Treatment with the dual 5-alpha- reductase inhibitor dutasteride (Avodart) does not compromise the utility of PSA to detect progression of disease in patients with low-risk localized prostate cancer who are being managed with active surveillance.
That finding comes from an examination of serial PSA measurements relative to prostate cancer progression in men who participated in the REDEEM (Reduction by Dutasteride of Clinical Progression Events in Expectant Management) study, and was presented by Neil Fleshner, MD, MPH, at the AUA annual meeting in Atlanta.
In REDEEM, men with low-risk (T1c-T2a), Gleason 5-6 prostate cancer followed with active surveillance were randomized to dutasteride, 0.5 mg/day, or placebo for 3 years. To be eligible, men had to have a life expectancy greater than 5 years.
Serum PSA was measured at baseline and every 3 months for the first year and every 6 months thereafter. The area under the receiver operating characteristic curve (AUC) was calculated using the final PSA and the change from PSA nadir to final PSA with the goal of detecting pathologic progression and Gleason score >6 progression. For patients with disease progression, the final PSA was the last PSA value prior to progression. Pathologic progression was defined by at least one of the following: four or more cores involved, ≥50% of any one core involved, or a Gleason pattern ≥4.
Some 276 patients had at least one biopsy during the 3-year study: 81 had no cancer on final biopsy, 100 had favorable-risk cancer (Gleason score 6 and no pathologic progression), and 95 had pathologic progression. Of the 95 with pathologic progression, 54 had Gleason score 6 with pathologic progression and 41 had Gleason score progression.
In the placebo group, patients who had Gleason grade progression had a rise in PSA over the 3 years of the study, said Dr. Fleshner, head of urology at the University Health Network, Toronto, and the Love Chair in Prostate Cancer Prevention at the Princess Margaret Hospital in Toronto. Placebo recipients who maintained a Gleason grade 6 with or without pathologic progression and those with no cancer had relatively stable PSA values over time.
Among the group randomized to dutasteride, "Patients who had Gleason score progression, at about month 12, started to get on average, an escape in their PSA," he said. "Patients with either no cancer, Gleason 6 with no pathological progression, or Gleason 6 with pathological progression had fairly similar outcomes."
AUC not statistically different
The AUC was higher but not statistically different between the dutasteride group and the placebo group using final PSA (0.689 vs. 0.599; p=.19) and using the change from nadir PSA (0.614 vs. 0.566; p=.51) for any pathologic progression.
For the outcome of any Gleason score >6, the AUC for the dutasteride group using the final PSA was 0.759 versus 0.668 for the placebo group (p=.34), and the AUC for the change from nadir PSA was 0.701 in dutasteride recipients versus 0.674 in placebo recipients (p=.79).
Among the dutasteride recipients, an increase in PSA level of 1.0 ng/mL above nadir (to final PSA) had a specificity of 85.6% for the occurrence of pathologic progression but would miss about 63% of those with pathologic progression. Among the placebo group, the sensitivity and specificity (for pathologic progression) of a rise in PSA of 1.0 ng/mL were each about 50%.
"At the individual patient level, these data, in my view, are a little bit disappointing, and would suggest that you would still have to do biopsies," Dr. Fleshner said.
The median PSA increase from nadir to final PSA was 0.1 ng/mL in those with no cancer, 0.3 ng/mL in those with Gleason score 6 without pathologic progression, 0.6 ng/mL in those with Gleason score 6 with pathologic progression, and 1.2 ng/mL in those with Gleason score >6.
"Patients who are followed by surveillance, if they're on dutasteride, should have a new baseline PSA established at about 6 months [after treatment], and any changes above 0.5 ng/mL should be looked at very carefully and with concern," said Dr. Fleshner.
Dr. Fleshner is an adviser for and receives honoraria/research funding from GlaxoSmithKline, and one of the study co-authors is an employee of GlaxoSmithKline.