Download Prediction of Prostate Cancer for Patients Receiving Finasteride

VOLUME
25
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NUMBER
21
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JULY
20
2007
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Prediction of Prostate Cancer for Patients Receiving
Finasteride: Results From the Prostate Cancer Prevention Trial
Ian M. Thompson, Donna Pauler Ankerst, Chen Chi, Phyllis J. Goodman, Catherine M. Tangen,
Scott M. Lippman, M. Scott Lucia, Howard L. Parnes, and Charles A. Coltman Jr
From the Department of Urology,
University of Texas Health Sciences
Center at San Antonio; Southwest
Oncology Group, San Antonio; Department of Clinical Cancer Prevention, The
University of Texas M.D. Anderson
Cancer Center, Houston, TX; The Fred
Hutchinson Cancer Research Center,
Seattle, WA; Department of Pathology,
University of Colorado Health Sciences
Center, Denver, CO; and the Department of Cancer Prevention, National
Cancer Institute, Washington, DC.
Submitted June 10, 2006; accepted
December 18, 2006.
Supported in part by PHS Cooperative
Agreement Grants No. CA37429,
CA35178, CA45808, and
5UO1CA86402-04 from the National
Cancer Institute, Department of Health
and Human Services.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Address reprint requests to Ian M.
Thompson, MD, Department of Urology, University of Texas Health Science
Center at San Antonio, 7703 Floyd Curl
Dr, San Antonio, TX 78229; e-mail:
[email protected].
A
B
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DOI: 10.1200/JCO.2006.07.6836
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Purpose
Using data from men in the finasteride group of the Prostate Cancer Prevention Trial (PCPT), we
evaluated the impact of prostate-specific antigen (PSA) and other risk factors on the risk of
prostate cancer.
Methods
Four thousand four hundred forty men in the finasteride group of the PCPT underwent prostate
biopsy, had at least one PSA and a digital rectal exam (DRE) during the year before biopsy, had at
least two PSA values from the 3 years before biopsy, and were on finasteride at the time of PSA
evaluation. Logistic regression was conducted using the variables age, race, family history of
prostate cancer, PSA, PSA velocity, and DRE adjusting for history of prior prostate biopsy.
Results
Six hundred forty-nine (14.6%) of 4,440 men were diagnosed with prostate cancer; 250 had
Gleason 7 or higher cancer. Factors associated with an increased risk of prostate cancer included
high PSA value and a rising PSA (24.9% risk for PSA value of 1.0 ng/mL and 24.8% risk for a rising
PSA), family history of prostate cancer, abnormal DRE result, African American race, and older age.
Factors associated with an increased risk of Gleason 7 or higher grade prostate cancer included
PSA, abnormal DRE, and older age. A prior negative biopsy was associated with decreased risk of
prostate cancer and high-grade prostate cancer.
Conclusion
Risk factors for prostate cancer on biopsy for men receiving finasteride include PSA, DRE, age,
race, family history, and history of a prior negative biopsy. With the exception of the approximate
reduction of PSA by half with finasteride, the impact of these risk factors is similar to men who do
not receive finasteride.
J Clin Oncol 25:3076-3081. © 2007 by American Society of Clinical Oncology
© 2007 by American Society of Clinical
Oncology
0732-183X/07/2521-3076/$20.00
R
INTRODUCTION
Prostate biopsy in a man undergoing regular prostate cancer screening is commonly prompted by an
elevated prostate-specific antigen (PSA), generally
of levels higher than 4.0 ng/mL, or an abnormal
digital rectal examination (DRE). The Prostate Cancer Prevention Trial (PCPT) results demonstrated
that PSA is not a dichotomous (normal/abnormal)
marker of prostate cancer, but reflects a range of risk
of the disease.1 We recently demonstrated that other
risk factors (including age, family history of prostate
cancer in a first-degree relative, ethnicity/race, and a
history of a prior negative prostate biopsy) provide
independent predictive information for the risk of
cancer or of high-grade disease, and more intensive
prostate cancer screening may now be augmented
using these risk factors.2
Despite a 25% reduction in prostate cancer
prevalence with finasteride in the PCPT, an increase
in high-grade disease diminished initial interest in
this strategy.3 Recent data suggest that an improved
sensitivity of PSA with finasteride for detection of
cancer and high-grade disease may have played a
role in this phenomenon, and an increased interest
in chemoprevention has emerged.2,4-6a As a result of
this interest and because of the substantial number
of men who are receiving finasteride for obstructive
voiding symptoms who are also being monitored for
prostate cancer with PSA, an investigation of the
relationship between the standard risk factors and
prostate cancer under finasteride use becomes relevant for clinical practice.3 Finasteride causes a fall in
PSA by approximately 50%, with a further fall over
time, depending on presence or absence of cancer.7
The drug also causes a reduction in prostate volume
by 25%.3 These factors affect interpretation of PSA
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Predicting Prostate Cancer With Finasteride
and could affect interpretation of DRE in men receiving finasteride,
thereby altering the decision to perform prostate biopsy and the risk of
a diagnosis of prostate cancer. We herein characterize the effect of risk
factors for prostate cancer under long-term finasteride use.
METHODS
The PCPT randomly assigned 18,882 men ages 55 or older with a normal DRE
and PSA level of less than 3 ng/mL to either finasteride or placebo for 7 years.3
A PSA test and DRE were performed annually. At annual visits, study participants were recommended to undergo prostate biopsy if DRE was abnormal or
if PSA value for men receiving placebo exceeded 4.0 ng/mL. In the finasteride
group, to achieve similar rates of biopsy recommendation in the two study
groups, PSA values were initially doubled. However, because of a continued
decline of PSA in this group, after 4 years of participation, finasteride PSA
values were multiplied by 2.3. At the end of 7 years, all men not previously
diagnosed with prostate cancer were requested to undergo an end-of-study
biopsy. The PCPT was approved by institutional review boards at all sites.
This analysis included all participants in the finasteride group who underwent prostate biopsy at any of the seven annual visits, including the endof-study required biopsy, and who had a PSA and DRE within 1 year of the
biopsy. An additional PSA measurement during the 3 years before the biopsy
was also required to compute PSA velocity. PSA measurements were excluded
if they were taken while the participant was off finasteride, and as a result, the
biopsies associated with the PSA and DRE tests used in this analysis were
typically performed while the participant was still on finasteride. For participants with multiple biopsies, the last biopsy was used so the effect of a prior
negative biopsy may be assessed. Similar qualitative results were obtained
when the first biopsy was used instead of the last. Family history was coded as
1 if brother, father, or son had prostate cancer, otherwise it was coded as 0;
current DRE result was coded as 0 for negative or normal and 1 for positive or
abnormal, indicating suspicion for cancer; and prior biopsy was coded as 0 for
no prior biopsy and 1 for one or more prior biopsies all negative for prostate
cancer. Two indicators for race and ethnicity were considered, African American (1 for African American and 0 for anyone else) and Hispanic (1 for
Hispanic ethnicity and 0 for anyone else). The value for age was the participant’s age at biopsy. PSA was transformed to the natural logarithm log (PSA)
for use in all models because the transformation improved the goodness of fit
of models to the observed data. All PSA values within 3 years before biopsy
were used to compute PSA velocity, defined as the slope of log PSA per year as
obtained by linear regression. For the case in which only two PSA measurements were available and linear regression could not be computed, velocity
was defined as the ratio of the change in log PSA to the change in time between
PSA measurements. Prostate cancer was defined as any indication of prostate
cancer of any grade on biopsy, and high-grade disease was defined as prostate
cancer with Gleason grade 7 or higher. Gleason score was assigned centrally by
the study pathologist.
The ␹2 tests were used for comparison of characteristics between participants included and excluded in the analysis. Univariate logistic regression was
used for associations between single risk factors, either as a factor variable or
continuous regressor, and multiple logistic regression was used for multivariable risk associations. All statistical tests and P values were for null hypotheses
versus two-sided alternatives. For both the prostate cancer and high-grade
multivariable risk analysis, a stepwise Akaike Information Criterion (AIC)
modeling strategy was used to search through the space of risk models containing all possible subsets of main effects and two-way interactions between
the risk factors: log PSA, log PSA velocity, DRE, age, family history, race,
ethnicity, and prior biopsy. The AIC objective function equals minus twice the
log likelihood plus 2 times the number of parameters in the model.8 Models with
minimal AIC were identified and among sets of models with statistically similar
AICs, models with no interaction terms were selected for reporting.
RESULTS
Of the 9,423 PCPT participants randomly assigned to finasteride,
5,676 men had at least one biopsy during study, either for cause or as
required at the end of study. Of these men, 357 were excluded from
this analysis because no PSA or DRE result within a year of biopsy was
available, 740 were excluded because they were off treatment when
their PSA level was measured, and 139 men were excluded from the
analysis because they did not have an additional PSA within 3 years
of biopsy. Thus, 4,440 men in the finasteride group were included in
the analysis.
Characteristics of the 4,440 PCPT finasteride arm participants
included in this risk association analysis are presented in Table 1 and
contrasted against 4,983 finasteride arm participants of the PCPT
excluded because of failure to meet the eligibility requirements of this
analysis. The subgroup of participants used in this analysis represents
a heavily screened group, measured by the increased PSA and DRE
screens, and increased number of biopsies. However, in part due to the
domination of the number of end-of-study biopsies relative to interim
PSA or abnormal DRE-prompted biopsies— of the 4,440 biopsy results used in this analysis, 3,563 (80.2%) were required end-of-study
Table 1. Characteristics of Participants From the Finasteride Arm of the
PCPT Included and Excluded From the Risk Analysis
Included in
Risk Analysis
(n ⫽ 4,440)
Characteristic
Age at baseline, years
55-60
60-64
65-69
70 or older
Family history
Negative
Positive
Race/ethnicity
White
African American
Hispanic
Other
No. of PSA screens
None
1-3
4-6
ⱖ7
No. of DRE measures
None
1-3
4-6
ⱖ7
No. of biopsies
0
1
ⱖ2
Years on finasteride
⬍5
ⱖ5
Excluded From
Risk Analysis
(n ⫽ 4,983)
No.
%
No.
%
P
1,399
1,436
1,005
600
31.5
32.3
22.6
13.5
1,556
1,534
1,105
788
31.2
30.8
22.2
15.8
.01
3,724
716
83.9
16.1
4,241
742
85.1
14.9
.10
4,128
152
121
39
93.0
3.4
2.7
0.9
4,552
207
141
83
91.4
4.2
2.8
1.7
.002
0
73
690
3,677
0
1.6
15.5
82.8
614
1,398
1,752
1,219
12.3
28.1
35.2
24.5
⬍ .001
0
72
561
3,807
0
1.6
12.6
85.7
599
1,389
1,798
1,197
12.0
27.9
36.1
24.0
⬍ .001
0
3,830
610
0
86.3
13.7
3,747
1,071
165
75.2
21.5
3.3
⬍ .001
197
4,243
4.4
95.6
3,082
1,901
61.9
38.1
⬍ .001
Abbreviations: PSA, prostate-specific antigen; DRE, digital rectal exam.
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Thompson et al
biopsies and 877 (19.8%) were interim—this differential has a minimum impact on results. Our previous analyses adjusting for population differences between participants included and excluded on the
operating characteristics of PSA found no difference between adjusted
and unadjusted estimates, which was driven by the required end-ofstudy biopsies of the PCPT.9 The subgroup of participants used for
analysis is a treatment-compliant group, measured by years on finasteride; 95.6% of the participants considered in this analysis were on
finasteride 5 years or more by the time of their last prostate biopsy.
Hence, results from the analysis are generally limited to men on
finasteride 5 years or more. Men included tended to be younger and
were more often white than those excluded, though the difference in
demographic distribution is small and the statistical significance is
likely driven by large sample sizes. For men with one or more
previous biopsies in this analysis, the median time between the
biopsy used for analysis and the previous biopsy was 3.1 years
(range, 25 days to 6.6 years).
Six hundred forty-nine (14.6%) of the finasteride group participants included in this analysis developed prostate cancer over the
course of the trial, and of these, 250 (38.5% of prostate cancers and
5.6% of participants) had high-grade tumors. The median PSA level
(measured within 1 year of biopsy) for the 4,440 participants in this
analysis was 0.5 ng/mL (range, 0.3 to 111.0), which is depressed from
the usual range as finasteride approximately halves PSA. Therefore, to
avoid confusion in interpretation, PSA will be referred to as finasteride
PSA (finPSA). The distribution of prostate cancer and high-grade
disease cases by finPSA level is presented in Tables 2 and 3. The risk of
prostate cancer starts at 6.2% for finPSA levels of less than 0.5 ng/mL
and increases to 24.9% by the threshold finPSA level of 1.0 ng/mL. A
finPSA level of 2.0 ng/mL correspondingly doubles prostate cancer
risk to 50%. Similarly, the risk of high-grade disease steadily increases
from 1% at finPSA levels of less than 0.5 ng/mL to 39.7% for finPSA
levels exceeding 3.0 ng/mL.
A steady or declining finPSA, measured by a velocity of less than
or equal to 0, corresponds to a risk of prostate cancer of 7.5% and
high-grade disease of 1.7%. A rising PSA, measured by a velocity of
greater than 0, increases the risk of prostate cancer from 7.5% to 24.8%
and high-grade risk from 1.7 to 11.3%. An abnormal DRE more than
doubles the risk of prostate cancer (13.0% for normal DRE and 30.5%
for abnormal) and nearly triples the risk of high-grade disease (4.7%
for normal DRE and 14.9% for abnormal). A positive family history
increases the risk of prostate cancer to 20.3% from 13.5% for a negative family history, and there is a significant increase in the risk of
prostate cancer and high-grade disease for African Americans. Tables
2 and 3 also present unadjusted odds ratios (ORs) for each of the risk
factors, which do not measure independent prognostic information
Table 2. Distribution of Prostate Cancer by Risk Factors and Odds Ratios From Univariate and Multivariate Models
Factor
Finasteride PSA, ng/mL
0.0-0.5
0.6-1.0
1.1-1.5
1.6-2.0
2.1-3.0
⬎ 3.0
Log finasteride PSA, log ng/ml
(continuous)†‡
Velocity of finasteride PSA,
log ng/mL/yr
ⱕ 0.0
⬎ 0.0
Velocity of finasteride PSA,
log ng/ml (continuous)‡
DRE
Normal
Abnormal
Family history
Negative
Positive
Age at biopsy
African American
No
Yes
Prior negative biopsy
No
Yes
Prostate Cancer
Univariate
Multivariate
No. of
Participants
No.
%
OR
P
2,489
1,073
378
198
186
116
155
164
94
71
98
67
6.2
15.3
24.9
35.9
52.7
57.8
1.0ⴱ
2.72
4.98
8.42
16.77
20.59
3.43
⬍ .001
2,611
1,829
196
453
7.5
24.8
⬍ .001
1.0ⴱ
4.06
9.96
⬍ .001
OR
P
3.48
⬍ .001
⬍ .001
4,030
410
524
125
13.0
30.5
1.0ⴱ
2.94
⬍ .001
1.0ⴱ
2.77
⬍ .001
3,724
716
504
145
13.5
20.3
1.0ⴱ
1.62
1.01
⬍ .001
1.0ⴱ
1.45
1.02
.001
.10
.02
4,288
152
614
35
14.3
23.0
1.0ⴱ
1.79
.003
1.0ⴱ
1.79
.01
3,830
610
539
110
14.1
18.0
1.0ⴱ
1.34
.01
1.0ⴱ
0.66
.002
Abbreviations: OR, odds ratio; PSA, prostate-specific antigen; DRE, digital rectal exam.
ⴱ
Denotes the reference value for the logistic regression.
†The logarithm of PSA treated as a continuous risk factor in logistic regression; OR corresponds to increase in odds for a unit increase in log PSA.
‡Log PSA velocity treated as a continuous risk factor in logistic regression; OR corresponds to increase in odds for a unit increase in log PSA velocity.
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Predicting Prostate Cancer With Finasteride
Table 3. Distribution of High-Grade Disease by Risk Factors and Odds Ratios From Univariate and Multivariate Models
No. of
Participants
Factor
Finasteride PSA (ng/mL)
0.0-0.5
0.6-1.0
1.1-1.5
1.6-2.0
2.1-3.0
⬎ 3.0
Log finasteride PSA, log ng/
ml (continuous)†
Velocity of finasteride PSA,
log ng/mL/year
ⱕ 0.0
⬎ 0.0
Velocity of finasteride PSA,
log ng/ml (continuous)‡
DRE
Normal
Abnormal
Family history
Negative
Positive
Age at biopsy
African American
No
Yes
Prior negative biopsy
No
Yes
2,489
1,073
378
198
186
116
2,611
1,829
High-Grade Disease
Univariate
No.
%
24
60
36
29
55
46
1.0
5.6
9.5
14.6
29.6
39.7
44
206
1.7
11.3
Multivariate
OR
P
1.0ⴱ
6.09
10.81
17.83
43.79
68.46
4.61
⬍ .001
⬍ .001
1.0ⴱ
7.43
OR
P
4.86
⬍ .001
⬍ .001
9.98
4,030
410
189
61
4.7
14.9
1.0ⴱ
3.57
⬍ .001
3,724
716
195
55
5.2
7.7
1.0ⴱ
1.51
1.03
⬍ .001
.01
4,288
152
235
15
5.5
9.9
1.0ⴱ
1.89
.02
3,830
610
200
50
5.2
8.2
1.0ⴱ
1.63
.003
⬍ .001
1.0ⴱ
3.06
⬍ .001
1.04
.001
1.0ⴱ
0.63
.02
Abbreviations: OR, odds ratio; PSA, prostate-specific antigen; DRE, digital rectal exam.
ⴱ
Denotes the reference value for the logistic regression.
†The logarithm of PSA treated as a continuous risk factor in logistic regression; OR corresponds to increase in odds for a unit increase in log PSA.
‡Log PSA velocity treated as a continuous risk factor in logistic regression; OR corresponds to increase in odds for a unit increase in log PSA velocity.
for each accounting for known risks, but rather the effect of each risk
factor in isolation of other known risks, and adjusted ORs from the
multivariable models, which combine all the significant risk factors,
for risk of prostate cancer and high-grade disease.
For calculation of adjusted risk of prostate cancer using a multivariable analysis, logarithm of finPSA (OR, 3.48; 95% CI, 3.08 to 3.92;
P ⬍ .001), DRE result (OR, 2.77; 95% CI, 2.14 to 3.57: P ⬍ .001),
family history of prostate cancer (OR, 1.45; 95% CI, 1.16 to 1.82;
P ⫽ .001), age (OR, 1.02; 95% CI, 1.00 to 1.04; P ⫽ .02), African
American race (OR, 1.79; 95% CI, 1.16 to 2.75; P ⫽ .01), and prior
negative biopsy (OR, 0.66; 95% CI, 0.51 to 0.86; P ⫽ .002) all remained
statistically significant.
For calculation of the risk of high-grade disease using a
multivariable analysis, logarithm of finPSA (OR, 4.86; 95% CI,
4.06 to 5.82; P ⬍ .001), DRE result (OR, 3.06; 95% CI, 2.16 to
4.33; P ⬍ .001), age (OR, 1.04; 95% CI, 1.02 to 1.07; P ⫽ .001),
and prior negative biopsy (OR, 0.63; 95% CI, 0.43 to 0.92;
P ⫽ .02) remained statistically significant, but family history
Table 4. Risk Factors in the Multivariable Risk Models for Participants No Finasteride 3 Placeboⴱ v Finasteride ⱖ 5 Years
OR for Prostate Cancer
Risk Factor
No Finasteride
3 Placebo
Log PSA
DRE
Family history
Prior negative biopsy
Age
African American
2.34
2.47
1.31
0.64
NS
NS
OR for High-Grade Disease
Finasteride ⱖ 5 Years
No Finasteride
3 Placebo
Finasteride ⱖ 5 Years
3.48
2.77
1.45
0.66
1.02
1.79
3.64
2.72
NS
0.70
1.03
2.61
4.86
3.06
NS
0.63
1.04
NS
Abbreviations: OR, odds ratio; PSA, prostate-specific antigen; DRE, digital rectal exam; NS, not significant.
Taken from the Prostate Cancer Prevention Trial placebo arm study.2
ⴱ
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Thompson et al
and African American race were no longer statistically significant (P ⬎ .05).
Table 4 summarizes which risk factors remained significant and
their magnitudes in the multivariable risk models for prostate cancer
and high-grade disease for this analysis of 4,440 PCPT participants on
finasteride contrasted with the analysis of 5,519 PCPT participants on
the placebo arm previously reported in Thompson et al.2 The effects of
PSA, DRE, family history, and prior negative biopsy remain similar
across finasteride and placebo for prediction of prostate cancer and
high-grade disease. The effect of age is similar between finasteride and
placebo for high-grade disease. Unlike for the placebo arm, age remained a statistically significant predictor for prostate cancer on finasteride. However, the OR approached 1.0. In the placebo analysis,
African Americans had statistically significant higher risk for highgrade disease but not for prostate cancer, yet in the finasteride arm, the
situation was reversed. This could be due to an enhanced effect of
finasteride against high-grade cancers in African Americans, but the
small numbers of African Americans in this analysis (N ⫽ 152) prohibits any determination.
DISCUSSION
A man who undergoes annual DRE and PSA determinations for the
early diagnosis of prostate cancer should currently expect not to be
told that his PSA is either normal or abnormal, but should expect an
evaluation of his level of risk; both for prostate cancer and for highgrade prostate cancer. We have recently developed a prostate cancer
risk calculator to help in this assessment.2 The calculator, based on the
results of prostate biopsies of 5,519 men from the PCPT, including
biopsies performed at the end of the study, which were performed
regardless of PSA and DRE findings, is less affected by previous estimates, which were confounded by ascertainment bias. Additionally,
the prospective collection of other risk factors allowed their incorporation into the estimate of risk.
A man undergoing annual screening should also have the expectation that his physician is familiar with the results of the PCPT,
demonstrating a 24.8% reduction in the risk of prostate cancer in men
who received finasteride.3 For a man who weighs the risks and benefits
of the use of finasteride and opts to take it for prevention or who uses
the drug for treatment of lower urinary tract symptoms from prostate
enlargement, the interpretation of both DRE and PSA are confounded
by the drug’s results. This study helps physicians and patients understand how risk of prostate cancer is affected by these measures.
As in our previous analysis of men in the placebo group of the
PCPT, a group of risk factors had a profound impact on a man’s risk of
both prostate cancer and high-grade disease if he was receiving finasteride. PSA was highly related to the risk of prostate cancer, reaching a
24.9% risk for values of 1.0 to 1.5 ng/mL; the risk of high-grade cancer
reached 29.6% for PSA values of 2.0 to 3.0 ng/mL. The change in PSA
over time (PSA velocity) had a close relationship with risk of both
cancer and high-grade disease with a steady or declining PSA value
having a risk of cancer of 7.5% and of high-grade disease of 1.7%
compared with risks of 24.8% and 11.3%, respectively, for men with
rising PSA. However, as we found and subsequently described in detail
in our analyses of the placebo arm of this trial, PSA velocity was not
statistically significant in any multivariable risk model accounting for
PSA. That is, PSA velocity added no independent diagnostic informa3080
tion to PSA for the prediction of prostate cancer in screened participants.2 This observation, which conflicts with that of previous reports,
could be explained by the high proportion of small, low-grade prostate cancers detected in PCPT because of end-of-study biopsies,
but could also be related to previous studies’ failures to examine the
correlation of PSA velocity and prostate cancer risk after accounting for the diagnostic effect of PSA, a highly-correlated measure.10
It has been speculated that finasteride could affect the detection
of prostate cancer by DRE. Our data demonstrate the significant
impact of DRE in men receiving finasteride, as illustrated by a 2.77fold increased risk of cancer and a 3.06-fold increased risk of highgrade disease for an abnormal DRE.
It is important to understand generalizability of these data. Men
in the PCPT were thought to be at a low risk for biopsy-detected
prostate cancer by enrollment PSA values ⱕ 3.0 ng/mL and a normal
DRE. The cohort was also predominantly white. Also, as men undergoing biopsy in this analysis either had an adjusted PSA of 4.0 ng/mL
or greater, abnormal DRE, or underwent end-of-study biopsy, this
estimate is optimal for men on finasteride with a value more than 2.0
ng/mL or who have been taking this medication for 7 years.
How do these results integrate with previous findings and with
clinical care? We hope that a man who seeks the counsel of his physician regarding prostate cancer risk would be educated regarding the
potential benefits and risks of early detection.11 If he opts for screening, initial assessment using the risk calculator previously described
would assist the patient-physician discussion regarding appropriateness of prostate biopsy.2 Thereafter or concurrently, patient education
would be initiated regarding chemoprevention of prostate cancer with
finasteride. For the individual who opts for finasteride chemoprevention, PSA should fall over the ensuing years. Although it is attractive to
consider the degree of fall within the first year or two related to
subsequent prostate cancer risk, the data in this analysis, most of which
are from 5 or more years of finasteride treatment, do not allow precise
early estimates of risk. Nonetheless, after 5 or more years of therapy,
the man with a low risk of prostate cancer should have a very low
absolute value of PSA—ideally, less than 0.5 ng/mL, and it should not
be increasing. This report shows that similar risk factors have a similar
effect on the risk of prostate cancer and high-grade disease to that
which we reported for equivalent men not on finasteride from the
same trial, and hence, the same calculator can be used, approximately
doubling the finPSA value observed; the area underneath the receiver
operating characteristic curve equals 76.8% for prostate cancer and
85.5% for high-grade disease in this population. Extending results
from analyses of the PCPT for use in the public will help physicians
and their patients assess their current risk of disease and their risk of
disease over time, whether or not they opt to use finasteride to reduce
that risk. Physicians should communicate that PCPT risk estimates
may be inflated due to inclusion of overdiagnosed cancers, but give an
accurate picture of the high prevalence of a disease for which currently
the field cannot reliably distinguish overdiagnosed from harmful cancers. Conversely, these results do reflect a sextant (6-core) biopsy,
whereas the majority of biopsies today are 10 to 12 cores, which would
be expected to lead to greater rates of detection.12 A reasonable recommendation would be to use the estimates of high-grade prostate cancer
from the risk calculator to help patients evaluate their risk of those
tumors of greatest biologic aggressiveness and to use these risks to then
evaluate their desire to undergo prostate biopsy.
JOURNAL OF CLINICAL ONCOLOGY
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Predicting Prostate Cancer With Finasteride
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
authors or their immediate family members indicated a financial interest.
No conflict exists for drugs or devices used in a study if they are not being
evaluated as part of the investigation. For a detailed description of the
disclosure categories, or for more information about ASCO’s conflict of
interest policy, please refer to the Author Disclosure Declaration and the
Disclosures of Potential Conflicts of Interest section in Information
for Contributors.
Employment: N/A Leadership: N/A Consultant: Ian M. Thompson,
Mission Pharmacal Stock: N/A Honoraria: Scott M. Lippman, Merck
Research Funds: M. Scott Lucia, GlaxoSmithKline; Ian M. Thompson,
Astra Zeneca Testimony: N/A Other: N/A
REFERENCES
1. Thompson IM, Pauler DK, Goodman PJ, et al:
Prevalence of prostate cancer among men with a
prostate-specific antigen level ⬍ or ⫽4.0 ng per
milliliter. N Engl J Med 350:2239-2246, 2004
2. Thompson IM, Ankerst DP, Chi C, et al:
Assessing prostate cancer risk: Results from the
Prostate Cancer Prevention Trial. J Natl Cancer Inst
98:529-534, 2006
3. Thompson IM, Goodman PJ, Tangen CM, et
al: The influence of finasteride on the development of prostate cancer. N Engl J Med 349:215224, 2003
4. Unger JM, Thompson IM, LeBlanc M, et al:
Estimated impact of the Prostate Cancer Prevention
AUTHOR CONTRIBUTIONS
Conception and design: Ian M. Thompson, Catherine M. Tangen,
Charles A. Coltman Jr
Financial support: Charles A. Coltman Jr
Administrative support: Ian M. Thompson, Charles A. Coltman Jr
Collection and assembly of data: Phyllis J. Goodman, M. Scott Lucia
Data analysis and interpretation: Donna Pauler Ankerst, Chen Chi,
Phyllis J. Goodman, Catherine M. Tangen, Scott M. Lippman, M. Scott
Lucia
Manuscript writing: Ian M. Thompson, Donna Pauler Ankerst, Scott M.
Lippman, Howard L. Parnes
Final approval of manuscript: Ian M. Thompson, Donna Pauler
Ankerst, Chen Chi, Phyllis J. Goodman, Catherine M. Tangen, Scott M.
Lippman, M. Scott Lucia, Howard L. Parnes, Charles A. Coltman Jr
Trial on population mortality. Cancer 103:1375-1380,
2005
5. Klein EA, Tangen CM, Goodman PJ, et al:
Assessing benefit and risk in the prevention of
prostate cancer: The Prostate Cancer Prevention
Trial revisited. J Clin Oncol 23:7460-7466, 2005
6. Lippman SM, Lee JJ: Reducing the “risk” of
chemoprevention: Defining and targeting high risk
– 2005 AACR Cancer Res and Prevention Foundation Award Lecture. Cancer Res 66:2893-2903,
2006
6a. Thompson IM, Chi C, Ankerst DP, et al:
Effect of finasteride on the sensitivity of PSA for
detecting prostate cancer. JNCI 98:1128-1133, 2006
7. Fetzioni RD, Howlader N, Shaw PA, et al:
Long-term effects of finasteride on prostate specific
antigen levels: Results from the Prostate Cancer
Prevention Trial. J Urol 174:877-881, 2005
8. Akaike H: A new look at the statistical model
selection. IEEE Transactions on Automatic Control
AC-19:716-723, 1974
9. Thompson IM, Ankerst DP, Chi C, et al: Operating characteristics of prostate specific antigen in
men with an initial PSA level of 3.0 ng/mL or lower.
JAMA 294:66-70, 2005
10. Carter HB: Assessing risk: Does this patient
have prostate cancer? J Natl Cancer Inst 98:506507, 2006
11. Chan EC, Vernon SW, O’Donnell FT, et al:
Informed consent for cancer screening with
prostate-specific antigen: How well are men getting
the message? Am J Public Health 93:779-785, 2003
12. Levine MA, Ittman M, Melamed J, et al: Two
consecutive sets of transrectal ultrasound guided
sextant biopsies of the prostate for the detection of
prostate cancer. J Urology 159:471-475, 1998
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