1. health and fitness
2. disease
3. cancer

USE OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND STATINS,
AND RISK OF PROSTATE CANCER IN MONTREAL
JOSE JOAO MANSURE
Department of Epidemiology, Biostatistics and Occupational Health
McGill University, Montreal
October 2011
A thesis submitted to McGill University in partial fulfillment of the requirements of
the degree of Master of Science (M.Sc.) in Epidemiology
© Jose Joao Mansure 2011
ABSTRACT
Objective: Non steroidal anti-inflammatory drugs (NSAIDs) and statins are associated
with many solid tumours. We conducted a case-control study among French-speaking
Montrealers (Canada) to estimate associations with use of NSAIDs or statins, and risk of
prostate cancer.
Methods : Data were collected from patients (n=1,429) aged 40 to 75 years, ascertained
across the 11 major French hospitals in the Montreal Metropolitan area, newly diagnosed
with prostate cancer between September 1, 2005 and December 31, 2010. Controls
(n=1,543) were selected from the general population, were registered on Quebec’s
permanent electoral list as French speakers, resident in the Montreal Metropolitan area,
were from the same electoral districts as cases, and were frequency-matched to cases by
age (±5 years). Unconditional logistic regression with adjustment for potential
confounding variables was used to estimate odds ratios and 95% confidence intervals.
Of the 2,972 subjects, 204 (6.9 %) were NSAID users, 589 (19.9 %) were daily low dose
users of aspirin, and 415 (14 %) were statins users. Ever use of NSAIDs (adjusted OR =
1.22; 95% CI: 0.88-1.69) was not associated with prostate cancer risk. Likewise, current
use or duration of use was also not associated with risk of prostate cancer. However, a
self-reported history of using NSAID between 6-10 years before the reference date was
inversely associated with prostate cancer risk (OR=0.43; 95% CI: 0.21-0.89). Use of
daily low dose of aspirin was not significantly associated with prostate cancer (OR=1.02;
95% CI 0.85-1.24). Nonetheless, 18 % reduced risk of developing prostate was found
with time since first use (2-5 years before reference date). There was no association
between statin use and risk of prostate cancer (OR=1.20; 95% CI: 0.90-1.60). By
2
contrast, men who had self-reported to have used statins for more than five years were
positively associated with prostate cancer risk (OR=1.56; 95% CI: 1.07-2.27).
Conclusion: Overall this study provides no strong evidence of either causation or
prevention of prostate cancer by NSAIDs or daily low dose of aspirin or statin. However,
timing in exposure and duration of use might have biological implications in the relation
between these medications and prostate cancer risk.
3
RÉSUMÉ
Objectif : Des médicaments anti-inflamatoires non stéroïdiens (AINSs) et les statines
sont associés au risque de développer plusieurs formes de tumeurs solides. Nous avons
entrepris une étude cas-témoins chez les montréalais de langue française (Canada) afin
d’estimer l’association entre l'utilisation d’AINS et de statines et le risque de cancer de la
prostate.
Méthodes :
Nous avons recruté 1,429 patients âgés de 40 à 75 ans, nouvellement
diagnostiqués avec un cancer de la prostate entre les 1er septembre 2005 et 31 décembre
2010 à travers les 11 hôpitaux français principaux de la région métropolitaine de
Montréal. Les témoins de la population gérérale (n=1,543) ont été sélectionnés à partir
des hommes francophones inscrits sur la liste électorale permanente du Québec, résidant
dans la région métropolitaine de Montréal, provenant des mêmes districts électoraux que
les cas, et appariés aux cas selon des groupes de 5 ans d’âge. La régression logistique
inconditionnelle a été utilisée afin d’estimer les rapports de cote (RC) et les intervalles de
confiance (IC) à 95% entre l’utilisation de médicaments et le risque de cancer de la
prostate, en ajustant pour les facteurs de confusion potentiels.
Résultats : Des 2,972 sujets participants, 204 (6.9 %) avaient déjà utilisé pendant au
moins 6 mois des AINS , 589 (19.9 %) avaient utilisé quotidiennement de faibles doses
d'aspirine, et 415 (14 %) avaient utilisé des statines. Le fait d’avoir déjà utilisé des AINS
n'était pas associé au risque de cancer de prostate (RC ajusté = 1.22 ; IC à 95% : 0.881.69).
L'utilisation courante ou la durée d'utilisation d’AINS n’était également pas
associée au risque de cancer de prostate. Cependant, des hommes ayant rapporté avoir
commencé à utiliser des AINS 6 à10 ans avant la date de référence avaient un risque
4
réduit de cancer de la prostate (RC=0.43; IC à 95%: 0.21-0.89). L'utilisation quotidienne
d’une faible dose d'aspirine n’était pas associée au cancer de prostate (RC=1.02; IC à
95% : 0.85-1.24) . Néanmoins, le risque était réduit de 18 % chez les hommes ayant
rapporté une première utilisation de ces médicaments 2 à5 ans avant date de référence.
Une tendance vers une faible augmentation de risque a été observée entre chez les
hommes ayant déjà utilisé des statines RC=1.20; IC à 95% : 0.90-1.60). Toutefois, cette
association positive était plus prononcée chez les hommes ayant utilisé des statines
pendant plus de cinq ans (RC=1.56; IC à 95% : 1.07-2.27).
Conclusion : De façon générale, cette étude ne fournit aucune évidence marquée
suggérant un rôle entre la consommation d’AINS, d’une faible dose quotidienne
d'aspirine ou de statines et le risque de cancer de la prostate. Cependant, il est possible
que la période ou la durée d’utilisation de ces médicaments puisse être impliquée dans
ces relations.
5
I dedicate this thesis to the most important people in my life. My deepest love, my
wife Claudia, my son Victor and my daughter Marcela.
6
A fact is a simple statement that everyone believes. It is innocent, unless found guilty.
A hypothesis is a novel suggestion that no one wants to believe. It is guilty, until found
effective. ~Edward Teller
7
ACKNOWLEDGEMENTS
I am extremely grateful to my supervisor, Dr. Eduardo Franco for the time, patience,
encouragement and support he provided me. I am thankful for his invaluable scientific
guidance. His journey serves as inspiration to us all.
I would like to extend my deepest appreciation to my co supervisor Dr. Marie-Elise
Parent for allowing me to take part in this interesting research project. I deeply appreciate
her continuing effort to supervise my study. The benefits I derive from it will remain with
me throughout the entirety of my career.
A special thank to Dr Louise Nadon and Marie-Claire Goulet who have contributed
immensely in helping me accessing and understanding the databases and finishing up this
thesis
I also would like to especially thank Dr Agnihotram Ramanakumar for always helping
me and finding time to assist me during my master’s research.
I sincerely thank Dr. Amee Manges who encouraged and supported me since the
beginning when I applied to the Master Program at the Division of Epidemiology at
McGill University
This research could not have been made possible without the support of Dr. Wassim
Kassouf and Dr. Armen Aprikian.
I am very grateful to Eugene Lee, who helped enormously with the data entry
8
Additionally, I thank all my colleagues and friends at the INRS and McGill’s Division of
Cancer Epidemiology, Deborah Weiss, Sylvia Moreau, Allita Rodrigues, Candida
Pizzolongo, Maaike Devries, Myriam Chevarie-Davis, Joseph Tota and Lyndsay
Richardson for their participation.
This study was supported financially through grants from the Canadian Cancer Society,
and from a partnership between the Cancer Research Society /the Fonds de la recherche
en santé du Québec , and the Ministère du Développement économique, de l’Innovation
et de l’Exportation du Québec.
9
TABLE OF CONTENTS
ABSTRACT………………………………………………………………………...
2
RESUME………………………………………………………………………..…
4
ACKNOWLEDGEMENTS……………………………………..……...…………
8
1. INTRODUCTION………………………………………………………….…
16
1.1 Study rationale……………………..…………………………………..
16
2. OBJECTIVES………………………………………………………………...
17
3. LITERATURE REVIEW……………….……………………………………
18
3.1 Prostate cancer…………………………………………………………
18
3.1.1. Incidence Mortality……………………………………...……….
19
3.2 Epidemiology of Prostate Cancer…………………………………….
21
3.2.1. Aging……………………………………………………………...
21
3.2.2. Ethnicity…………………………………………………………..
22
3.2.3. Family History of Prostate Cancer……………………………….
23
3.2.4. Other putative risk factors……………………………………….
23
3.2.4.1. Hormones and growth factors…………………………...…
23
3.2.4.2. Diet………………………...……………………………….
24
3.2.4.3. Obesity……………………………………………………...
26
3.2.4.4. Diabetes mellitus……………………………………......….
27
3.3. Inflammation and Cancer…………………………………………….
28
3.3.1. Possible causes of inflammation in prostate cancer……………...
29
3.3.2. Epidemiology of Inflammation and prostate cancer………...…...
30
3.3.2.1. Sexually transmitted infections and other infection agents
30
3.3.2.2. Prostatitis…………………………………………………...
31
3.3.2.3. Genes encoding factors involved in response to infection….
31
3.3.2.4. Meat and prostate carcinogenesis………………………….
32
3.3.2.5. Role of Cytokines……………………………………………
34
10
3.3.2.6. Role of cyclooxigenases (COX) enzymes…………………...
35
3.3.2.7. COX and cancer……………………………………………
38
3.3.2.8. Expression fo COX and prostate cancer…………………...
39
3.4. Epidemiology of NSAIDs and cancer………………………..….……
40
3.4.1. Epidemiology of NSAID and prostate cancer…………………….
42
3.5. Statins .................................................…………….……...…………..
45
3.5.1. Epidemiology of statins and cancer…............…………………..
46
3.5.2. Epidemiology of statins and prostate cancer……………………..
48
4. METHODOLOGY…………………………………………………...........
52
4.1. Study Population…………………………………………….……….
52
4.2. Data Collection……………………………..…………..……………..
53
4.3. Exposure Assessment…………………………………………………
53
4.3.1. NSAIDs assessment…………………………..…………………..
53
4.3.2. Daily low dose of aspirin assessment…………………………….
54
4.3.3. Statins assessment……………………………………..…………
54
4.3.4. Lifetime of exposure………………………………………………
56
4.4. Measurement of tobacco consumption……………………………...
56
4.5. Measurement of alcohol consumption………………………………
57
4.6. Statistical Analyses……………………………………………………
57
4.7. Method for selection of potential confounders………….…………..
57
4.8. Sensitivity Analyses…………………………………………………...
58
5. RESULTS…………………………………………………………………..
61
5.1. Descriptive Analyses………………………………………………….
61
5.2. Characteristics of exposure…………………………………………..
67
5.2.1. NSAIDs...........................................................................................
67
5.2.2. Daily low dose use of aspirin.........................................................
74
5.2.3. Statins.............................................................................................
79
11
5.3. Association of exposure and risk of prostate cancer………………..
86
5.3.1. Use of NSAIDs and risk of prostate cancer…………...………….
86
5.3.2. Use of COX-2 and risk of prostate cancer………………………..
88
5.3.3. Use of daily low dose of aspirin and risk of prostate cancer…….
89
5.3.4. Use of statins and risk of prostate cancer………..………………
91
5.4. Association of Medication and Prostate cancer aggressiveness…….
93
5.5. Sensitivity analyses……………………………………………………
95
6. DISCUSSION………………………………………………………………
100
6.1. Overview of key findings……………………………………………..
100
6.2. Strength and Limitations of this study……………………………...
104
6.3. Future directions……..………………………………………………
107
7. CONCLUSION…………………………………………………………….
108
8. REFERENCES……………………………………………………….……
109
9. APPENDIX…………………………………………………………………
123
12
LIST OF TABLES
Table 1
Definition of selected factors examined as potential confounding variables
Table 2
Distribution of cases and controls according to socio-demographic
characteristics in a French-Speaking population, in Montreal, Canada,
2005-2010.
Table 3
Distribution of cases and controls according to tobacco smoking and
alcohol consumption in a French-Speaking population, in Montreal,
Canada, 2005-2010.
Table 4
Distribution of cases and controls according to clinical factors in a FrenchSpeaking Population, in Montreal, Canada, 2005-2010.
Table 5
Distribution of cases and controls according to characteristics of use
NSAIDs in a French-Speaking population-based case-control study in
Montreal, Quebec, 2005-2010.
Table 6
Distribution of cases and controls according to characteristics of use
COX-2 inhibitors in a French-Speaking population, in Montreal, Canada ,
2005-2010.
Table 7
Comparison of socio-demographic characteristics among
according to use of NSAIDs, Montreal, Canada, 2005-2010.
Table 8
Comparison of tobacco smoking and alcohol consumption among controls
according to use of NSAIDs, Montreal, Canada, 2005-2010.
Table 9.
Comparison of clinical characteristics among controls according to use of
NSAIDs, Montreal, Canada, 2005-2010.
Table 10.
Distribution of cases and controls according to use of daily-low dose of
acetylsalicylic acid (Aspirin) in a French-Speaking population in Montreal,
Canada, 2005-2010.
Table 11.
Comparison of socio-demographic characteristics among controls
according to use of daily-low dose of acetylsalicylic acid (Aspirin),
Montreal, Canada, 2005-2010.
Table 12.
Comparison of tobacco and alcohol consumption among controls
according to use of daily-low dose of acetylsalicylic acid (Aspirin),
Montreal, Canada, 2005-2010
controls
13
LIST OF TABLES (CONTINUED)
Table 13.
Comparison of clinical characteristics among controls according to use of
daily-low dose of acetylsalicylic acid (Aspirin), Montreal, Canada, 20052010.
Table 14.
Distribution of cases and controls according to characteristics of use statins
in a French-Speaking population in Montreal, Quebec, 2005-2010.
Table 15.
Comparison of socio-demographic characteristics among
according to use of statins, Montreal, Canada, 2005-2010.
Table 16.
Comparison of tobacco and alcohol consumption among controls
according to use of statins, Montreal, Canada, 2005-2010.
Table 17.
Comparison of clinical characteristics among controls according to use of
statins, Montreal, Canada, 2005-2010.
Table 18.
Distribution of relevant clinical conditions according to statins
consumption.
Table 19.
Association between use of NSAIDs and prostate cancer in a FrenchSpeaking population in Montreal, Canada, 2005-2010.
Table 20.
Association between use of COX-2 inhibitors and prostate cancer in a
French-Speaking population in Montreal, Canada, 2005-2010.
Table 21.
Association between use of daily low dose of Aspirin and prostate cancer
in a French-Speaking population in Montreal, Canada, 2005-2010.
Table 22.
Association between use of statins and prostate cancer in a FrenchSpeaking population in Montreal, Canada, 2005-2010.
Table 23.
Association between medication use and aggressiveness of prostate
cancer, in a French-Speaking population in Montreal, Canada, 2005-2010.
Table 24.
Association between use of NSAIDs and prostate cancer, limited to
controls screened recently for prostate cancer in a French-Speaking
population, in Montreal, Canada, 2005-2010.
Table 25.
Association between use of COX-2 inhibitors and prostate cancer, limited
to controls screened recently for prostate cancer in a French-speaking
population, in Montreal, Canada, 2005-2010.
controls
14
LIST OF TABLES (CONTINUED)
Table 26.
Association between use of daily low dose AAS (aspirin) and prostate
cancer, limited to controls screened recently for prostate cancer in a
French-Speaking population, in Montreal, Canada, 2005-2010.
Table 27.
Association between use of statins and Prostate Cancer, limited to controls
screened recently for prostate cancer in a French-Speaking population, in
Montreal, Canada , 2005-2010.
LIST OF FIGURES
Figure 1
Overview of prostaglandin (PG) synthesis and prostaglandin PGE2
carcinogenesis.
Figure 2
Algorithm used to define variable for statins consumption.
15
1. INTRODUCTION
1.1 Study Rationale
Prostate cancer is the most common neoplasm among men in Western countries. In 2011,
the Canadian Cancer Society estimates that about 25,500 new cases of prostate cancer
will be diagnosed resulting in 4,100 deaths from prostate cancer1. Additionally, as the
population of males over the age of 50 grows worldwide, it is anticipated that the overall
incidence will continue to rise. As such, finding new strategies for preventing prostate
cancer is crucial. Nonetheless, this disease is not an intrinsic feature of aging, as
incidence of prostate cancer is low among men in South Eastern Asian countries, but
rapidly increases after immigration to the West2. Therefore, the aetiology of prostate
cancer reflects both hereditary and environmental components. Of interest, at least 20%
of all human cancers and most epithelial cancers arise from chronic or recurrent
inflammation and prostate cancer seems to be affected by these conditions3. Indeed,
several studies have provided evidence linking inflammation to the pathogenesis of
prostate cancer4-8. For these reasons, nonsteroidal anti-inflammatory drugs (NSAIDs)
have gained attention and may be considered as potential agents for prostate cancer
prevention.
Another factor that may relate to prostate cancer risk is HMG-CoA (3-hydroxy-3methylglutaryl-coenzyme A reductase) inhibitors (statins), a therapeutic class of drugs
that reduce plasma cholesterol levels. As numerous large-scale randomized controlled
trials (RCTs) demonstrate the beneficial effects of statins on cardiovascular morbidity
and mortality, it is among the most commonly prescribed drugs worldwide9. Furthermore,
as cholesterol precursors play important role in various cellular functions, such as cell
16
proliferation, differentiation and survival10-12, statins have been shown to exhibit
significant antiproliferative and pro-apoptotic activity10,13,14. Based on these findings,
statins are thought to have chemopreventive potential in several cancers, including
prostate cancer15.
Nonetheless, evidence to date is limited and results for NSAIDs and statins use and risk
of prostate cancer are inconclusive. This Montreal-based study provides additional
evidence on the subject.
2. OBJECTIVES
To investigate via a case-control study whether there is an association between use of
nonsteroidal anti-inflammatory drugs, and statins and the risk of developing prostate
cancer among French-speaking men from the Montreal Metropolitan area.
17
3. LITERATURE REVIEW
3.1. Prostate Cancer
Prostate cancer is a malignant tumor in the prostate gland, a small walnut-sized gland in
men that makes seminal fluid, which helps carry sperm out of the body. The prostate is
located beneath the bladder and surrounds the urethra, the tube that carries urine out
through the penis. Prostate tumors can be benign or cancerous. With benign tumors, the
prostate enlarges and squeezes the urethra, interrupting the normal flow of urine. This
condition, benign prostate hyperplasia (BPH), is common and rarely serious. On the other
hand, prostate cancer can spread beyond the prostate gland and be life threatening.
However, most cancerous tumors in the prostate tend to grow slowly and do not spread or
cause symptoms for decades.
Cells of prostate gland produces prostate-specific antigen (PSA), which is a protein
present in small quantities ( 0-4 ng/ml ) in the serum of men with healthy prostates, but is
often elevated in the presence of prostate cancer and in other prostate disorders, such as
BPH and prostatitis16. Therefore, the PSA test is one of the most frequent examinations to
evaluate abnormality in the prostate. Since the introduction of PSA screening in the early
1990s, an increase in prostate cancer detection was observed17 but it was not followed by
a decreased in mortality18. Another, screening test that is mainly used to detect
abnormalities in the prostate gland is the digital rectal examination (DRE), which is
recommended for men aged 40 years and over. In this screening test, the physician
palpates the prostate gland with his gloved index finger in the rectum and evaluates if
there is a lump, irregularity or hardness felt on the surface of the gland.
18
Prostate cancer is finally diagnosed after biopsy of the prostate gland when prostate
cancer is suspected. After diagnosis, the extension to which a cancer has spread is
classified according to the American Joint Committee of Cancer (AJCC) TNM system,
which is the most widely used system. The TNM system describes the extent of the
primary tumor (T category); whether the tumor has spread to nearby lymph nodes (N
category) and the absence of presence of distant metastasis (M category). Usually, all 3
categories are taken into account, along with the Gleason score and the PSA level to
determine the staging and prognosis of the prostate cancer. The Gleason score, developed
by Dr Donald Gleason in 197419 is a sum of the primary grade (representing most of the
tumor volume) and a secondary grade (assigned to the minority of the tumor). The
Gleason score is a number ranging from 2 to 10, with 10 having the worst prognosis. The
Gleason grade, also known as Gleason pattern ranges from 1 to 5 and is determined
subjectively depending on histological features such as loss of normal glandular structure
caused by the cancer. The Gleason pattern 3 is the most common with 5 having the worst
prognosis. Therefore, if the common tumor pattern is graded as 3 and the next most
common tumor pattern is graded as 4, the Gleason score would be 4 + 3=7, which in turn,
is a more aggressive cancer than one with a Gleason 3 + 4.
3.1.1. Incidence and mortality
The American Cancer Society estimates that 240,890 new cases of prostate cancer will be
diagnosed in 2011 and about 33,720 deaths are expected in the U. S20, which means that
one in six men will get prostate cancer during his lifetime and that one in 36 will die from
this disease. In Canada, the Canadian Cancer Society estimates that 25,500 new cases of
19
prostate cancer diagnosed will be diagnosed in 2011 and that 4,300 deaths will occur in
the same year1.
Rates within Europe vary substantially and tend to be generally lower than rates reported
in the U. S. Western Europe has incidence rates 2-3 times higher than those reported in
Eastern Europe. Considerable variation is also observed in Asia, the continent having the
lowest incidence of prostate cancer, and higher incidence rates are seen in westernized
countries such as Japan21. The significant differences in worldwide incidence rates could
be related to the extent of prostate cancer screening, especially the less-frequent use of
PSA testing in developing countries, but are unlikely to explain the nearly 60-fold
difference in prostate cancer risk between high and low-risk populations22. Although,
mortality rates are higher in Western nations as compared to Asian countries, overall
mortality rates between countries show less variation.
The incidence of prostate cancer peaked in 1992, approximately 5 years after introduction
of PSA as a screening test; and it fell precipitously until 1995 and has been rising slowly
since, at a rate of increase similar to that observed before the PSA era. Nonetheless, the
fall in incidence between 1992 and 1995 has been attributed to the fact of identifying
previously unknown cancers in the population by the use of PSA, followed by a return to
baseline, when fewer cases were detected in previously screened individuals. Indeed, this
hypothesis was confirmed by McDavid and colleagues23, who conducted a study to
compare prostate cancer incidence and mortality rate trends between the United States
and Canada over a period of approximately 30 years. Findings from this study, indicate
that the Canadian age-standardized prostate cancer incidence increased 3.0% per year for
the period 1969-1990, followed by an accelerated increase of 12.7 % for 1990-1993, and
then by a decline of 8.4% for 1993-1996. A similar pattern was observed in the U.S. for
20
the age-standardized incidence rates (increase of 18.7% for the period 1989-1992 and
steep decline of 12.3 for the period 1992-1995). Both countries experienced a significant
decline in prostate cancer mortality rate; the decrease was of 2.7% per year from 1993-99
in Canada while decreases of 1.2% and 4.5% were observed during 1992-94 and 199499, , respectively, in the United States. These results suggest a strong relationship of
incidence patterns and PSA test use, in both countries. Lately, however, the effectiveness
of PSA screening test has been questioned, since it has a positive predictive value of only
about 35%24,25. Indeed, a recent Cochrane systematic review that combined in a metaanalysis the findings from five RCTs, which included 341,351 participants, showed that
prostate cancer screening did not significantly decrease all-cause or prostate cancerspecific mortality [relative risk (RR) 0.95, 95% CI 0.85–1.07] and it was not affected by
age at which participants were screened26.
3.2 Epidemiology of Prostate Cancer
The aetiology of prostate cancer remains obscure, and so far, increasing age, race and
family history of prostate cancer are the only established risk factors. Many putative risk
factors, such as hormones, dietary factors, obesity, physical inactivity, occupation,
vasectomy, smoking, sexual factors and genetic susceptibility have been implicated in
prostate cancer but the epidemiologic evidence is still inconclusive.
3.2.1. Aging
The risk of developing prostate cancer is strongly associated with aging. In U.S., 80% of
all prostate tumors are diagnosed in men over 6527, whereas the incidence of prostate
cancer is very low in men under 40 years old. Of interest, the exponential increase in
21
incidence of prostate cancer with advancing age is not seen in any other malignancy. For
instance, the Surveillance Epidemiology, and End results (SEER) program estimates that
in the U.S., from 1992-2000, the incidence rate of prostate cancer for men under 65 was
56.8 per 100,000 person-years while men of 65 years and over showed an incidence rate
of 974.7 per 100,000 person-years28. Up to 30% of men have foci of prostate cancer by
age 4029, while most of deaths due to prostate cancer occur among men aged 70 or over.
This association could be explained by the fact that most prostate cancers have a long
latency and progress slowly over prolonged period of time30.
3.2.2.Ethnicity
Although, poorly understood, ethnicity is another risk factor that is consistently
associated with the risk of developing prostate cancer. For instance, it is well recognized
that African-American men have the highest incidence rates in the world, while Chinese
men living in China have the lowest rates. These differences are unlikely to be due to
screening practices differences (i.e. PSA screening), as even before the era of PSA,
African-Americans had a 1.8 fold higher risk of prostate cancer than that of white
Americans31. Moreover, detection alone could not explain the variability in prostate
cancer risk between populations, since Japanese men still experience a markedly lower
incidence than American, even after incidence rates have been adjusted for prevalence of
latent disease at autopsy32. Additionally, it has been reported that African-Americans
have age-adjusted mortality rates from prostate cancer higher than white Americans,
Japanese and Chinese, over the period 1989-9233. The extremely high prostate cancer
incidence and mortality seen among black Americans, does not seem to be explained by
differences in socioeconomic position (SEP), as it has been shown that low SEP is
22
associated with poorer clinical prostate cancer outcome, but not with higher prostate
cancer incidence34. An important observation for research aiming at identifying causes of
prostate cancer come from migrant studies. Indeed they indicate that factors others than
genetic may affect prostate cancer risk and explain much of the ethnic differences, since
incidence increases among men who move from low- to high-risk countries. This
suggests that environmental and lifestyle factors may be important in prostate cancer
aetiology32,35,36.
3.2.3. Family history of prostate cancer
Several studies have consistently reported familial aggregation of prostate cancer,
showing a 2-3 fold increased risk of prostate cancer among men who have an affected
first-degree male relative (father, brother, son), and it accounts for about 10-20 percent of
all cases of the disease in the general population37. Furthermore, three recently published
meta-analysis reached similar conclusions38-40. This pattern may be due to shared
environment, shared genes, or a combination of shared environmental and genetic factors.
Recent data from a large twin study suggest that as much as 42 % (95% confidence
intervals: 29-50%) of the risk of prostate cancer may be accounted for by genetic factors,
which includes individual and combined effects of rare, highly penetrant genes, more
commonly weakly penetrant genes, and genes acting in concert with each other41.
3.2.4. Others putative risk factors
3.2.4.1. Hormones and growth factors
The prostate is an androgen-dependent organ. Consequently, androgens (mostly
testosterone) play a key role in the development, growth and maintenance of the prostate
23
gland42. Several epidemiological studies have suggested an etiologic role of androgens in
prostate carcinogenesis, but overall the findings are still inconclusive43-49. For instance,
prostate cancer is remarkably rare in castrated men, and high-risk groups, such as
African-American have higher serum testosterone levels compared to low-risk groups50.
Furthermore, laboratory studies show that administration of testosterone is necessary for
the development of prostate cancer in castrated male animals, and androgens promote cell
proliferation, and inhibit prostate cell death51-53. Additionally, deprivation of androgen,
which is achieved by surgical removal of testicles, or taking estrogens or drugs called
anti-androgens has been shown to reduce prostate cancer incidence by 25% in a clinical
trial 54. So far, only one of 17 prospective studies, only observed a statistically significant
higher risk of prostate cancer (OR=2.6, 95% CI: 1.3,5.0), when comparing highest to
lowest tertiles of serum testosterone levels55. Others non-androgen steroid hormones,
such as vitamin D and its analogs, have been investigated as potential preventive agent
against prostate cancer. However, although laboratory data are consistent in showing that
vitamin D inhibits prostate cancer in vitro and in vivo, epidemiologic studies investigating
the association between vitamin D and prostate cancer risk have been inconsistent56-58.
On the other hand, the evidence for an etiologic role of insulin-like growth factors (IGFs)
in prostate cancer is more consistent. For instance, several prospective epidemiologic
studies have demonstrated a positive association between prostate cancer and IGF-1 and
low serum levels of IGFBP3, which is an IGF binding protein, and mediates IGF effects,
by preventing activation of IGF receptor 59-64.
3.2.4.2. Diet
The considerable geographic and ethnic variability in prostate cancer incidence, and the
pronounced excess risk of prostate cancer associated with westernization, suggest that
24
factors such as dietary habits and obesity may be positively associated with prostate
cancer risk. Indeed, early ecologic studies have shown a fairly strong correlation between
the incidence of prostate cancer and dietary fat intake65. The rationale for these studies is
supported by the fact, that a western diet, which is typically high in fat, would entail a
higher production and availability of androgens and estrogens, while Asian and
vegetarian diets would be associated with lower levels of these hormones65. However,
whereas positive association with intake of animal, monounsaturated, and saturated fats
has been reported in many studies66,67, scientific support for such
association has
diminished in recent years as more epidemiologic evidence has accrued68. Higher intake
of fatty fish and marine fatty acids (omega-3 fat) has been associated with reduced
prostate cancer risk69,70. Nonetheless, a review of 17 studies, which included 8
prospective studies, found suggestive but inconsistent results68. Although several
epidemiologic studies have reported that consumption of fruits and vegetables may be
associated with a reduced risk of several cancers, their role in prostate cancer still needs
confirmation. The only generally consistent findings are for a modest inverse association
with consumption of cruciferous vegetables (broccoli, cabbage, cauliflower, Brussels
sprouts)71 and an inverse association with intake of tomatoes and tomato pasta, probably
due to the antioxidant effect of lycopene72.
Consumption of red meat and processed meat, particularly meats cooked at high
temperature has been modestly linked to an increased risk of prostate cancer73. However,
it is unclear whether the excess risk is due to the high fat content or heterocyclic amines,
which are induced during high-temperature cooking. The effect of these mutagens will be
discussed in more detailed in the inflammation section of this thesis.
25
Dietary supplements such as vitamin A and other retinoids, vitamin E and minerals, and
selenium, particularly, have been also investigated as per their link to prostate cancer. In
the case of vitamin A, the results are unclear74-77, whereas vitamin E has been shown to
be associated with a reduced risk of prostate cancer77-79. The results from a large body of
epidemiologic studies suggest that selenium may reduce prostate cancer risk in humans80.
However, a large randomized clinical trial to determine the efficacy of vitamin E and
selenium in chemoprevention of prostate cancer has demonstrated that both, alone or in
combination at the doses and formulations used, did not prevent prostate cancer in a
population of relatively healthy men81.
3.2.4.3. Obesity
Findings from several epidemiologic studies are contradictory to show an association
between obesity, as measured by body mass index (BMI), and prostate cancer risk. One
of the reasons for these conflicting results may the fact that most of these studies used
BMI, which is an imperfect measure of body fat content. However, a recent systematic
review has shown that an elevated BMI is associated with risk of prostate cancer-specific
mortality (RR: 1.15, 95% CI: 1.06-1.25) and biochemical recurrence (a rise in PSA levels
post-treatment normalization) (RR: 1.21, 95% CI: 1.11-1.31) in prostate cancer patients82.
On the other hand, some reports suggest that obesity is more consistently related to
aggressive prostate tumors and that abdominal obesity, measured as the ratio of waist to
hip circumferences (WHC), may be associated with an increased risk of prostate
cancer83,84. Indeed, recently, a prospective multicenter Italian cohort study, has
demonstrated that obesity with central adiposity (BMI ≥ 30kg/m2 and WC ≥102 cm) was
significantly associated with prostate cancer (OR 1.66, CI 95% 1.05–2.63) and highgrade disease (OR 2.56, CI 95% 1.38–4.76)85. There are a number of plausible biological
26
mechanisms whereby obesity could promote the development and progression of cancer,
including prostate cancer86,87. Obesity, which is characterized by excess of fatty tissue,
leads to increased production of growth-promoting steroid hormones that can bind to
nuclear receptors in hormone-dependent tumor cells88,89. Nonetheless, there are no
definitive large-scale clinical intervention studies demonstrating that weight loss or
dietary changes reduce the incidence of cancer.
3.2.4.4. Diabetes mellitus
Diabetes mellitus has been associated with increased risk of several malignancies, such as
liver, kidney, biliary tract, pancreas, endometrium, and esophagus90. However, a reduced
risk of prostate cancer has been observed among diabetic men90-94. Furthermore, mixed
results have suggested that the relation between diabetes and prostate cancer may be time
dependent. For instance, in the Health Professionals Follow-up Study cohort, prostate
cancer incidence was higher immediately after diabetes diagnosis and lower among men
with diagnosis of diabetes years earlier92. Although the epidemiologic evidence is not
entirely consistent, the inverse association between diabetes mellitus and prostate cancer
is thought to be biologically plausible. The timing of relation between diabetes mellitus
diagnosis and prostate cancer is likely to be quite complex and may be explained by
specific hormonal changes of insulin or testosterone levels. Diabetes is associated with
higher levels of circulating insulin and possibly higher freeIGF-1, due to the fact that
insulin decreases IGF-1 binding proteins. These factors would presumably be growthenhancing and may increase risk. Initially, many type 2 diabetics are hyperinsulinemic,
but with lack of good blood glucose control and worsening diabetes mellitus, the levels of
both insulin and testosterone tend to decrease over time, and the risk of prostate cancer
appears to decrease with increasing time since diagnosis of diabetes92. A meta-analysis,
27
which includes 19 studies published between 1971 and 2005, found an inverse
association between diabetes mellitus and prostate cancer [RR, 0.84, 95% confidence
interval (CI), 0.76-0.9)95. Additionally, preclinical and clinical studies have recently
demonstrated metformin, which is the most commonly used oral hypoglycemic drug for
treatment of type-2 diabetes96, has potential antitumor effect. Of note, metformin
decreases circulating insulin and may be particularly important for the treatment of
cancers known to be associated with hyperinsulinemia, such as that of the prostate cancer.
Nonetheless, very few observational studies have investigated the effects of metformin on
the incidence of prostate cancer and are inconclusive97-99. Recently, a large populationbased cohort study from the UK General Practice Research Database, indicates that
metformin use did not decrease the risk of prostate cancer (RR: 1.23, 95% CI: 0.99–1.52)
100
.
3.3. Inflammation and cancer
Although studying the functional relationship between cancer and inflammation is recent
, it was first described by Rudolf Virchow in 1863, after he noted the presence of
leucocytes in neoplastic tissues101. He hypothesized that some classes of irritants, together
with the tissue injury and ensuing inflammation they cause, enhance cell proliferation101.
Nowadays, it is well accepted that inflammation is associated with cancer. As previously
described, 20% of most cancers, including prostate cancer,
are associated with
inflammation, including prostate cancer3. Indeed, many cancers arise from sites of
infection,
chronic
irritation
and
inflammation,
suggesting
that
the
tumour
microenvironment, which is largely mediated by inflammatory cells, is an indispensable
participant in the neoplastic process, fostering proliferation, survival and migration.
28
Chronic inflammation has long been linked to cancers with an infectious aetiology, such
as in the stomach (Helycobacter pylori), liver (Hepatitis B and C viruses), bile duct and
bladder (Schistosomes)102. For instance, in response to infection, phagocytic cells
generate bactericidal reactive oxygen (e,g. neutrophils, superoxide and singlet oxgen) and
nitrogen (e.g. macrophages, nitric oxide) species that in turn, damage cells (e,g.
membrane lipid peroxidation and protein sulfhydryl group oxidation) and DNA (e.g.
alkylation, deamination, oxidation and strand breaks). DNA damage in turn leads to
mutations, some of which may provide cells with a growth and/or antiapoptotic
advantages102.
In summary, whether chronic inflammation is caused by infection,
exposure to irritants or by an autoimmune process, it is a result of a multifactorial
network of cellular components, chemical signals and tissue repair mechanism to initiate
and maintain a host response to ―heal‖ the injured tissue. Consequently, these genotoxic
and cytotoxic effects support that inflammation may be an initiator or promoter of
carcinogenesis.
3.3.1. Possible causes of inflammation in prostate cancer
In prostate and regenerative lesions, it is frequent to observe inflammation in biopsies
performed following an increased PSA and/or abnormal DRE103, radical prostatectomy
specimens104 and tissue resected for treatment of benign prostatic hyperplasia
(BPH)105,106. Interestingly, prostates of older men very often contain a spectrum of
lesions characterized by atrophic epithelium or focal epithelial atrophy107-111. In fact,
these foci contain cells with an increased proliferative index relative to normal
epithelium109,112,113 and emerging evidence suggests that these types of lesions represent
regenerative epithelium in response to environmental insults. As these lesions are usually
associated with inflammatory infiltrates, they are referred collectively as proliferative
29
inflammatory atrophy (PIA)111. Of interest, several studies have reported histological
transitions between areas of PIA and high-grade prostate intraepithelial neoplasia (PIN),
and between PIA and prostate cancer 114.
The source of intraprostatic inflammation and PIA is mostly unknown, but might be
caused by infection (for example, with sexually transmitted agents), cell injury (exposure
to chemical and physical trauma from urine reflux and prostatic calculi formation),
hormonal variations and/or exposures, or dietary factors such as charred meats, which
could cause a disruption in immune tolerance and the development of an autoimmune
reaction to the prostate4.
3.3.2. Epidemiology of inflammation and prostate cancer
The role of chronic inflammation in prostate carcinogenesis has been indirectly examined
by epidemiological studies, and is supported by the association of pro-inflammatory and
anti-inflammatory factors, such as sexually transmitted infections and other infections,
prostatitis, antioxidants, and nonsteroidal anti-inflammatory agents and prostate cancer
risk115 114,116.
3.3.2.1. Sexually transmitted infections and others infectious agents.
A meta-analysis of 23 case-control studies published between 1971 and 2000 reported an
elevated relative risk (RR) of prostate cancer among men with a history of sexually
transmitted infections (STI) (RR 1.44; 95% CI 1.2–1.7), syphilis (RR 2.30; 95% CI 1.3–
3.9) and gonorrhoea (RR 1,34, 95% CI 1.10-1.64). Additionally, risk of prostate cancer
was also associated with increasing frequency of sexual activity and increasing number of
sexual partners. However, although the results suggest that STIs may represent one
mechanism through which prostate cancer develops, the studies were very heterogeneous
(P < 0.001)117. Another meta-analysis conducted with 29 case-controls studies found
30
similar results for the association of any STI with prostate cancer (OR 1.48, 95% CI
1.26–1.73) and for gonorrhoea (OR 1.35, 95% CI 1.05-1.83). Significantly elevated OR
was also observed for those exposed to human papillomavirus (OR 1.39, 95% CI 1.122.06)118. In the case of HPV, several other seroepidemiological studies of HPV infection
in relation to prostate cancer have been conducted119-124, some of which reporting an
association and others not.
3.3.2.2. Prostatitis
Clinical prostatitis is a common urological condition characterized by uncomfortable
symptoms, such as perineal pain and burning during urination125. While the incidence of
prostatitis is uncertain, it is thought to be 5-10% among men aged > 40 years who have
the condition but are asymptomatic126. Prostate cancer is diagnosed more frequently
among men with symptomatic prostatitis due to increased prevalence of biopsies. In
many cases of symptomatic prostatitis, the offending pathogen is not known. It can be
caused by acute bacterial infection, typically Escherichia coli
127
, whereas several other
infectious agents may also cause chronic bacterial prostatitis128,129. A meta-analysis of 11
case-control studies conducted between 1971 and 1996 revealed a summary odds ratio
between prostatitis and
prostate cancer of 1.57 (95% CI 1.01-2.45). However, the
causality in these epidemiological studies is unclear, because of potential confounders
such as recall bias, variable quality of prostatitis information, inability to classify the type
of prostatitis or to detect asymptomatic prostatitis,
has not been assessed in such
epidemiological studies114.
3.3.2.3. Genes encoding factors involved in response to infection
Studies of genes encoding factors involved in infection response have provided additional
support for the hypothesis of association of prostate cancer and inflammation. One
31
possibility, as previously described, is that recurrent microbial infections can lead to the
production of inflammatory cytokine mediators and genotoxic reactive oxygen radicals
that increase cell proliferation and promote tumorigenesis
114
. The precise host response
to this inflammatory cascade might determine the likelihood of tumour development.
Genetic studies have identified RNASEL, encoding an interferon inducible ribonuclease,
and MSR1, encoding subunits of the macrophage scavenger receptor, as candidate
inherited susceptibility genes for familial prostate cancer and are considered crucial
modulators of the host response to infection. RNASEL degrades viral and cellular RNA
and can produce apoptosis on viral infection130. This locus has shown a linkage in
familial prostate cancer131. For instance, the variant Arg462Gln allele, which has lower
activity, has been reported to be associated with an increased risk of prostate cancer
132
(OR 1.46, 95% CI 1.09 to 1.95 for heterozygotes and OR 2.12, 95% CI 1.19 to 3.68 for
homozygotes) in a case control study. MSR1 encodes a MSR responsible for the cellular
uptake of molecules, including bacterial cell wall products 133,134. In a case control study,
a series of rare germline MSR1 mutations (e.g. Pro36Ala, Ser41Tyr, Val113Ala,
Asp174Tyr, Gly369Ser, His441Arg and Arg293X) appeared to be linked to prostate
cancer susceptibility in some families at high risk for prostate cancer133.
3.3.2.4. Meat and prostate carcinogenesis
The key features of the molecular pathogenesis of prostate cancer that hint at a role for
prostatic inflammation in prostatic carcinogenesis are the somatic inactivation of GSTP1,
the gene encoding the -class glutathione S-transferase (GST) and the strong possibility
that PIA and PIN lesions are prostate cancer precursors
110,135,136
. GSTP1 expression is
typically induced to high levels at sites of prostatic inflammation and the loss of GSTP1
expression is characteristic of PIN lesions and prostatic carcinomas110,136. In fact, it has
32
been reported that the absence of GSTP1 expression can be attributed to hypermethilation
of somatic GSTP1 CpG islands, which is not present in normal tissues or BPH, but it is
evident in 70 % of PIN lesions and more than 90% of prostate cancers136,137. GSTP1 is
responsible for detoxifying nutritional carcinogens and inflammatory oxidants and loss of
the GSTP1 function in the transition from PIA to PIN makes prostatic cells more
susceptible to genomic damage due to inadequate defences against chemical
carcinogenesis136,138. Of note, as previously mentioned, the risk of developing prostate
cancer increases with duration of exposure to a Western lifestyle
139
. Additionally, Asian
men born in the US also experience a risk of developing prostate that is similar to that of
Caucasian men140. These findings point to diet as a potentially important environmental
and lifestyle factor modulating prostate cancer risk. Stereotypical Asian diets are
noticeably different from conventional Western diets, whereas diets rich in red meat and
animal fat, and low in vegetables and fruits, are consumed. In fact, epidemiological
studies support a link between prostate cancer incidence and mortality and the
consumption of red meat and animal fats141-145. One mechanism by which meat
consumption may stimulate cancer risk can be explained by the formation of heterocyclic
amines (HCAs) generated during cooking meats at high temperatures146-148. HCAs can be
metabolized to biologically active metabolites that can bind covalently to DNA,
generating adducts DNA. If these DNA lesions are not repaired, the adducts can lead to
base substitution mutations, small insertions or deletions, or more complex gene
rearrangements. GSTs have long been thought to contribute to cancer protection by
catalyzing conjugation reactions between glutathione and a variety of reactive chemicals
species, preventing carcinogen-induced cell and genome damage149. These hypotheses
have been supported by recent data, which suggests that heterocyclic amine carcinogens
33
present in well-done meats may be detoxified by GSTP1150. For instance, prostate cancer
cell lines, such as LNCaP, which have no expression of GSTP1, accumulate more
mutations
by adduction to
DNA,
when
exposed
to,
2-amino-1-methyl- 6-
phenylimidazo[4,5-b] pyridine (PhIP), a metabolically activated HCA, which is a
carcinogen present in charred or well done meats151,152, compared to LNCaP cells,
ectopically expressing GSTP1150. Similarly, laboratory rats exposed to PhIP, results in
develop carcinomas of the intestine in both sexes, in the mammary gland in females, and
in the prostate in males148,153-155. Likewise, rats fed wih PhIP display an increase in the
mutation frequency in all lobes of the prostate cancer4.
3.3.2.5. Role of cytokines
Inflammatory network consists mainly of humoral (cytokines) and cellular (leukocytes,
monocytes and macrophages) components6,156. There are primarilytwo types of
cytokines: pro-inflammatory cytokines that promote inflammation and usually make
disease worse, whereas anti inflammatory cytokines serve to reduce inflammation and
promote healing16,157.
In chronic inflammation, mainly composed of chronically
activated T cells and mononuclear phagocytes (monocytes and macrophages), antiinflammatory cytokines are synchronically upregulated after the pro-inflammatory
cytokines are produced in order to resolve inflammation16,158,159. Like other normal
tissues, the prostate has a fully active immunologic response, which involves a broad
spectrum of immune responses and activation of intraepithelial endogenous inflammatory
cells, such as T and B lymphocytes, macrophages and mast cells160,161. Interestingly, Tcells increase with age, which explain increase in prostate inflammation frequency during
the aging process162. Pro-inflammatory cytokines, such as interleukins (IL-1, IL-1α, IL-2,
IL-4, IL-6, IL- 7, IL-8, and IL-17), are simultaneously secreted by T-cells, prostatic
34
stromal and epithelial cells. In turn, these cytokines may induce fibromuscular growth
and proliferation of prostatic stromal or epithelial cell by an autocrine or paracrine loop
or via induction of Ciclooxigenase-2 (COX-2) expression163-166. In summary, cytokines
may contribute to carcinogenesis in several ways. Some cytokines, particularly TNF-α,
induce the nuclear factor NF-κB, which functions to promote cell survival and cell
growth167. Additionally, TNF-α also increases the generation of free radicals, such as
nitric oxide (NO) and reactive oxygen species (ROS), which present in regions of
prostatic inflammation, as well. In turn, these free radicals induce hyperplastic or
precancerous transformation through the oxidative stress to the tissue and DNA168.
Normally, these oxidative stress reactions produce arachidonic acid from membranes,
which consequently is converted by the COXs to various eicosanoids, in particular
prostaglandins that have long been recognized as important factors in the regulation of
cell proliferation156,169. In this scenario, association between inflammation and prostate
growth is determined by NO and COX activity. For instance, it has been reported that
expression of inducible NO synthase (iNOS), the enzyme that activates reactive nitrogen,
is increased in the epithelial cells of cases with BPH and, even more pronouncedly, with
high grade PIN and prostate cancer, when compared to human normal prostate tissue166 .
3.3.2.6. Role of Cyclooxigenase (COX) enzymes
COX enzymes catalyze the rate-limiting step for prostaglandin synthesis, which together
with leukotrienes compose a large family of regulatory molecules termed eicosanoids,
which include almost all long-chain oxygenated polyunsaturated fatty acids derived from
arachidonic acid (20:4u6)170. Interestingly, prostaglandins (PGs) were named based on
the fact they were first discovered in semen or extract of prostate, and therefore were
believed to be derived from prostate171. By now, it is clear that PGs can be produced in
35
almost every human cell type and act as autocrine and/or paracrine mediators through
their specific receptors169. Synthesis of PGs starts with the oxidative cyclization of the
five carbons at the center of arachidonic acid, which is released by phospholipase A2
(PLA2) from the cell membrane. The free arachidonic acid is then converted by COX
enzymes to a biocyclic endoperoxide intermediate—prostaglandin G2 (PGG2), which is
then reduced to prostaglandin H2, (PGH2)172. Specific PG synthases in turn metabolise
PGH2 to at least five structurally related bioactive lipid molecules, including PGE2,
PGD2, PGF2a, PGI2, and thromboxane A2 (TxA2) depending on the cell type and
physiological condition173. An increasingly large body of evidence support the notion
that PGE2 promotes tumor growth by stimulating prostaglandin E receptors (EP)
downstream signalling and subsequent enhancement of cellular proliferation, promotion
of angiogenesis, inhibition of apoptosis, stimulation of invasion/motility, and suppression
of immune function (Figure 1). For instance, it has been shown that PGE2 significantly
enhances carcinogen-induced colon tumour incidence and multiplicity in rats and
accelerates intestinal adenoma growth in mice 174,175.
36
Figure 1. Overview of prostaglandin (PG) synthesis and Prostaglandin PGE2
carcinogenesis. PGE2 promotes tumor growth by stimulating downstream signalling
associated with cell proliferation, angiogenesis, invasion and inhibition of apoptosis. .
COX enzymes exist in two isoforms commonly referred to as COX-1 and COX-2.
Although both COX-1 and COX-2 are upregulated in a variety of circumstances,
normally expression of COX-1 remains constant under most physiological or
pathological conditions in a broad range of cells and tissues, while COX-2 is an
immediate early response gene and its expression is normally absent in most cells and
tissues.
COX-1 derived prostaglandins is normally linked to renal function, gastric
mucosal maintenance, stimulation of platelet aggregation, and vasoconstriction176,
whereas COX-2 derived PGE2 is
highly induced in response to proinflammatory
cytokines177, hormones, and is considered the major prostaglandin produced in many
human solid tumours, including cancer of the colon178, stomach179, and breast180.
37
COX-1 and COX-2 have very similar structures and share mainly the same substrates,
generate the same products, and catalyze mostly the same reaction using identical
catalytic mechanisms. However, the isoleucine 590 around the substrate channel of COX1 is replaced by valine in COX-2181,182, which gives COX-2 a larger substrate binding
pocket and consequently a broader substrate spectrum. This isoleucine/valine substitution
is the structural basis for the COX-2 selective inhibitors. For instance, the smaller valine
present in COX-2 allows the bulk of COX-2 selective inhibitors to access the substratebinding site, while the larger isoleucine in COX-1 prevents their binding181,182. This
explains, for example, the different degree of inhibition that aspirin promotes in COX-1
and COX-2.
3.3.2.7. Cyclooxigenase and cancer
Evidence of changes in COX-1 expression in cancer cells is more limited. Nonetheless, a
number of studies have demonstrate over-expression of COX-2 in multiple tissues,
including colon183, breast184, lung185 and pancreas186. Furthermore, over-expression of
COX-2 has also been demonstrated in prostate carcinoma and PIN
187-189
. In most solid
tumors, cancer cells show a great ability to induce angiogenesis, which plays an
important role in tumor progression. At this point, inflammatory response is directly
associated with tumor angiogenesis, and particularly COX-2 has shown to be implicated
to angiogenesis. For instance, COX-2 expression ensures the continued generation of
prostaglandins, which in turn, result in the production of multiple angiogenesis factors.
These angiogenic factors the stimulate neovascular formation at the site of tumorigenesis
providing additional nutrients for oncogenesis and a potential route for metastasis as
well190. In fact, numerous studies have reported a co-localization of angiogenesis factors,
such as VEGF, PDGF, basic fibroblast growth factor (bFGF) and tumor growth factor-b
38
(TGF-b) with COX-2 by immunohistochemical staining in different cancer types191. In
breast and cervical cancers, enhanced COX-2 expression has been further associated with
increased micro-vascular density (MCD) and with poor prognosis192,193. Additionally, it
has been demonstrated in vitro, that over-expression of COX-2 in colon cancer cell lines
increased vascular permeability and induced endothelial cell proliferation and migration,
an effect that could be blocked by COX-2 specific inhibitor and non-selective inhibitor,
such as aspirin194.
Increasing resistance to apoptosis mediated by COX has been also been proposed as
another major mechanism for the effect of COX-2 in tumorigenesis. This hint came
firstly from findings that NSAID could induce apoptosis in culture cells195. Moreover,
over-expression of COX-2 has shown to increase the cellular level of Bcl-2 and induces
resistance to apoptosis of premalignant cells196, which suggest that the anti-carcinogenic
effect of non-steroidal anti-inflammatory drugs (NSAIDs) could be mediated via COX-2
inhibition. However, the notion that the anti-apoptotic effects of selective or non-selective
COX inhibitors are always mediated through the COX enzymes themselves has been
challenged recently, as apoptosis caused by NSAIDs could not be fully explained by the
COX inhibition. For example, it has been found that NSAIDs increase apoptosis
irrespective of their levels of expression of COX-1 or COX-2
197
, and that this effect is
likely to occur via both COX-dependent and COX independent mechanisms (e.g.
involving PPARs, lipo-oxygenases, NF-kB, and Bcl-2-mediated pathways198-201.
3.3.2.8. Expression of ciclooxigenase and prostate cancer
Several groups have investigated the expression and function of COX-2 in prostate tissue
and prostate cancer187-189,202. Most of these studies have demonstrated that normal
prostate tissue have either weak or negative expression of COX-2. Although elevated
39
level of COX-2 protein has been observed in prostate cancer tissues, a consensus has not
been reached yet. For instance, a recent study, has found that expression of COX-2 is
higher in PIN, which is the proposed precursor lesion, or in established prostate cancer
(n=144 cases)203. On the other hand, a consistent expression of COX-2 protein was
observed in PIA lesions, which has been considered an important etiological factor for
prostate cancer203. The relevance of COX-2 expression in cancer is also highlighted by
clinical studies indicating that the presence of COX-2 correlates, in certain tumors, with a
more aggressive phenotype and, importantly, with an overall worse clinical prognosis.
Thus, patients with prostate cancer overexpressing COX-2 have a higher incidence of
metastatic disease204. Taken together, these findings suggest that the hypothesized
chemopreventive and/or chemotherapeutic role of NSAIDs in prostate cancer could be
due to its effect in COX-2 activity in either inflammatory cells or atrophic epithelial cells
or by affecting COX-2 through an independent mechanism.
3.4. Epidemiology of NSAIDs and cancer
As mentioned earlier, assuming that inflammation has a significant pathogenic role in
cancer development, particularly in prostate cancer, it might be expected that the use of
NSAIDs could reduce the incidence of this disease based on its effects on the eicosanoid
pathways. Indeed, several epidemiological studies examined this association, with
somewhat mixed results126,205,206.
The findings that PGs are present at high levels in breast cancer207 has raised the interest
in the role of COX-2 in this type of cancer. Thus, several relatively large studies have
examined the association between NSAIDs and breast cancer. A meta-analysis performed
on 6 cohort studies and 8 case–control studies has demonstrated the combined estimate of
40
relative risk for breast cancer was 0.82 (95% confidence interval [CI] = 0.75–0.89)
amongst NSAIDs users as compared to NSAIDs non-users. However, the available data
are insufficient to estimate the dose–response effect for duration and frequency of use of
any particular types of NSAID208.
A recent systematic review has also evaluated the effect of NSAIDs in colorectal cancer
(CRC) with inconsistent results209. A small study of aspirin in patients with familial
adenomatous polyposis (FAP) produced no statistically significant reduction in polyp
number but a possible reduction in polyp size. There was a statistically significant 21%
reduction in risk of adenoma recurrence [relative risk (RR) 0.79, 95% confidence interval
(CI) 0.68 to 0.92] in an analysis of aspirin versus no aspirin in individuals with a history
of adenomas or CRC209. In the general population, a significant 26% reduction in CRC
incidence was demonstrated in studies with a 23-year follow-up (RR 0.74, 95% CI 0.57
to 0.97). Non-aspirin NSAIDs use in FAP individuals produced a non-statistically
significant reduction in adenoma incidence after 4 years of treatment and follow-up and
reductions in polyp number and size. In individuals with a history of adenomas there was
a statistically significant 34% reduction in adenoma recurrence risk (RR 0.66, 95% CI
0.60 to 0.72) and a statistically significant 55% reduction in advanced adenoma incidence
(RR 0.45, 95% CI 0.35 to 0.58)209. No studies assessed the effect of non-aspirin NSAIDs
in the general population.
Several case-controls studies have shown that regular use of nonsteroidal antiinflammatory drugs (NSAIDs) decreases bladder cancer risk210-212. Lately, a pooled
analysis of three large prospective studies (NIH-AARP Diet and Health Study; Prostate,
Lung, Colorectal and Ovarian Cancer Screening Trial; and U.S. Radiologic Technologists
Study) has evaluated the association of NSAIDs and bladder cancer213. In this study, a
41
reduction in risk was not observed for individuals who reported regular use (>2
times/week) of nonaspirin NSAIDs compared with those who reported no use (hazard
ratio (HR) = 0.92, 95% confidence interval (CI): 0.81, 1.04). However, the risk reduction
was limited to nonsmokers (HR = 0.58, 95% CI: 0.41, 0.83). Moreover, no statistically
significance association was observed between regular aspirin use and bladder cancer risk
(HR = 1.04, 95% CI: 0.94, 1.15), which suggests that nonaspirin NSAIDs, are associated
with a reduction in risk of bladder cancer, particularly for nonsmokers.
3.4.1. Epidemiology of NSAIDs and prostate cancer
Despite fairly consistent data from experimental cell or animal models supporting a
protective role for aspirin or other NSAIDs against prostate cancer214,215, the data for
humans have been more ambiguous216-223. Recently, a population-based case-control
study was designed to investigate the relation between these medications and prostate
cancer risk224. In summary, a significant 21% reduction in the risk of prostate cancer was
observed among current users of aspirin compared with nonusers (95% CI: 0.65, 0.96).
Moreover, long-term use of aspirin (>5 years: OR = 0.76, 95% CI: 0.61,0.96) and daily
use of low-dose aspirin (OR = 0.71, 95% CI: 0.56, 0.90) were also associated with
decreased risk. However, no evidence for the association of aspirin use and disease
aggressiveness was observed. Furthermore, prostate cancer risk was not related to use of
either nonaspirin NSAIDs (NA-NSAIDs) or acetaminophen224. In a nested case-control
study, using data from the General Practice Research Database in United Kingdom,
aspirin use was associated with a reduced risk of prostate cancer (OR = 0.70, 95% CI:
0.61,0.79). Furthermore, paracetamol use with treatment duration longer than 1 year also
showed a decreased risk (OR = 0.65, 95% CI: 0.54,0.78). On the other hand, NANSAIDs and paracetamol short-term uses were associated with a small increased risk,
42
with ORs of 1.26 (95% CI: 1.09, 1.45) and 1.14 (95% CI: 1.00, 1.31), respectively116.
The association between NSAIDs use and prostate cancer incidence was also examined
among 70 144 men in the American Cancer Society’s Cancer Prevention Study II
Nutrition Cohort222. In this study, neither current aspirin use nor current use of NSAIDs
was associated with prostate cancer risk. Nonetheless, long-duration regular use, defined
as 30 or more pills per month for 5 or more years of NSAIDs was associated with
reduced risk of prostate cancer (RR = 0.82, 95% CI: 0.71, 0.94). Long-duration regular
use of aspirin was also associated with reduced risk of prostate cancer (RR = 0.85, 95%
CI: 0.73, 0.99). In another study, Perron et al.
216
addressed the effect of cumulative
duration and timing of exposure to NSAIDs and risk of prostate cancer. No association
was observed between prostate cancer risk and NSAIDs use, other than aspirin. However,
exposure to a mean daily dose of aspirin of at least 80 mg, maintained for 8 years, was
associated with an 18% reduction in prostate cancer risk (OR=0.82; 95% CI: 0.71, 0.95).
In another large cohort study (VITAL study)225, the association between long-term
NSAIDs use and risk of prostate cancer was evaluated. In summary, low-dose aspirin,
regular-strength aspirin, ibuprofen, and any nonaspirin NSAIDs (ibuprofen, naproxen,
and COX-2 inhibitors) were not associated with prostate cancer risk, even though there
was a suggestion that regular-strength aspirin was inversely associated with risk of highgrade cancer (HR 0.73, 95% CI: 0.53–1.02) in the VITAL cohort226.
The association between NSAIDs and survival among men who underwent radical
prostatectomy (RP) or radiotherapy (RT) has also been examined retrospectively. Overall
NSAIDs ever-use was also associated with a reduced risk of all-cause mortality after RP
(HR 0.47, 95% CI 0.30–0.75) and RT (0.39, 0.25–0.59)227.
43
A positive association between NSAIDs use and prostate cancer risk has also been
observed. Using data from the population-based North Jutland Prescription Database and
the Danish Cancer Registry, a large cohort study205 was conducted to compare cancer
incidence among 172 057 individuals prescribed nonaspirin NSAIDs with expected
incidence (based on county-specific cancer rates) during a 9-year study period. A
standardised incidence ratio (SIR) for several cancers among persons who obtained 10 or
more prescriptions showed a protective association of NSAIDs against colon, rectal,
stomach, and ovarian cancers, but not for lung or kidney cancers. Of interest, an
increased SIR was also observed in prostate cancer (SIR = 1.3, 95% CI: 1.2, 1.5) and it
was even higher among those with 10 or more prescriptions (SIR = 1.6, 95% CI: 1.3,
2.0). Recently, a positive association was also observed in a cross-sectional case-control
study nested within a large UK-wide population-based study228. In this study, non aspirinNSAIDs (OR=1.32, 95% CI: 1.04-1.67) and all-NSAIDs (OR=1.25, 95% CI:1.07-1.47)
use were positively associated with prostate cancer, while no statistically significance
was observed among aspirin users.
Recently, a more comprehensive and detailed study reviewed not only the hypothesis that
NSAIDs may reduce the risk of prostate cancer but the consistency of the association and
sources of variability between the studies as well229. The systematic review and metaanalysis comprised of 10 cases-control and 14 cohort studies with a total of 24,230
prostate cancer cases. The prevalence of aspirin use varied significantly (from 3 to 66%),
which reflects high variability, possibility due to differences in the sources of information
or definition of drug use. The pooled odds ratio (POR) showed a statistically significant
effect of aspirin to reduce risk of prostate cancer (POR= 0.83, 95% CI: 0.77, 0.89), but
44
with some evidence of heterogeneity (p=0.05). When the effect of aspirin was examined
only in advanced prostate cancers, no appreciable difference from total prostate cancer
was observed (POR= 0.81, 95% CI: 0.72, 0.92) with little heterogeneity among studies
(p=0.655). A restricted analysis of the effect of non-aspirin NSAIDs suggested an
inverse, albeit small association with the risk of total prostate cancers (POR=0.90, 95%
CI: 0.8,1.01); this association disappeared when analyses were restricted to advanced
prostate cancers (POR=1.0, 95% CI: 0.63, 1.58). Nonetheless, both analyses were less
consistent and showed higher heterogeneity compared to the corresponding results from
aspirin use. Moreover, subgroup analyses of all-NSAIDs and risk of total prostate cancer
in 10 studies, were much less suggestive of an association (POR=0.89, 95% CI: 0.73,
1.09) and were very heterogeneous (p < 0.001), whereas 3 studies that examined the
effect of all-NSAIDs on advanced prostate cancers were more consistent in showing an
inverse association (POR= 0.75, 95% CI: 0.60, 0.93; p for heterogeneity=0.96). Lately,
the association of five different classes of NSAIDs and prostate cancer risk was
systematically examined230. In summary, use of propionates, such as ibuprofen and
naproxen was associated with a modest reduction in prostate cancer risk (OR = 0.90;
95%CI 0.84-0.95), whereas use of other NSAIDs was not. No association with aspirin
use was observed as well (OR=1.01; 95% CI: 0.95–1.07). Additionally, there was no
clear evidence of dose-response or duration-response relationships for any of the
examined NSAIDs classes.
3.5. Statins
Statins or 3-Hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitors are a
therapeutic class of drugs used for treatment of lipid disorders such as
45
hypercholesterolemia. As increased cholesterol levels have been associated with
cardiovascular diseases (CVD)231, statins have been prescribed to manage and prevent
coronary heart disease (CHD)232. Moreover, numerous large-scale randomized controlled
trials (RCTs) have demonstrated the beneficial effects of statins on patients without
previous CVD but with elevated cholesterol levels and other risk factors for heart disease,
such as diabetes and high blood pressure233-236.
As such, their use has increased
dramatically in the past decade and statins are now among the most commonly prescribed
drugs worldwide237. There are currently seven statins on the market: Atorvastatin (Lipitor
and Torvast), which is the best-selling of the statins, Fluvastatin (Lescol), Lovastatin
(Mevacor, Altocor, Altoprev), Pitavastatin (Livalo, Pitava), Pravastatin (Pravachol,
Selektine, Lipostat), Rosuvastatin (Crestor) and Simvastatin (Zocor, Lipex). HMG-CoA
reductase, which is the rate limiting step for conversion of HMG-CoA to mevalonic acid,
is a precursor of cholesterol and of a variety of nonsterol isoprenoid derivatives that are
important for various cellular functions, including cell proliferation, differentiation, and
survival
10-12
. Therefore, disruption of this process in neoplastic cells by statins may
result in the control of tumor initiation. In fact, a growing body of evidence suggests that
statins may be considered as good candidates for novel anticancer agents10,238 .
3.5.1. Epidemiology of statins and cancer
Several epidemiologic studies have been conducted to evaluate the association between
statins and cancer risk. Recently, a comprehensive review has summarized these findings,
particularly for cancers at specific sites such as the breast, colorectal, lung, prostate, and
reproductive organs239. For breast cancer, numerous epidemiologic studies have been
conducted, but the overall evidence does not lend strong support for an association
between statin use and breast cancer risk240-243. In fact, they are largely inconclusive, as
46
some studies reported an inverse association of statins use and breast cancer, while others
reported null or positive associations. Interestingly, one large cohort study244, found that
statin use was associated with a 18% lower risk of breast cancer (HR= 0.82, 95% CI:
0.70,0.97), only when statin use was limited to hydrophobic statin users (i.e, simvastatin,
lovastatin, and fluvastatin), while use of other lipophylic statins (i.e., pravastatin and
atorvastatin) was not associated with breast cancer incidence. In contrast, of other metaanalyses that evaluated site-specific cancers, one study found an increased risk of breast
cancer with pravastatin use only (Relative Risk [RR]=3.3, 95% CI: 1.7,6.3)245. Most
epidemiologic studies on statin use and breast cancer risk lacked information on potential
confounders, such as diet, physical activity and breast cancer screening. However, a
meta-analysis conducted by Bonovas et al.246, which attempted to address these issues,
did not support the hypothesis of a protective effect of statins against breast cancer
(RR=1.03, 95% CI: 0.93,1.14). Nonetheless, some limitations such as relatively short
statin exposure and follow-up period still remained. The association of statin use and risk
of colorectal cancer has been also assessed in several studies in recent years247-251.
Overall, no association emerged. Indeed, a meta-analysis involving 18 studies with more
than 1.5 million participants confirmed the absence of an association between statin use
and risk of colorectal cancer, among six RCTs (RR=0.95, 95% CI: 0.80, 1.13) and among
3 cohort studies (RR=0.96, 95% CI: 0.84, 1.11). However, when analyses were limited to
case-control studies (n=6) , a modest reduction in the risk of colorectal cancer among
statins users was found (RR=0.91, 95% CI: 0.87,0.96)246.
For lung cancer, no evidence supporting an association with statin use was found in four
case-control studies243,252-254 and two cohort studies247,248. Of note, all of these casecontrol studies had small number of cancer cases among statins users. In contrast, a large
47
case-control study, with almost 2000 lung cancer cases found a 45% reduction in lung
cancer risk among statins users compared to non users255. Recently, a published study of
statins and numerous site-specific cancer found a lower incidence of lung cancer among
statins users compared to non-users (RR=0.81, 95% CI: 0.77,0.86)256. Another study that
compared various types of cancer (breast, prostate, colorectal, lung, bladder, pancreatic,
kidney, and endometrial cancers, along with non-Hodgkin’s lymphoma and leukemia) to
controls in a hospital-based case–control surveillance study, did not support either
positive or negative associations between statin use and the occurrence of those 10 cancer
types253. Moreover, for the cancer sites with the largest sample sizes, odds ratios (OR) did
not vary significantly by duration of statin use. Recently, these findings have been
confirmed by a large US cohort study that showed no relevant associations between longterm use of cholesterol-lowering drugs, predominantly statins (current use for five or
more years) and overall cancer incidence or incidence of prostate, breast, colorectal, lung,
bladder, renal cell or pancreatic cancers257,258.
3.5.2. Epidemiology of statin use and risk of prostate cancer
Several studies have examined the association of statin use and risk of prostate cancer,
but overall the results are very inconclusive243,248,252,253,259-268.
In two case-control
studies, statin use was associated with a reduction (54%-65%) in risk of prostate
cancer261,269. In a large cohort study conducted within a health plan, no association
between ever statin use or <5 years use and prostate cancer was observed. Conversely,
long-term users (>5 years) showed a 28% lower risk for developing prostate cancer
compared with non-users (OR=0.72; 95% CI: 0.53,0.99). Of note, this association
seemed to be restricted to NSAIDs users (OR=0.64; 95% CI:0.44,0.93); there was no
significant association between long-term use of statins and risk of prostate cancer was
48
found among NSAIDs non-users (OR=1.05; 95% CI: 0.55,1.98)263. In another large
cohort study conducted using health plan data, users of hydrophobic statins (lovastatin,
simvastatin, fluvastatin, atorvastatin, and cerivastatin) showed a reduced risk of prostate
cancer as compared to non-users (Hazard Ratio (HR) = 0.79; 95% CI, 0.66–0.94).
Moreover, results were suggestive of a reduced risk among ever users of statins (HR =
0.88; 95% CI, 0.76–1.02), as well as for users of hydrophilic statins (pravastatin and
rosuvastatin) (HR = 0.67; 95% CI, 0.33–1.34). There was no trend in risk by duration of
statin use, and no association between statin use and cancer aggressiveness, stage, or
grade266.
The association of statin use with the risk of prostate cancer mortality and improved
survival was also examined retrospectively among patients who underwent radical
prostatectomy (RP) or radiotherapy (RT) for prostate cancer. In this study, statin ―everuse‖ was associated with a reduced risk of all-cause mortality after RP (HR=0.35; 95%
CI: 0.21,0.58) and RT (HR=0.59, 95% CI: 0.37,0.94)270. Another longitudinal,
population-based cohort study of 2,447 men between 40 and 79 years of age who were
followed from 1990 to 2007 reported that statin use was associated with a decreased risk
of undergoing prostate biopsy (HR=0.31; 95% CI: 0.24, 0.40), receiving a prostate cancer
diagnosis (HR=0.36; 95% CI: 0.25, 0.53) and receiving a high grade (Gleason 7 or
greater) prostate cancer diagnosis (HR 0.25; 95% CI: 0.11, 0.58)271.
Most of the observational studies243,248,253,259,262,265,266, meta-analyses245,257,272, and a
review of the evidence between statins and prostate cancer risk264 do not support an
association between statin use and overall prostate cancer risk. However, findings
consistent with a reduction of advanced prostate cancer and aggressive disease with statin
use have been consistently reported at least in specific circumstances by several recent
49
studies261,262,264,265. For instance, Platz and colleagues did not find an association between
statin use and risk of total prostate cancer, but reported a decreased risk of advanced
prostate cancer with any statin use and even lower risk with use for 5 years or longer. In
another prospective study, the same authors reported that men with low cholesterol levels
had a lower risk of Gleason 8 to 10 prostate cancer (OR=0.41; 95% CI: 0.22,0.77) than
men with high cholesterol levels, while no association was present for prostate cancer
overall (OR=0.97; 95% CI, 0.85,1.11)273. These findings were confirmed in a metaanalysis of 6 RCTs and 13 observational studies that examined statin use in relation to
both total prostate cancer and the more clinically important advanced prostate cancer. In
this study, no association between statin use and overall prostate cancer risk (RR = 1.06,
95% CI: 0.93,1.20) for RCTs and (RR=0.93, 95% CI: 0.77,1.13) for observational studies
was found, while a protective association in studies that examined advanced prostate
cancer risk (RR = 0.77, 95% CI: 0.64–0.93) was supported274.
A few studies have also reported that statin use is associated with an increased risk of
prostate cancer. In a matched case-control study using information from the General
Practice Research Database (GPRD), a moderately increased risk of prostate cancer was
observed among current statin users as compared to controls (RR=1.3, 95%
CI:1.0,1.9)254. In a population-based study, no overall association was found between
statin use and prostate cancer risk or for risk of more advanced disease. Nonetheless,
obese men (BMI ≥30 kg/m2) who used statins had an increased risk (OR=1.5, 95% CI:
1.0, 2.2) relative to obese nonusers, with a stronger association for longer-term use (OR=
1.8, 95% CI: 1.1, 3.0 for >5 years’ use)267. A population-based case-control study in
Taiwan with 388 prostate cancer cases and 1,552 controls, matched to cases on age, sex,
and index date, found that ever-use of any statins was associated with a significant
50
increase in prostate cancer risk (OR= 1.55, 95% CI: 1.09,2.19). Compared with no use of
statins, the adjusted ORs (95%CI) were 1.17 (0.60–2.28) for the group with cumulative
dose ≤ 29.44 DDD (daily dose drug), 1.59 (1.02–2.48) for the group with cumulative
dose between 29.44 DDD and 321.33 DDD, and 1.86 (1.03–3.37) for the group with the
highest cumulative dose (≥321.33 DDD). Also, there was a significant trend toward
increasing prostate cancer risk with increasing cumulative dose (2 for linear trend =
7.23, P = 0.007)275. Long-term follow-up post-completion of a randomized controlled
trial that compared pravastatin with placebo in the West of Scotland Coronary Prevention
Study revealed a trend toward an increased risk of prostate cancer in the pravastatin
group relative to placebo 2.7% to 1.8% (P = 0.03). However, this finding was not
significant after adjustment for multiple testing (Bonferroni correction)276.
51
4. METHODOLOGY
4.1. Study Population
Study Base: PROtEuS (Prostate Cancer & Environment Study) is an ongoing casecontrol study of environmental risk factors for prostate cancer. Study subjects were men,
age 75 or less at time of diagnosis or selection, residents of the greater Montreal area,
listed on the Province of Quebec’s permanent electoral list (continually updated), and
Canadian citizens.
Eligible cases : Patients newly diagnosed with primary prostate cancer, were ascertained
from 11 major French hospitals in the Montreal area between September 1, 2005 and
December, 31 2010. Potential cases were identified by active monitoring of hospital
pathology reports with a histologically-confirmed diagnosis of prostate cancer
(International Classification of Diseases, 10th revision, code C61). Ethics approvals were
obtained from all participating institutions.
Eligible controls: Control subjects were selected from the Provincial electoral Frenchspeaking list, and approximately frequency-matched to the cases by age within 5 years.
Controls were drawn randomly from an area comprising 39 electoral districts (about
40,000 electors each), corresponding to those of the case series.
Case and control accrual: A total of 1,429 cases and 1,543 controls accepted to
participate in the study. Participation rates were 84% among prostate cancer patients,
considered excellent as compared to other studies, and 62% among controls subjects.
Relevant information about eligible cases, including staging of cancer and histological
grade, was obtained from the pathology departments or hospital tumour registries of
52
participating hospitals. Both cases and controls were sent and introductory package and
were reached by telephone by interviewers to set up an appointment.
4.2. Data Collection
As part of in-person interviews, trained interviewers elicited information using a
standardized questionnaire covering a wide range of factors, such as socio-demographic
characteristics, lifestyle factors (including lifetime histories of active and passive
smoking, alcohol consumption, anthropometric factors), family history of cancer and
medical history. In addition, subjects were asked to provide a recent history of prostate
cancer screening, defined as having had a prostate-specific antigen (PSA) test and/or a
digital rectal exam (DRE) within the past five years. The degree of aggressiveness of
prostate cancers, as defined by the Gleason score (http://gleasonscore.net/), was extracted
from the pathology reports. Ethics committees at all participating hospitals and affiliated
universities approved the protocol and informed consent was obtained from all
participating subjects.
4.3. Exposure assessment
4.3.1. NSAIDs assessment
Participants were first asked if they had ever had rheumatism/arthritis, arthrosis, chronic
pain or migraine for at least 6 months. If so, they were asked to provide information
about the medication they had used, if any, to treat any of these illnesses during their
lifetime. Participants who had ever taken ―Ibuprofen‖, ―Advil‖, ―Motrin‖, ―Nuprin‖,
―Novo-Profen‖, ―Naproxen‖, ―Naprosyn‖, ―Aleve‖, ―Anaprox‖, ―Aspirin‖, ―Anacin‖,
―Ascriptin‖, ―Bufferin‖, ―Entrophen‖, ―Ansaid‖, ―Froben‖, ―ApoDiclo‖, ―Artrotec‖,
53
―Novo-Difenac‖,
―Voltaren‖,
―Bextra‖,
―Celebrex‖,
―Mobicox‖,
―Vioxx‖,
―Indomethacin‖, ―Indocid‖, ―Indotec‖, ―Lodine‖, ―Ultradol‖, ―Surgam‖, ―Tiafen‖ to
treat those diseases were considered to be NSAIDs users. All other subjects were
considered non users. For users, information was elicited on the ages when each
medication was started and ended, allowing for the possibility of interruptions.
4.3.2. Daily-low dose of Aspirin assessment
Participants who had ever taken acetylsalicylic acid (AAS), such as ―Asaphen‖,
―Aspirin‖, ―Entrophen‖, or ―Novasen‖ (at least 6 months) during their lifetime to prevent
blood clots were considered and defined as daily-low dose of aspirin users. Ages at
beginning and end of use of daily-low dose of aspirin were recorded. All others subjects
were considered non users.
4.3.3. Statins assessment
There was no specific question asking for previous use of statins. However, subjects were
asked to report any medication that they had taken regularly (at least 6 months), during
their lifetime, that was not listed in the questionnaire. A multistep algorithm was used to
determine statins consumption (Figure 2.). Participants who had ever had hypertension or
a high cholesterol level for at least 6 months and who reported having taken ―Advicor‖,
―Altoprev‖, ―Mevacor‖, ―Caduet,‖ ―Lipitor‖, ―Crestor‖, ―Lescol‖, ―Pravachol‖, ―Zocor‖
were considered statins users. Participants who had not reported taking any statins
medications and who had no diabetes, no hypertension and no high cholesterol levels
were considered Probable statins non users. Participants who had not reported taking any
54
medication, but whose history cannot rule out hypercholesterolemia, hypertension or
diabetes, were defined as possible statin non users.
Is statins consumption reported in connection with a specific condition
such as hypertension or hypercholesterolemia for at least 6 months?
NO
YES
USER
Are clinical conditions such as
hypercholesterolemia, hypertension
and diabetes ruled out ?
NO
YES
Probable non user
Possible non user
FIGURE 2. Algorithm used to define variable for statins consumption
55
4.3.4. Duration and period of exposure
Current use of NSAIDs, low-dose aspirin or statins was assigned if usage continued up to
the index date or ended in the year prior to the index date. Former use was assigned when
usage ended more than one year before the index date. Treatment duration was calculated
using the age at beginning and age at end of use, taking into account interruptions)). Time
since first use was defined as the years elapsed from the date of first use, until the index
date. As often done in similar studies, a one-year lag period was applied.
4.4. Measurement of tobacco consumption
Participants were asked if they had smoked at least 100 cigarettes in their entire life. For
those having responded yes to the previous questions, they were asked if there has been a
period when they had smoked cigarettes regularly (at least 1 cigarette per week for at
least 1 year). Among those who did, the ages at start and at end of cigarette use (if
applicable), along with the frequency of cigarette use, were recorded. Smoking
interruptions and changes in the frequency of use of cigarettes were recorded.
A
cumulative exposure variable (pack-years) was defined to translate the intensity and
duration of tobacco consumption. One pack-years was calculated as the number of
cigarettes per day * number of years / 20 (1 pack= 20 cigarettes). Six categories of
tobacco consumption were used in the data analysis: One reference category for nonexposure, four categories defined by the quartile cut-off values among exposed controls,
and one category for missing values. These categories were as follows : 1) ―Never
smokers‖; 2) ―1-24 pack-years‖, 3) ―25-49 pack-years‖; 4) ―50-99 pack-years‖; 5) ―≥100
pack-years and 6) ―Unknown‖.
56
4.5. Measurement of alcohol consumption
Participants were asked if they had ever consumed beer, wine, or spirits at least once a
month for at least one year. If so, the age started and age ended, along with the frequency
of use of each beverage, was recorded. Interruptions in use of each beverage, and changes
in their frequency of consumption were recorded. The duration and intensity of alcohol
consumption (drink-year) was determined as the number of drink per day*number of
years. Following the same procedure used for grouping tobacco consumption, six
categories of alcohol consumption were defined : 1) ―Never drinker‖; 2) ―1-49 drinkyears‖, 3) ―50-199 drink-years‖; 4) ―200-499 pack-years‖; 5) ―≥500 pack-years and 6)
―Unknown‖.
4.6. Statistical Analyses
Unconditional logistic regression was used to compute odds ratios (ORs) and their 95%
confidence intervals (CI) to evaluate the association between use of NSAIDs, daily low
dose of aspirin or statins, and risk of prostate cancer.
4.7. Method for selection of confounding variables
Selection of potential confounding variables was determined by fitting models using a
stepwise forward addition of variables and then evaluating the change in the estimated
parameter for the main effect. If inclusion of any variables changed the relative risk
estimated for any of the study’s main exposures (NSAIDs, daily low dose of aspirin or
statin) by 2% or more in either direction, negative or positive, [(1-adjusted OR/baseline
OR) ≥2%] these variables were then considered as empirical confounders and were thus
incorporated in the final model. Age, ethnicity and first-degree family history of prostate
57
cancer were considered to be a priori confounders and were forced for inclusion in all
models. Table 1 shows detailed information on all selected factors examined as potential
confounding variables.
4.8. Sensitivity analyses
It is possible that some men in the control series had undiagnosed prostate cancer.
In an attempt to address this issue, sensitivity analyses were conducted where we limited
analyses to men with at least one PSA test and one DRE examination in the 5 years
preceding the index date.
58
Table 1 . Definition of selected factors examined as potential confounding variables
Variables
Categories
Age
Continuous
Ethnicity
French descent
Black
Asian
Others
Marital Status
Married
Common Law
Separated
Divorced
Single
Widower
Religious member
Education
<Elementary
≤High School
College Degree
Bachelor
Graduate Degree
Family Income
< $ 10,000
$10,000-$29,000
$ 30,000-$49,000
$50,000-$79,000
$80,000-$99,000
≥$100,000
Tobacco consumption (pack-years)
Continuous
Alcohol consumption (drink-years)
Continuous
Body Mass Index, in kg/m2 (BMI)
Continuous
Ever being screened for prostate cancer
Yes/No
PSA test in the previous 5 years
Yes/No
Number of PSA tests in the previous five years
Continuous
59
Table 1. (continued) : Definition of selected factors examined as potential confounding
variables.
Variables
Categories
DRE test in the previous 5 years
Yes/No
Number of DRE examinations in the previous five years
continuous
Prostatitis
Yes/No
Inflammation of urethra
Yes/No
Inflammation of testicles
Yes/No
Inflmmation of epididymis
Yes/No
Benign Prostatic Hypertrophy (BPH)
Yes/No
Diabetes
Yes/No
Migraine
Yes/No
Chronic pain (rheumatism, arthritis)
Yes/No
Hypertension
Yes/No
Hypercholesterolemia
Yes/No
*Blood Clot
Yes/No
*Stroke, thrombosis or phlebitis
60
5. RESULTS
5.1 Descriptive statistics
Socio-demographic characteristics
The study population comprised 1,429 patients newly diagnosed with prostate cancer and
1,543 controls. The distribution of the study population with regards to sociodemographic characteristics is shown in Table 2. Given the frequency matching for age
used in the study, the age distributions for cases and controls were very similar. At the
reference date (age at diagnosis for cases, age at interview for controls), cases were on
average aged 63.6 years (range 40-75) and controls were on averaged aged 64.9 years
(range 41- 78). Age distributions did not differ significantly between cases and controls,
except among subjects aged over 70 years old. This reflects the slightly longer period of
time necessary to secure interviews with older controls. Regarding ethnicity, an expected
high frequency of French descendents was observed among cases and controls. Most
subjects were married (63.2 % of cases, 65.6 % of controls), and prostate cancer cases has
similar educational levels as controls, with approximately half of them having completed
high school (52.4% and 48.3%, for cases and controls, respectively). Likewise, little
differences were observed between cases and controls with respect to family income.
61
Table 2. Distribution of cases and controls according to socio-demographic
characteristics in a French-Speaking population, in Montreal, Canada, 2005-2010.
40 - 50
51 - 55
56 - 60
61 - 65
66 - 70
≥ 70
Mean (± SD)
Cases
(n=1429)
No
%
61
4.3
139
9.7
252
17.6
376
26.3
337
23.6
264
18.5
63.6 (6.8)
Controls
(n=1543)
No
%
47
3.0
115
7.5
212
13.7
386
25.0
403
26.1
380
24.6
64.9 (6.9)
Ethnicity
French descent
Black
Asian
Others
Unknown
1064
97
18
240
10
74.5
6.8
1.3
16.8
0.7
930
72
44
483
14
60.3
4.7
2.9
31.3
0.9
Marital Status
Married
Common Law
Separate
Divorced
Single
Widower
Religious member
903
174
36
146
113
50
7
63.2
12.2
2.5
10.2
7.9
3.5
0.5
1011
164
35
157
110
60
5
65.6
10.6
2.3
10.2
7.1
3.9
0.3
Education
<Elementary
≤High School
College Degree
Bachelor
Graduate Degree
50
748
210
224
194
3.5
52.4
14.7
15.7
13.6
61
744
274
271
191
4.0
48.3
17.8
17.6
12.4
Family Income
< $10,000
$10,000 - $19,999
$20,000 - $29,999
$30,000 - $49,999
$50,000 - $79,999
$80,000 - $ 99,999
≥$100,000
Unknown
49
122
204
342
306
124
183
99
3.4
8.5
14.3
23.9
21.4
8.7
12.8
7.0
47
147
191
375
304
131
199
148
3.0
9.5
12.4
24.3
19.7
8.5
12.9
9.2
Variable
Categories
Age, years at
reference date
62
Tobacco smoking and alcohol consumption
Cases and controls were quite similar according to tobacco smoking and alcohol
consumption. As shown in Table 3, 31.2 % of cases had never smoked compared to 30.5
% of controls. Approximately, 30% of subjects had smoked 1-24 pack-years of cigarettes
in their entire life. Likewise, for alcohol consumption, 12.8% of cases were never
drinkers compared to 13.2 % of controls. For both cases and controls, more than 45%
were in the 1-49 drink-lifetime consumption category.
Table 3. Distribution of cases and controls according to tobacco smoking and alcohol
consumption in a French-Speaking population, in Montreal, Canada, 2005-2010.
Variable
Categories
Tobacco smoking
(Pack-years of
consumption)
Never smoker
1-24
25 -49
50-99
>100
Unknown
Cases
(n=1429)
No
%
444
31.1
449
31.4
290
20.3
214
15.0
25
1.8
7
0.5
Alcohol consumption
(Drink-years)
Never drinker
1-49
50-199
200-499
>500
Unknown
177
648
432
96
27
49
12.8
47.0
31.3
7.0
2.0
3.4
Controls
(n=1543)
No
%
469
30.5
467
30.3
360
23.3
211
13.7
33
2.1
3
0.2
200
686
519
81
28
29
13.2
45.3
34.3
5.3
1.8
1.9
63
Distribution of clinical conditions
Cases and controls were very similar with respect to Body Mass Index (BMI). As shown
in Table 4, the mean BMI 2 years before index date was 26.5 kg/m2 among cases and
27.0 kg/m2 among controls. The majority of subjects were found to be slightly
overweight, with BMI ranging between 25.0 to 27.4 kg/m2. Compared to controls, cases
were more likely to report any cancer in family members and a first-degree family history
of prostate cancer. In addition, as expected, cases had undergone prostate cancer
screening more often than controls. Cases and controls differed also with respect to other
clinical characteristics, with cases reporting more frequently prostatitis, BPH, migraine,
chronic pain, and blood clots compared to controls. Of interest, prevalence of diabetes
was higher among controls than among cases. No significant differences were found
between cases and controls regarding the distribution of other clinical conditions.
64
Table 4. Distribution of cases and controls according to clinical factors in a FrenchSpeaking population, in Montreal, Canada, 2005-2010.
Variable
Categories
Cases
(n=1429)
BMI (kg/m2), 2 years before
index date
< 20
20-22.4
22.5-24.9
25.0-27.4
27.5-30.0
>30
MEAN (± SD)
No
%
41
2.9
153
10.8
348
24.5
410
28.9
227
16.0
242
17.0
26.5 (4.0)
Controls
(n=1543)
No
%
46
3.0
137
9.0
328
21.4
430
28.1
274
17.9
317
20.7
27.0 (4.4)
Any cancer in family
members
No
Yes
Unknown
467
924
38
32.7
64.7
2.7
646
855
42
41.9
55.4
2.7
First-degree family history
of prostate cancer
No
Yes
Unknown
1060
322
47
74.2
22.5
3.3
1334
161
48
86.5
10.4
3.1
Ever been screened for
prostate cancer
No
Yes
Unknown
3
1425
1
0.2
99.7
0.1
145
1375
23
9.4
89.1
1.5
Screened for prostate cancer
in last 5 years (DRE and PSA)
No
Yes
Unknown
34
1383
12
2.4
96.8
0.84
259
1106
178
16.8
71.7
11.54
PSA test in the last 5 years
No
Yes
Unknown
2
1410
14
0.1
98.9
1.0
61
1251
63
4.4
91.0
4.6
Number of PSA test in the
last 5 years
0-2
3-5
6-10
>10
Unknown
310
747
262
21
89
21.7
52.3
18.3
1.5
6.2
318
782
89
10
344
20.6
50.7
5.8
0.7
22.3
DRE test in the last 5 years
No
Yes
Unknown
25
1392
9
1.7
97.6
0.6
176
1188
11
12.8
86.4
0.8
65
Table 4. (continued). Distribution of cases and controls according to clinical factors in a
French-Speaking population, in Montreal, Canada, 2005-2010.
Variable
Cases
(n=1429)
Categories
%
28.9
53.5
11.4
0.8
5.3
Controls
(n=1543)
No
%
520
33.7
606
39.3
43
2.8
3
0.2
371
24.4
Number of DRE tests in the
last 5 years
0-2
3-5
6-10
>10
Unknown
No
413
765
163
12
76
Prostatitis
No
Yes
Unknown
1215
181
33
85.0
12.7
2.3
1404
118
21
91.0
7.6
1.4
Inflammation of urethra
No
Yes
Unknown
1254
150
25
87.8
10.5
1.8
1371
155
17
88.9
10.0
1.1
Inflammation of testicles
No
Yes
Unknown
1339
74
16
93.7
5.2
1.1
1471
56
16
95.3
3.6
1.0
Inflammation of epididymis
No
Yes
Unknown
1383
20
26
96.8
1.4
1.8
1497
26
20
97.0
1.7
1.3
Benign Prostate Hypertrophy (BPH)
No
Yes
Unknown
813
542
74
56.9
37.9
5.2
1197
322
24
77.6
20.9
1.6
Gleason score
1-3
4-6
7-9
Unknown
4
634
778
13
0.3
44.4
54.5
0.9
Diabetes
No
Yes
Unknown
1214
212
3
85.0
14.9
0.2
1228
313
2
79.6
20.3
0.1
Migraine
No
Yes
1324
105
92.7
7.3
1473
70
95.5
4.5
Chronic pain
No
Yes
Unknown
1028
399
2
71.9
27.9
0.1
1190
353
0
77.1
22.9
0
66
Table 4. (continued). Distribution of cases and controls according to clinical factors in a
French-Speaking population, in Montreal, Canada, 2005-2010.
Variable
Cases
(n=1429)
Categories
%
52.1
47.8
0.1
Controls
(n=1543)
No
%
834
54.1
706
45.8
3
0.2
Hypertension
No
Yes
Unknown
No
744
683
2
High cholesterol level
No
Yes
968
461
67.7
32.3
1024
519
66.4
33.6
*Blood clotting conditions
No
Yes
Unknown
1290
137
2
90.3
9.6
0.1
1407
136
0
91.2
8.8
0
*Stroke, thrombosis, phlebitis
5.2. Characteristics of exposure
5.2.1. NSAIDs
Table 5 presents the frequency of NSAID use for cases and controls. The prevalence of
ever using any NSAIDs was slightly higher among cases as compared to controls.
However, in both groups, current users were predominant. Cases differed from controls
with respect to duration of use. Although the majority of participants reported using any
NSAIDs for less than 10 years, cases were somewhat more likely to report longer NSAID
use (over 10 years) than controls. Among the different types of NSAIDs used, COX-2
inhibitors were the most frequently reported. As seen in Table 6, cases and controls were
comparable with respect to history of intake of Cox-2 inhibitors.
67
Table 5. Distribution of cases and controls according to characteristics of use NSAIDs in a French-Speaking population, in
Montreal, Quebec, 2005-2010.
Variable
Categories
Ever use
Nonuser
Current user
Former user
Unknown†
Cases
(n=1429)
No
%
1,313
91.9
76
5.3
34
2.4
6
0.4
Duration of use, years
Non user
≤ 10
> 10
1,313
80
36
91.9
5.6
2.5
1,454
68
21
94.2
4.4
1.4
Time since first use before
interview, years
Non user
0-1
2-5
6-10
> 10
Unknown
1,313
22
30
16
40
9
91.9
1.5
2.1
1.1
2.8
0.6
1,454
7
21
27
28
6
94.2
0.5
1.4
1.7
1.8
0.4
Types of NSAIDs *
Advil, Ibuprofen, Motrin, Novo-Profen, Nuprin
Aleve, Anaprox, Naprosyn, Naproxen
Aspirin**, Anacin, Bufferin, Entrophen
Ansaid, Froben
ApoDiclo, Artrotec, Novo-Difenac, Voltaren
Bextra, Celebrex, Mobicox, Vioxx
Indocid, Indotec, Indomethacin
Lodine, Ultradol
Surgam, Tiafen
21
14
21
1
18
46
4
0
1
14.7
12.8
7.3
1.8
16.5
41.3
2.7
1.8
0.9
14
4
7
1
10
44
5
1
1
15.8
5.2
7.9
1.3
11.8
50.0
5.3
1.3
1.3
*Types of NSAIDs among those reported use for at least 6 months; **Excluding daily low dose aspirin;
† Missing data on status of usage among users
Controls
(n=1543)
No
%
1,454
94.2
55
3.6
27
1.8
7
0.5
Table 6. Distribution of cases and controls according to intake of COX-2 inhibitor
medications in a French-Speaking population, in Montreal, Canada, 2005-2010.
Never user
Current user
Former user
Unknown†
Cases
(n=1429)
No
%
1384
96.8
29
2.0
15
1.1
1
0.1
Controls
(n=1543)
No
%
1505
97.5
21
1.4
15
1.0
2
0.1
Duration of use, years
Non user
≤5
>5
Unknown
1384
25
17
3
96.8
1.8
1.2
0.2
1505
22
15
1
97.5
1.4
1.0
0.1
Time since first use before
interview, years
Non user
≤5
>5
Unknown
1384
22
19
4
96.8
1.5
1.3
0.3
1505
12
23
3
97.5
0.8
1.5
0.2
Variable
Categories
COX-2 inhibitors
† Missing data on status of usage among users
Selected demographic characteristics were also compared between users and non users of
NSAIDs among controls and are shown in Table 7. The prevalence of any NSAID use
was 6%. There was no clear differential pattern in NSAID use according to age. Users
tended to be more likely of French descend. The proportion of users was slightly lower
among subjects of Black descent and slightly higher among subjects of Asian descent.
NSAID users were comparable to non-users with respect to marital status but had
somewhat higher (albeit non-statistically significant) educational attainment and family
income than non-users. No significant differences were observed with respect to tobacco
smoking and alcohol consumption as presented in Table 8. As shown in Table 9, NSAID
users tended to have a higher BMI, were more likely than non users to report having been
screened for prostate cancer in the last 5 years and also more frequently than non-users.
Use of any NSAID among controls had a higher prevalence of self-reported hypertension,
hypercholesterolemia and blood clot as compared to non-users.
Table 7. Comparison of socio-demographic characteristics among controls according to
use of NSAIDs, Montreal, Canada, 2005-2010.
Variable
Users
(n=89)
Categories
Nonusers
(n=1454)
No
%
356
24.5
362
24.9
377
25.9
359
24.7
64.9 (6.9)
Chi-square
P value
Age, years at
reference date
≤60
61 - 65
66 - 70
≥ 70
Mean (± SD)
No
%
18
20.2
24
27.0
26
29.2
21
23.6
64.7 (7.1)
Ethnicity
French descent
Black
Asian
Others
Unknown
61
2
3
22
1
68.5
2.3
3.4
24.7
1.1
869
70
41
461
13
59.8
4.8
2.8
31.7
0.9
0.45
Marital Status
Married
Common Law
Separate
Divorced
Single
Widower
Religious member
57
14
0
10
5
3
0
64.0
15.7
0
11.2
5.6
3.4
0
954
150
35
147
105
57
6
65.7
10.3
2.4
10.1
7.2
3.9
0.3
0.51
Education
<Elementary
≤High School
College Degree
Bachelor
Graduate Degree
3
38
15
16
17
3.4
42.7
16.8
18.0
19.1
59
707
259
255
174
4.0
48.6
17.8
17.5
12.0
0.51
0.61
Family Income
< $19,999
11
12.4
183
12.6
0.38
$20,000 - $29,999
5
5.6
186
12.8
$30,000 - $49,999
20
22.5
355
24.4
$50,000 - $79,999
20
22.5
284
19.5
$80,000 - $99,999
10
11.2
121
8.3
≥$100,000
15
16.8
184
12.7
Unknown
8
9.0
141
9.7
*NSAIDs among those reported use for at least 6 months; **Daily low dose aspirin is excluded
70
Table 8. Comparison of tobacco smoking and alcohol consumption among controls
according to use of NSAIDs, Montreal, Canada , 2005-2010
Variable
Categories
Tobacco smoking
(Pack-years)
Never smoker
1-24
25 -49
50-99
>100
No
21
32
23
10
3
Users
(n=89)
%
23.6
36.0
25.8
11.2
3.4
Nonusers
(n=1454)
No
%
448
30.9
435
30.0
337
23.2
201
13.8
30
2.1
Chi-square
P value
0.55
Alcohol consumption
(Drink-years)
Never drinker
11
12.3
189
13.0
0.06
1-49
38
42.7
648
44.6
50-199
32
35.9
487
33.5
200-499
1
1.2
80
5.5
>500
2
2.2
26
1.8
Unknown
5
5.7
24
1.6
*NSAIDs among those reported use for at least 6 months; **Daily low dose aspirin is excluded
71
Table 9. Comparison of clinical characteristics among controls according to use of
NSAIDs, Montreal, Canada , 2005-2010
Variable
Users
(n=89)†
Categories
Nonusers
(n=1454)†
No
%
44
3.1
131
9.1
314
21.7
410
28.4
253
17.5
292
20.2
26.9 (4.2)
Chi-square
P value
BMI (kg/m )
< 20
20.0-22.4
22.5-24.9
25.0-27.4
27.5-30.0
>30
MEAN (±SD)
No
%
2
2.3
6
6.8
14
15.9
20
22.7
21
23.9
25
28.4
28.8 (6.00)
Any cancer in family members
No
Yes
30
57
34.5
65.5
616
798
43.6
56.4
0.09
First-degree family history
of prostate cancer
No
Yes
76
10
88.4
11.6
1258
151
89.3
10.7
0.96
Ever been screened** for
prostate cancer
in the last 5 years
No
Yes
9
75
10.7
89.3
250
1031
19.5
80.5
0.05
PSA test in the last 5 years
No
Yes
2
77
2.5
97.5
59
1174
4.8
95.2
0.36
Number of PSA test in the
last 5 years
0-2
3-5
6-10
>10
19
41
9
3
26.4
57.0
12.5
4.2
299
741
80
7
26.5
65.7
7.1
0.6
0.13
DRE test in the last 5 years
No
Yes
4
79
4.8
94.0
172
1109
13.3
85.9
0.02
Number of DRE test in the
last 5 years
0-2
3-5
6-10
>10
33
37
4
1
37.1
41.6
4.5
1.1
487
569
39
2
33.5
39.1
2.7
0.1
0.09
2
0.001
*NSAID use does not include low dose aspirin ** DRE examination and PSA test
†Numbers may not add to total because of missing data
72
Table 9. (continued). Comparison of clinical characteristics among controls according to
use of NSAIDs, Montreal, Canada, 2005-2010.
Variable
Users
(n=89)
Categories
%
89.9
9.0
1.1
Nonusers
(n=1454)
No
%
1324
91.1
110
7.6
20
1.3
Chi-square
P value
Prostatitis
No
Yes
Unknown
No
80
8
1
Inflammation
of urethra
No
Yes
Unknown
74
14
1
83.2
15.7
1.1
1297
141
16
89.2
9.7
1.1
0.07
Inflammation
of testicles
No
Yes
Unknown
82
6
1
92.1
6.7
1.1
1389
50
15
95.5
3.4
1.0
0.105
Inflammation
of epididymis
No
Yes
Unknown
83
3
3
93.3
3.4
3.4
1414
23
17
97.3
1.6
1.2
0.19
BPH
No
Yes
Unknown
66
21
1
74.2
23.7
1.1
1131
301
22
77.8
20.7
1.5
0.49
Diabetes
No
Yes
Unknown
67
21
1
75.3
23.6
1.1
1161
292
1
79.8
20.1
0.1
0.39
Migraine
No
Yes
70
19
78.6
21.3
1403
51
96.5
3.5
<0.0001
Chronic pain
No
Yes
9
80
10.1
90.0
1181
273
81.2
18.8
<0.0001
Hypertension
No
Yes
35
54
39.3
60.7
799
652
55.1
44.9
0.004
High
cholesterol level
No
Yes
50
39
56.2
43.8
974
480
66.9
33.1
0.04
**Blood clotting
conditions
No
Yes
76
13
85.4
14.6
1331
123
91.5
8.5
0.05
0.6
*NSAIDs use does not include low dose aspirin. **Stroke, thrombosis, phlebitis
73
5.2.2. Daily low-dose aspirin (AAS)
Aspirin may be used in low dose on a daily basis to prevent blood clot formation.
Therefore, as previously described in the methodology section, we considered those
subjects who reported using aspirin for such condition, as daily low-dose aspirin users.
Table 10 presents their distribution among cases and controls. The prevalence of daily
low dose aspirin (AAS) was very similar in cases and controls (20%) and did not differ in
terms of current use, duration of use or time at first use.
Table 10. Distribution of cases and controls according to use of daily-low dose of
acetylsalicylic acid (Aspirin) in a French-Speaking population, in Montreal, Quebec,
2005-2010.
Variable
Categories
AAS * (Aspirin, Asaphen,
Entrophen, Novasen)
Never user
Current user
Former user
Unknown†
Cases
(n=1429)
No
%
1149
80.4
260
18.2
6
0.4
14
1.0
Controls
(n=1543)
No
%
1234
80.0
274
17.8
16
1.0
19
1.2
Duration of use, years
Non user
0-1
1.1-6
6.1-11
>11
Unknown
1149
39
122
59
51
9
80.4
2.7
8.5
4.1
3.6
0.6
1234
54
140
68
40
7
80.0
3.5
9.1
4.4
2.6
0.4
Time since first use,
before interview, years
Non user
0-5
6-10
>10
Unknown
1149
147
62
48
23
80.4
10.3
4.3
3.4
1.6
1234
160
69
54
26
80.0
10.4
4.5
3.5
1.7
*Reportedly used to prevent blood clot (stroke, thrombosis or phlebitis)
† Missing data on status of usage among users
Table 11 presents the distribution of selected socio-demographic factors with respect to
self-reported use of daily low dose of aspirin among controls. In comparison to non users,
users of daily low dose of aspirin were older and more frequently of French descent.
Users of daily low dose aspirin were somewhat more educated than non-users.
74
Differences were also observed with respect to family income, which was somewhat
higher for non-users.
Table 11. Comparison of socio-demographic characteristics among controls according to
use of daily-low dose of acetylsalicylic acid (Aspirin), Montreal, Canada , 2005-2010.
Variable
Categories
Age, years at
reference date
≤60
61 - 65
66 - 70
≥ 70
Mean (± SD)
Users
(n=309)
No
%
41
13.3
72
23.3
89
28.8
107
34.6
67.1 (5.7)
Nonusers
(n=1234)
No
%
344
27.9
312
25.3
311
25.2
267
21.6
64.3 (7.1)
Chi-square
P value
Ethnicity
French descent
Black
Asian
Others
Unknown
204
10
8
84
3
66.0
3.2
2.6
27.2
1.0
726
62
36
399
11
58.8
5.0
2.9
32.3
0.9
0.2
Marital status
Married
Common Law
Separated
Divorced
Single
Widower
Religious member
213
22
4
34
19
15
2
68.9
7.1
1.3
11.0
6.2
4.9
0.6
798
142
31
123
91
45
4
64.7
11.5
2.5
10.0
7.3
3.7
0.3
0.15
Education
<Elementary
≤High School
College Degree
Bachelor
Graduate Degree
14
168
55
46
26
4.5
54.4
17.8
14.9
8.4
48
576
219
225
166
3.9
46.7
17.7
18.2
13.4
0.03
Family income
< $19,999
$20,000 - $29,999
$30,000 - $49,999
$50,000 - $79,999
$80,000 - $99,999
≥$100,000
Unknown
51
43
70
59
28
25
33
16.5
13.9
22.6
19.1
9.1
8.1
10.7
143
148
305
245
103
174
116
11.6
12.0
24.7
19.8
8.3
14.1
9.4
0.05
<0.0001
75
As presented in Table 12, users and non-users of daily low dose aspirin users did not
differ in terms of tobacco smoking and alcohol consumption.
Table 12. Comparison of tobacco and alcohol consumption among controls according to
use of daily-low dose of acetylsalicylic acid (Aspirin), Montreal, Canada , 2005-2010.
Variable
Categories
Users
(n=309)
Tobacco smoking
(Pack-years)
Never smoker
1-24
25 -49
50-99
>100
No
76
97
81
46
9
%
24.7
31.5
26.3
15.0
2.6
Nonusers
(n=1234)
No
%
393
31.8
370
30.0
279
22.6
165
13.4
27
2.2
Alcohol
consumption
(Drink-years)
Never Drinker
1-49
50-199
200-499
>500
Unknown
47
131
98
22
5
6
15.2
42.4
31.7
7.1
1.6
1.9
153
555
421
59
23
23
12.4
44.5
34.2
4.8
1.9
1.9
Chi-square
P value
0.201
0.412
Table 13 shows the comparison between users and non users with respect to selected
clinical factors in the control group. Compared to non users, daily low dose aspirin users
had a higher mean BMI, and were more likely to have been screened for prostate cancer.
Additionally, the prevalence of daily low dose use was higher among controls that
reported certain urologic complications, such as prostatitis, inflammation of the testicles
and BPH, as compared to non users. There were also differences observed with respect to
diabetes, hypertension, hypercholesterolemia, as those clinical conditions were more
prevalent among users than non users.
76
Table 13. Comparison of clinical characteristics among controls according to use of
daily-low dose of acetylsalicylic acid (Aspirin), Montreal, Canada , 2005-2010
Variable
Categories
BMI (kg/m2)
< 20
20.0-22.4
22.5-24.9
25.0-27.4
27.5-30.0
>30
MEAN (±SD)
Users
(n=309)†
No
%
2
0.7
19
6.2
61
19.9
88
28.7
63
20.5
74
24.1
27.8 (4.5)
Nonusers
(n=1234)†
No
%
44
3.6
118
9.7
265
21.8
341
28.0
208
17.1
240
19.7
26.8 (4.3)
Chi-square
P value
Any cancer in family
members
No
Yes
125
178
41.2
58.8
516
671
43.5
56.5
0.49
First-degree family
history of prostate
cancer
No
Yes
261
39
87.0
13.0
1,065
119
89.9
10.0
0.32
Ever been screened
for prostate cancer
No
Yes
13
567
2.2
97.8
135
2,220
5.7
94.3
<0.0001
PSA test
in the last 5 years
No
Yes
6
272
2.2
97.8
55
970
5.4
94.6
0.02
Number of PSA test
in the last 5 years
0-2
3-5
6-10
>10
65
164
21
4
25.6
64.6
8.3
1.6
252
614
66
6
26.9
65.5
7.0
0.7
0.13
DRE test
in the last 5 years
No
Yes
Unknown
36
248
4
12.5
86.1
1.4
140
931
6
13.0
86.4
0.6
0.86
Number of DRE test
In the last 5 years
0-2
3-5
6-10
>10
Unknown
109
120
11
0
69
35.3
38.8
3.6
0
22.3
408
483
31
3
298
33.4
39.5
2.5
0.2
24.4
0.61
Prostatitis
No
Yes
271
32
89.4
10.6
1,124
86
92.9
7.1
0.04
Inflammation
of urethra
No
Yes
265
39
87.2
12.8
1,101
113
90.7
9.3
0.07
0.01
77
Table 13 (continued). Comparison of clinical characteristics among controls according
to use of daily-low dose of acetylsalicylic acid (Aspirin), Montreal, Canada , 2005-2010
No
Yes
Users
(n=309)†
No
%
288
95.0
15
5.0
Nonusers
(n=1223)†
No
%
1,175
96.6
41
3.4
Inflammation
of epididymis
No
Yes
298
4
98.7
1.3
1,191
22
98.2
1.8
0.56
BPH
No
Yes
226
79
74.1
25.9
964
240
80.1
19.9
0.02
Diabetes
No
Yes
191
118
61.8
38.2
1,031
190
84.4
15.6
<0.0001
Migraine
No
Yes
297
12
96.1
3.9
1,166
57
95.3
4.7
0.55
Chronic pain
No
Yes
227
82
73.5
26.5
953
270
77.9
22.1
0.1
Hypertension
No
Yes
45
263
14.6
85.4
788
433
64.5
35.5
<0.0001
High cholesterol
level
No
Yes
128
181
41.4
58.6
889
334
72.7
27.3
<0.0001
*Blood clotting
condition
No
Yes
248
61
80.3
19.7
1155
68
94.4
5.6
<0.0001
Variable
Categories
Inflammation
of testicles
Chi-square
P value
0.03
*Stroke, thrombosis, phlebitis
†Numbers may not add to total because of missing data
78
5.2.3. Statins
The patterns of use of statins among cases and controls are presented in Table 14. The
prevalence of any statin use was around 15% among cases and 10% among controls.
Most users reported to be current users in both groups. In addition, a slight difference was
observed in terms of duration, as cases, reported more frequently than controls to have
used statin for more than 5 years. With respect to different types of statins, Atorvastatin
(Lipitor, Caduet) were by far the most commonly used type among cases and controls.
Comparison of selected socio-demographic characteristics between users and probable
nonusers among controls are shown in Table 15. Statin users tended to be older and more
commonly of French and Asian descent and less frequently of black ancestry than nonusers. Users had also somewhat lower educational attainment than probable non-users.
As seen in Table 16, statins users were more likely to be smokers than probable nonusers, while no differences were found with respect to alcohol consumption. Selected
clinical characteristics were also compared between users and probable non users of
statins among controls and are shown in Table 17. Users of any statins medication had
higher BMI and were more likely to have reported to be screened for prostate cancer than
probable non-users. In addition, control users were more likely to have reported
inflammation of urethra, BPH, diabetes, chronic pain or blood clotting conditionsthan
probable non-users.
79
Table 14. Distribution of cases and controls according to characteristics of use statins in a
French-Speaking population in Montreal, Quebec, 2005-2010.
Probable non user
Possible non user
Current user
Former user
Unknown†
Cases
(n=1429)
No
%
539
37.7
665
46.5
208
14.6
1
0.1
16
0.1
Controls
(n=1543)
No
%
608 39.4
745 48.3
166 10.8
6
0.4
18
1.1
Duration of use,
years
Probable non user
Possible non user
≤5
>5
Unknown
539
665
99
122
4
37.7
46.5
6.9
8.5
0.3
608
745
97
88
5
39.4
48.3
6.3
5.7
0.3
Time since first
use before
reference date
years
Probable non user
Possible non user
0-1
1.1-5
5.1-10
>10
539
665
61
62
56
46
37.7
46.5
4.3
4.3
3.9
3.2
608
745
37
63
44
44
39.4
48.3
2.4
4.1
2.9
2.9
Variable
Categories
Ever use
Types of
statins
®
®
®
Lovastatin (Advicor , Altoprev , Mevacor )
Atorvastatin (Caduet®, Lipitor®)
Rosucastatin (Crestor®)
Fluvastatin (Lescol®)
Pravastatin (Pravachol®)
Simvastatin (Zocor®)
† Missing data on status of usage among users
N=225
1
0.4
147
65.3
43
19.1
1
0.4
16
7.1
17
7.6
N=190
4
2.1
115 60.5
42 22.1
1
0.5
13
6.8
15
7.9
80
Table 15. Comparison of socio-demographic characteristics among controls according to
use of statins, Montreal, Canada , 2005-2010.
Variable
Categories
Users
(n=190)
Probable non
users
(n=608)
No
%
209
34.4
152
25.0
132
21.7
115
18.9
63.2 (7.5)
Chi-square
P value
Age, years at
reference date
≤60
61 - 65
66 - 70
≥ 70
Mean (± SD)
No
%
32
16.8
49
25.8
48
25.3
61
32.1
66.1 (6.4)
Ethnicity
French descent
Black
Asian
Others
Unknown
138
5
7
38
2
72.6
2.6
3.7
20.0
1.1
358
32
17
193
8
58.9
5.3
2.8
31.7
1.3
0.008
Marital
status
Married
Common Law
Separated
Divorced
Single
Widower
Religious member
134
21
1
10
16
8
0
70.5
11.1
0.5
5.3
8.4
4.2
0
379
67
22
65
50
24
1
62.3
11.0
3.6
10.7
8.2
4.0
0.2
0.08
Education
<Elementary
≤High School
College Degree
Bachelor
Graduate Degree
5
108
35
28
14
2.6
56.8
18.4
14.4
7.4
22
278
108
116
84
3.6
45.7
17.8
19.1
13.8
0.03
Family
income
< $19,999
$20,000 - $29,999
$30,000 - $49,999
$50,000 - $79,999
$80,000 - $99,999
≥$100,000
Unknown
16
28
53
33
22
21
17
8.4
14.7
27.9
17.4
11.6
11.1
8.9
75
70
141
124
51
92
55
12.3
11.5
23.2
20.4
8.4
15.1
9.1
0.26
<0.0001
81
Table 16. Comparison of tobacco and alcohol consumption among controls according to
use of Statin, Montreal, Canada , 2005-2010.
Variable
Categories
Users
(n=190)
Tobacco smoking
(Pack-years)
Never smoker
1-24
25 -49
50-99
>100
No
49
58
43
31
9
Alcohol consumption
(Drink-years)
Never drinker
1-49
50-199
200-499
>500
Unknown
23
82
65
11
4
5
%
25.8
30.5
22.6
16.3
4.7
Probable non
users
(n=608)
No
%
210
34.5
187
30.8
134
22.0
69
11.4
8
1.3
12.1
43.1
34.2
5.8
2.1
2.6
74
287
203
25
7
12
12.2
47.2
33.4
4.1
1.1
2.0
Chi-square
P value
0.008
0.75
82
Table 17. Comparison of clinical characteristics among controls according to use of
statins, Montreal, Canada , 2005-2010.
Variable
Users
(n=190)†
Categories
2
No
2
11
37
46
39
54
%
1.1
5.8
19.6
24.3
20.6
28.6
28.1 (4.5)
Probable non
users
(n=608)†
No
%
30
5.0
67
11.1
160
26.5
177
29.3
81
13.4
89
14.7
25.9 (3.8)
Chi-square
P value
BMI (kg/m )
< 20
20.0-22.4
22.5-24.9
25.0-27.4
27.5-30.0
>30
MEAN (±SD)
Any cancer in
family members
No
Yes
66
119
35.7
64.3
253
334
43.1
56.9
0.07
First-degree family
history of prostate cancer
No
Yes
162
21
88.5
11.5
535
49
91.6
8.4
0.2
Ever being screened for
prostate cancer
No
Yes
7
180
3.8
96.2
103
495
17.2
82.8
<0.0001
Screened** for prostate
cancer in last 5 years
No
Yes
22
156
12.4
87.6
106
386
21.5
78.5
0.01
PSA test
in the last 5 years
No
Yes
10
164
5.8
94.2
25
443
5.3
94.7
0.84
Number of PSA test
in the last 5 years
0-2
3-5
6-10
>10
35
93
21
3
23.0
61.2
13.8
2.0
145
261
25
1
33.6
60.4
5.8
0.2
<0.0001
DRE test
in the last 5 years
No
Yes
Unknown
15
163
2
8.3
90.6
1.1
66
425
4
13.3
85.9
0.8
0.20
Number of DRE test
in the last 5 years
0-2
3-5
6-10
>10
Unknown
65
85
8
0
32
34.2
44.7
4.2
0
16.8
197
216
10
1
184
32.4
35.5
1.6
0.2
30.3
0.001
No
168
Yes
19
**Screened by PSA test and DRE examination
89.8
10.2
564
39
93.5
6.5
0.09
Prostatitis
<0.0001
83
Table 17 (continued). Comparison of clinical characteristics among controls according
to use of statins, Montreal, Canada, 2005-2010.
Users
(n=190)†
Variable
Categories
Inflammation
of urethra
No
Yes
No
159
30
%
84.1
15.9
Probable non
users
(n=608)†
No
%
548
90.9
55
9.1
Chi-square
P value
Inflammation
of testicles
No
Yes
180
9
95.2
4.8
585
18
97.0
3.0
0.46
Inflammation
of epididymis
No
Yes
187
0
100.0
0.0
589
14
97.7
2.3
0.07
BPH
No
Yes
143
44
76.5
23.5
500
96
83.9
16.1
0.02
Diabetes
No
Yes
119
70
63.0
37.0
608
0
100.0
0.0
<0.0001
Migraine
No
Yes
182
8
95.8
4.2
583
25
95.9
4.1
0.95
Chronic pain
No
Yes
114
76
60.0
40.0
505
103
83.1
16.9
<0.0001
Hypertension
No
Yes
42
148
22.1
77.8
608
0
100.0
0.0
<0.0001
High
cholesterol level
No
Yes
51
139
26.8
73.2
608
0
100.0
0.0
<0.0001
*Blood clotting
condition
No
Yes
157
33
82.6
17.4
576
32
94.7
5.3
<0.0001
0.01
*Stroke, thrombosis, phlebitis
†Numbers may not add to total because of missing data
84
Table 18 presents the distribution of clinically relevant conditions according to statin use
status. As expected, because of the algorithm to define statin use, the higher prevalence of
hypercholesterolemia was observed among statin users, even when compared with
possible non-users. Of note, cases were more likely to use statins than controls for the
same clinical condition.
.
Table 18. Distribution of relevant clinically conditions according to statins consumption
(as defined in figure 2)
Disease Status
Clinical Condition
Statin Use
Cases
Diabetes
High Cholesterol
Hypertension
Users
N=415
No
%
64
15.4
185 44.6
161 38.8
Control
Diabetes
High Cholesterol
Hypertension
70
139
148
16.9
33.5
35.7
Possible nonusers
N=1410
No
%
148
10.5
276
19.6
522
37.0
243
380
558
17.2
26.9
39.6
Probable non users
N=1147
No
%
0
0
0
0
0
0
0
0
0
0
0
0
0
0
85
5.3. Association of exposure with risk of prostate cancer
5.3.1. Use of NSAIDs and risk of prostate cancer
In a univariate analysis, ever use of NSAIDs was associated with a small increase in risk
of prostate cancer (OR=1.43; 95% CI 1.07-1.90) (Table 19). A similar positive
association was observed among current users (OR=1.53; 95% CI:1.07-2.18), while for
former users the association with prostate cancer risk was not significant (OR=1.39; 95%
CI: 0.83-2.32). There was no increase in risk among those who reported to use NSAIDs
for less than 10 years (OR=1.28; 95% CI: 0.92-1.78). However, a significant increase in
prostate cancer risk was observed when NSAIDs had been used for more than 10 years
(OR=1.89; 95% CI: 1.10-3.27). In relation to time since first use, there was little
difference in risk among subjects who had reported to have started using NSAIDs 2-5
years earlier (OR=1.58; 95% CI: 0.90-2.77), or more than 10 years earlier (OR=1.58;
95% CI: 0.97-2.58). However, although nonsignificant, a protective effect of NSAID was
observed among those who reported to have started using NSAIDs 5 to10 years before
the reference date. Following adjustment for empirical confounders the associations were
mostly attenuated (i.e., ORs closer to the null than in the univariate analysis). The only
statistically significant risk effect of NSAID use that remained was the lower risk of
prostate cancer (OR=0.43; 95% CI: 0.21-0.89) among subjects who had started to use
NSAID between 6-10 years before the reference date.
86
Table 19. Association between use of NSAIDs and prostate cancer in a French-speaking
population in Montreal, Canada, 2005-2010.
NSAIDs
Categories
Cases
Controls
(N=1429) (N=1543)
†No
†No
Unadjusted OR
(95% CI)
Adjusted OR *
(95% CI)
Ever use
Never
Ever
1314
115
1,454
89
1.0 (REF)
1.43 (1.07-1.90)
1.0 (REF)
1.22(0.88-1.69)
Recency of use
Non user
Former
Current
1312
34
78
1452
27
56
1.0 (REF)
1.39 (0.83-2.32)
1.53 (1.07-2.18)
1.0 (REF)
1.11 (0.62-2.01)
1.29(0.87-1.92)
Duration of use,
years
Non user
≤ 10
> 10
1313
80
36
1453
69
21
1.0 (REF)
1.28 (0.92-1.78)
1.89 (1.10-3.27)
1.0 (REF)
1.09 (0.74-1.59)
1.58 (0.87-2.84)
Time since first use,
years
Nonuser
2-5
6-10
>10
1312
30
16
40
1452
21
27
28
1.0 (REF)
1.58 (0.90-2.77)
0.65 (0.35-1.22)
1.58 (0.97-2.58)
1.0 (REF)
1.30 (0.70-2.41)
0.43 (0.21-0.89)
1.42 (0.82-2.47)
*Adjusted for age at reference date, ethnicity, fist degree of family history of prostate
cancer, BMI, screening for prostate cancer (PSA test and/or DRE examination), number
of psa tests, number of DRE examinations, BPH, statin use.
†Numbers may not add up to total because of missing data.
87
5.3.2. Use of COX-2 inhibitors and risk of prostate cancer
A separate analysis was conducted to evaluate the effect of only COX-2 inhibitors and
risk of prostate cancer. As shown in Table 20, in univariate analysis, among those who
reported ever using COX-2 inhibitors, a weak trend for a positive association was found
(OR=1.28; 95% CI: 0.83-1.99). Likewise, other measures of COX-2 use such as current
use (OR=1.50; 95% CI: 0.85-2.64), duration of use (≤ 5 years, OR=1.23: 95% CI: 0.692.20; and >5 years, OR=1.23; 95% CI: 0.61-2.47), and time since first use (2-5 years,
OR=1.63; 95% CI: 0.73-3.64; and > 5 years, OR=0.89; 95% CI: 0.49-1.65) generally
exhibited weak positive trends. As above, associations were largely attenuated after
adjusting for empirical confounders, with no consistent risk patterns emerging.
Table 20. Association between use of COX-2 inhibitors and prostate cancer in a Frenchspeaking population in Montreal, Canada, 2005-2010.
COX-2 Use
Categories
Cases
Control
(N=1429) (N=1543)
†No
†No
1384
1505
45
38
Unadjusted OR
(95% CI)
Adjusted OR*
(95% CI)
Ever use
Never
Ever
1.0 (REF)
1.28 (0.83-1.99)
1.0 (REF)
1.00(0.61-1.66)
Recency of use
Non user
Former
Current
1384
15
29
1505
15
21
1.0 (REF)
1.08 (0.53-2.23)
1.50 (0.85-2.64)
1.0 (REF)
0.82 (0.35-1.92)
1.12 (0.61-2.10)
Duration of use,
years
Non user
≤5
>5
1384
25
17
1505
22
15
1.0 (REF)
1.23 (0.69-2.20)
1.23 (0.61-2.47)
1.0 (REF)
0.98 (0.50-1.90)
0.93 (0.43-2.00)
Time since
first use, years
Nonuser
2-5
>5
1384
15
19
1505
10
23
1.0 (REF)
1.63 (0.73-3.64)
0.89 (0.49-1.65)
1.0 (REF)
1.23 (0.52-2.93)
0.66 (0.32-1.32)
*Adjusted for age at reference date, ethnicity, first degree family history of prostate
cancer, BMI, screening for prostate cancer (PSA test and/or DRE examination), number
of psa tests, number of DRE examinations, BPH, migraine
† Numbers may not add up to total because of missing data.
88
5.3.3. Use of daily low dose aspirin and risk of prostate cancer
Association between use of daily low dose of aspirin and risk of prostate cancer was also
investigated. Table 21 presents the unadjusted and empirically-adjusted ORs for all
measures of daily low dose of aspirin (ever use, current use, duration and time since first
use). No association was observed in the crude model for ever use (OR=0.97; 95 % CI:
0.81-1.16). After controlling for empirical confounders, the same absence of an
association was observed (OR=0.99; 95 % CI: 0.79-1.25). Prior use (OR=0.40; 95% CI:
0.16-1.03) and current use (OR=1.02; 95% CI: 0.84-1.23) were also not associated with
risk of prostate cancer and these results remained essentially unchanged
following
adjustment for empirical confounders for former use (OR=0.34; 95% CI: 0.10-1.17) and
current use (OR=1.04; 0.82-1.32). With respect to duration of use, a non-significant trend
for a protective effect was observed in the crude model (OR=0.85; 95% CI: 0.68-1.08)
and after adjusting for empirical confounders (OR=0.89; 95 % CI: 0.67-1.17) among
those who reported to have used daily low dose of aspirin for less than 5 years. By
contrast, this trend was reversed (but non-statistically significant) among those who
reported to have used daily low dose aspirin for more than 5 years (unadjusted OR=1.13:
95% CI: 0.87-1.46; adjusted OR=1.19; 95% CI: 0.87-1.64). Regarding time since first
use, in the crude model, a 28% reduction in the risk of prostate cancer was found among
men who reported to have started using daily low dose of aspirin between 2 to 5 years
before the reference date. The protective effect remained after adjusting for empirical
confounders (OR=0.72; 95% CI: 0.52-1.00). However, no association was found for
those who reported to have started between 5 to 10 years and more than 10 years before
the reference date.
89
Table 21. Association between use of daily low dose of Aspirin and prostate cancer in a
French-speaking population in Montreal, Canada, 2005-2010.
Daily low dose
Aspirin Use
Categories
Cases
(N=1429)
†No
1,146
280
Control
(N=1543)
†No
1,234
309
Unadjusted OR
(95% CI)
Adjusted OR *
(95% CI)
Ever use
Never
Ever
1.0 (REF)
0.97 (0.81-1.16)
1.0 (REF)
0.99 (0.79-1.25)
Recency of use
Non user
Former
Current
1,146
6
260
1,234
16
274
1.0 (REF)
0.40 (0.16-1.03)
1.02 (0.84-1.23)
1.0 (REF)
0.34 (0.1-1.17)
1.04 (0.82-1.32)
Duration of use,
years
Non user
≤5
>5
1,146
144
127
1,234
181
121
1.0 (REF)
0.85 (0.68-1.08)
1.13 (0.87-1.46)
1.0 (REF)
0.89 (0.67-1.17)
1.19 (0.87-1.64)
Time since first
use, years
Nonuser
2-5
5-10
>10
1,146
86
62
48
1,234
128
69
54
1.0 (REF)
0.72 (0.54-0.96)
0.96 (0.68-1.38)
0.95 (0.64-1.42)
1.0 (REF)
0.72 (0.52-1.00)
1.04 (0.68-1.58)
0.95 (0.96-1.52)
*Adjusted for age at reference date, ethnicity, first degree family history of prostate
cancer, BMI, screening for prostate cancer (PSA test and/or DRE examination), number
of PSA tests, number of DRE examinations, BPH, statin use, diabetes, hypertension
† Numbers may not add to total because of missing data.
90
5.3.4. Use of statins and risk of prostate cancer
We have also examined the association between statin use and prostate cancer risk (Table
22). Ever use of statins was associated with an increased risk of prostate cancer in the
crude model (OR=1.33; 95% CI: 1.07-1.67). However, after adjusting for empirical
confounders, the effect was attenuated and no longer achieved statistical significance
(OR=1.20; 95% CI: 0.90-1.60). In the univariate analysis, current use of statins
medications was also associated with increased prostate cancer risk (OR=1.40; 95% CI:
1.11-1.78). With respect to former users, only one case contributed to this observation.
Nonetheless, no clear association was observed in the adjusted OR for current use
(OR=1.23; 95% CI: 0.92-1.66). Regarding duration of use, in both models, no association
was found between men who reported to have used statins for less than 5 years and risk
of prostate cancer (unadjusted OR=1.15; 95% CI: 0.85-1.55, adjusted OR=0.91: 95% CI:
0.63-1.32). On the other hand, in the crude model, long term use of statins was associated
with an increase in risk, with men who used statins for longer than five years having an
excess risk of 55% (OR=1.55; 95% CI:1.16-2.10). Following adjustment for empirical
confounders, we observed a similar risk elevation effect for statins with respect to
prostate cancer risk (OR=1.56; 95% CI: 1.07-2.27). Results were suggestive of an
increased risk of prostate cancer among men who had reported using statins 5 to10 years
prior to the reference date (OR=1.67; 95% CI: 0.99-2.79). However, there was no
association between time since first use and prostate cancer risk, even after excluding the
year preceding the reference date.
91
Table 22. Association between use of statins and prostate cancer in a French-speaking
population in Montreal, Canada, 2005-2010.
STATIN
Categories
Cases
Control
(n=1429)
(n=1543)
Unadjusted OR
(95% CI)
Adjusted OR *
(95% CI)
Ever use
Probable non user
Ever
†No
539
225
†No
608
190
1.0 (REF)
1.33 (1.07-1.67)
1.0 (REF)
1.20 (0.90-1.60)
Recency
of use
Probable non user
Former
Current
539
1
208
606
6
166
1.0 (REF)
0.18 (0.02-1.56)
1.40 (1.11-1.78)
1.0 (REF)
0.12 (0.01-2.52)
1.23 (0.92-1.66)
Duration
of use, years
Probable non user
≤5
>5
539
99
122
606
97
88
1.0 (REF)
1.15 (0.85-1.55)
1.55 (1.16-2.10)
1.0 (REF)
0.91 (0.63-1.32)
1.56 (1.07-2.27)
Time since
first use,
years
Probable non user
2-5
5-10
>10
539
62
56
46
606
63
44
44
1.0 (REF)
1.11(0.77-1.60)
1.43 (0.95-2.17)
1.18 (0.77-1.81)
1.0 (REF)
0.81 (0.52-1.25)
1.67 (0.99-2.79)
1.01 (0.61-1.69)
*Adjusted for age at reference date, ethnicity, first degree family history of prostate
cancer, any cancer in family member, BMI, screening for prostate cancer (PSA test
and/or DRE examination), number of PSA tests, number of DRE examinations, BPH,
chronic pain, blood clot, daily-low dose aspirin use.
† Numbers may not add to total because of missing data
92
5.4 Association between medication use and prostate cancer aggressiveness
Table 23 presents adjusted ORs for the association between medication use and
aggressiveness of prostate cancer. There was no clear evidence of an association between
any of the medications under study here (NSAIDs, COX-2 inhibitors, daily low dose of
aspirin or statins), and prostate cancer aggressiveness, as measured by the Gleason score.
The only potential trends were for somewhat higher risks between NSAIDs use and less
aggressive prostate cancers (OR =1.32: 95%CI 0.89-1.97), and for statin use and more
aggressive prostate cancers (OR=1.25; 95% CI: 0.90-1.73).
93
Table 23. Association between medication use and aggressiveness of prostate
cancer, in a French-Speaking population in Montreal, Canada, 2005-2010.
Gleason < 7
Gleason ≥ 7
Medication
Categories
of use
Adjusted OR
(95% CI)
Adjusted OR
(95% CI)
NSAIDs
Never users
Ever users
1.0 (REF)
1.32 (0.89-1.97)a
1.0 (REF)
1.22 (0.83-1.80)a
COX-2 inhibitors
Never users
Ever users
1.0 (REF)
1.00 (0.53-.1.86)b
1.0 (REF)
1.04 (0.58-1.87)b
Daily low dose of
AAS (Aspirin)
Never users
Ever users
1.0 (REF)
0.94 (0.70-1.25)c
1.0 (REF)
1.00 (0.77-1.31)c
Statins
Probable non
users
Ever users
1.0 (REF)
1.0 (REF)
0.97 (0.67-1.40)d
1.25 (0.90-1.73)d
a
Adjusted for age at the reference date, ethnicity, fist degree of family history
of prostate cancer, BMI, screening for prostate cancer (PSA test and/or DRE
examination), number of PSA tests, number of DRE examinations, BPH, statin
use.
b
Adjusted for age at reference date, ethnicity, first degree family history of
prostate cancer, BMI, screening for prostate cancer (PSA test and/or DRE
examination), number of PSA tests, number of DRE examinations, BPH,
migraine
c
Adjusted for age at reference date, ethnicity, first degree family history of
prostate cancer, BMI, screening for prostate cancer (PSA test and/or DRE
examination), number of PSA tests, number of DRE examinations, BPH, statin
use, diabetes, hypertension
d
Adjusted for age at reference date, ethnicity, first degree family history of
prostate cancer, any cancer in family member, BMI, screening for prostate
cancer (PSA test and/or DRE examination), number of PSA tests, number of
DRE examinations, BPH, chronic pain, blood clot, daily-low dose aspirin use.
94
5.5. Sensitivity analyses
We performed a set of sensitivity analyses as an attempt to reduce the possibility of
undiagnosed prostate cancers among controls. Accordingly, we excluded from the
analyses all control subjects who had indicated to us that they had not being screened for
prostate cancer by PSA test and DRE examination in the last five years before the
reference date. As seen from Tables 24-27, there was no difference in the adjusted ORs
obtained from the main analyses and from those restricting to control subjects to men
who had recently been screened for prostate cancer.
95
Table 24. Association between use of NSAIDs and prostate cancer, limiting controls to
men recently screened for prostate cancer, French-Speaking population in
Montreal, Canada, 2005-2010.
NSAIDs Use
Categories
Cases *Controls
N=1429
N=968
†No
†No
1314
904
115
64
Adjusted OR
(95% CI)
Adjusted OR
(95% CI)
Ever Use
Never
Ever
1.0 (REF)
1.22(0.88-1.69)
1.0 (REF)
1.19 (0.85-1.67)
Recency of Use
Non user
Former
Current
1312
34
78
903
18
43
1.0 (REF)
1.11 (0.62-2.01)
1.29(0.87-1.92)
1.0 (REF)
1.19(0.64-2.21)
1.24 (0.83-1.86)
Duration of use,
years
Non user
≤ 10
> 10
1313
80
36
1453
69
21
1.0 (REF)
1.09 (0.74-1.59)
1.58 (0.87-2.84)
1.0 (REF)
1.11 (0.75-1.66)
1.35 (0.75-2.43)
Time since first use,
years
Nonuser
2-5
5-10
>10
1312
30
16
40
902
17
18
22
1.0 (REF)
1.30 (0.70-2.41)
0.43 (0.21-0.89)
1.42 (0.82-2.47)
1.0 (REF)
1.29 (0.69-2.43)
0.45 (0.21-0.96)
1.30 (0.74-2.28)
Adjusted for age at the reference date, ethnicity, fist degree of family history of prostate
cancer, BMI, screening for prostate cancer (PSA test and/or DRE examination), number
of PSA tests, number of DRE examinations, BPH, statin use.
*Only men who have undergone PSA screening and DRE examination at least once in
the last five years before the reference date.
† Numbers may not add up to total because of missing data.
96
Table 25. Association between use of COX-2 inhibitors and prostate cancer, limiting
controls to men recently screened for prostate cancer in a French-speaking population in
Montreal, Canada, 2005-2010.
COX-2 Use
Categories
Cases *Control
N=1429 N=968
†No
†No
Adjusted OR
(95% CI)
Adjusted OR
(95% CI)
Ever use
Never
Ever
1384
45
940
28
1.0 (REF)
1.00(0.61-1.66)
1.0 (REF)
1.02 (0.61-1.71)
Recency of use
Non user
Former
Current
1384
15
29
940
8
19
1.0 (REF)
0.82 (0.35-1.92)
1.12 (0.61-2.10)
1.0 (REF)
0.93 (0.37-2.33)
1.08 (0.58-2.03)
Duration of use,
years
Non user
≤5
>5
1384
25
17
940
16
11
1.0 (REF)
0.98 (0.50-1.90)
0.93 (0.43-2.00)
1.0 (REF)
0.96 (0.49-1.90)
0.98 (0.44-2.21)
Time since first use,
years
Nonuser
≤5
>5
1384
15
19
940
8
16
1.0 (REF)
1.23 (0.52-2.93)
0.66 (0.32-1.32)
1.0 (REF)
1.17 (0.49-2.78)
0.67 (0.32-1.39)
Adjusted for age at reference date, ethnicity, first degree family history of prostate
cancer, BMI, screening for prostate cancer (PSA test and/or DRE examination), number
of PSA tests, number of DRE examinations, BPH, migraine
*Only men among controls who have undergone PSA screening and DRE examination at
least once in the last five years before the reference date.
† Numbers may not add to total because of missing data
97
Table 26. Association between use of daily low dose AAS (aspirin) and prostate cancer,
limiting controls to men recently screened for prostate cancer in a French-speaking
population in Montreal, Canada, 2005-2010.
Daily Low dose
Aspirin
Categories
Cases
N=1429
†No
1,146
280
*Control
N=968
†No
760
208
Adjusted OR
(95% CI)
Adjusted OR
(95% CI)
Ever use
Never
Ever
1.0 (REF)
0.97 (0.81-1.16)
1.0 (REF)
0.99 (0.78-1.26)
Recency of use
Non user
Former
Current
1,146
6
260
760
9
185
1.0 (REF)
0.40 (0.16-1.03)
1.02 (0.84-1.23)
1.0 (REF)
0.38 (0.11-1.31)
1.06 (0.83-1.35)
Duration of use,
years
Non user
≤5
>5
1,146
144
127
760
123
82
1.0 (REF)
0.85 (0.68-1.08)
1.13 (0.87-1.46)
1.0 (REF)
0.88 (0.66-1.17)
1.22 (0.88-1.71)
Time since first
use, years
Nonuser
2-5
5-10
>10
1,146
86
62
48
760
87
43
40
1.0 (REF)
0.72 (0.54-0.96)
0.96 (0.68-1.38)
0.95 (0.64-1.42)
1.0 (REF)
0.75 (0.53-1.06)
1.08 (0.69-1.68)
0.95 (0.59-1.53)
Adjusted for age at reference date, ethnicity, first degree family history of prostate
cancer, BMI, screening for prostate cancer (PSA test and/or DRE examination), number
of PSA tests, number of DRE examinations, BPH, statin use, diabetes, hypertension
*Only men among controls who have undergone PSA screening and DRE examination at
least once in the last five years before the reference date.
† Numbers may not add up to total because of missing data.
98
Table 27. Association between use of statins and prostate cancer, limiting controls to
men recently screened for prostate cancer in a French-speaking population in Montreal,
Canada, 2005-2010.
STATIN
Categories
*Control
N=968
†No
337
129
Adjusted OR
(95% CI)
Adjusted OR
(95% CI)
Probable non user
Ever
Cases
N=1429
†No
539
225
Ever use
1.0 (REF)
1.20 (0.90-1.60)
1.0 (REF)
1.17 (0.87-1.58)
Recency
of use
Probable non user
Former
Current
539
1
208
335
4
113
1.0 (REF)
0.12 (0.01-2.52)
1.23 (0.92-1.66)
1.0 (REF)
0.13 (0.1-2.1)
1.22 (0.9-1.67)
Duration
of use,
years
Probable non user
≤5
>5
539
99
122
335
71
56
1.0 (REF)
0.91 (0.63-1.32)
1.56 (1.07-2.27)
1.0 (REF)
0.5 (0.58-1.25)
1.59 (1.08-2.35)
Time since
first use,
years
Probable non user
2-5
5-10
>10
539
62
56
46
375
46
25
31
1.0 (REF)
0.81 (0.52-1.25)
1.67 (0.99-2.79)
1.01 (0.61-1.69)
1.0 (REF)
0.82 (0.52-1.29)
1.71 (0.99-2.95)
1.03 (0.61-1.74)
Adjusted for age at reference date, ethnicity, first degree family history of prostate
cancer, any cancer in family member, BMI, screening for prostate cancer (PSA test
and/or DRE examination), number of PSA tests, number of DRE examinations, BPH,
chronic pain, blood clot, aspirin use.
*Only men among controls who have undergone PSA screening and DRE examination at
least once in the last five years before the reference date.
† Numbers may not add up to total because of missing data.
99
6. DISCUSSION
6.1. Overview of key findings
Overall, we found no evidence of an association between use of any NSAIDs and risk of
prostate cancer in the French-speaking population in Montreal. As previously mentioned,
although data in the literature have been conflicting216-223, our findings are in line with
those of other studies216,224,225,230, which have also reported that prostate cancer risk was
not related to use of NSAIDs. Most of these inconsistencies have been attributed to
limited information on dose and duration of use or by the presence of bias related to
screening216,229. Unfortunately, we could not address the issue of dosage because NSAID
use was ascertained based on self-report and information on dose was not elicited.
Nonetheless, we were able to measure the cumulative duration of use of NSAIDs, timing
of exposure (years prior reference date) and adjusted for screening. Of interest, in
univariate analysis, while current users and long-term users (defined as more than 10
years) had increased risks of prostate cancer, controlling for potential confounders
rendered the effect statistically not significant. By contrast, following adjustments, a
statistically significant reduction in prostate cancer risk was observed, among subjects
who had reported using NSAIDs 6 to 10 years prior to the reference date. These findings
could have occurred by chance. There was no evidence of a dose-response effect.
Possibly, these results could indicate the presence of an ―induction period‖ for NSAID
effects. As defined by Rothman, induction period would be the interval between the time
of action of the component cause (in our case, NSAID) and the time of initiation of
disease (in our case, inhibition of inflammatory process related to prostate cancer
promotion) 277. Taking it in consideration, even though these findings are in line with the
100
possible biological effects of NSAID use, they should be interpreted with caution.
Interestingly, Mahmud et al230, reported similar findings, particularly for propionates, a
class of NSAIDs, for which the strongest inverse association was observed during the
11.1-16 years period before diagnosis (OR=0.85; 95% CI: 0.76-0.94). Unfortunately, we
did not have enough power to investigate the effect of different classes of NSAIDs,
except for COX-2 inhibitors, which accounted for the majority of NSAIDs in our study
(cases, 22%; controls, 18.6%). We observed a slight, but not statistically significant
inverse association between COX-2 inhibitors and prostate cancer risk in most measures
of COX-2 inhibitors (ever use, former use, duration, time since first use before reference
date). We lacked information on prescription and non-prescription (over-the-counter) use.
Therefore, it is possible that non-differential misclassification would have biased our ORs
towards the null and masked a true association. Additionally, we have to consider the
limited power to detect a significant association, as only 45 subjects reported using COX2 inhibitors.
Despite the fact that aspirin can be used primarily to treat inflammation, mild to moderate
pain, and fever, it is the only NSAID that has shown a prolonged effect to inhibit blood
clots when used as a daily low dose. In our study, we found a higher proportion of men
who reported taking
aspirin for preventing heart attack and stroke (cases, 19.6 %,
controls, 20.2 %), than for treating other conditions. Consequently, as investigated in a
number of other studies, we decided to evaluate also the association between use of a
daily low dose of aspirin and prostate cancer risk. Although epidemiologic data are
ambiguous, the majority of the studies have observed a lower risk of prostate cancer with
use of a daily low dose of aspirin. In our study, we did find an inverse association for
ever use of daily low dose of aspirin, former use and exposure duration (less than 5
101
years). However, it did not achieve statistical significance. On the other hand, timing of
exposure seemed to play a role, since men who had started taking a daily low dose of
aspirin 2 to 5 years prior to de reference date showed a statistically significant 28%
reduction in risk as compared to nonusers. Nonetheless, these results should be
interpreted cautiously in the absence of a dose-response trend. Similar results were
reported by Salinas et al.224 who reported a borderline significant 25% reduction in risk
associated with time since first use (5-10 years) compared to never use. These findings
are interesting, and provide support for a biological implication of anti-inflammatory
drugs, particularly COX-1 and COX-2 inhibitors (Aspirin) in the chronic inflammation
process, which is hypothesized to be an initiator or promoter of carcinogenesis.
Moreover, discrepancies in case-control studies may be explained by a dilution of effect,
when considering the history of exposure outside the time span, which corresponds to the
range of the empirical induction period277. Of note, we excluded the first year
immediately prior to the reference date in order to avoid protopathic bias278,279. In fact,
analyses taking into consideration the first year provided relatively high estimates for
both NSAIDs (OR=1.62; 95% CI:0.97-2.71) and daily low dose aspirin use (OR=1.0;
95% CI: 0.75-1.32). In both situations, the protective effect was no longer observed when
the medication was first used several years (more than 10 years) before the reference
date. Taken together, these findings suggest that the drugs appear to need to be taken
regularly and over a certain time, in order to have a positive effect on the risk of prostate
cancer. Additionally, one could argue that the medication probably delays cancer
development rather than prevents it. Difference in timing of exposure (time since first
use) between NSAIDs and daily low dose of aspirin, are expected due to their
pharmacological differences. Moreover, daily low dose of aspirin, which is often
102
prescribed for cardiovascular prophylaxis, are usually used more regularly as compared
to NSAIDs, which are mainly prescribed to relieve pain.
Some studies218,280 have observed a stronger protective effect of NSAIDs (RR = 0.73;
95% CI 0.50-1.07) or total aspirin (RR = 0.71; 95% CI 0.47-1.08) in advanced prostate
cancer compared to total prostate cancer. However, although these associations failed to
reach statistical significance in those studies, their results suggest that NSAIDs could act
differentially, more on aggressive tumours than on small tumours, which could imply a
role for cyclo-oxygenase activity in prostate cancer progression. We also investigated the
effect of NSAIDs and daily low dose use of aspirin in advanced prostate cancer. Our
findings do not confirm a protective effect of NSAIDs against aggressive prostate cancer.
With respect to statin use, we found no association between use of statins (ever use and
current use) and risk of prostate cancer. In fact, our findings are consistent with most
observational studies and randomized clinical trials267,274,281, although several other
epidemiologic studies have reported a prostate cancer risk reduction associated with statin
use252,261,263. We did observe a borderline increased risk of prostate cancer among men
who had self-reported to use statin for more than 5 years. Other studies have reported
elevated risks with statin use254,264. For instance, Agalliu et al.267 found no overall
association between statin use and prostate cancer. However, an increased risk of prostate
cancer was observed among obese men (BMI≥30 kg/m2), who reported current use of
statin (OR=1.5; 95% CI: 1.0,2.1) when compared to non users. Moreover, a stronger
association was found for those with long-term use (OR=1.8, 95% CI: 1.1-3.0 for > 5
years of use). In contrast with their findings, no difference was observed when our
analyses were stratified by BMI (data not shown). Recently, another population based
case-control study, which found that ever use of any statins was associated with increased
103
prostate cancer risk (OR= 1.55; 95% CI: 1.09-2.19), also reported that there was a
significant trend toward increasing risk of prostate cancer with increasing cumulative
dose (2 for linear trend=7.23, P=0.007)275.
Several studies have shown a significant reduction in risk of advanced prostate cancer
and an association between statin use and aggressiveness of the disease261,262,264,265,273,274.
Nevertheless, our study results fail to corroborate these findings.
6.2. Strengths and limitations of this study
When interpreting our results, it is important to consider that our study have
several strengths and limitations. This study focused on the French-speaking population
in Montreal, representing a large majority of individuals in that city. Montreal is the
largest French-speaking city in North-America and second in the world after Paris, when
counting the number of native-language Francophones. Over 86% of the population on
the Island of Montreal can speak French; in the adjacent suburbs, this figure reaches up to
95%. Cases were ascertained across all 11 French hospitals, of the total of 14 hospitals
that diagnose prostate cancer in the area. Therefore, our study covered over 80% of all
new cases in the region. In order to reduce the potential for referral bias, we selected
French-speaking controls that came from the same electoral districts as the cases. A
comparison of the distribution of residential postal codes amongst cases and controls
indeed confirmed that both groups resided in the same geographical areas. Access to
medical care is entirely free across all Montreal hospitals, and it is reasonable to assume
that French-speaking controls would be referred to the French-speaking hospitals where
the cases arose. So although this is not a full population-based series, as about 20% of
new cases would have been referred to hospitals other than the ones participating in this
104
study, we are confident that both cases and controls selected here were drawn from the
same base population.
The study benefited from a large sample size (2,972 subjects) and it is, to our knowledge,
the first study conducted in Montreal to investigate the effect of NSAIDs, daily low dose
of aspirin and statin use in prostate cancer risk. Participation rates were reasonably high
and were comparable to those achieved in other case-control studies. Nevertheless,
participation among controls was lower as compared to cases (84% among cases and 62%
among controls, respectively). While it is possible that a selection bias would have been
introduced, the proportion of non-responses was not at a level that would be expected to
be associated with a strong selection bias.. Indeed, it would have taken a marked
difference in patterns of use of medications between participants and non-participants to
influence results in a substantial way. Still this possibility cannot be ruled out entirely,
especially among controls, who exhibited a lower response rate.
Our questionnaire enabled us to obtain detailed lifetime information about medication
usage that rendered possible the evaluation of the effect according to duration of use, time
since first use, status of use (current or former). However, one concern in any such
retrospective study is the potential for recall bias. Information on drug exposure relied on
patients’ self-reports rather than prescription databases or written by general practitioners.
Moreover, controls might have tended to underreport use as compared to cases. One
argument against this possibility is that none of the medications is widely known at this
point to have a link with prostate cancer so that preferential reporting based on personal
beliefs would have been a minor issue. Potential reporting error is of greater concern with
respect to statin use, as our study was not designed to investigate specifically the effect of
105
statin use in prostate cancer risk. For that reason, we used an algorithm to define statin
consumption. Statins are used regularly at a daily basis, and therefore, are more likely to
be remembered and reported than other medications used sporadically. Nevertheless, we
adopted a more conservative approach in our analyses, considering probable non users,
only the subjects who reported no clinical conditions such as hypercholesterolemia,
hypertension and diabetes, knowing to be primary indications for statin use. However,
our questionnaire did not elicit information on cardiovascular diseases, which is also a
clinical indication for use of statins. These could explain a lower prevalence of statin use
in our study (14%), compared to other studies (around 23%). Taken together, this
potential misclassification would tend to be nondifferential among cases and controls,
which would lead us to underestimate the effect of the drugs investigated in the study.
Furthermore, it is plausible that participation rates could have been associated with
general health status, with the healthier individuals being the ones accepting to participate
as controls. If true, one would expect to see a higher use of statins among cases than
among controls, which could explain why an increase risk was observed with this drug.In
order to diminish the possibility of potential confounding, we decided to adopt a
conservative approach to consider as potential confounders covariates that changed the
risk estimated of any of the study’s main exposures (NSAIDs, low dose Aspirin or
statins) by 2% or more in either the negative or positive direction. For instance, it has
been suggested223 that men taking NSAIDs or statins regularly are more likely to have
regular contacts with the health care system and might be prone to be screened for
prostate cancer, such as through DRE examination, PSA measurements and consequently
more likely to be diagnosed, hence introducing some degree of bias. Additionally, this
group of subjects would tend to have higher prevalence of others comorbidities and other
106
drugs as compared to non users. In fact, covariates associated with frequency and various
measures of prostate cancer screening among others, changed significantly the estimates
and therefore were included in our multivariate model. Another main concern to be
considered, particularly in case-control studies of diseases with a long latency period,
such as prostate cancer, is the presence of asymptomatic and/or undiagnosed cases among
the control group. However, our sensitivity analyses, which excluded controls that did not
undergo DRE examination and PSA measurements in the last five years before the
reference date, provided similar results. This suggests that it is unlikely that major
detection bias occurred or that we have failed to detect a clinically important effect of
using those medications on overall prostate cancer risk. Finally, it is unlikely that the
effect of timing in exposure observed with NSAIDs and daily low dose use of aspirin
were affected by protopathic bias, as we excluded from the analyses subjects that had
started to use the medications one year prior to the reference date. In addition, we would
have expected to have an increase in the estimate in the opposite direction than what we
observed as result of a protopathic bias, which would have induced changes in drug use
during the period preceding the diagnosis of prostate cancer.
6.3. Future directions
Like most other cancers, prostate cancer exhibits a long latency period, which implies
that anti-inflammatory or cholesterol-lowering drugs may be needed to be used regularly
and maintained over many years, particularly during the period when there is a possible
increased risk of the disease, such as inflammatory process or hypercholesterolemia. As a
whole, results from this case-control study are consistent with the absence of an
association between anti-inflammatory or cholesterol-lowering drugs and prostate cancer
107
risk. However, some of our findings suggest that the duration and timing of use of those
drugs might be important in influencing risks. We hope that the limitations identified in
our study can be addressed by future studies, especially those investigating the effect of
such medications at different clinical stages and with more accuracy in terms of dosage,
duration and timing of exposure. In addition, it will be important to investigate
concomitantly the expression of genes associated to the inflammatory and detoxification
processes, in order to consider their biological effects and relation to medications and
prostate cancer risk.
7. CONCLUSION
In conclusion, we did not find any clear evidence of an association between lifetime use
of NSAIDs or statins, and risk of prostate cancer. While timing in exposure might play a
particular role in the effect of NSAIDs - prostate cancer risk association, this issue must
be further explored.
108
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and cancer risk: a meta-analysis. JAMA 295, 74-80 (2006).
Platz, E. A. et al. Men with low serum cholesterol have a lower risk of high-grade
prostate cancer in the placebo arm of the prostate cancer prevention trial. Cancer
Epidemiol Biomarkers Prev 18, 2807-2813 (2009).
Bonovas, S., Filioussi, K. & Sitaras, N. M. Statin use and the risk of prostate
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studies. Int J Cancer 123, 899-904 (2008).
Chang, C. C., Ho, S. C., Chiu, H. F. & Yang, C. Y. Statins increase the risk of
prostate cancer: A population-based case-control study. Prostate (2011).
Ford, I. et al. Long-term follow-up of the West of Scotland Coronary Prevention
Study. N Engl J Med 357, 1477-1486 (2007).
Rothman, K. J. Induction and Latent periods. American Journal of Epidemiology
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124
STUDYID
Intervicq.'erName
Questionnaire
Study of the Environmental Causes
of ProstateDiseases
Uns€{sird.du**lroc
lnfiitut
natfsnal do In rscftcrche seientifique
lHRS"lhS{rTUT llnt tJU\P.FRAFF:[*
J$t
universitd
de Montrdal
ry tuK*ffiAgi
Dr. Marie-EliseParent
I NRS-InstitutArmand-Frappier
Universit6du Qu6bec
Stttdy tl tlrc Envirotrntcnlttl L'urtsesoJ'Frostttte l)iseasrs
I N RS-lttstittrt Ar mand Fr cLnnier
SOCIO.DEMOGRAPHICS
. Socio-demographicCharacteristics
Whcn vvereyou born?
Dtty/Month/Year (Example: 26/I 2l I 935)
which meansyou are now
yearsold
2. In which country \,\,'ere
you born?
O Canadaor
3. In r.vhichcountry\.vasyour biologicalmotherborn'/
O Canadaor
4. In r,vhichcountry\,vasyour biologicalfatherborn'/
O Canadaor
5. To whichcthnicor culturalgroup(s)did your anccstorsbelong'?(checkas manyas applicabtc).
E
E
E
E
E
fl
fl
I
2
3
4
5
6
7
Frcnchdescent
English,Scottishor Irishdcsccnt
Italian
Grcck.
Portugucsc
Jovish (Europcandcsccnt)
Othcr Europcan,spccil'y:
tr 9 Black
D l0 Latino-Amcric:an
tr ll Asian(cx: Carribtilia,China,Hong Kong,lndoncsia,
Japan,Laos,Philippincs,Singaporc,Tair,van,
Thailantl
Victnam)spccil'y:
tr 12N;u;;
tr l3 orher,spccily:
EI8 Rrab (c.r:Mtxrcco, Lcbanon,Egypt,Atgcria)
6. a)
bt
What did your lather do lirr a living rl'hcn you w'crc bclrn'/
What u'asthe longcstjob1'ourf athercvcr held'/
7. a) What did your mothcrdo lbr a living
r,vhenyou r,verebom?
b)
What was the longestjob your mother
everheld'i
O homemakeror
O homemakeror
8 What \,vasyour family's financial situationrvhenyc'rutverca
child or an adolescent?
o Very dif'l'icult
o Fairly difficult
o Middle
o Fairll'comfortable
o Very comfortable
o DK
Stutly of the Environmental Causesof Prostate Diseases
INRS-Institut Armcud Frappier
Seprember
17rh.2007
MEDICAL
D. Family History of Cancer
We rvouldlike to ask you somequcstionson thc healthof ccrtainmembersof your f amily (alive and
dcceased),
includingyour parcnts,your brothersand sisters(or half-brothcrsand half-sisters,if
applicablc)
andyour biologicalchildren.
l. Did any memberol-1'ourlamill', including1'ourparcnts,
brothersand sisters(or half-brothersandhalf-sisters,
if
applicablc)and y>ur biokrgicalchildrcnevcr havcany typeolcancer?
o !'es
3 3.,- l-+c"
3
t. Qucsti.n
If yesto the precedin-e
question,fill in the following tablenamingfather,brothers,half-brothers,sons,
mother.sisters.half-sisters.
daushtcrs.
FirstNamcor Initial
)
Tl pc o1'Canccr
In summary,includingyour l'athcr,brothcrs,hall-brothcrs
and sons
havchad pnrstatecanccr.
Agc at Diagnosis
mcmber(s)
o1'y'our
lamily
_
3 . Did your matemalgrandfbthcreverhavepmstatccanccr'/
o ycs
Ono
O DK
4. Did your paternalgrandlatherevcr havcproslatecancer?
o ycs
Ono
ODK
o yes
Qno
ODK
5.
Did one or severalof your uncles(bmthcrsof your motheror ol'your
litther)cr,crhal'c prcrslate
cancer'?
If yes,hr>u'manl' uncleshavebeenafl'ccted?
Septemberl7th,
uncles
Studyof tlte EnvironmentalCausesof ProstateDiseuses
I NRS-I nstitut Ar mttnd-F r appier
II
E. Personal Medical Historv
l. Norv, I rvouldlike to ask you somequestionsconccrning1'ourhealth.I lvill namesomediseasesor conditions
and I rvouldlike to knor,vif you haveever had them for at least6 months and if yes,at lvhat ages.For some
diseases/conditions,
I would alsolike to know i[ you havecvcr takenany medicationto treatthem.
Have you ever had the following diseases
for at least 6 months?
Did you take
medication
for this disease?
Age
If yes,which medication? Staft
Total
Years
Age
if interStop
ru pted)
o yes
a) Diabetes
Ono
ODK
Oyes
Ono
O DK
Pill or tablet(Diabeta,Glybunde,
Glucophage,Metlbrmine)
Olcs
Ono
ODK
Otherpill or tablet,specify
Oyes
Ono
O DK
t)
2)
3)
b) Rheumatism/arthritis,arthrosis or chronic
pain
t2
o ycs
o n()
o DK
Chcckthis box il-"no" to
all mcdications:
tr
n."U.,tt'^rpfon.f tu"tl, E*.cdnn.Esclol.
'f
vlcnol
Adt'il. Ibuprol'cn,
Motrin,Novr>Pnrf'en,
Nuprin
O)'cs
Qno
ODK
O1'cs
Ono
ODK
Alcvc,Anapnx, Naprclsyn,
Napnxcn
Oycs
Ono
O DK
A nacin,Aspirin,Buif'crin,Entrophcn
Oycs
Qno
ODK
Ansaid.Froben
Olcs
Ono
ODK
ApoDiclo,Arthrotcc,Novc>Dincf
ac, VolLrrcn
Oycs
Ono
ODK
Bcrtra,Cclebryx,
]{r!1c9x, Vitlx
Oycs
Ono
O DK
Crxleine,Empracct,Emtcc,Exdol
Oycs
Ono
ODK
Cortisone,Decadnrn,Dcxamcthasone,
Prednisone
Oyes
Ono
ODK
I ndricid. I ndotec. Indomethacin
Oycs
Ono
ODK
Lodinc.Ultradol
Olcs
Ono
ODK
Surgol! Tiaf.en
OtherparnmeOication
or anti-inhamfut.;t]a
Specil'y:
Oyes
Ono
ODK
Oy'es Ono
ODK
Stutlyof tlte Environnentol Cousesof ProstuteDiseases
I N RS I nstitulAr nn nd -F'rappier
Septembert7th, 2007
Have you ever had the following diseases
for at least 6 months?
Did you take
medication
for this disease?
Age
If yes,which medication? Start
Total
Years
Age
(if inter
Stop
O yes
O nr>
ODK
c) Migraine
Fiorinal,Imitrer
Caf-ergot,
Inderal,Pnrpranolol
Oycs
Qno
ODK
oycs
ono
o DK
Othcr,specily:
Oycs
Ono
ODK
--- ---l O l c r - - O n , ,
Ono
b)*
Olcs eno
O DK
d) Hypertension (high blood pressure)
o}*--r
Ono
ODK
Cardizcm,Diltiazcm,Isoptin,Vcrapamil
Indcral,Loprcssor,MctopK)lol,Pmpantllol
Othcr,spccil'y:
O DK
ODK
l) ..... ....
2) ...................
3 ) . , . . .. . . "
6)
7\
"
s, phlcbitis)
) gtood-"lot, (r*rkc, thrombosi
o ycs
Q ntt
ODK
Nol'ascn
Asaphcn,Aspirin,Entnrphcn,
Coumadin,Fragmin,Hcparin,Warlarin
Othcr,spccily:
o ycs
fl nulan"tt (trarrt,rss)
Ono
ODK
Iry:gqrryrq2
Othcr.spccil'1:
g) Benign Prostatic Hypertrophy
(prostatlsm)
Proscar.Fkrmar
Other,spccily:
1)
Iov"'
Qno
ODK
Oycs
Oycs
Qno
Ono
ODK
ODK
Oycs
O ycs
Qno
O ntr
ODK
ODK
Oycs
Ono
ODK
L
l
-_T--
f-
n\
3)
h) Allergies,hay fever
o ycs
Qno
ODK
September17th,2007
Stutly of the Environmental CausesoJ Prostate Disectses
I NRS-I nstittrt Armancl-F rappier
i,1
Have you ever had the following diseases
for at least 6 months?
Did you take
medication
Age
for this disease?
Start
medication?
which
If ves.
Total I
Years
Age
if inter-\
Stop
rupted)
lo*
lOno
i ) Psoriasis.eczema
loor<
j) Asthma
o yes
k) I--";"
O ncr
ODK
o yes
O ncr
ODK
*
t,tto-i--rlne
disease
I ) Depressiontreated with medication
m) Repeated or prolonged infections (longer
tlrun 6 monllts)
o ycs
Ono
ODK
O ycs
Ono
ODK
n) Need to urinate very frequentlY
O YCS
Ono
ODK
o) Cancer 1,
specify:
o ycs
p)
2,
specify:
q; oirrerair""t" t,
specify:
r) Other disease2,
specify:
s) Other disease3,
specify:
O ncr
ODK
O yes
O n<r
ODK
O yes
O ncr
ODK
o yes
[or"'
I O nt''
-t
lov.'
I
lOncr
loot<
ul Ottreraisease5,
specify:
I
O ncr
ODK
lonrc
t) Oaher disease4,
specify:
l
lou".
]o""
T
IODK
t4
Causesof Prostate Diseases
stuclyof the F,nvironnrental
I N IIS-I nstitut Arn and-F r aPPier
September17th' 2007
2. About5 yearsago,horvlrequentlydid you scca
physician?
O Lessthanoncca ),'ear
O About 1to3 timesayear
O Morc than3 timesa 1'ear
ODK
F. ProstateScreeningHistory
l. Do you remembcrevcrhavinghada
meciicalexaminationor a testlo dctcctil'
you had prostatecanccr'?
n \cs
5 i,.
O DK
2. whcn did you har.'eyour fitsl pn)sratc
screcningtcstor cxamination'/
(Chooseonly one answcr)
o In thc last 12months
o Betrvccn1 ancl5 ycarsago
O Morc than5 y'carsauo
ODK
3. Whcn did you havc your last prostatc
'/
scrccningtcstor cxamination
F--*
Go to sectionG
specify the year
4. Which tcst(s)or cramination(s)did 1'ouhavc'/
a) Bltxtdtcstto dcteotprostatccanccr
(PSA)'?
O y"t
e no
ODK
b)
Digitalrcctalcxamination(DRE)
-*ll'1-,cs,
holv manyhavcy,ouhadin thc
last5 ycars'/
PSA
O ycs -->
Il'ycs,hou,'manyhavcyou hadin thc
O no
litsl 51's11s')
O DK
c)
d;
Prostatcbiopsy(tcmovaloi'a samplc
ol'thc pmstate)
Othcr
O ycs +
O n.
DRE
ODK
Il.ycs,horvr.nanyhar.c1'ouhaclin thc
last5 ycars?
biopsics
O y"t +
Spccil'y:
O DK
Il'yes,how manyhavc)'ouhadin thc
last5 vears'/
ono
G. History of Prostate Cancer
l. Havc you everhad prostatecancer'/
o yes
3 ilt
2. Hor,vold r.vercyou lvhen you were
diagnclsed'/
September17th,2007
f*Go
toQuestion
5
yearsold
Study of tlrc Environrnental Causesof Proslttte Disectses
I N RS-I ns:ritutArntand-F rappier
t5