HOUSTON, July 7 -- Treatment-induced prostate shrinkage likely unmasked
high-grade cancers, resulting in a detection bias in the finasteride (Proscar/Propecia)
arm of the Prostate Cancer Prevention Trial (PCPT), data from a large patient
series suggest.
The value of prostate specific antigen (PSA) as a marker for prostate cancer
declined steadily as prostate volume increased. A similar inverse relationship
existed for high-grade cancer, Christopher S. Elliott, MD, of Stanford
University, and colleagues reported in the July 15 issue of Clinical Cancer
Research.
"Decreases in prostate volume over time and the resultant change in
prostate-specific antigen performance characteristics may have contributed a
bias toward the detection of high-grade disease in the finasteride arm of the
Prostate Cancer Prevention Trial," the authors concluded.
The observations could explain why the increased risk of high-grade cancer in
the finasteride arm was limited to the subgroup of men who had symptom-driven
biopsies during the trial, they added. The findings also are consistent with
those from analyses that PCPT investigators have performed in the six years
since the trial ended.
The PCPT involved 19,000 healthy men who were randomized to finasteride or
placebo for seven years. The principal finding was a 25% reduction in prostate
cancer incidence in the finasteride arm.
However, the beneficial effect has been overshadowed by the finding that
finasteride-treated men had a small but statistically significant increase in
the rate of high-grade cancer compared with the placebo group.
Closer examination of the PCPT data revealed inconsistencies in the occurrence
of high-grade cancer. Specifically, the increase was limited to men who had
"for-cause" biopsies, triggered by an abnormal digital rectal exam (DRE) or a
rise in PSA. End-of-study biopsies showed an almost-identical incidence of
high-grade cancer in the two treatment arms.
Prostate volume at the time of biopsy was 25% lower in the finasteride arm (25.5
cm3 versus 33.6 cm3), the authors noted.
Dr. Elliott and colleagues hypothesized that the increased rate of high-grade
cancer in the finasteride arm resulted from the drug's volume-reducing effect on
the prostate. The shrinkage could have improved PSA's performance
characteristics for detecting prostate cancer.
To test their hypothesis, investigators retrospectively reviewed records on
1,304 men referred for an initial prostate biopsy. The referrals were prompted
by a PSA value of 4 to 10 ng/mL or an abnormal digital rectal exam.
The study group had a median age of 66, median prostate volume of 42.9 cm3, and
median PSA value of 5.5 ng/mL. Digital rectal exam was abnormal in 507 (38.9%).
The investigators calculated receiver-operator curves and positive predictive
values for PSA, stratified by diagnosis and prostate volume.
For detection of any cancer, the area under the curve (AUC) decreased from 0.758
to 0.520 as prostate volume increased from <30 cm3 to >50 cm3. For detection of
high-grade cancer, AUC decreased from 0.712 to 0.497 as organ volume increased.
A similar pattern emerged from calculations of positive predictive values.
For a prostate volume <30 cm3, the positive predictive value of a PSA of ≥4 ng/mL
was 25%, declining to 17.3% for a prostate volume >50 cm3. The differences
increased for detection of high-grade cancer: 39% for a prostate volume <30 cm3
versus 10.7% for a volume >50 cm3.
Continued analysis of PCPT data has led to similar conclusions regarding the
relationships among finasteride, prostate volume, and PSA performance
characteristics for detection of prostate cancer, PCPT investigator Catherine
Tangen, DrPH, of the Fred Hutchinson Cancer Research Center in Seattle, said in
a statement.
Collectively, the data suggest that men should be offered finasteride, if they
and their physicians agree that chemoprevention might be beneficial, she added.
Earlier this year, the American Society of Clinical Oncology and the American
Urological Association recommended that healthy men ages 55 and older and with
no signs of prostate cancer talk to their physicians about taking a 5-alpha
reductase inhibitor to prevent prostate cancer.
Primary source: Clinical Cancer Research
