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PSADT Predicts Survival After Biochemical
Relapse Following Primary Therapy
(August 2005)
Prostate-Specific Antigen doubling time (PSADT) has emerged
as a strong independent predictor of risk of disease recurrence after
primary therapy and prostate cancer specific survival. Application of this
information can be useful in decisions about the timing of therapeutic
interventions with chemotherapy and/or androgen deprivation for patients
with a high risk of disease progression. Additionally, PSADT needs to be
incorporated into the stratification schema of clinical trials, since
categorization by PSADT has often been found to better explain outcome
results than the effects of the different treatments under comparison.
An early review of this topic was presented by Walch,
Partin and Pound in UROLOGY 62 (Suppl 6B), 2003: “Prostate-specific
antigen doubling time in the identification of patients at risk for
progression after treatment and biochemical recurrence for [clinically
localized] prostate cancer”. They studied 304 men post surgery who were
followed without additional therapy after relapsing with a PSA value of >
0.2 ng/mL and analyzed for metastatic disease. At 5 and 10 years after
relapse 50% and 75% respectively of those whose PSADT was faster than 10
months developed clinical metastasis, respectively, compared to 15% and
55% for those with PSADT > 10 months (P <0.001). They argued that the
calculation of the doubling time based on only the first two PSA values
(separated by at least 3 months) after progression [less than the three or
four values that are considered optimal] “provided useful information 6 to
12 months sooner in the course of recurrent disease” allowing an earlier
decision regarding intervention. “The actuarial systemic progression-free
survival for patients with a PSADT of >0.5 year, 0.5 to 1.0 years, 1 to
9.9 years, and > 10 years was 64% + 12%, 93% + 12%,
95% + 3%, and 99% + 1%, respectively.” On multivariate
analysis PSADT was the “sole factor in prediction of the likelihood of
systemic progression after biochemical recurrence”, although on univariate
analysis the Gleason score was also significant.
A succinct review of this issue in Clinical Prostate
Cancer, March 2003, confirmed the predictive correlation between PSADT and
clinical failure. In a group of 1289 men with post RP biochemical failure
(set as PSA > 0.4 ng/mL), a PSADT of greater or less than 12 months was
the “only factor with significant association with clinical failure (P
<0.0001), e.g.: approximately 80% of men were free from clinical
recurrence at 5 years for a PSADT of longer than 12 months compared to
about 60% for PSADT less than12 months.
Several ASCO abstracts from the 2004 and 2005 meetings
addressed PSADT as a predictor of prostate cancer-specific survival (PCSS):
1) In #4555 (2004) Walsh, Partin et al. reported that in
825 men post RP whose PSA values exceeded 0.2 ng/mL the PCSS was 98% and
85% at 5 and 10 years for PSADT longer than 10 months and 90% and 47% for
a shorter PSADT.
2) In #4549 (2005) Sandler, Shipley et al. analyzed the
PSADT values for 1514 men with T2C-T4 PC and PSA <150 ng/mL in the RTOG
protocol 92-02, which compared EBRT with and without androgen deprivation.
A PSADT of < 12 months was a surrogate endpoint for prostate cancer
specific mortality, and importantly, categorizing outcomes as to PSADT <
or > 12 months better predicted survival outcome than
whether androgen deprivation was or was not given (RR 6.17 for PSADT < 12
months vs longer compared to a RR of 1.59 for AD vs. no AD)
3) In #4546 (2005) Partin, Walsh, Eisenberger et al.
analyzed cancer-specific mortality in 5096 men post surgery for localized
PC with a median follow-up of 10.3 years after BCR. They presented a table
integrating three predictors: PSADT ( > 15, 9.0-14.9, 3.0-8.9, and
< 3 months), BCR before or after 3 years following RP, and Gleason sum <
or > 8. The 15 year survival for any combination was distinctly
worse if it included a PSADT of less than 8.9 years. Example: the 15 year
survival was 86% for the favorable combination of PSADT 9.0-14.9, combined
with BCR of > 3 years and Gleason < 8. But in this example by changing
only the value of PSADT to 3.0- 8.9 survival fell to 59%, and fell further
to 19% when the PSADT value was faster than 3 months.
4) In #4548 D’Amico et al. reported the now well known data
that prostate cancer-specific mortality (PCSM) at 5 years following RP or
RT in men with a PSADT of < 3 months was significantly worse (P = 0.0001)
than those with longer doubling times, particularly if the Gleason score
was > 8: 31% for those with PSADT > 3 months compared to 1%
for those at PSADT less than 3 months. For men post RT with both PSADT
less than 3 months and Gleason score 8 or greater the PCSM at 5
years was 75% vs. 35% for those with PSADT > 3 months and Gleason score
< 7. They suggested this data would help identify men who might
benefit from additional therapy.
The aggregate implication from all these
studies suggests that a significant decrement takes place in the prognoses
for metastases-free survival and overall survival at the breakpoint of a
PSADT of less that 10 to 12 months. The relevant question is whether
intervention based on this awareness alters outcome.
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