Merrick_edit.qxp 26/11/08 03:00 Page 56
Prostate Cancer
Figure 1: Overall Survival for Radical Prostatectomy, External-beam
considered inadequate by today’s standards. As such, debate surrounds
Radiation, and Brachytherapy, Stratified by Androgen-deprivation
the role of androgen suppression with higher doses of radiation and a
Therapy Status
suggestion that ADT was simply compensating for inadequate doses.
There are retrospective data suggesting that the benefit of escalated
100
doses is greater than the addition of ADT to conventional doses and, as
such, ADT cannot replace radiation dose.
20
However, to date there has
80
been no survival benefit shown with dose escalation; therefore, one
could argue that even with increasing radiation doses ADT may still
confer an additional benefit in highly selected patients. This remains to
60 be answered in a randomized trial.
Androgen-deprivation Therapy and Brachytherapy
40
The use of prostate seed brachytherapy has historically been reserved for
EORTC 22863:
1
EBRT alone
low- to intermediate-risk prostate cancer, as early outcomes of high-risk
EORTC 22863:
1
EBRT + ADT
Merrick brachytherapy series:
23
RT alone
disease treated with brachytherapy were poor.
21
However, this was prior to
20
Merrick brachytherapy series:
23
RT + ADT
the era of rigorous dosimetric cut-points and coverage of peri-prostatic
German RP series:
32
RP alone
German RP series:
32
RP + ADT tissue. Numerous modern series from high-volume institutions have now
0
demonstrated superior control rates with the use of brachytherapy.
22–24
The
02468 10 12
Time (years)
more favorable disease profile of high-risk brachytherapy series compared
with EBRT studies must be borne in mind: in the largest series average
EORTC = European Organization for Research and Treatment of Cancer; EBRT = external-
Gleason scores were 7–8 and PSA was 12–15ng/ml.
23,25
ADT is commonly
beam radiotherapy; ADT = androgen deprivation therapy; RT = radiation therapy; used prior to brachytherapy for the purpose of reducing prostate size to
RP = radical prostatectomy.
improve the technical feasibility and side effect profile; however, it is not
routinely used for the purpose of achieving better tumor control. There has
Androgen-deprivation Therapy and been no randomized trial investigating the impact of ADT on outcomes in
External-beam Radiotherapy conjunction with brachytherapy; therefore, we currently rely on
Numerous phase III randomized trials have been completed investigating retrospective series to guide management.
the role of ADT with EBRT in high-risk patients (see Table 1). Three trials
demonstrated an OS benefit and all studies found an improvement in Merrick et al. reported 204 high-risk patients treated with pelvic EBRT
prostate cancer mortality; these trials form the basis for the current standard followed by brachytherapy and found that men treated with ADT had a
use of ADT in the high-risk setting. One of the landmark studies was a significant improvement in biochemical control, with 10-year biochemical
European collaborative trial that randomized 415 patients with high-grade progression-free survival (PFS) of 80% in hormone-naïve patients
and/or T3–4 prostate cancer to EBRT alone or EBRT plus concurrent and compared with 90–95% in patients who received ADT.
23
This provides
adjuvant ADT for three years.
1
At five years, there was a 26% statistically some evidence that even with ablative radiation dose to the prostate, it
significant OS benefit in patients who received hormone therapy. Recent may still be beneficial to use ADT in high-risk disease. There was no
important updates of two Radiation Therapy Oncology Group (RTOG) difference in cause-specific survival (CSS) or OS, although with long-term
studies provided 10-year outcomes that remarkably also showed CSS rates greater than 90% it would likely require a large sample size to
improvement in OS of 26%.
13,14
Given that it has been 10–20 years since the detect a difference. A published series of intermediate- to high-risk
inception of these trials, it is important to note the changes in practice over patients treated at Mount Sinai also showed an improvement in
this period in order to appropriately apply these data to current times. First, biochemical control with the addition of neoadjuvant and adjuvant ADT.
with the exception of one,
15
these studies primarily used clinical staging as Five-year freedom from biochemical failure (FBF) for high-risk patients was
eligibility criteria and represent a more locally advanced group than what is 74% with ADT versus a dismal 46% without.
25
However, there was no
diagnosed today as high-risk. For example, in the European Organization for difference among all patients who received a good-quality implant with a
Research and Treatment of Cancer (EORTC) trial, 91% of patients had five-year FBF of 80% with or without ADT, whereas in patients who
T3–T4 tumors and 33% had PSA >40ng/ml;
1
however, this is not a common received a low-dose implant the five-year FBF was 79 versus 38%
presentation today. A more typical high-risk patient of the current era with (p=0.0037). Based on disease risk to assess the impact of both dose and
a moderately elevated PSA, normal digital rectal exam, and a Gleason score androgen suppression specifically in high-risk patients, the patients were
of 8 formed the minority of the historic trials. In the setting of gross tumor not subdivided further; however, in high-risk patients who received both
and higher disease burden seen in earlier studies, ADT likely played a more ADT and a high-dose implant the reported four-year FBF was 77%. In a
critical role, as EBRT alone compared with conventional doses without multivariate analysis, ADT use was the most significant predictor of
image guidance was likely to be insufficient. biochemical control in both the high-risk patients and the low-dose group.
A recent multicenter analysis investigating the impact of radiation doses
The second major change in the landscape of prostate cancer is that in noted a significant improvement in five-year biochemical control with ADT
recent years a number of dose escalation trials have shown improvement from 77.5 to 96% (p=0.001) in patients who received high-dose
in biochemical control rates with doses greater than 70Gy
16–19
and, as a implants.
26
Longer follow-up is necessary to confirm these results and allow
result, the radiation doses of 65–70Gy utilized in all of the ADT trials are for the restoration of testosterone levels.
56 US ONCOLOGY
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