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Cancer Prevention Research
Finasteride Does Not Increase the Risk of High-Grade Prostate Cancer:
A Bias-Adjusted Modeling Approach
Mary W. Redman,1 Catherine M. Tangen,1 Phyllis J. Goodman,1 M. Scott Lucia,2 Charles A. Coltman, Jr.3
and Ian M. Thompson4
Abstract Finasteride taken for 7 years in the Prostate Cancer Prevention Trial (PCPT) reduced the
risk of prostate cancer by 25%, but with an apparent increased risk of high-grade disease.
Subsequent analyses found that finasteride biases toward improved prostate cancer
detection and accuracy in prostate cancer grading at biopsy. In our first analysis of the
present study, we accounted for these biases in estimating the effect of finasteride on the
risk of overall and high-grade prostate cancer. This analysis used PCPT data that included
3-month longer collection of endpoints than in the original report with observed prostate
cancer rates of 22.9% (4.8% with high grade; placebo) versus 16.6% (5.8% with high
grade; finasteride). Based on these updated results, the bias-adjusted prostate cancer
rates are estimated to be 21.1% (4.2% high grade; placebo) and 14.7% (4.8% high grade;
finasteride), a 30% risk reduction in prostate cancer [relative risk (RR), 0.70; 95% confidence
interval (95% CI), 0.64-0.76; P < 0.0001] and a nonsignificant 14% increase in
high-grade cancer (RR, 1.14; 95% CI, 0.96-1.35; P = 0.12) with finasteride. We then estimated
rates of high-grade prostate cancer based on an analysis that incorporated grading
information from radical prostatectomies in 500 subjects diagnosed with cancer. The
resulting estimates were high-grade cancer rates of 8.2% (placebo) versus 6.0% (finasteride),
a 27% risk reduction (RR, 0.73; 95% CI, 0.56-0.96; P = 0.02) with finasteride. Our
third analysis examined the impact of biopsy sensitivity on the risk relative of high-grade
prostate cancer and found that differential sensitivity of biopsy between the treatment
arms can have a significant impact on risk ratio estimates. These collective results suggest
that the observed, unadjusted higher risk of high-grade disease with finasteride
seems to have been due to facilitated diagnosis resulting primarily from increased biopsy
sensitivity with finasteride. Therefore, men undergoing regular prostate cancer screening
or who express an interest in cancer prevention should be informed of the opportunity to
take finasteride for preventing prostate cancer.
One in seven men in the United States is expected to be diagnosed
with prostate cancer in his lifetime primarily because of
aggressive screening. The effect of screening on morbidity and
mortality is uncertain; and the human and economic cost of
prostate cancer treatment is substantial. These circumstances
make preventing this common disease an attractive public
health strategy (1–3). The Prostate Cancer Prevention Trial
(PCPT) tested the ability of finasteride, a selective inhibitor of
5α-reductase type 2, to reduce the risk of prostate cancer. The
independent Data and Safety Monitoring Committee recommended
closure of the PCPT 15 months early because of overwhelming
evidence that the primary end point had been
reached: Finasteride had reduced the risk of prostate cancer by
25% (4). Concurrently, finasteride apparently had increased the
risk of high-grade disease. Although high-grade tumors were a
relatively small proportion of all detected tumors in the finasteride
group, the potentially increased risk of aggressive disease
and an unfavorable editorial accompanying the initial publication
led to a general lack of acceptance of finasteride for cancer
prevention (5). In the United States, early detection and treatment
remain the primary focus for controlling this disease.
Since the initial publication of primary PCPT outcomes, analyses
of these contrasting conclusions have continued, as has a
widespread debate on finasteride for prostate cancer prevention.
We now know that finasteride enhances the detection of
prostate cancer through the following effects on the performance
characteristics of for-cause biopsies (see "Materials and
Authors' Affiliations: 1Fred Hutchinson Cancer Research Center, Seattle,
Washington; 2Department of Pathology, The University of Colorado at Denver,
Denver, Colorado; 3The Southwest Oncology Group; and 4Department of
Urology, The University of Texas Health Science Center at San Antonio,
San Antonio, Texas
Received 04/25/2008; accepted 05/02/2008.
Grant support: NCI grant CA37429.
Requests for reprints: Mary W. Redman, Southwest Oncology Group
Statistical Center, Fred Hutchinson Cancer Research Center, 1100 Fairview
Avenue North, M3-C102, Seattle, WA 98109. Phone: 206-667-4767; Fax:
206-667-4408; E-mail: mredman@fhcrc.org.
©2008 American Association for Cancer Research.
doi:10.1158/1940-6207.CAPR-08-0092
www.aacrjournals.org OF1 Cancer Prev Res 2008; Online First 2008
Published Online First on May 18, 2008 as 10.1158/1940-6207.CAPR-08-0092
Methods" section for definition): (a) improved sensitivity of
prostate-specific antigen (PSA) for overall and high-grade cancer
detection, (b) improved sensitivity of digital rectal examination
(DRE) for cancer detection, and (c) more accurate grading
of high-grade prostate cancer (5, 6). Although these three detection
biases would be expected to lead to cancer overdetection in
study subjects receiving finasteride, there was a counteracting
bias for greater cancer detection in the placebo group because
these men more commonly underwent biopsy.
To better understand the cumulative effect of these biases on
prostate cancer detection in the PCPT, we conducted three analyses.
First, we analyzed the effect of finasteride on overall and
high-grade prostate cancer in all study participants including
those who did not have (but were eligible for) an end point determination.
This analysis accounted for the selection biases of
finasteride in improving detection of cancer by for-cause biopsies.
Second, we estimated the true prevalence of high-grade
prostate cancer among men with biopsy-detected cancer based
on the subset of patients who underwent radical prostatectomy
(which is more definitive than is biopsy for cancer grade, especially
when comparing grades between the finasteride and placebo
groups). Third, we examined the effect of imperfect
biopsy sensitivity for prostate cancer on the prevalence of
high-grade prostate cancer within each study arm and on the
overall risk reduction associated with finasteride.
Materials and Methods
The PCPT randomized 18,882 eligible men to receive either placebo
or finasteride for 7 year and to be followed for 7-year period prevalence
of prostate cancer. Prostate biopsy was done either due to an abnormal
DRE or an “elevated” PSA. An elevated PSA was defined as either a
value above 4.0 ng/mL in the placebo group or an adjusted value in
the finasteride group that annually resulted in a similar number of
biopsy recommendations (9, 10). A biopsy associated with either an abnormal
DRE or elevated PSA is referred to as a for-cause biopsy. All
cancer-free men were recommended to undergo an end-of-study prostate
biopsy after 7 year of study participation, regardless of PSA or DRE
findings. The trial was closed early due to overwhelming evidence that
finasteride significantly reduced the risk of prostate cancer. At the time
of the initial publication of results, a 25% reduction in the 7-y period
prevalence of prostate cancer attributable to finasteride was observed.
These results were based on a data set frozen in March 2003. Subsequent
analyses use data through the day of the trial unblinding (June
23, 2003) yielding additional cases that result in an observed risk reduction
of 28%. It is this larger data set we use for the present analyses.
For the present analyses, a man was defined to have an end point if he
had an interimdiagnosis of prostate cancer or if he underwent an end-ofstudy
biopsy within 90 d of his 7-y anniversary of his randomization or
by June 23, 2003 (whichever came first). Due to early closure of the study,
15,990 (85%) of the 18,882 men were assessable for the endpoint. End
points were observed in 5,223 men on the placebo arm and 4,958 men
on the finasteride arm for a total of 10,182 (64%) of the 15,990 men.A60%
compliance rate for end point ascertainment was specified in the protocol
design assumptions. For the purposes of this article, we will consider
the sample size of the study to be the 15,990 men who reached their 7-y
anniversary when the study was reported and unblinded. High-grade
prostate cancer was defined as a Gleason score of ≥7.
Predicting prostate cancer prevalence if all subjects
had an end point
It is likely that men who did not have an end point evaluated have
a different underlying probability of prostate cancer than those who
did have an end point evaluated. To estimate the cancer prevalence if
all subjects had an end point, a reasonable and often used assumption
is that there are measured study covariates, which both explain the
differences between men with and without end points and are related
to the risk of prostate cancer (11). Under this assumption, for two men
with similar covariate values, such as age, family history of prostate
cancer, and treatment arm assignment, one with an end point evaluated
and one without, the outcome data from the man with the evaluated
end point inform the cancer status for the man without the end
point evaluation.
An approach that uses this assumption and can be used to estimate
the prevalence of prostate cancer and high-grade disease is the inverse
probability of censoring weighted estimation (12). Use of this analysis
approach is a two-step process; the first step is to estimate the probability
of having an end point evaluated conditional on covariates,
and the second step is to estimate the probability of cancer given
the probabilities estimated in the first step. The probability of cancer
is estimated by the weighted average of cancers within each treatment
arm among men with observed end point, using the inverse of the
probabilities from the first step as weights.
To estimate the probability of having an end point evaluated in the
first step, logistic regression was used. To model the predicted probabilities,
we chose study covariates related to both (a) having the
study end point and (b) having a diagnosis of prostate cancer. The
baseline covariates that were included in these analyses were treatment
arm, age, ethnicity/race, PSA value, and family history of prostate
cancer. Covariates measured after randomization that were
included in this analysis were interim biopsy prompts based on
PSA levels or DRE and ever having a negative biopsy result during
follow-up and before end of study. The weights were then calculated
as the inverse of the fitted (predicted) probabilities for men with an
end point evaluated. The same weights and approach were used to
estimate the prevalence of biopsy-detectable high-grade cancers in
each treatment arm.
Predicting high-grade prostate cancer by integrating
prostatectomy data
The previous analysis attempts to account for selection bias between
the treatment arms on which participants have a study end
point evaluated. In particular, it addresses the bias that fewer biopsies
were conducted in the finasteride group (a bias in favor of finasteride)
and the bias associated with improved performance of PSA and DRE
for indication of for-cause biopsies (a bias in favor of placebo).
The next analysis done was to account for the effect of finasteride
on the improved accuracy of prostate biopsy on Gleason grading in
men on finasteride due to reduced prostate gland volume. Prostatectomies
were known to be done and data were available on 500 of
2,017 subjects with cancer. This analysis proceeded as the first analysis.
First, a logistic regression model was used to estimate the probability
of prostatectomy conditional on covariates for the subset of
men diagnosed with prostate cancer. Next, the prevalence of highgrade
cancer among men with a cancer diagnosis was estimated by
the weighted proportion of men with high-grade disease determined
by prostatectomy, using a weight that is the inverse of the probability
of having had both a biopsy and prostatectomy. The overall prevalence
of high-grade cancer within each treatment arm was then estimated
by the product of (a) the estimates from this analysis (the
probability of high-grade disease among men with cancer) and (b)
the estimates of prostate cancer prevalence from the first analysis.
Effect of differential biopsy sensitivity on disease
prevalence
The first two analyses addressed biases related to imperfect ascertainment
of biopsy end points on all study participants and differentially
inaccurate grading of disease severity by biopsy between the
treatment arms. The first analysis accounted for biases related to missing
end points to estimate the overall prevalence of biopsy-detectable
prostate cancer and high-grade cancer. The second analysis accounted
for biases related to more accurate grading of high-grade disease with
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finasteride to estimate the prevalence of true high-grade cancer (as determined
by prostatectomy) among participants with biopsy-detectable
prostate cancer.
These analyses use the assumption that biopsy perfectly detects
cancer, although there is substantial evidence that (a) biopsy operating
characteristics are less than perfect and (b) the operating characteristics
are improved under finasteride. The final analysis addressed
the effect that a plausible range of biopsy sensitivity values would
have on the true underlying risk of prostate cancer and high-grade
cancer in each arm. For this analysis, we assumed that biopsy has
perfect specificity (the probability of a negative biopsy given no cancer
equals 1.0) and perfect positive predictive value (the probability of
cancer given a positive biopsy equals 1.0; ref. 13). The probability of
true cancer within each treatment arm is then estimated by the proportion
of observed cancers divided by the sensitivity (the probability
of a positive biopsy given cancer). Biopsy sensitivity to detect cancer
was also incorporated into estimates of high-grade cancer prevalence
in the same way. This used an additional assumption that the true
presence of high-grade cancer did not depend on whether cancer status
was observed or not. This is a somewhat strong assumption if, in
fact, the hypothesis that high-grade tumors are more prominent is
true, thereby making cancer more easily detectable on biopsy. If the
sensitivity was equal across treatments, then the risk ratio would be
unaffected by imperfect sensitivity. Alternatively, if the sensitivities
are not equal across treatments, then the true risk ratio is equal to
the observed ratio multiplied by the sensitivity of biopsy under placebo
divided by the sensitivity under finasteride. Therefore, if biopsy
sensitivity under finasteride is larger than under placebo, the risk reduction
is underestimated, and if the sensitivity is smaller under finasteride
then the risk reduction is overestimated.
All of the analyses presented include weights that are a function of
measured covariates. Because the weights are estimated, their inclusion
affects the variability of overall prevalence and risk estimates.
To account for estimation of the weights, 10,000 bootstrap samples
of the observed data were constructed. The analysis procedures were
repeated on each data set and the variance of the prevalence estimates
was estimated by the variance over all samples. All analyses were
done in Splus (Insightful Co.).
Results
Table 1presents a comparison of the characteristics of men
with and without a study end point. Characteristics determined
to be associated with a reduced odds of having an
end point were randomization to finasteride (RR, 0.89) and
older age (OR [odds ratio], 0.9 . Additionally, White race versus
other race/ethnicities, family history of prostate cancer, interim
biopsy prompts based on PSA or DRE, and a negative
interim biopsy were all associated with an increased odds of
having an end point. Whereas PSA at randomization was
marginally associated with an increased odds of observed
end point (RR, 1.14; P < 0.0001), the association was no longer
significant after adjusting for other covariates (P = 0.6).
Predicting prostate cancer prevalence if all subjects
had an end point
Prostate cancer prevalence results from the analyses accounting
for nonrandom missing biopsy results are presented
in Table 2. The observed rates of prostate cancer for the 5,223
Table 1. Comparison of men with and without endpoint evaluated
N (%) / mean ± std End point evaluated OR* (95% CI) P*
No Yes
n = 5,809 n = 10,181
Treatment arm
Finasteride 3,008 (52%) 4,958 (49%) 0.89 (0.84-0.95) 0.0007
Placebo 2,801 (48%) 5,223(51%) 1.0 (reference)
Age at randomization† 63.4 ± 5.9 62.9 ± 5.4 0.98 (0.97-0.99) <0.0001
Race
White 5,297 (91%) 9,483 (93%) 1.37 (1.21-1.55) <0.0001
Other 512 (9%) 699 (7%) 1.0 (reference)
Family history of PCA
Yes 782 (13%) 1,698 (17%) 1.23 (1.12-1.35) <0.0001
No 1,200 (79%) 383 (77%) 1.0 (reference)
PSA at randomization‡ 63.4 ± 5.9 62.9 ± 5.4 0.99 (0.94-1.04) 0.59
Prior negative study biopsy
Yes 463 (8%) 1,349 (13%) 1.60 (1.43-1.80) <0.0001
No 5,345 (92%) 8,833 (87%) 1.0 (reference) <0.0001
Biopsy prompt for elevated PSA
Yes 69 (1%) 803(8%) 6.80 (5.32-8.84) <0.0001
No 5,739 (99%) 9,381 (92%) 1.0 (reference)
Biopsy prompt for suspicious DRE
Yes 82 (1%) 830 (8%) 5.66 (4.52-7.1 <0.0001
No 5,726 (99%) 9,352 (92%) 1.0 (reference)
*From a multivariable logistic regression model with endpoint evaluated (yes/no) as the outcome, adjusting for other factors in Table 1.
OR = odds ratio, CI = confidence interval.
†The OR represents the difference in odds of endpoint comparing men 1-year apart in age.
‡OR for each 1-unit increase in PSA level.
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men in the placebo group and 4,959 men in the finasteride
group with an end point were 22.9% and 16.6%, respectively.
Had all subjects had a biopsy endpoint, our analysis suggests
that the true rate of cancer in the 8,024 men in the placebo
group would have been 21.1% and in the 7,966 men in the
finasteride group would have been 14.7%. As expected, these
percentages are slightly smaller than what was observed,
suggesting that the men without the end point evaluated
were slightly less likely to have prostate cancer. Similarly,
whereas the observed rates of high-grade cancer in the placebo
and finasteride groups were 4.8% and 5.8%, respectively,
our analysis estimates that the true rates of high-grade cancer
are 4.2% and 4.8%, respectively. Of interest, the relative risk
of prostate cancer is changed minimally from the raw data
(0.72 versus 0.70). The risk of high-grade disease associated
with finasteride after accounting for the missing data decreased
from an observed and significant 21% increased risk
to a nonsignificant 14% increased risk (P = 0.12).
Predicting high-grade prostate cancer by integrating
prostatectomy data
The target of this analysis was to estimate the high-grade
prostate cancer status if all biopsy-detected cancers had undergone
prostatectomy. Study participants who underwent radical
prostatectomy were not a random sample of the participants
with cancer detected on biopsy. Whereas treatment group,
Table 2. Observed and estimated numbers and proportions of prostate cancer detected on biopsy
Placebo arm Finasteride arm RR (95% CI) P-value
n = 8,024 n = 7,966
Prostate cancer
Estimate of overall prevalence 1,693(21.1%) 1,171 (14.7%) 0.70 (0.64-0.76) 0.0001
Observed 1,194 (22.9%) 823(16.6%) 0.72 (0.67-0.79) 0.0001
High-grade cancer
Estimate of overall prevalence 337 (4.2%) 382 (4.8%) 1.14 (0.96-1.35) 0.12
Observed 252 (4.8%) 288 (5.8%) 1.21 (1.02-1.42) 0.02
Table 3. Comparison of men with and without prostatectomy verification of biopsy result
No prostatectomy Prostatectomy OR (95% CI)* P-value*
n = 1,517 n = 500
Treatment arm
Finasteride 617 (41%) 206 (41%) 0.97 (0.78-1.21) 0.80
Placebo 900 (59%) 294 (59%) 1.0 (reference)
Age at randomization 64.6 ± 5.6 61.1 ± 4.2 0.86 (0.84-0.8 <0.0001
1.0 (reference)
Race
White 1,403(92%) 466 (93%) 1.41 (0.94-2.16) 0.11
Other 114 (8%) 34 (7%) 1.0 (reference)
Family history of prostate cancer
Yes 317 (21%) 117 (23%) 1.02 (0.78-1.31) 0.90
No 1,200 (79%) 383 (77%) 1.0 (reference)
PSA at randomization 1.6 ± 0.8 1.7 ± 0.7 1.25 (1.07-1.82) 0.006
1.0 (reference)
Prior negative biopsy
Yes 206 (14%) 67 (13%) 1.05 (0.76-1.44) 0.78
No 1,311 (86%) 433 (87%) 1.0 (reference)
Biopsy prompt for PSA
Yes 350 (23%) 154 (31%) 1.4 (1.07-1.82) 0.01
No 1,167 (77%) 346 (69%) 1.0 (reference)
Biopsy prompt for DRE
Yes 281 (19%) 123(25%) 1.69 (1.30-2.1 <0.0001
No 1,236 (81%) 377 (75%) 1.0 (reference)
High grade on biopsy
Yes 391 (26%) 149 (30%) 1.26 (0.98-1.61) 0.07
No 1,126 (74%) 351 (70%) 1.0 (reference)
*From a multivariable logistic regression model with prostatectomy (yes/no) as the outcome, adjusting for other factors in Table 3.
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family history, White race, a prior negative study biopsy,
and high-grade cancer on biopsy did not have a significant
effect on whether a prostatectomy was done and the results
were available, younger age, PSA at randomization, and
biopsy prompt by PSA or DRE were positively and significantly
associated with having a prostatectomy (Table 3). The
majority of biopsies associated with a prompt by PSA or
DRE (for-cause biopsies) were interim biopsies. It follows,
for interim biopsies, that there was a longer time observed
postdiagnosis to both have a prostatectomy and to observe
and obtain the prostatectomy results.
High-grade cancer prevalence estimates from the analysis
that incorporated the prostatectomy data are 8.2% in the placebo
arm and 6.0% in the finasteride arm (see Fig. 1). This results
in an estimated number of high-grade cancers to be 478
on the finasteride arm and 658 on the placebo arm.
The estimated risk reduction with finasteride for Gleason
≤6 is 34% [RR, 0.66; 95% confidence interval (95% CI), 0.55-
0.80; P ≤ 0.0001] and for Gleason ≥7 is 27% (RR, 0.73; 95%
CI, 0.56-0.96; P = 0.02).
Effect of differential biopsy sensitivity on disease
prevalence
Lastly, we explored what ranges of biopsy sensitivity pairs
would need to be operational to change the original conclusions
of the study with respect to high-grade disease. From
the prostatectomy data, there is evidence that finasteride improves
the biopsy sensitivity, and therefore there is likely
greater sensitivity of biopsy to detect both cancer and highgrade
cancer on the finasteride arm. The most likely cause
of improved sensitivity of biopsy under finasteride is its effect
on prostate volume.
To understand how different sensitivities of prostate biopsy
for detection of prostate cancer and high-grade cancer in men
receiving finasteride or placebo might affect observed rates of
disease, we constructed Table 4 using data from this last analysis.
We used a range of values of biopsy sensitivity from 50%
to 90%. Prevalence estimates are presented for both highgrade
disease detected by biopsy and as determined by prostatectomy.
The prevalence estimates in the first two columns
represent the probability of true high-grade cancer accounting
for biopsy sensitivity to detect high-grade cancer. The second
set of prevalence estimates in the last two columns represent
the true high-grade cancer prevalence accounting for biopsy
sensitivity to detect prostate cancer, using the prostatectomy
data to determine the severity of cancer. It is likely that within
a treatment arm, the sensitivity of biopsy to detect high-grade
cancer versus any cancer is not the same. This table allows an
understanding of how different pairs of sensitivities of biopsy
may affect observed rates of cancer detection. For example, if
Table 4. High-grade cancer prevalence estimates under sensitivity of biopsy to detect cancer
Biopsy sensitivity (%) High grade on biopsy (%) High grade on prostatectomy (%)
Placebo Finasteride Placebo Finasteride
50 8.4 9.6 16.4 12.0
60 7.0 8.0 13.7 10.0
70 6.0 6.9 11.7 8.6
80 5.2 6.0 10.2 7.5
90 4.7 5.39.1 6.7
Fig. 1. Estimated actual fractions of total subjects with
low-grade and high-grade cancer using prostatectomy
data.
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the sensitivity for high-grade prostate cancer is 80% for the finasteride
arm and 70% for the placebo arm, the resulting
actual risk of high-grade disease on biopsy would be 6% for
both, equal to no difference in high-grade prostate cancer prevalence
on biopsy. Alternatively, if the sensitivity for prostate
cancer is 80% in the finasteride arm and 70% for the placebo
arm, taking into account the change in grade anticipated with
prostatectomy, the risk of high-grade disease being truly present
would be 7.5% and 11.7%, respectively, equal to a 36%
reduction in risk of high-grade cancer prevalence with finasteride.
The observed risk ratios estimate the risk reduction in
biopsy-detectable high-grade prostate cancers whereas the
sensitivity-adjusted risk ratios are estimates of the risk reduction
in true high-grade prostate cancer prevalence.
Using these data, Figs. 2 and 3 present the risk ratios under
all pairs of sensitivity of prostate biopsy (for finasteride and
placebo) to detect high-grade cancer. Beginning with Fig. 2,
the reader's attention is directed first to the thicker 45-degree
line, which represents the risk ratios when the sensitivity is the
same under placebo and finasteride. If biopsy sensitivity for
cancer detection in both finasteride and placebo-treated subjects
is presumed equal, from Table 2, one can see that the relative
risk for high-grade disease on biopsy is ∼1.14,
representing the overall 14% higher risk of high-grade prostate
cancer that was estimated if everyone had a biopsy. The
values above this line represent risk estimates where biopsy
has a greater sensitivity for high-grade cancer detection if
the subject is receiving finasteride, whereas the values below
the line represent risk estimates where biopsy has a greater
sensitivity for high-grade cancer detection if the subject is receiving
placebo. The upper shaded region with risk ratio estimates
<1repr esent values where the 95% CI excludes 1 where
we would conclude that finasteride is protective against highgrade
cancer; conversely, the lower shaded region with risk
ratios >1r epresent values for which the conclusion would
be that finasteride increases the risk of high-grade cancer.
The white area represents the region where the 95% CI around
the relative risk estimate includes 1, and we would conclude
that there is no significant difference in high-grade cancer
rates between the treatment arms.
Figure 2 shows that if biopsy sensitivity under finasteride is
greater than under placebo, the risk of high-grade disease on
finasteride is either not different from or less than the risk of
high-grade disease on placebo. More specifically, this figure
shows that small differences in biopsy sensitivity between
the treatment arms could explain the observed increased risk
of high-grade cancer with finasteride.
Figure 3 presents the risk ratio estimates of high-grade disease
under various values of sensitivity of biopsy to detect
cancer incorporating the prostatectomy data to account for
differential misclassification of grade. As in Fig. 2, the white
area represents the region where the 95% CI around the relative
risk estimate includes 1and the upper shaded region represents
the values of placebo biopsy sensitivity and
finasteride biopsy sensitivity where finasteride reduces the
risk of high-grade cancer. There are no pairs of biopsy sensitivity
values between 50% and 100% where the conclusion
would be an increased risk of high-grade prostate cancer with
finasteride. Of note, a conclusion that there is an increased risk
of high-grade disease with finasteride only occurs if biopsy
sensitivity were >85% on the placebo arm and 25% to 30%
in the finasteride arm, values strongly contradicted by the observed
prostatectomy data.
Discussion
Although finasteride significantly reduced the risk of prostate
cancer in the PCPT (by 25% in the initial report), it was not
generally accepted for prostate cancer prevention because of
the observed higher risk of high-grade tumors. Since the original
PCPT report in 2003, investigators have uncovered the
Fig. 2. Risk ratios for high-grade prostate
cancer under imperfect sensitivity of biopsy
to detect high-grade cancer with placebo
and finasteride.
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following biases in cancer detection caused by finasteride: a
shift in the receiver operating characteristics curve of PSA, enhanced
detection of overall and high-grade prostate cancer,
and increased sensitivity of DRE for cancer detection and increased
sensitivity of biopsy for high-grade cancer detection,
all of which were statistically significant (6–. These three
biases of finasteride were accompanied by a greater likelihood
of biopsy in the PCPT placebo group, a placebo bias.
The present analyses systematically controlled for these and
other factors in estimating the true rate of cancer in the two
study groups. Multiple factors, including baseline and annual-
visit characteristics of participants, significantly influenced
whether a man underwent the end-of-study biopsy
required by the PCPT primary end point. Older age and finasteride
lowered the likelihood of biopsy; race (White), family
history of prostate cancer, and an interim prostate biopsy recommendation
increased biopsy likelihood.
Our first analysis incorporated adjustments for all of the
aforementioned biases in showing that the biopsy cancer detection
rates in the entire PCPT population (15,990 men)
would have been similar, albeit slightly lower, than were observed
in the 10,182 men who actually had an end point determination
(Table 2). Estimated overall prostate cancer rates
were 14.7% (finasteride) and 21.1% (placebo) in the entire population
and 16.6% (finasteride) and 22.9% (placebo) in men
with actual end points. High-grade prostate cancer estimates
were 4.8% (finasteride) and 4.2% (placebo) in the entire population
and 5.8% (finasteride) and 4.8% (placebo) in men
with actual endpoints. Whole estimates of prostate cancer
prevalence were not substantially different from the observed
data, accounting for PSA and DRE biases did result in a
now-significant estimate of increased risk of high grade disease
with finasteride.
The second analysis incorporated the finding of the increased
sensitivity of biopsy for detecting high-grade prostate
cancer in finasteride-treated men diagnosed with cancer. We
extended the changes from biopsy grade (of prostate cancer)
to prostatectomy grade (calculated in the subset of men who
had a prostatectomy) to the entire PCPT population. The resulting
rates, or “true” rates, of high-grade disease in this analysis
were 8.2% (placebo) and 6.0% (finasteride), a 27% relative
risk reduction. This outcome suggests that it was highly unlikely
that finasteride actually increased the risk of high-grade
cancer in the PCPT (Fig. 1).
The third and final analysis incorporated biopsy sensitivity
across a range of plausible values. Biopsy sensitivity for high
grade disease is lower under placebo than under finasteride, as
has been shown previously (. As shown in Fig. 2 and Table 4,
different ranges of biopsy sensitivity for high-grade cancer
resulted in either a null or a reduced relative risk in the finasteride
group for high-grade cancer. Limiting the analysis to
gleason grade 8-10, prevalence estimates were 0.8 % in the
placebo arm and 1.0% in the finasteride arm, a clinically insignificant
difference and imprecise given very small numbers of
cases. This analysis shows how small differences in biopsy sensitivity
between the study arms could result in the apparent
finasteride-associated increase in high grades on biopsy that
was reported in 2003 (4).
Limitations of these analyses include an imprecision of the
27% reduction in high-grade cancer risk because of the relatively
small numbers of high-grade cancers in the PCPT, assumptions
that the weights were modeled correctly and
included all relevant information, and assumptions that all
study participants diagnosed with cancer could have had a
prostatectomy. It should be noted, however, that confounding
factors would only have an effect if they related to having
both an end point and prostate cancer. A major limitation of
all estimates is inherent with the prostate biopsy itself, which
only samples the prostate. The majority of PCPT men had a
six-core biopsy, which would be expected to have missed
Fig. 3. Risk ratios for sensitivity to biopsy
incorporating the prostatectomy data.
Finasteride Does Not Increase Prostate Cancer Risk
www.aacrjournals.org OF7 Cancer Prev Res 2008; Online First 2008
many cancers that would have been detected with currently
more standard 10- to 12-core biopsies. The advantage of the
six-core biopsy, however, was in detecting cancers that were
more likely to be clinically significant (versus detection with
10- to 12-core biopsies).
A complex set of factors bear upon the recommendation
and decision to take finasteride or virtually any other cancer
preventive agent. Important factors in the finasteride recommendation/
decision include the general burden of prostate
cancer, clinical significance of the prevented cancers, and
drug benefit-risk ratio. Consideration of each of these factors
tends to throw a favorable light on finasteride prevention of
prostate cancer. First, prostate cancer has a substantial medical,
emotional, and financial burden, especially with its frequency
of detection in the atmosphere of a strong emphasis
on screening in the United States. Second, the prevented cancers
in the PCPT have been evaluated for, and found to have,
a substantial proportion of clinically significant tumors (15).
Even men with less consequential low-grade prostate cancers
frequently seek and receive treatment. This treatment has the
consequences of high expenses, risk of sexual, urinary, and
bowel side effects, and an emotional toll on patients and families
from lifetime follow-up surveillance for prostate cancer
recurrence (16).
The last consideration, and most relevant to the debate
about finasteride prevention, is the benefit-risk ratio of
the agent. Men must weigh the established benefits of a
25% reduction in prostate cancer (estimated to be 30% in
the present analysis), decreased urinary symptoms, and decreased
complications of an enlarged prostate against the
established side effects, which include reduced sexual function.
We found no evidence that finasteride increased the
risk of high-grade prostate cancer in the PCPT. Therefore,
we conclude that men 55 years or older have no need to
be concerned about an increased risk of high-grade prostate
cancer with finasteride.
Disclosure of Potential Conflicts of Interest
P.J. Goodman: GlaxoSmithKline consultant; M.S. Lucia: GlaxoSmithKline
consultant and commercial research grant; C.A. Coltman: Seno Medical consultant;
I.M. Thompson: Veridex consultant? The other authors declared no potential
conflicts.
Acknowledgments
This work benefited from many helpful discussions with Bryan Shepherd and
Donna Pauler Ankerst while working on “Does finasteride affect risk and severity
of prostate cancer? A causal sensitivity analysis” by Shepherd, Redman, and
Ankerst; Journal of the American Statistical Association (In press).
References
1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun
MJ. Cancer statistics, 2007. CA Cancer J Clin
2007;57:43–66.
2. Gohagan JK, Prorok PC, Hayes RB, et al. The
Prostate, Lung, Colorectal and Ovarian (PLCO)
Cancer Screening Trial of the National Cancer Institute:
history, organization, and status. Control Clin
Trials 2000;21:251–72S.
3. de Koning HJ, Auvinen A, Berenguer Sanchez A,
et al. Large-scale randomized prostate cancer
screening trials: program performances in the European
Randomized Screening for Prostate Cancer
trial and the Prostate, Lung, Colorectal and Ovary
Cancer trial. Int J Cancer 2002;97:237–44.
4. Thompson IM, Goodman PJ, Tangen CM, et al.
The influence of finasteride on the development of
prostate cancer. N Engl J Med 2003;349:215–24.
5. Scardino PT. The prevention of prostate cancer—
the dilemma continues. N Engl J Med 2003;349:
297–9.
6. Thompson IM, Chi C, Ankerst DP, et al. Effect of
finasteride on the sensitivity of PSA for detecting
prostate cancer. J Natl Cancer Inst 2006;98:
1128–33.
7. Thompson IM, Tangen CM, Goodman PJ, et al.
Finasteride improves the sensitivity of digital rectal
examination for prostate cancer detection. J Urol
2007;177:1749–52.
8. Lucia MS, Epstein JI, Goodman PJ, et al. Finasteride
and high-grade prostate cancer in the Prostate
Cancer Prevention Trial. J Natl Cancer Inst 2007;
99:1375–83.
9. Goodman PJ, Thompson IM, Tangen CM, Crowley
JJ, Ford LG, Coltman CA, Jr. The Prostate Cancer
Prevention Trial: design, biases, and interpretation
of study results. J Urol 2006;175:2234–42.
10. Goodman PJ, Tangen CM, Crowley JJ, et al.
Implementation of the Prostate Cancer Prevention
Trial (PCPT). Control Clin Trials 2004;25:
203–22.
11. Rubin DB. Inference and missing data. Biometrika
1976;63:581–92.
12. Robins JM, Rotnitzky A, Jewell N, Dietz K,
Farewell V. Recovery of information and adjustment
for dependent censoring using surrogate markers.
AIDS epidemiology—methodological issues 1992.
Boston (MA): Birkhäuser 297–331.
13. Magder LS, Hughes JP. Logistic regression
when the outcome is measured with uncertainty.
Am J Epidemiol 1997;146:195–203.
14. Lucia MS, Darke AK, Goodman PJ, et al. Pathologic
characteristics of cancers detected in the
Prostate Cancer Prevention Trial: implications for
prostate cancer detection and chemoprevention.
Cancer Prev Res 2008. In press.
15. Moinpour CM, Darke AK, Donaldson GW, et al.
Longitudinal analysis of sexual function reported
by men in the Prostate Cancer Prevention Trial.
J Natl Cancer Inst 2007;99:1025–35Epub 2007
Jun 27.
Cancer Prevention Research
Cancer Prev Res 2008; Online First 2008 OF8 www.aacrjournals.org |
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