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interaction
(0.79, 1.35)
(0.73,1.26)
P . =
* interaction
(0.69, 1.20)
(0.88,1.51)
P. . =
L
interaction
(0.45, 0.78)
(0.50, 0.85)
P =
* interaction
(1.27,2.16)
(1.38,2.43)
P =
* interaction
(0.73, 1.27)
(0.90, 1.59)
P =
1
interaction
Current Smoker
No. cases/
controls
17/14
12/14
20/13
0.66
21/14
17/14
12/13
0.43
12/14
13/14
25/14
0.17
22/12
11/14
16/15
0.19
13/8
15/14
21/19
0.69
17/14
10/11
23/16
0.92
OR
1.00
0.54
1.05
1.00
0.85
0.69
1.00
0.91
2.75
1.00
0.22
0.58
1.00
0.40
1.15
1.00
0.93
1.70
(95% CI)
(0.17, 1.69)
(0.35,3.10)
(0.29, 2.48)
(0.22,2.14)
(0.28, 2.93)
(0.87, 8.72)
(0.07, 0.69)
(0.17,1.98)
(0.13, 1.20)
(0.36, 3.64)
(0.29, 3.05)
(0.58, 5.02)
'Adjusted for matching covariates, and body mass index(linear)
65
Table 2.8. Associations of CRP and cytokines with Benign Prostatic Hyperplasia risk,
stratified by physical activity
3
CRP, (mg/L)
Tl
T2
T3
TNF-a, (pg/mL)
Tl
T2
T3
Sedentary/Light Activity
No. cases/
controls OR (95% CI)
123/127
121/126
161/127
133/130
142/125
137/127
sTNF-RI, (pg/mL)
Tl 120/129
T2
T3
118/125
174/128
sTNF-RII, (pg/mL)
Tl 185/129
T2
T3
IL-6, (pg/mL)
Tl
T2
T3
IFN-Y, (pg/mL)
Tl
T2
T3
89/125
131/126
101/131
159/131
145/118
107/106
15/152
150/124
1.00
0.96
1.22
1.00
1.12
1.06
1.00
1.00
1.43
1.00
0.50
0.70
1.00
1.54
1.52
1.00
0.99
1.18
0.67, 1.37
0.86,1.74
P =
* interaction
(0.79, 1.58)
0.75,1.49
P - =
* interaction
0.70, 1.43
1.02,2.03
P -
x
interaction
0.35,0.71
0.50,0.98
P =
* interaction
1.08,2.18
1.06,2.20
P =
* interaction
0.70, 1.41
0.82, 1.70
P =
-* interaction
Moderate/Very Active
No. cases/
controls OR (95% CI)
70/100
92/99
95/99
0.88
99/100
87/99
75/100
0.25
96/101
81/99
84/99
0.07
121/100
70/101
66/97
0.36
58/101
91/105
108/92
0.34
93/112
66/91
102/96
0.80
1.00
1.30
1.32
1.00
0.89
0.77
1.00
0.86
0.88
1.00
0.57
0.55
1.00
1.49
2.02
1.00
0.88
1.28
0.85,1.98
0.86,2.03
0.59, 1.33)
0.51,1.17
0.57,1.29
0.58, 1.32
0.38, 0.85
0.36, 0.83
0.97,2.30
1.31,3.12
0.58, 1.35
0.86, 1.91
'Adjusted for matching covariates, and body mass index(linear)
66
Table 2.9. Associations of CRP and cytokines with Benign Prostatic Hyperplasia risk,
stratified by age'
CRP, (,mg/L)
Tl
T2
T3
TNF-a, (pg/mL)
Tl
T2
T3
No. cases/
controls
120/131
118/132
151/130
137/133
142/132
114/130
sTNF-RI, (pg/mL)
Tl
T2
T3
119/133
123/130
151/132
sTNF-RII, (pg/mL)
Tl
T2
T3
EL-6, (pg/mL)
Tl
T2
T3
IFN-Y, (pg/mL)
Tl
T2
T3
202/132
92/132
95/129
91/134
102/131
196/128
109/118
124/149
160/128
Age 55-65
OR
1.00
0.96
1.23
1.00
1.05
0.84
1.00
1.03
1.26
1.00
0.45
0.48
1.00
1.15
2.24
1.00
0.88
1.34
(95% CI)
(0.68, 1.37)
(0.86,1.80)
P =
-* interaction
(0.75, 1.18)
(0.59, 1.18)
p. . =
-* interaction
(0.72,1.46)
(0.90,1.78)
P =
J
interaction
(0.32, 0.64)
(0.34, 0.68)
P =
1
interaction
(0.80, 1.67)
(1.57,3.18)
P =
J
interaction
(0.61, 1.25)
(0.94, 1.90)
P =
-* interaction
No. cases/
controls
75/96
91/93
110/95
0.53
93/97
94/96
96/95
0.30
103/98
78/95
102/95
0.41
98/97
81/95
100/95
0.02
82/97
100/102
94/88
0.03
105/114
73/81
105/93
0.71
Age 65+
OR
1.00
1.18
1.36
1.00
1.05
1.12
1.00
0.78
0.98
1.00
0.85
1.03
1.00
1.14
1.17
1.00
1.03
1.25
(95% CI)
(0.77, 1.81)
(0.89, 2.07)
(0.70, 1.59)
(0.74, 1.68)
(0.51, 1.17)
(0.66, 1.47)
(0.56, 1.28)
(0.69, 1.54)
(0.76,1.70)
(0.77, 1.79)
(0.68, 1.57)
(0.85, 1.86)
a
Adjusted for matching covariates, and body mass index(linear)
67
Table 2.10. Associations of CRP and cytokines with Benign Prostatic Hyperplasia
risk, stratified by type of BPH defining event
3
CRP, (mg/L)
Tl
T2
T3
TNF-a, (pg/mL)
Tl
T2
T3
Type of BPH
BPH Treatment
b
No. cases/
controls
111/227
109/229
155/227
101/231
102/225
98/227
sTNF-RI, (pg/mL)
Tl
T2
T3
95/230
89/225
117/228
sTNF-RII, (pg/mL)
Tl
T2
T3
BL-6, (pg/mL)
Tl
T2
T3
IFN-y, (pg/mL)
Tl
T2
T3
175/232
91/223
109/228
99/243
109/207
167/233
89/190
102/273
110/220
OR
1.00
0.93
1.08
1.00
0.98
0.90
1.00
0.86
1.16
1.00
0.53
0.67
1.00
1.52
1.60
1.00
1.04
1.33
(95% CI)
(0.66, 1.32)
(0.77, 1.53)
p
c
-* difference
(0.72, 1.34)
(0.66, 1.23)
p
c
r
difference
(0.62, 1.19)
(0.85, 1.58)
p
c
=
* difference
(0.38, 0.75)
(0.48, 0.92)
p
c
difference
(1.07,2.16)
(1.13,2.25)
P
c
r
difference
(0.75,1.43)
(0.96,1.85)
p
c
r
difference
Defining Event
BPH
No. cases/
controls
97/227
92/229
112/227
0.27
133/231
127/225
115/227
0.63
123/230
107/225
145/228
0.74
140/232
71/223
90/228
0.71
77/243
100/207
124/233
0.67
93/190
140/273
142/220
0.27
Sympi
OR
1.00
0.94
1.29
1.00
1.04
0.99
1.00
0.97
1.24
1.00
0.54
0.62
1.00
1.27
1.68
1.00
0.81
1.06
toms
b
(95% CI)
(0.68, 1.31)
(0.94, 1.78)
(0.74, 1.45)
(0.71, 1.38)
(0.68, 1.36)
(0.89, 1.73)
(0.39, 0.74)
(0.46, 0.84)
(0.91, 1.77)
(1.22,2.31)
(0.57, 1.14)
(0.75, 1.49)
"Adjusted for matching covariates, and body mass index(linear)
'Treatment includes men who received drug or surgical intervention(n=322); BPH Symptoms includes men with
two IPSS scores >14 or two IPSS scores at least 5 units higher than baseline plus at least one score >12 (n=405)
c
Pdiffetence is calculated as the difference in risk between BPH Treatment and BPH Symptoms as estimated from a
polychotomous logistic model
68
Table 2.11. Associations of CRP and cytokines with Benign Prostatic Hyperplasia
risk, stratified by time from baseline to BPH event'
Time from baseline to BPH event
CRP, (mg/L)
Tl
T2
T3
TNF-a, (pg/mL)
Tl
T2
T3
No. cases/
controls
34/227
38/229
48/227
37/231
41/225
42/227
sTNF-RI, (pg/mL)
Tl
T2
T3
33/230
43/225
44/228
sTNF-RII, (pg/mL)
Tl
T2
T3
IL-6, (pg/mL)
Tl
T2
T3
IFN-y, (pg/mL)
Tl
T2
T3
57/232
26/223
37/228
27/243
42/207
51/233
30/190
47/273
43/220
0 - 3 years
OR
1.00
1.11
1.30
1.00
1.20
1.19
1.00
1.35
1.30
1.00
0.47
0.68
1.00
1.86
1.89
1.00
1.11
1.26
(95% CI)
(0.67, 1.84)
(0.78,2.14)
p *-
r
difference
(0.74,1.95)
(0.73, 1.94)
p
b
-
r
difference
(0.82, 2.22)
(0.79,2.15)
p
b
-
* difference
(0.29, 0.79)
(0.43, 1.07)
p
b
-
r
difference
(1.10,2.16)
(1.12,3.17)
p
b
-
r
difference
(0.67, 1.83)
(0.75,2.10)
p
b
-
* difference
No. cases/
controls
174/227
163/229
219/227
0.69
197/231
188/225
171/227
0.25
185/230
153/225
218/228
0.78
258/232
136/223
162/228
0.84
149/243
167/207
240/233
0.68
152/190
195/273
209/220
0.89
4 - 7 years
OR
1.00
0.91
1.18
1.00
0.97
0.89
1.00
0.83
1.17
1.00
0.55
0.63
1.00
1.29
1.60
1.00
0.89
1.18
(95% CI)
(0.68, 1.21)
(0.89, 1.56)
(0.74,1.28)
(0.68,1.18)
(0.62,1.10)
(0.89, 1.54)
(0.41,0.73)
(0.48, 0.83)
(0.97, 1.73)
(1.21,2.12)
(0.67, 1.18)
(0.89, 1.58)
"Adjusted for matching covariates, and body mass index(linear)
b
p-difference is calculated as the difference in risk between BPH Treatment and BPH Symptoms as estimated from
a polychotomous logistic model
69
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72
Chapter 3
Prostatic Hyperplasia and Risk of Prostate Cancer
Abstract
This study examined the association between benign prostatic hyperplasia
(BPH) and prostate cancer risk in 5,068 placebo-arm participants of the Prostate
Cancer Prevention Trial (1993-2003). These data include 1,225 men who had cancer
detected during the 7-year trial, 556 which were detected following abnormal PSA or
DRE ('For-cause') and 669 detected without indication ('Not-for-cause'), and 3,843
men who had biopsy proven absence of prostate cancer at the trial end. BPH was
assessed hierarchically as self-report of surgical or medical treatment, moderately
severe symptoms (average recruitment and baseline International Prostate Symptom
Score (IPSS)> 14), or physician diagnosis only at baseline, and analyses were
completed using BPH status at baseline ('prevalent') or any evidence of BPH prior to
cancer diagnosis or end of study biopsy ('prevalent plus incident'). Controlled for age,
race and body mass index, there was no association of 'prevalent' nor 'prevalent plus
incident' symptomatic BPH with prostate cancer risk. This lack of association was
consistent across subgroups defined by type of BPH defining event (treatment,
symptoms or physician diagnosis), prompt for prostate cancer diagnosis and prostate
grade. This study provides the strongest evidence to date that BPH does not increase
the risk of prostate cancer.
Introduction
Benign prostatic hyperplasia (BPH) and prostate cancer are common urological
73
conditions in older men and there is a large body of evidence supporting a relationship
between these conditions. Original hypotheses of an association between BPH and
prostate cancer were based on studies documenting the presence of both conditions at
autopsy [82-84]. In more recent studies, BPH and prostate cancer frequently coexist;
more than 20% of men with prostate cancer also have BPH and cancer is found
incidentally in a significant percentage (10-20%) of surgically removed BPH
specimens.[88,89,101,123] In addition, epidemiologic studies have reported an
association between BPH and prostate cancer[95,96] There are also several similarities
between the two conditions: the prevalence of both BPH and prostate cancer increase
in parallel with age[88]; both conditions require androgens for growth and
development[88,90]; and both respond to androgen-deprivation treatments.[91,92]
Gene expression studies have identified similarities in genetic alterations between BPH
and prostate cancer, particularly in the growth regulatory genes[93]. An expanding
body of evidence also supports an important role and inflammation in both. [78,94]
Despite these similarities, there are also strong arguments that BPH and prostate cancer
are unrelated, both clinically and biologically. Differences in the histology and
anatomical location of these two conditions fuel the current opinion that BPH and
prostate cancer are not linked in origin.[87] BPH is characterized by hyperplasia of
primarily stromal and, to a lesser extent, epithelial cells, whereas prostate cancer
involves hyperplasia of only the epithelium in the glandular compartment of the
prostate[5,86]. Nearly all BPH arises in the transition zone of the prostate, while only
74
24% of prostate cancers occur in the transition zone, two-thirds in the peripheral zone,
and the rest in the central zone.[85]
From the perspective of epidemiologic research, the most substantial problem
in interpreting studies of the association between BPH and prostate cancer is the
potential for detection bias. Autopsy studies have shown that clinically significant
prostate cancer is undiagnosed in up to 15.6 percent of men[124]; therefore any
condition that increases the rate of urologic evaluation or PSA testing is likely to
increase the detection rate of prostate cancer that would otherwise have gone
undetected. Symptoms of BPH can increase the detection rate of prostate cancer by
increasing the number and extent of urologic examinations^ 100,125] and treatment of
BPH via trans-uretheral resection of the prostate (TURP) can result in the detection of
incidental prostate cancer. [101] In addition, BPH can increase prostate specific antigen
(PSA) levels, thereby increasing the likelihood of detecting latent prostate cancer. [102]
BPH also causes an enlargement of the prostate gland which could lead to increased
biopsies due to abnormal digital rectal examination[126], although increased prostate
size could also make it more difficult to detect cancer[103].
The Prostate Cancer Prevention Trial (PCPT) offers a unique opportunity to
investigate the association between BPH and prostate cancer. In the PCPT, all men
were subject to standardized diagnostic scrutiny for prostate disease regardless of
symptomatology; every participant completed an annual assessment of lower urinary
tract symptoms and received annual DRE and PSA tests. Furthermore, all men who
75
were not diagnosed with prostate cancer during the trial were asked to undergo an end-
of-study biopsy to confirm the absence or presence of prostate cancer. Here we give
results of a prospective study examining the association between BPH and prostate
cancer risk among placebo-arm participants in the PCPT. This study addresses many of
the limitations of previous studies, and allows a rigorous test of the association
between BPH and prostate cancer risk.
Materials and Methods
Data are from the Prostate Cancer Prevention Trial (PCPT), a randomized,
placebo-controlled trial testing whether finasteride reduced prostate cancer risk. [92]
Briefly, 18,880 men age 55 years and older with normal digital rectal exam (DRE),
prostate-specific antigen (PSA) levels of <3 ng/ml, no history of prostate cancer or
other clinically significant coexisting conditions, and no severe BPH symptoms,
defined as an International Prostate Symptom Score (IPSS)[6] of 20 or higher, were
randomized to receive finasteride (5 mg/day) or placebo.
During the PCPT, men underwent DRE and PSA determinations annually. A
prostate biopsy was recommended for participants who had an abnormal DRE or a
PSA >4.0 ng/mL. At the final study visit in Year 7, all men who had not previously
been diagnosed with prostate cancer were offered an end-of-study (EOS) biopsy. All
biopsies were collected under transrectal ultrasonographic guidance and involved a
minimum of 6 specimens (cores). All biopsies were reviewed to confirm diagnoses of
adenocarcinoma by both the pathologist at the local study site and by a central
76
pathology laboratory. Tumors were graded centrally using the Gleason scoring system.
Cancers were categorized as low-grade (Gleason sum, 2 to 7 (3+4 only)), and high-
grade (Gleason sum 7 (4+3 only) to 10) to distinguish those more likely to be clinically
significant. Prostate cancers were also categorized by prompt for diagnosis: cancers
detected following abnormal PSA or DRE were classified as 'For-cause'; and cancers
detected without indication, primarily at the study exit biopsy, were classified as 'Not-
for-cause'.
Study Population
This study is conducted in the 9,457 placebo arm participants because
finasteride prevents both BPH and prostate cancer[92]. We first excluded 3,637 men
who did not have a prostate cancer diagnosis or end-of-study biopsy, which included
585 men who died, 2,804 men who were medically unable or refused and 248 men
who, due to early completion of the trial (June 24, 2003) were not yet eligible for the
end-of-study biopsy. We then excluded 183 men whose end-of-study biopsy was
completed > 180 days before or after their planned end-of-study visit, and 376 men
whose end-of-study biopsy was completed after the end of the trial. Prostate cancer
events that occurred > 180 days after the planned end-of-study visit or after the end of
the trial were ignored. From the 5,261 remaining eligible men (1,264 cases; 3,997 non-
cases), we excluded 85 men (19 cases, 66 controls) who reported taking anabolic
hormones (including testosterone gel/injection/patch, nandrolone or
dehydroepiandrosterone) and 40 (9 cases, 31 controls) men who reported taking
77
finasteride during the PCPT. Furthermore, we excluded 68 (11 cases, 57 controls) men
who reported treatment (3 surgery, 65 medical) for BPH during the PCPT without
evidence of lower urinary tract symptoms (LUTS) (IPSS>10) or physician diagnosis of
BPH, whose surgery or use of alpha blockers was likely unrelated to BPH, leaving
5,068 men (1,225 cases, and 3,843 controls) for these analyses.
Data Collection
At baseline, age, race/ethnicity, family history of prostate cancer in first-degree
relatives, physical activity, usual alcohol consumption, and history of smoking were
collected using self-administered questionnaires and height and weight were measured
by clinic staff. Body mass index (BMI) was calculated as weight (kg) divided by
height
2
(m). Extensive medical data, including physician diagnosis of and treatment
for BPH was collected at the baseline, 6-month, and annual clinic visits and at every 3-
and 9-month phone contact between clinic visits. At recruitment, baseline, and each
annual clinic visit, participants completed the IPSS[6], a 7-item self-administered
questionnaire assessing the frequency of LUTS. DRE and PSA were assessed at
baseline and each annual clinic visit, and prostate volume was assessed by trans-rectal
ultrasound at the time of diagnostic biopsy (for interim cancers) or the end of study
biopsy.
Prevalent BPH (at baseline) was defined hierarchically as self report of surgical
(TURP, balloon dilation or prostatectomy) or medical (tamsulosin, doxazosin,
terazosin) treatment for BPH, presence of moderately severe LUTS (average IPSS from
78
recruitment and baseline > 14) or self-report of physician diagnosis of BPH at baseline.
Incident BPH (post-baseline) was defined hierarchically as the most severe BPH
defining event (surgical or medical treatment, moderately severe lower urinary tract
symptoms (2 EPSS > 14) or self-report of physician diagnosis of BPH) during follow-
up prior to cancer diagnosis or end-of-study biopsy.
Methods
Although data are from a clinical trial, prospective data analyses are
inappropriate because the presence/absence of prostate cancer was not ascertained
annually, and for most men, was determined at the end-of-study biopsy. Therefore, the
seven-year period prevalence of prostate cancer was used as the primary outcome.
Relative risk regression methods[127] were used to evaluate the association
between BPH and prostate cancer, since biopsy-confirmed prostate cancer was
common (24.4% of men) and thus the odds ratio would not be a good estimate of the
relative risk. [92] Risk ratios were estimated using the SAS GENMOD procedure with
Log-link function and binomial distribution[128]. When log-binomial models did not
converge, the GENMOD procedure was used with a Poisson distribution, and robust
error variances were estimated using a repeated statement and the subject identifier as
the class variable[128].
Multivariate models were used to estimate associations of BPH with risks of
total, and low-grade and high-grade prostate cancer while controlling for covariates.
Analyses were completed using BPH status at baseline ('prevalent' BPH) or any
79
evidence of BPH preceding cancer diagnosis ('prevalent plus incident' BPH) as the
exposure. Associations of incident BPH and prostate cancer were not investigated
alone due to recency of exposure and smaller sample size. Results are given adjusted
for age (linear), and race (white, black, and other) (Model 1), and body mass index
(continuous) (Model 2). Additional control variables associated with BPH or prostate
cancer risk in this sample, including alcohol consumption[107,129] and smoking status
[130], did not affect risk estimates and were not included in the final models. Models
were not controlled for prostate volume because it was missing differentially among
men diagnosed with interim cancer.
For both 'prevalent' and 'prevalent plus incident' BPH we investigated the
individual associations between type of BPH defining event (treatment, symptoms or
physician diagnosis) and prostate cancer risk. To assess potential biases, additional
analyses investigated the associations of BPH with 'for-cause' and 'not-for-cause'
prostate cancer. All statistical tests were 2-sided and were considered statistically
significant at P<0.05. Statistical analyses were conducted using SAS software (version
9.1; SAS Institute, Inc., Cary, NC).
Results
Among the total 5,068 men in this analysis, 1,549 (30.6%) had BPH at baseline:
286 (18.5%) had surgical (281) or medical (5) treatment for BPH; 276 (17.8%) had an
average of 2 IPSS>14; and 987 (63.7%) had a physician diagnosis only. Post-
randomization, 763 men had an incident BPH defining event: 350 (45.9%) had surgical
80
(31) or medical (319) treatment; 329 (43.1%) had 2 IPSS>14; and 84 (11.0%) reported
a physician diagnosis of BPH. The median age of participants was 64.9 5.4 years,
and most men were Caucasian, former or never smokers, overweight, light or
moderately active, and were not heavy drinkers (Table 3.1). Most participants also had
a baseline PSA <1.1 ng/ml, did not have a family history of prostate cancer, and had a
prostate volume <3 3.5 cm (Table 3.1).
'Prevalent' BPH was more common among older men, men of 'other' race,
men who did not smoke, were not overweight or obese and were not heavy drinkers,
men with a higher baseline PSA and IPSS, and a larger prostate volume (Table 3.2).
'Prevalent plus incident' BPH was more common among older men, men who were not
heavy drinkers, men with a higher baseline PSA and IPSS, and a larger prostate
volume (Table 3.3).
Among the total 5,068 men in this analysis, 1,225 (24.2%) were diagnosed with
prostate cancer: 1,074 (87.7%) had Gleason scores from 2 to 7 (3+4), 105 (8.6%) had
Gleason scores >7 (4+3) and 46 (3.8%) had unknown Gleason scores. 556 (45.4%)
cancers were detected following abnormal PSA or DRE and were classified as 'For-
Cause', while 669 (54.6%) were diagnosed at the end-of-study biopsy without clinical
indication ('Not-For-Cause'). Prostate cancer was more common among older men,
African-American men, men who were not overweight or obese, men with a higher
baseline PSA, and men who had a family history of prostate cancer (Table 3.4).
Tables 3.5 and 3.6 give associations of 'prevalent' and 'prevalent plus incident'
81
BPH with cancer risk. There were no associations of prevalent BPH or prevalent plus
incident BPH with prostate cancer risk. Results were similar when BPH was
categorized by type of BPH defining event (surgery, symptoms, physician diagnosis),
and when prostate cancer was categorized by grade (low, high) and prompt for
diagnosis ('For-cause', 'Not-for-cause'). Associations were similar when controlled
for age and race only (Model 1) and controlled in addition for body mass index (Model
2). There were no substantial differences in results when analyses excluded 47 prostate
cancer cases occurring within 1 year of the first BPH defining event, or when high
grade cancers were restricted to Gleason sum 8+ (3.7, 3.8).
Discussion
In this large prospective study among placebo-arm participants in the PCPT
there were no associations of symptomatic BPH with prostate cancer risk. This lack of
association was consistent across subgroups defined by type of BPH diagnosis
(treatment, symptoms or physician diagnosis), prompt or reason of prostate cancer
diagnosis ('For-cause' or 'Not-for-cause') and prostate cancer grade (Gleason score 2-
7(3+4) vs. 7(4+3)-10).
Six previous studies examined associations between BPH and prostate cancer
risk. These include: two hospital-based case-control studies that estimated the risk of
prostate cancer among men with BPH compared to men hospitalized for non-
neoplastic diseases[95,97]; 2 studies that calculated standardized incidence and/or
mortality ratios by comparing the incidence/mortality of prostate cancer in a cohort of
82
men hospitalized with BPH to the general population[96,98], and two studies that
compared prostate cancer incidence or mortality in a cohort of men hospitalized with
BPH to a cohort of men hospitalized with non-neoplastic diseases[95,99]. Of these, 3
studies reported an increased risk of prostate cancer. The first was a case-control study
that reported an increased risk of prostate cancer among men previously hospitalized
for non-cancer prostatic disease[95], the second was a prospective study that reported
an increased risk of prostate cancer mortality among men hospitalized with a primary
diagnosis of BPH [95], and the third was a prospective study that reported an increased
prostate cancer incidence among men who had a TURP as well as increased prostate
cancer incidence and mortality among men with a diagnosis of BPH without surgical
treatment [96].
Bias is a likely explanation of all the previously published studies showing an
association between BPH and prostate cancer. The largest single source of bias in
these studies is due to the increased likelihood of prostate cancer detection in men with
symptomatic urinary disease. Men with more severe urinary symptoms and larger
prostate size seek more health care for urinary symptoms[100,131]. In studies
investigating the association between BPH surgery and prostate cancer risk, men being
considered for surgical treatment of BPH are more likely to be thoroughly evaluated
for prostate cancer because surgical treatment of BPH can increase the chance of
detecting latent prostate cancers[101]. This may explain the findings in studies by
Chokkalingam and Armenian, in which the initial significant elevations in prostate
83
cancer incidence[96] and mortality [95]in the first few years of follow-up after initial
BPH diagnosis decrease with increasing duration of follow-up.
Additional issues also contribute to bias in previously published studies,
including differential exclusion criteria between men with and without BPH, and use of
the general population as a comparison group. In the prospective study by Armenian et
al., the exclusion of men at high prostate cancer risk (positive DRE) from men without
BPH likely resulted in a spuriously low rate of prostate cancer among men without
BPH, and the inclusion of men at high prostate cancer risk among men with BPH
(positive DRE) resulted in a spuriously high rate of prostate cancer among men with
BPH; thus yielding an increased prostate cancer mortality[95]. In addition, the
differential exclusion of men with latent prostate cancer from men with surgically
treated BPH without a similar exclusion for either men with BPH symptoms only or
from the contrast group of men without BPH introduces bias[96]. Furthermore, the use
of the general population as a comparison group without control for established
prostate cancer risk factors (age, race, obesity and physical activity), is likely to
introduce bias since the distribution of these factors among men with BPH differs from
that in the general population. [96] Overall, given both detection bias and shortcomings
in study design, we do not feel that previous studies of BPH and prostate cancer risk
could validly test whether or not there was a true association.
To evaluate the extent to which detection bias could have affected the results of
our study, we completed analyses stratified by whether prostate cancer was diagnosed
84
due to an elevated PSA or abnormal DRE ('For-cause') or was diagnosed without
clinical indication ('Not-for-cause'). If the presence of BPH was increasing the
likelihood of prostate cancer detection, we would expect BPH to be associated with an
increased risk for 'For-cause' prostate cancers. There was a suggestion of increased
risk between prevalent BPH and 'For-cause' prostate cancers diagnosed within the first
four years of the PCPT (OR=1.16, 95% CI: 0.82, 1.66), compared to cancers diagnosed
in years 5-7 (OR=1.03; 95%CI: 0.84, 1.25), which is consistent with detection bias;
however, neither association was statistically significant.
The evaluation of BPH and prostate cancer risk without control for PSA or
prostate volume deserves comment. PSA is produced by the prostate proportionally to
prostate volume, and the benign enlargement characteristic of BPH is associated with
increased PSA levels. [102] However, surgical treatment of BPH, which removes
tissue from the transition zone of the prostate, also lowers PSA levels[132]. In our
study population, baseline PSA was strongly associated with both total BPH and
prostate cancer (Tables 1 and 2), though for men with BPH treatment at baseline, 98%
of which were BPH surgery, the distribution of PSA at baseline was much lower than
for men with symptoms or physician diagnosis (Table 1). We assessed a model
adjusted for baseline PSA in addition to the covariates in model 2; which resulted in a
risk ratio of 0.96 (95% CI 0.85, 1.09) for the association between total prevalent BPH
and total cancer. However, this model yielded a spurious positive association between
'prevalent' BPH surgery and prostate cancer risk, while minimizing the associations
85
between BPH symptoms and physician diagnosis and prostate cancer risk. This model
is inappropriate and leads to biased results because adjustment for baseline PSA has a
differential affect on the associations between type of BPH defining event and prostate
cancer risk. We also considered controlling models for prostate size, because an
enlarged prostate could lead to increased biopsies due to abnormal digital rectal
examination[126] or could also make it more difficult to detect cancer. [103] However,
prostate size tended to be measured more frequently at end-of-study biopsies and less
frequently during interim biopsies, and because high grade disease was more likely to
be detected on interim biopsies, prostate volume was also missing more frequently for
high grade cancers (prostate volume was missing for: 42% of cancers detected during
interim biopsies, 10% of cancers detected at the end-of-study biopsy, and 31% of high-
grade, 21% of low-grade cancers). A model adjusted for prostate volume would be
problematic because high-grade prostate cancers are differentially missing.
There are several elements of the PCPT study design which serve to minimize
bias in this study of BPH and prostate cancer risk. First, men with possible prostate
cancer, defined as abnormal DRE or PSA>4, were excluded from participation in the
PCPT. Second, during the PCPT all men were subject to the same diagnostic scrutiny
for prostate disease (both BPH and prostate cancer), regardless of symptomatology;
every participant received an annual DRE and PSA test, and completed an assessment
of lower urinary tract symptoms, and men with an abnormal DRE or PSA were
recommended for prostate biopsy. Therefore, by standardizing screening of all men for
86
prostate disease, the PCPT minimized the impact of BPH symptoms on the number and
extent of urologic exams. Third, all men who were not diagnosed with prostate cancer
during the trial were asked to undergo an end-of-srudy biopsy to confirm the absence
or presence of prostate cancer. Although men with BPH were more likely to have a
prompt for biopsy due to abnormal DRE and/or PSA, the end-of-study biopsy provided
an equivalent opportunity to detect latent prostate cancer in men who had no biopsy
prompt. Therefore, the restriction of our study population to men with a known cancer
status minimized detection bias. The restriction of our study population to men with
known cancer status also reduced the possibility that undetected cancers could affect
study results. Lastly, the PCPT collected data that allowed us to investigate the
association between BPH and prostate cancer risk separately for subgroups defined by
prompt for BPH diagnosis, including physician diagnosis, symptoms and surgical and
medical treatment, and this is the only study to incorporate medical treatment in
definitions of BPH. In addition, all cancers were graded centrally, and this is the first
study to look at cancers stratified by grade.
There are several limitations to this study. Our analyses were restricted to men
with known cancer status; therefore, men who did not complete the end of study
biopsy, for whom cancer status was unknown, may differ from this study population.
For example, men who had a negative interim biopsy were more likely to have an end
of study biopsy (73.0% vs. 62.4% of men who did not have a negative interim biopsy;
p<0.0001), and therefore were more likely to be included in these analyses. However,
87
the completion the end-of-study biopsy was not related to BPH status (62.4% of men
with and 64.4% of men without BPH completed the end-of-study biopsy); therefore
this study population is likely representative of the overall PCPT population. In
addition, the relatively strict eligibility criteria of the PCPT (no major co-morbidities,
PSA less than 4 and IPSS less than 20) yielded a unique study population which limits
the generalizability of findings.
Conclusion
This study confirms the current opinion that BPH is not associated with prostate
cancer risk. This is the only study to report on the association between BPH and
prostate cancer risk in a study population where diagnostic surveillance of both BPH
and prostate cancer was rigorous and complete, and thus provides the strongest
evidence to date that BPH does not increase the risk of prostate cancer.
88
Table 3.1. Distribution of demographic and lifestyle
characteristics among the total study population
Total Sample
N=5,068
n %
Age
55-59
60-64
65-69
70+
Race
Caucasian
African American
Other
Smoking Status
Current
Former/Never
Body mass index(kg/m
2
)
Normal (<25)
Overweight (25-29.9)
Obese (>30)
Physical activity
Sedentary
Light activity
Moderate activity
Very active
Alcohol (grams/day)
a
<0.25
0.25- 1.74
1.75- 12.9
13-26.9
>27
Baseline PSA (ng/ml)
b
0-1.0
1.1-2.0
2.1-4.0
Family history prostate
cancer
c
Yes
No
Baseline IPSS
d
0-3.5
3.6-6.5
6.6-14.0
14.1-20.0
1291 32.0
1229 31.8
849 22.9
474 13.3
3603 93.6
101 3.0
139 3.4
268 6.9
3571 93.1
995 26.9
1978 51.8
826 21.3
633 16.5
1609 41.7
1198 32.0
385 9.8
998 26.1
642 16.9
1275 32.6
551 14.3
376 10.1
2002 46.9
1292 35.5
549 17.6
609 17.1
3234 82.9
1052 27.3
990 25.3
923 24.1
878 23.4
89
Table 3.1. Continued. Distribution of demographic and
lifestyle characteristics among the total study population
Total Sample
N=5,068
n %
Prostate volume (cm
3
)
e
10.0-18.8 cm
3
18.9-25.1 cm
3
25.2-33.5 cm
3
33.6-100.0 cm
3
846
945
834
794
25.2
28.0
24.2
19.6
* <0.25 grams/day(<l drink/month), 0.25-1.74 grams/day(l-3 drinks/month),
1.75-12.9 grams/day(l-6 drinks/week), 13.0-26.9 grams/day(7-13
drinks/week), >27 grams/day( >14 drinks/week)
b
Men with PSA>4.0 at baseline were excluded from participating in the
PCPT
c
Self-report of father, brother or son having prostate cancer
d
Average IPSS from recruitment and baseline visits, men with IPSS at
baseline > 20 were excluded from participating in the PCPT
e
Excludes 626 men missing prostate volume and 76 men with prostate
volume <10 or>100; prostate volume captured at the EOS prostate biopsy
(men without cancer) or diagnostic biopsy (men with cancer)
90
Table 3.2. Percent of men with prevalent BPH by demographic and lifestyle characteristics
Age
55-59
60-64
65-69
70+
Race
Caucasian
African American
Other
Smoking Status
Current
Former/Never
Body mass index(kg/m )
Normal (<25)
Overweight (25-29.9)
Obese (>30)
Physical activity
Sedentary
Light activity
Moderate activity
Very active
Alcohol (grams/day)
f
<0.25
0.25- 1.74
1.75-12.9
13-26.9
>27
Baseline PSA (ng/ml)
8
0-1.0
1.1-2.0
2.1-4.0
Family history prostate cancer
11
Yes
No
Total BPH
n=
%
22.6
28.1
37.5
43.6
30.8
19.5
33.5
21.9
31.2
33.7
30.4
26.7
31.8
30.6
28.9
34.0
34.8
31.5
28.9
28.6
26.3
26.0
32.6
38.5
30.6
30.2
=1,549
P
b
O.0001
0.01
0.0003
0.001
0.14
0.0006
O.0001
0.78
Prevalent BPH"
Type
Treatment'
n=286
%
1.9
3.9
8.1
14.7
5.6
3.3
9.4
2.6
5.9
6.9
5.2
5.0
5.2
5.9
5.8
4.9
7.1
5.5
5.8
4.0
4.1
6.6
4.9
4.5
5.7
5.6
of BPH defining
Symptoms'
1
n=276
%
5.0
5.2
5.8
6.5
5.5
2.0
8.2
5.1
5.5
5.3
5.8
4.9
5.9
5.5
4.9
6.3
6.3
5.5
5.8
4.0
4.1
4.7
5.5
7.4
4.7
5.6
event
Physician
Diagnosis
6
n=987
%
15.7
19.0
23.7
22.4
19.8
14.3
15.9
14.3
19.8
21.5
19.3
16.8
20.7
19.2
18.2
22.9
21.5
20.7
17.4
19.4
19.1
14.7
22.2
26.6
19.8
19.4
91
Table 3.2. Continued. Percent of men with prevalent BPH by demographic and lifestyle
characteristics
Prevalent BPH
a
Total BPH
n=
%
15.2
20.7
31.8
57.8
28.1
25.9
31.0
37.3
=1,549
p o
O.0001
O.0001
Type
Treatment'
n=286
%
4.2
4.1
6.7
7.9
10.3
1.5
1.3
3.0
of BPH defining
Symptoms'
1
n=276
%
0.0
0.0
0.0
23.3
4.1
4.5
6.6
6.6
event
Physician
Diagnosis
6
n=987
%
11.0
16.6
25.1
26.6
13.7
16.9
20.1
27.6
IPSS baseline
1
0-3.5
3.6-6.5
6.6-14.0
14.1-19.9
Prostate volume (cm
3
)*
10.0-18.8 cm
3
18.9-25.1 cm
3
25.2-33.5 cm
3
33.6-100.0 cm
3
a
Prevalent BPH categorized hierarchically as surgical or medical treatment for BPH, an average IPSS > 14, or physician diagnosis
of BPH at baseline
b
P value from chi-square comparing total 'prevalent' BPH to no BPH
c
Surgical or drug treatment for BPH with or without physician diagnosis and 2 IPSS >14
d
Average IPSS >14 at baseline, with or without a history of physician diagnosis and no history of treatment
e
Physician diagnosis only (no symptoms or treatment)
f
<0.25 g/day(<l drink/month), 0.25-1.74 g/day(l-3 drinks/month), 1.75-12.9 g/day(l-6 drinks/week), 13.0-26.9 g/day(7-13
drinks/week), >27 g/day( >14 drinks/week)
8
Men with PSA>3.0 at baseline were excluded from participating in the PCPT
h
Self-report of father, brother or son having prostate cancer
1
Average IPSS from recruitment and baseline visits, men with IPSS at baseline > 20 were excluded from participating in the PCPT
' Excludes 626 men missing prostate volume and 76 men with prostate volume <10 or >100; prostate volume captured at the EOS
prostate biopsy (men without cancer) or diagnostic biopsy (men with cancer)
92
Table 3.3. Percent of men with
characteristics
Age
55-59
60-64
65-69
70+
Race
Caucasian
African American
Other
Smoking status
Current
Former/never
Body mass index (kg/m )
Normal (<25)
Overweight (25-29.9)
Obese (>30)
Physical activity
Sedentary
Light activity
Moderate activity
Very active
Alcohol (grams/day)
f
<0.25
0.25-1.74
1.75-12.9
13-26.9
>27
Baseline PSA (ng/ml)
8
0-1.0
1.1-2.0
2.1-4.0
Family history prostate cancer
11
Yes
No
prevalent plus incident BPH by demographic and
Prevalent plus incident BPH
ab
Total BPH
n=
%
36.3
43.4
54.2
58.5
45.6
39.0
51.8
41.6
45.9
46.0
46.2
43.6
48.0
45.6
43.7
48.6
50.9
47.0
43.4
43.2
40.6
40.3
47.8
55.6
46.2
45.5
=2,312
F
O.0001
0.07
0.12
0.32
0.11
O.0001
O.0001
0.69
lifestyle
Type of BPH defining event
Treatment
1
"
n=636
%
7.9
10.5
15.8
23.0
12.3
14.3
19.4
10.5
12.7
12.3
12.6
12.9
11.3
13.0
12.6
12.8
14.5
12.9
12.3
10.1
11.1
12.9
11.9
13.0
12.7
12.5
Symptoms'
n=605
%
11.1
12.3
12.6
12.0
11.9
9.1
16.5
13.7
11.8
10.7
12.6
12.3
14.2
11.5
11.3
12.2
13.4
11.2
11.9
12.0
9.4
11.1
12.0
14.1
11.9
11.9
c
Physician
Diagnosis'
1
n=l,071
%
17.3
20.6
25.8
23.6
21.5
15.6
15.9
17.4
21.4
23.1
21.0
18.4
22.5
21.1
19.8
23.7
23.0
22.8
19.1
21.0
20.8
16.4
23.9
28.1
21.6
21.0
93
Table 3.3. Continued. Percent of men with prevalent plus incident BPH by demographic and
lifestyle characteristics
IPSS baseline'
0-3.5
3.6-6.5
6.6-14.0
14.1-19.9
Prostate volume (cm
3
)*
10.0-18.8 cm
3
18.9-25.1 cm
3
25.2-33.5 cm
3
33.6-100.0 cm
3
Total BPH
n=
%
21.2
32.9
51.6
81.6
41.2
39.5
44.9
57.2
=2,312
P*
<0.0001
O.0001
Prevalent plus incident BPH
a
Type
Treatment
1
*
n=636
%
7.7
10.3
15.1
18.0
15.6
10.9
10.8
12.6
of BPH defining
Symptoms'
n=605
%
0.8
3.9
9.3
36.3
10.4
10.1
12.4
15.3
event
Physician
Diagnosis'
1
n=l,071
%
12.7
18.7
27.2
27.2
15.2
18.6
21.7
29.4
a
Prevalent plus incident BPH categorized hierarchically as surgical or medical treatment for BPH, an average IPSS > 14, or
physician diagnosis of BPH at baseline or during PCPT
b
Surgical or medical treatment for BPH with or without physician diagnosis and 2 IPSS >14
c
Average IPSS >14 at baseline, with or without a history of physician diagnosis and no history of treatment
d
Physician diagnosis only (no symptoms or treatment)
* P value from chi-square comparing total 'prevalent plus incident' BPH to no BPH
f
<0.25 g/day(<l drink/month), 0.25-1.74 g/day(l-3 drinks/month), 1.75-12.9 g/day(l-6 drinks/week), 13.0-26.9 g/day(7-13
drinks/week), >27 g/day( >14 drinks/week)
g
Men with PSA>3.0 at baseline were excluded from participating in the PCPT
h
Self-report of father, brother or son having prostate cancer
' Average IPSS from recruitment and baseline visits, men with IPSS at baseline > 20 were excluded from participating in the PCPT
J
Excludes 626 men missing prostate volume and 76 men with prostate volume <10 or >100
94
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VITA
Jeannette Kisser (formerly Schenk) was born in Anaheim, California and permanently
resides in Seattle, Washington. She earned a Bachelor of Science degree in Molecular
Biology from the University of California at San Diego, and a Master of Science
degree in Clinical Nutrition from New York University. In 2010 she earned a Doctor
of Philosophy at the University of Washington in Epidemiology