ORLANDOHigher baseline PSA and rapid PSA doubling time (PSADT)
are adversely associated with bone metastasis and death in patients with
castrate nonmetastatic prostate cancer, according to a study presented at the
2005 Multidisciplinary Prostate Cancer Symposium (abstract 268).
Matthew R. Smith, MD, PhD, assistant professor of medicine,
Harvard Medical School, studied the natural progression of castrate
nonmetastatic prostate cancer. He found that high baseline PSA and the rate of
PSA rise were key factors in determining which men receiving hormonal therapy
will likely experience metastasis. Dr. Smith said these indicators appear to
provide a reliable way to help estimate risk and the need for additional
Routine early use of hormonal therapy, before metastasis,
has become more common. More than half a million American men are treated with
androgen-deprivation therapy each year, Dr. Smith said. "While hormone therapy
works, the disease inevitably progresses," he said.
Dr. Smith and his colleagues attempted to describe the
disease state and look for predictors of clinical outcomes. They studied 201
placebo-control subjects from an aborted randomized, controlled trial that was
to evaluate the effects of zoledronic acid (Zometa) on time to first bone
metastasis. All of the men had rising PSA levels despite androgen-deprivation
The patients’ median age was 73 years. About 7 years had
passed since their prostate cancer diagnosis. At diagnosis, 29% of the men had
Gleason scores of 8 to 10. Seventeen percent were lymph-node positive. About
one-third of patients had received a prostatectomy.
Median PSA at the start of the study was 13.8 ng/mL and
doubling time was 9.7 months. Patients received a bone scan every 4 months
throughout the study. Median time to bone metastasis or death was 2.5 years.
"At 2 years, only one-third of patients had developed bone
metastasis," Dr. Smith said. "The event rate was far lower than expected at the
2-year time point."
The researchers conducted Cox regression analysis to assess
which clinical features predicted adverse outcomes. They assessed baseline PSA,
PSA velocity (doubling time), prior prostatectomy, Gleason grade at diagnosis,
node positivity, and time since diagnosis.
"Only two covariates consistently predicted clinical
outcomes, and those were baseline PSA greater than 10 ng/mL and PSA velocity,
which was analyzed as a continuous variable," Dr. Smith said. "They were very
robust predictors of bone-metastasis-free survival, as well as overall survival
and time to first bone metastasis."
In patients with PSA levels greater than 24 ng/mL, 70%
experienced metastasis or death at 2 years, while only 25% of men with a PSA
below 7.7 ng/mL had bone metastasis or died. Similarly, in men with slow PSA
doubling time, greater than 18.8 months, 80% were alive and free of metastasis
at 2 years, whereas only 25% of men with a PSA doubling time of less than 6.3
months were alive and free of cancer spread at that endpoint.
"From this body of data, we conclude that castrate
nonmetastatic prostate cancer has a relatively indolent natural history," Dr.
Smith said. "PSA and PSA velocity independently predict time to first bone
metastasis, bone-metastasis-free survival, and overall survival." He concluded
that risk stratification with PSA and PSA volicity "may facilitate the design
of future clinical trials."