5].

Regarding prostate cancer, the presence of inflammatory
infiltrations localized near zones of proliferative inflam-
matory atrophy and prostatic intraepithelial neoplasia,
considered to be potentially precancerous prostatic lesions,
has contributed to reinforce the hypothesis of a possible
link between chronic inflammation and prostate cancer
[7]. Moreover, prostate tissues with histological evidence
of inflammation were more likely to develop prostate cancer
than those without inflammation [8]. The mechanism of
inflammation is based on the action of the cyclooxygenase
(COX), enzyme that catalyzes messenger molecules in
inflammation pathways [9]. There are two distinct isoforms
of the COX enzyme: COX-1, constitutively expressed in
most tissues and involved in physiological functions, and
COX-2, expressed in several tissues during inflammation.
Indeed, an overexpression of COX-2 in human prostate
cancer tissue compared to benign prostate tissue has been
reported [10]. Therefore, nonsteroidal anti-inflammatory
drugs (NSAIDs), used for their analgesic and antipyretic
properties, and at higher doses, for their anti-inflammatory
effects, have received attention for their potential as chemo-
preventive drugs against cancer. They may be characterized
according to their ability to preferentially inhibit COX-1
as aspirin or COX-2 as coxibs or oxicams [11].

Most epidemiological studies reported an inverse asso-
ciation between aspirin and cancer risk, especially for
colorectal cancer [12]. Modest inverse associations were
also reported with aspirin use and prostate cancer occur-
rence in observational studies or meta-analysis [13–17].
Evidence for nonaspirin NSAIDs (NA-NSAID) use and
inverse association with cancer are even more scarce, with
at least three observational studies showing even a posi-
tive association with prostate cancer risk [18–20] and
others showing null or weak negative association [21–28].
Meta-analysis could not give strong conclusions because
of striking heterogeneity between studies [14–16, 29], with
only one showing modest inverse association [16] and
three of them null association.

Few of these studies provided data on type of NSAIDs
and anti-COX preferential activity, frequency, duration,
recency of use, circumstances of prescription, and addressed
the aggressiveness of cancer.

In this context, our main objective was to study the
association between NSAIDs use (aspirin and nonaspirin

NSAIDs) and prostate cancer risk based on the data from
the EPICAP study.

**Materials and Methods**

Study population

EPICAP (EPIdemiology of Prostate CAncer) is a
population-based case-control study which details of the
study protocol have been published elsewhere [30]. Cases
were men newly diagnosed with histologically confirmed
prostate cancer between 2012 and 2013, aged less than
75 years old, and living in the *département* of Hérault,
France at the time of diagnosis. The identification of the
cases was realized by clinical research nurses, specifically
trained for the study, by active search in all public and
private cancer care centers of the *département*. Only cases
who gave their informed consent were included in the
study. Controls were men randomly selected in the general
population, frequency matched to the cases, living in the
*département* of Hérault as the cases, and with no history
of prostate cancer at the time of inclusion. Quotas by
age were established as a preliminary to yield the control
group similar to the case group in terms of age in order
to achieve frequency matching (5 year age group). Quotas
by socioeconomic status (SES) were also set a priori to
control for potential selection bias arising from differential
participation rates across SES categories. These quotas by
SES were calculated from the census data available in the
*département* of Hérault, in order to obtain a distribution
by SES among controls identical to the SES distribution
among general male population, conditionally to age.

A total of 1098 cases and 1109 controls were eligible,
of which 819 and 879, respectively, were included in the
study representing a participation rate of 75% for cases
and 79% for controls.

Data collection

Trained clinical research nurses conducted face to face
interviews of cases and controls using a standardized
questionnaire based on a CAPI system (Computer-Assisted
Personal Interview). Detailed information on socioeco-
nomic characteristics, personal medical history and drugs
use, family history of cancer, diet, tobacco, and alcohol
consumption, physical activity, and residential and occu-
pational history were gathered.

Cases and controls were asked about their lifetime aspirin
and NA-NSAIDs consumption, and more specifically about
the name, the frequency, and the duration of the specific
NSAID they used. They were also asked about the reason
of NSAID use and if the use was under medical prescrip-
tion or over the counter.
For prostate cancer cases, medical information such as Gleason score or PSA at diagnosis had been extracted from their medical record or from the Hérault Cancer Registry.

## Statistical analysis

All analyses were performed using SAS 9.4 software (SAS Institute Inc., Cary, NC). NSAIDs were divided into three categories: overall users (all-NSAIDs), aspirin users (aspirin), and nonaspirin NSAID users (NA-NSAIDs). All-NSAIDs users were defined as users of aspirin or NA-NSAIDs at least once a month. Men who never took, or less than once a month, any kind of NSAIDs were considered as nonusers (reference class). The frequency of use (<1/day, =1/day, ≥1/day), duration of use (<5 years, 5–10 years, >10 years), and recency of use (former, current) were analyzed for all-NSAIDs, aspirin, and NA-NSAIDs users. We also classified NSAIDs according to their anti-COX-1 or anti-COX-2 preferential activity based on the known COX-1/COX-2 ratio of each NSAID. Coxib, diclofenac, etodolac, and oxicams inhibit preferentially COX-2 (ratio <1), while aspirin, propionates, and indometacin inhibit preferentially COX-1 [11].

Unconditional logistic regression models were used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs). Analyses were systematically adjusted for age (5-year period), family history of prostate cancer in first-degree relatives and race (Caucasians, others). Analyses were also adjusted for other potential confounding factors such as educational level, body mass index (BMI) (<25/25–30/≥30) or waist to hip ratio (WHR) (<0.95/≥0.95), and personal prostatitis history (no: no personal history of prostatitis/yes: at least one personal history of acute or chronic prostatitis).

Separate analyses were also conducted by prostate cancer aggressiveness according to the Gleason score (low or intermediate score ≤7 [including 3 + 4], high score ≥7 [including 4 + 3]).

## Ethics statement

Each subject enrolled in the study provides their written informed consent. The EPICAP study was approved by the Institutional Review Board of the French National Institute of Health and Medical Research (IRB-Inserm No. 01-040, November 2010) and by the French data Protection Authority (CNIL No. 910485, April 2011).

## Results

The characteristics of prostate cancer cases and controls are presented in Table 1. We enrolled 819 prostate cancer

cases and 879 population-based controls, and among them, age distribution in 5-year groups was the same in both cases and controls ($P = 0.19$). Among cases of prostate cancer, 76% had a low or intermediate Gleason score ≤7 (including 3 + 4), and 22% had a high score ≥7 (including 4 + 3), that is, aggressive cancer, and among them, 10% had a Gleason score over 7. Our study population was predominantly Caucasian (>95% for both cases and controls). Family history of prostate cancer in first-degree relatives was more frequent in cases than in controls (22% in cases vs. 9% in controls, $P < 0.0001$), consistent with the literature. Considering anthropomorphic data, BMI was similar in cases and controls ($P = 0.79$), while WHR was significantly higher in cases than in controls (73% of cases vs. 67% of controls, $P = 0.03$). Personal history of certain comorbidities, such as cardiovascular background (myocardial infarction, hypertension, stroke, diabetes) and rheumatologic background, were similarly distributed between cases and controls ($P = 0.56, P = 0.52$, respectively), while personal history of prostatitis was significantly more frequent in cases than in controls ($P = 0.02$).

Sociodemographic and lifestyle characteristics of all-NSAID users and nonusers among controls are shown in Table 2. NSAIDs users and nonusers were similar in terms of age, family history of prostate cancer in first-degree relatives, educational level, and smoking status ($P = 0.23, P = 0.15, P = 0.31, P = 0.35$, respectively). In the contrary, NSAIDs users were more likely to have a BMI of 30 and above, a personal history of prostatitis, a cardiovascular or a rheumatologic background than nonusers ($P = 0.002, P = 0.002, P < 0.0001, P < 0.0001$, respectively).

We observed that 220 (27%) cases and 272 (31%) controls had ever used all-NSAIDs (OR 0.77, 95% CI 0.61–0.98) (Table 3). The association decreased with the frequency of use (OR 0.93, 95% CI 0.68–1.27 for less than 1 use per day; OR 0.75, 95% CI 0.54–1.04 for 1 use per day; OR 0.38, 95% CI 0.18–0.79 for more than 1 use per day; $P$ trend = 0.003) and was more pronounced for a duration of 5–10 years (OR 0.55, 95% CI 0.33–0.92), for a current use (OR 0.68, 95% CI 0.50–0.94), and when the NSAIDs use had a preferentially anti-COX-2 activity (OR 0.48, 95% CI 0.28–0.79).

Associations for aspirin use and NA-NSAIDs use are presented in Table 4. Aspirin use was slightly negatively, but not significantly, associated with prostate cancer (OR 0.86, 95% CI 0.65–1.14). Nevertheless, a frequency of 1 use per day, a duration of 5–10 years, and a current use were significantly negatively associated with prostate cancer (OR 0.59, 95% CI 0.39–0.89; OR 0.49, 95% CI 0.27–0.90; OR 0.70, 95% CI 0.48–1.00, respectively). NA-NSAIDs use was also negatively associated with prostate cancer (OR 0.72, 95% CI 0.53–0.99), especially under medical
<table><caption>**Table 1.** Study population characteristics.</caption><thead><tr><th></th><th>Cases<br>n = 819 (%)</th><th>Controls<br>n = 879 (%)</th><th>P-value<sup>1</sup></th></tr></thead><tbody><tr><td>Gleason score</td><td></td><td></td><td></td></tr><tr><td>≤7 (3 + 4)</td><td>623 (76)</td><td>—</td><td></td></tr><tr><td>≥7 (4 + 3)</td><td>180 (22)</td><td>—</td><td></td></tr><tr><td>Age at diagnosis/interview, years</td><td></td><td></td><td>0.19</td></tr><tr><td>40–55</td><td>48 (6)</td><td>59 (7)</td><td></td></tr><tr><td>55–60</td><td>99 (12)</td><td>99 (11)</td><td></td></tr><tr><td>60–65</td><td>217 (27)</td><td>201 (23)</td><td></td></tr><tr><td>65–70</td><td>274 (33)</td><td>285 (32)</td><td></td></tr><tr><td>70–75</td><td>181 (22)</td><td>235 (27)</td><td></td></tr><tr><td>Race</td><td></td><td></td><td>0.43</td></tr><tr><td>Caucasian</td><td>795 (97)</td><td>859 (98)</td><td></td></tr><tr><td>Other</td><td>24 (3)</td><td>20 (2)</td><td></td></tr><tr><td>Family history of prostate cancer at first degree</td><td></td><td></td><td>&lt;0.0001</td></tr><tr><td>No</td><td>549 (67)</td><td>723 (82)</td><td></td></tr><tr><td>Yes</td><td>181 (22)</td><td>77 (9)</td><td></td></tr><tr><td>Educational level</td><td></td><td></td><td>0.22</td></tr><tr><td>No diploma</td><td>70 (9)</td><td>72 (8)</td><td></td></tr><tr><td>Up to high school</td><td>376 (46)</td><td>436 (50)</td><td></td></tr><tr><td>High school</td><td>113 (14)</td><td>110 (13)</td><td></td></tr><tr><td>College</td><td>260 (32)</td><td>260 (30)</td><td></td></tr><tr><td>Smoking status</td><td></td><td></td><td>0.077</td></tr><tr><td>Never</td><td>240 (29)</td><td>246 (28)</td><td></td></tr><tr><td>Ex-smoker</td><td>455 (56)</td><td>476 (54)</td><td></td></tr><tr><td>Smoker</td><td>123 (15)</td><td>157 (18)</td><td></td></tr><tr><td>Body mass index (BMI)</td><td></td><td></td><td>0.79</td></tr><tr><td>&lt;25</td><td>231 (28)</td><td>248 (28)</td><td></td></tr><tr><td>25–29</td><td>399 (49)</td><td>397 (45)</td><td></td></tr><tr><td>≥30</td><td>182 (22)</td><td>207 (24)</td><td></td></tr><tr><td>Waist to hip ratio (WHR)</td><td></td><td></td><td>0.03</td></tr><tr><td>&lt;0.95</td><td>214 (26)</td><td>265 (30)</td><td></td></tr><tr><td>≥0.95</td><td>594 (73)</td><td>590 (67)</td><td></td></tr><tr><td>Prostatitis history</td><td></td><td></td><td>0.02</td></tr><tr><td>No</td><td>735 (90)</td><td>816 (93)</td><td></td></tr><tr><td>Yes</td><td>84 (10)</td><td>63 (7)</td><td></td></tr><tr><td>Cardiovascular background<sup>2</sup></td><td></td><td></td><td>0.56</td></tr><tr><td>No</td><td>432 (53)</td><td>443 (51)</td><td></td></tr><tr><td>Yes</td><td>384 (47)</td><td>427 (49)</td><td></td></tr><tr><td>Rheumatologic background<sup>3</sup></td><td></td><td></td><td>0.52</td></tr><tr><td>No</td><td>626 (78)</td><td>662 (77)</td><td></td></tr><tr><td>Yes</td><td>175 (21)</td><td>202 (23)</td><td></td></tr></tbody></table>

prescription (OR 0.71, 95% CI 0.51–0.97). There was neither frequency nor duration clear effect, but current use was strongly negatively associated (OR 0.52, 95% CI 0.30–0.91).

We performed all analyses according to the aggressiveness of prostate cancer (Table 5). NA-NSAIDs use was negatively associated with aggressive prostate cancer (OR 0.49, 95% CI 0.27–0.89 vs. OR 0.78, 95% CI 0.56–1.09 for low or intermediate score); especially NA-NSAID with preferential anti-COX-2 activity (OR 0.33, 95% CI 0.11–0.94). This association was not found with aspirin use.

Finally, stratifying on history of prostatitis (Table 6), the inverse association observed with NSAIDs was reinforced among patients with a personal history of prostatitis (OR 0.32, 95% CI 0.15–0.71) compared to men with no history of prostatitis (OR 0.85, 95% CI 0.67–1.09); especially among NA-NSAID users (OR 0.21, 95% CI 0.07–0.59 vs. OR 0.82, 95% CI 0.59–1.12, respectively). Interaction was statistically significant for all-NSAIDs use (P = 0.02).

All analyses were also adjusted for the reason of NSAIDs use such as cardiovascular and rheumatologic backgrounds, and results remained unchanged.

<footnote n="1">¹Adjusted for age.</footnote>

<footnote n="2">²Myocardial infarction, hypertension, stroke, diabetes.</footnote>

<footnote n="3">³Rheumatoid polyarthritis, spondylarthropathies, arthrosis.</footnote>
<table><caption>**Table 2.** Characteristics of NSAIDs users and nonusers among controls.</caption><thead><tr><th></th><th>All<br>n = 879</th><th></th><th></th></tr><tr><th></th><th>Nonusers<br>n = 593 (67%)</th><th>NSAID users<br>n = 272 (31%)</th><th>P-value<sup>1</sup></th></tr></thead><tbody><tr><td>Age at diagnosis/interview, years</td><td></td><td></td><td>0.10</td></tr><tr><td>40-55</td><td>42 (7)</td><td>13 (5)</td><td></td></tr><tr><td>55-60</td><td>69 (12)</td><td>30 (11)</td><td></td></tr><tr><td>60-65</td><td>141 (24)</td><td>58 (21)</td><td></td></tr><tr><td>65-70</td><td>189 (32)</td><td>92 (34)</td><td></td></tr><tr><td>70-75</td><td>152 (26)</td><td>79 (29)</td><td></td></tr><tr><td>Race</td><td></td><td></td><td>0.06</td></tr><tr><td>Caucasian</td><td>583 (98)</td><td>262 (96)</td><td></td></tr><tr><td>Other</td><td>10 (2)</td><td>10 (4)</td><td></td></tr><tr><td>Family history of prostate cancer at first degree</td><td></td><td></td><td>0.05</td></tr><tr><td>No</td><td>495 (83)</td><td>215 (79)</td><td></td></tr><tr><td>Yes</td><td>45 (8)</td><td>32 (12)</td><td></td></tr><tr><td>Educational level</td><td></td><td></td><td>0.28</td></tr><tr><td>No diploma</td><td>45 (8)</td><td>24 (9)</td><td></td></tr><tr><td>Up to high school</td><td>295 (50)</td><td>134 (49)</td><td></td></tr><tr><td>High school</td><td>69 (11)</td><td>39 (14)</td><td></td></tr><tr><td>College</td><td>184 (31)</td><td>74 (27)</td><td></td></tr><tr><td>Smoking status</td><td></td><td></td><td>0.58</td></tr><tr><td>Never</td><td>169 (29)</td><td>76 (28)</td><td></td></tr><tr><td>Ex-smoker</td><td>320 (54)</td><td>147 (54)</td><td></td></tr><tr><td>Smoker</td><td>104 (18)</td><td>49 (18)</td><td></td></tr><tr><td>Body mass index (BMI)</td><td></td><td></td><td>0.002</td></tr><tr><td>&lt;25</td><td>177 (30)</td><td>67 (25)</td><td></td></tr><tr><td>25-29</td><td>281 (47)</td><td>106 (39)</td><td></td></tr><tr><td>≥30</td><td>122 (21)</td><td>85 (31)</td><td></td></tr><tr><td>Waist to hip ratio (WHR)</td><td></td><td></td><td>0.67</td></tr><tr><td>≤95</td><td>184 (30)</td><td>78 (29)</td><td></td></tr><tr><td>&gt;95</td><td>396 (67)</td><td>183 (67)</td><td></td></tr><tr><td>Prostatitis history</td><td></td><td></td><td>0.002</td></tr><tr><td>No</td><td>561 (95)</td><td>241 (89)</td><td></td></tr><tr><td>Yes</td><td>32 (5)</td><td>31 (11)</td><td></td></tr><tr><td>Cardiovascular background<sup>2</sup></td><td></td><td></td><td>&lt;0.0001</td></tr><tr><td>No</td><td>333 (57)</td><td>103 (38)</td><td></td></tr><tr><td>Yes</td><td>255 (43)</td><td>165 (61)</td><td></td></tr><tr><td>Rheumatologic background<sup>3</sup></td><td></td><td></td><td>&lt;0.0001</td></tr><tr><td>No</td><td>476 (81)</td><td>175 (64)</td><td></td></tr><tr><td>Yes</td><td>111 (19)</td><td>88 (32)</td><td></td></tr></tbody></table>

Discussion

This study showed that NSAIDs consumption was negatively associated with prostate cancer occurrence, with a 23% reduction in prostate cancer risk, with convincing inverse associations of both aspirin and NA-NSAIDs use. This association was more pronounced with a frequency of one or more pill a day and a current and chronic duration for all-NSAIDs users, reaching a 52% decreased risk for anti-COX-2 activity users.

Our results are based on a large carefully designed population-based case-control study conducted specifically to assess environmental and genetic factors in prostate cancer risk. Cases were identified in all cancer hospitals, either public or private, that recruited prostate cancer patients in the *département* of Hérault. In 2012, the Hérault Cancer Registry observed 770 new cases of prostate cancer, of which 575 were under 75 years of age. Considering that the number of cases observed in 2011 was identical, approximately 1150 new cases were expected during the

<footnote n="1">¹Adjusted for age.</footnote>

<footnote n="2">²Myocardial infarction, hypertension, stroke, diabetes.</footnote>

<footnote n="3">³Rheumatoid polyarthritis, spondylarthropathies, arthrosis.</footnote>
<table><caption>**Table 3.** Associations between NSAIDs use and prostate cancer risk.</caption><thead><tr><th></th><th>Cases<br>n = 819 (%)</th><th>Controls<br>n = 879 (%)</th><th>OR (95% CI)<sup>1</sup></th></tr></thead><tbody><tr><td>All-NSAIDs</td><td></td><td></td><td></td></tr><tr><td>Nonuse</td><td>596 (73)</td><td>593 (67)</td><td>1.00</td></tr><tr><td>Ever-use</td><td>220 (27)</td><td>272 (31)</td><td>0.77 (0.61–0.98)</td></tr><tr><td>Drug issuance</td><td></td><td></td><td></td></tr><tr><td>Over the counter</td><td>34 (4)</td><td>33 (4)</td><td>1.00 (0.57–1.75)</td></tr><tr><td>Medical prescription</td><td>181 (22)</td><td>229 (26)</td><td>0.76 (0.59–0.98)</td></tr><tr><td>Anti-COX activity</td><td></td><td></td><td></td></tr><tr><td>Preferential anti-COX-1</td><td>160 (20)</td><td>186 (22)</td><td>0.85 (0.65–1.11)</td></tr><tr><td>Preferential anti-COX-2</td><td>32 (4)</td><td>57 (7)</td><td>0.48 (0.28–0.79)</td></tr><tr><td>Frequency</td><td></td><td></td><td></td></tr><tr><td>&lt;1/day</td><td>109 (13)</td><td>108 (12)</td><td>0.93 (0.68–1.27)</td></tr><tr><td>=1/day</td><td>93 (11)</td><td>121 (14)</td><td>0.75 (0.54–1.04)</td></tr><tr><td>&gt;1/day</td><td>11 (1)</td><td>30 (3)</td><td>0.38 (0.18–0.79)</td></tr><tr><td>Duration (years)</td><td></td><td></td><td></td></tr><tr><td>&lt;5</td><td>62 (8)</td><td>81 (9)</td><td>0.67 (0.45–0.99)</td></tr><tr><td>5–10</td><td>33 (4)</td><td>53 (6)</td><td>0.55 (0.33–0.92)</td></tr><tr><td>&gt;10</td><td>120 (15)</td><td>133 (15)</td><td>0.94 (0.69–1.27)</td></tr><tr><td>Recency</td><td></td><td></td><td></td></tr><tr><td>Former use</td><td>119 (15)</td><td>125 (14)</td><td>0.87 (0.64–1.18)</td></tr><tr><td>Current use</td><td>101 (12)</td><td>147 (17)</td><td>0.68 (0.50–0.94)</td></tr><tr><td>Current use ≤10 years</td><td>41 (5)</td><td>69 (8)</td><td>0.55 (0.35–0.87)</td></tr><tr><td>Current use &gt;10 years</td><td>58 (7)</td><td>78 (9)</td><td>0.79 (0.52–1.20)</td></tr><tr><td>Former use ≤10 years</td><td>54 (7)</td><td>65 (7)</td><td>0.69 (0.45–1.06)</td></tr><tr><td>Former use &gt;10 years</td><td>62 (8)</td><td>55 (6)</td><td>1.11 (0.73–1.69)</td></tr></tbody></table>

study period (2012–2013) [31]. We identified 1098 eligible cases over the study period suggesting that the recruitment of cases in the EPICAP study was exhaustive, thus limiting a potential selection bias. Even though participation rate in cases was 75%, the age distribution and the Gleason score were comparable to those of the Hérault Cancer Registry for the years 2009–2011 (private communication), which indicates that cases included in the study were representative of all eligible cases. Controls were randomly selected from the general population of the *département* of Hérault using quotas on age (5 years) to reflect the age distribution of the cases. Moreover, quotas by socioeconomic status (SES) have been established to yield the control group similar to the general population of the *département* of Hérault of the same age in terms of SES. After the selection process, we compared the distribution by SES between our control group and the male general population of the *département* of Hérault and found no significant difference, indicating that no major selection bias by SES had occurred.

To minimize misclassification of exposure, data were collected by a trained research clinical nurse using a standardized questionnaire. Many details on former and current use of NSAIDs with exhaustive questions on name of the drug, indication, prescription by a doctor or over the counter, frequency, recency, and duration of use were

collected. In our study, prevalence of exposure to all-NSAIDs was 31% among controls which was similar to other studies using questionnaires [19,27]. Recall bias is often an issue in case-control studies. Nevertheless, the use of a standardized questionnaire, a face to face interview by a research clinical nurses, and the fact that cases and controls were interviewed under the same conditions minimize the possibility of such bias. Moreover, a recall bias is usually more frequent in cases than in controls which may explain a positive association but not an inverse association as we observed in our results.

Our results were unchanged after adjustment for potential major confounding factors such as family history of prostate cancer, anthropometric indicators, or reason for NSAIDs use (cardiovascular and rheumatologic backgrounds), limiting potential confounding.

Detection bias, meaning that patient under NSAIDs would have had more frequent contact with doctors and therefore more cancers detected could not be excluded, but it could have only weakened the association as it would have gone toward positive association. In the same way, reverse causation bias would have been very unlikely to occur as it would have also gone toward a positive association.

Finally, an indication bias may have occurred if the reason for NSAIDs use (cardiovascular and rheumatologic

<footnote n="1">¹Adjusted for age, family history of cancer at first degree, race, educational level, history of prostatitis, WHR.</footnote>
<table><caption>**Table 4.** Associations between aspirin, NA-NSAIDs use, and prostate cancer risk.</caption><thead><tr><th rowspan="2"></th><th colspan="3">Aspirin</th><th colspan="3">NA-NSAIDs</th></tr><tr><th>Cases<br/>n = 819 (%)</th><th>Controls<br/>n = 879 (%)</th><th>OR (95% CI)<sup>1</sup></th><th>Cases<br/>n = 819 (%)</th><th>Controls<br/>n = 879 (%)</th><th>OR (95% CI)<sup>1</sup></th></tr></thead><tbody><tr><td>Nonuse</td><td>596 (73)</td><td>593 (67)</td><td>1.00</td><td>596 (73)</td><td>593 (67)</td><td>1.00</td></tr><tr><td>Ever-use</td><td>143 (17)</td><td>166 (19)</td><td>0.86 (0.65-1.14)</td><td>107 (13)</td><td>143 (16)</td><td>0.72 (0.53-0.99)</td></tr><tr><td>Drug issuance</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Over the counter</td><td>39 (5)</td><td>41 (5)</td><td>0.91 (0.54-1.53)</td><td>2 (0)</td><td>2 (0)</td><td>1.96 (0.17-22.7)</td></tr><tr><td>Medical prescription</td><td>102 (12)</td><td>120 (14)</td><td>0.86 (0.62-1.19)</td><td>100 (12)</td><td>136 (15)</td><td>0.71 (0.51-0.97)</td></tr><tr><td>Frequency</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;1/day</td><td>83 (10)</td><td>58 (7)</td><td>1.39 (0.93-2.06)</td><td>49 (6)</td><td>72 (8)</td><td>0.70 (0.46-1.06)</td></tr><tr><td>=1/day</td><td>54 (7)</td><td>90 (10)</td><td>0.59 (0.39-0.89)</td><td>43 (5)</td><td>40 (5)</td><td>0.88 (0.53-1.45)</td></tr><tr><td>&gt;1/day</td><td>4 (0)</td><td>13 (1)</td><td>0.32 (0.10-1.03)</td><td>8 (1)</td><td>18 (2)</td><td>0.53 (0.22-1.30)</td></tr><tr><td>Duration (years)</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;5</td><td>33 (4)</td><td>43 (5)</td><td>0.66 (0.38-1.13)</td><td>38 (5)</td><td>56 (6)</td><td>0.70 (0.43-1.13)</td></tr><tr><td>5-10</td><td>23 (3)</td><td>41 (5)</td><td>0.49 (0.27-0.90)</td><td>16 (2)</td><td>19 (2)</td><td>0.88 (0.40-1.93)</td></tr><tr><td>&gt;10</td><td>85 (10)</td><td>81 (9)</td><td>1.14 (0.79-1.65)</td><td>49 (6)</td><td>64 (7)</td><td>0.70 (0.45-1.09)</td></tr><tr><td>Recency</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Former use</td><td>66 (8)</td><td>59 (7)</td><td>1.11 (0.73-1.67)</td><td>81 (10)</td><td>94 (11)</td><td>0.82 (0.58-1.18)</td></tr><tr><td>Current use</td><td>77 (9)</td><td>107 (12)</td><td>0.70 (0.48-1.00)</td><td>26 (3)</td><td>49 (6)</td><td>0.52 (0.30-0.91)</td></tr><tr><td>Current use ≤10 years</td><td>32 (4)</td><td>55 (6)</td><td>0.54 (0.32-0.90)</td><td>10 (1)</td><td>21 (2)</td><td>0.41 (0.17-1.00)</td></tr><tr><td>Current use &gt;10 years</td><td>43 (5)</td><td>52 (6)</td><td>0.85 (0.52-1.40)</td><td>16 (2)</td><td>28 (3)</td><td>0.61 (0.30-1.23)</td></tr><tr><td>Former use ≤10 years</td><td>24 (3)</td><td>29 (3)</td><td>0.64 (0.34-1.22)</td><td>44 (5)</td><td>54 (6)</td><td>0.88 (0.55-1.41)</td></tr><tr><td>Former use &gt;10 years</td><td>42 (5)</td><td>29 (3)</td><td>1.60 (0.94-2.71)</td><td>33 (4)</td><td>36 (4)</td><td>0.76 (0.44-1.31)</td></tr></tbody></table>

backgrounds) was associated to prostate cancer. To our knowledge, there is no evidence of such an association in the literature.

Many observational studies investigated the potential protective effect of NSAIDs in cancer and there is striking evidence in colorectal cancer through the diminution of adenomas incidence (preneoplastic state) in group of patients taking NSAIDs, especially anti-COX-2 or aspirin [32–34]. In prostate cancer, results were less convincing especially among nonaspirin NSAIDs users. Considering aspirin use, our results were consistent with those of recent meta-analyses that reported a modest 5–15% reduction in prostate cancer risk associated with aspirin use [12, 14–17]. A recent cohort study observed that low dose of aspirin was associated with a decreased risk of prostate cancer (HR 0.64, 95% CI 0.48–0.86) especially after at least 5 years of use (HR 0.42, 95% CI 0.21–0.91) [35]. The Cancer Prevention Study II Nutrition Cohort also showed that daily aspirin use for at least 5 years was associated to a 15% risk reduction of prostate cancer [36].

Regarding NA-NSAIDs, results are less convincing in the literature. Our results are consistent with three studies reaching statistical significance with inverse association (OR 0.71, 95% CI 0.58–0.86) [21, 23, 24] with neither duration nor frequency-related trends. A study using the Danish registry nationwide data found a slightly increased prostate cancer risk among NA-NSAIDs users (OR 1.13,

95% CI 1.10–1.15) [35], concurring with two Finnish studies, one nationwide [37] and one conducted within the Finnish Prostate Cancer Screening Trial [20], that found an increased risk of prostate cancer associated with NA-NSAIDs use, but no apparent trends with either increasing cumulative dose or duration of NA-NSAIDs use, not supporting causal relationship between NA-NSAIDs use and prostate cancer risk. All these positive associations could have been due to reverse causation bias and detection bias, exposing to the risk of false-positive associations. Also, administrative data often lack information about confounding factors and sometimes no latency is taken into account. Due to important heterogeneity in studies, meta-analysis had failed to show inverse associations of NA-NSAIDs use on prostate cancer [14–16, 29].

Considering grade of cancer, we reported a decreased risk of aggressive prostate cancer occurrence in patients using all type of NSAIDs (high Gleason score, OR 0.62, 95% CI 0.41–0.95 vs. intermediate or low Gleason score, OR 0.82, 95% CI 0.64–1.06). This is in agreement with one study finding significant inverse association of daily aspirin taken in the 12 previous months with highly aggressive tumors with Gleason score ≥7 or Stage III or IV (OR 0.88, 95% CI 0.78–0.99 vs. less aggressive tumors OR 0.94, 95% CI 0.85–1.04) and another showing significant inverse association with all type of NSAID use and tumors with Gleason score ≥7 (OR 0.80, 95% CI 0.64–0.99) versus no association for Gleason score <7

<footnote n="1">¹Adjusted for age, family history of cancer at first degree, race, educational level, history of prostatitis, WHR.</footnote>
<table><caption>**Table 5.** Associations between NSAIDs use and prostate cancer risk according to Gleason score.</caption><thead><tr><th rowspan="2"></th><th colspan="3">Low- or intermediate-grade prostate cancer<br>Gleason score ≤7 (3 + 4)</th><th colspan="2">High-grade prostate cancer<br>Gleason score ≥7 (4 + 3)</th></tr><tr><th>Controls<br>n = 879 (%)</th><th>Cases<br>n = 623 (%)</th><th>OR (95% CI)<sup>1</sup></th><th>Cases<br>n = 183 (%)</th><th>OR (95% CI)<sup>1</sup></th></tr></thead><tbody><tr><td>All-NSAIDs</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Nonuser</td><td>593 (67)</td><td>446 (72)</td><td>1.00</td><td>140 (77)</td><td>1.00</td></tr><tr><td>Ever-user</td><td>272 (31)</td><td>175 (28)</td><td>0.82 (0.64–1.06)</td><td>42 (23)</td><td>0.62 (0.41–0.95)</td></tr><tr><td>Preferential anti-COX-1</td><td>186 (21)</td><td>126 (20)</td><td>0.88 (0.66–1.18)</td><td>33 (18)</td><td>0.77 (0.49–1.21)</td></tr><tr><td>Preferential anti-COX-2</td><td>57 (6)</td><td>25 (4)</td><td>0.48 (0.28–0.84)</td><td>5 (3)</td><td>0.33 (0.11–0.94)</td></tr><tr><td>Aspirin</td><td>166 (19)</td><td>113 (18)</td><td>0.89 (0.66–1.21)</td><td>29 (16)</td><td>0.77 (0.48–1.24)</td></tr><tr><td>NA-NSAIDs</td><td>143 (16)</td><td>86 (14)</td><td>0.78 (0.56–1.09)</td><td>18 (10)</td><td>0.49 (0.27–0.89)</td></tr></tbody></table>

<table><caption>**Table 6.** Associations between NSAIDs use and prostate cancer risk according to personal history of prostatitis.</caption><thead><tr><th rowspan="2"></th><th colspan="3">No history of prostatitis<br>(n = 1551)</th><th colspan="3">History of prostatitis<br>(n = 147)</th></tr><tr><th>Cases<br>n = 735 (%)</th><th>Controls<br>n = 816 (%)</th><th>OR (95% CI)<sup>1</sup></th><th>Cases<br>n = 84 (%)</th><th>Controls<br>n = 63 (%)</th><th>OR (95% CI)<sup>1</sup></th></tr></thead><tbody><tr><td>All-NSAIDs</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Nonuser</td><td>534 (73)</td><td>561 (69)</td><td>1.00</td><td>62 (74)</td><td>32 (51)</td><td>1.00</td></tr><tr><td>Ever-user</td><td>198 (27)</td><td>241 (30)</td><td>0.85 (0.67–1.09)</td><td>22 (26)</td><td>31 (49)</td><td>0.32 (0.15–0.71)</td></tr><tr><td>Aspirin</td><td>130 (18)</td><td>152 (19)</td><td>0.91 (0.68–1.22)</td><td>13 (15)</td><td>14 (22)</td><td>0.43 (0.17–1.14)</td></tr><tr><td>NA-NSAIDs</td><td>96 (13)</td><td>123 (15)</td><td>0.82 (0.59–1.12)</td><td>11 (13)</td><td>20 (32)</td><td>0.21 (0.07–0.59)</td></tr></tbody></table>

(OR 0.90, 95% CI 0.77–1.04). The Danish study showed no real trend considering Gleason score [35]. Regarding anti-COX-2 activity, no special effect was found in the literature [38], except one case-control study focusing on coxibs that found a 55% significant decreased risk of prostate cancer, which is consistent with our findings [39].

Interestingly, the inverse association observed with all-NSAIDs use was more pronounced in men with a personal history of prostatitis reinforcing the hypothesis that inflammation provides favorable conditions for carcinogenesis [40, 41].

In conclusion, our study provides convincing evidence that a frequent and chronic NSAIDs use decreased the risk of prostate cancer, especially aggressive prostate cancer. The specific decreased risk observed among men with a personal history is an additional evidence that targeting chronic inflammation may help preventing prostate carcinogenesis.

## Acknowledgments

We would like to thank the clinical research nurses who were in charge of participants' interview, anthropometric measurements, and biological sample collection (Anne-Laure Astolfi, Coline Bernard, Oriane Boyer, Marie-Hélène

De Campo, Sandrine Margaroli, Louise N'Diaye, Sabine Perrier-Bonnet). We also would like to thank Christian Prad and Nadine Soller for help with patient medical data collection within the Hérault Cancer Registry (Registre des tumeurs de l'Hérault, Montpellier, France). Finally, we are grateful to the EPICAP study group.

Urologists: Drs Didier Ayuso, Bruno Ségui, Vincent Abd El Fattah (Centre Hospitalier Bassin de Thau, Sète, France); Alain Guillaume, Jean-Paul Constans, Olivier Delbos, Pierre Lanfray, Damien Rizet, Etienne Cuénant (Cabinet Urologie du Polygone, Montpellier, France); Michel Locci (Centre Hospitalier, Béziers, France); Etienne Cuénant (Clinique Ste Thérèse, Sète, France); Nicolas Drianno, Bernard Marc, Paulo Soares (Polyclinique Saint Privat, Béziers, France); Antoine Faix, Samer Abdel Hamid, Bruno Ségui (Service urologie, Clinique Beau Soleil, Montpellier, France); Samer Abdel Hamid (Clinique Saint Louis, Ganges, France); Thibaut Murez, Grégoire Poinas, Laurent Cabaniols, Maxime Robert, Rodolphe Thuret (Centre Hospitalo-Universitaire Hôpital Lapeyronie, Montpellier, France).

Pathologists: Drs Didier Brel, Lysiane Schweizer, Philippe Nayraud, C. Lecam-Savin (Béziers); Roland Daniel, Jean Baptiste Perdigou, Chantal Compan, Mireille Granier, A Granier, Ruth Borges-Reis, A Badsi, Jean Louis Bouzigues, Elisabeth Broquerie, Joëlle Simony, Frédéric Bibeau, Pierre

<footnote n="1">¹Adjusted for age, family history of cancer at first degree, race, educational level, history of prostatitis, WHR.</footnote>

<footnote n="1">¹Adjusted for age, family history of cancer at first degree, race, educational level, WHR.</footnote>
Baldet, Isabelle Serre, Valérie Costes (Centre Hospitalo-Universitaire, Hôpital Lapeyronie, Montpellier), Marie Laure Gaume (Sète).

Biologists: Drs F. Montels (Service de Biologie Médicale, Institut du Cancer de Montpellier, Montpellier, France); and Labosud laboratories: Drs François et Pascal Dumas (Béziers, France); Martine Buono (Sète, France); Isabelle Bonnefille (Lodeve, France); Georges Ruiz (Lunel, France); Didier Paleirac (Clermont-l'Hérault, France).

## Conflicts of Interest

All authors have completed and submitted the ICMJ form for disclosure of potential conflicts of interest. No financial disclosures were reported.

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