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Integrating Hormonal Therapy With External-Beam Radiation and Brachytherapy for Prostate Cancer

Integrating Hormonal Therapy With External-Beam Radiation and Brachytherapy for Prostate Cancer

ABSTRACT: The use of hormonal therapy with external-beam radiation (EBRT) to treat prostate cancer is a topic that has been well explored. The potential use of hormonal therapy and brachytherapy in the treatment of prostate cancer, however, continues to be controversial. This review is based on our current interpretation of the available literature assessing the outcomes of patients treated with EBRT and brachytherapy with or without hormonal therapy. Extrapolating from the findings of the Radiation Therapy Oncology Group (RTOG) 9413 trial, there appears to be a favorable interaction between hormonal therapy and irradiation in the lymph nodes. The benefits demonstrated with whole-pelvic EBRT and hormonal therapy are likely to extend to patients treated with brachytherapy as well. Studies suggest that the role of hormonal therapy in brachytherapy is limited without the application of wholepelvic EBRT due to the inability of brachytherapy to address potential lymph nodes at risk. The potential role of hormonal therapy in conjunction with brachytherapy without pelvic radiotherapy, is limited by inconclusive data and abbreviated follow-up times.

The role of hormonal therapy in
the management of clinically
localized prostate cancer is controversial.
Extensive questions remain
about how to implement hormonal
therapy and what would be considered
optimal. Part of the confusion
comes from the different roles that
the urologist and radiation oncologist
play, both independently and when
treating the disease as a team. It is a
fair statement to suggest that, at times,
different schools of thought affect how
patients are ultimately treated. To
close this theoretical gap, it is best to
rely on prospective randomized studies
and extrapolate applicable data as
needed.

In early randomized surgical series
reported by Labrie et al,[1] patients
were treated with several months
of neoadjuvant and concurrent hormonal
therapy prior to radical prostatectomy.
This series showed an
approximate 90% response rate, defined
as decreasing the size of both
the prostate and the tumor. More recent
series, such as those reported by
Soloway et al[2] and Aus et al,[3]
randomized patients to radical prostatectomy
vs neoadjuvant hormonal
therapy plus radical prostatectomy.
These studies demonstrated a statistically
significant decrease in the incidence
of extracapsular extension and
positive surgical margins.

Neoadjuvant hormonal therapy did
not, however, improve freedom from
biochemical failure or survival at
5 years. In contrast, intermediate- and
high-risk patients who have received
hormonal therapy and external-beam
radiotherapy (EBRT) appeared to benefit
when compared to the same patients
treated with EBRT alone. A
good explanation for the benefit of
neoadjuvant hormonal therapy in the
setting of EBRT but not radical prostatectomy
has only recently become
clear and will be discussed.

Several prospective randomized
studies addressed the role of neoadjuvant
and adjuvant hormonal therapy
with EBRT. These trials have shown
an improvement in local control, disease-
free survival, and overall survival.
The role of hormonal therapy and
permanent prostate implants is less
established. Before discussing hormonal
therapy plus permanent prostate
implants, it is essential to establish
which prostate patients benefit
from hormonal therapy. The role of
hormonal therapy and EBRT will be
discussed initially as a springboard
for how hormonal therapy should be
applied in conjunction with permanent
prostate implants.

What Is the Role of
Hormonal Therapy in
Patients Receiving EBRT?

Based on the Radiation Therapy
Oncology Group (RTOG) 8610[4] and
9202[5] trials, different subpopulations
of patients have emerged as
groups likely to benefit from short- and
long-term hormonal therapy. RTOG
8610 included patients with locally
advanced bulky prostate cancer who
were evaluated for the benefit of neoadjuvant
hormonal therapy and EBRT
or EBRT alone. RTOG 9202 assessed
4 months of neoadjuvant hormonal
therapy with or without 2 years of adjuvant
hormonal therapy. The results
of these studies and other phase III prospective
randomized studies have led
to answers to classic questions addressing
whether there is a biologic interaction
between hormonal therapy and
EBRT, the timing of hormonal therapy,
the optimal duration of hormonal
therapy, and the volume to be irradiated.
It is now clear that the benefits
experienced by different subgroups receiving
short- or long-term hormonal
therapy appear to depend on the risk
that patients have for dying of prostate
cancer.

Defining Risk of Death
From Prostate Cancer

Randomized studies have shown
that patients with low-risk disease do
not benefit from hormonal therapy,
whereas patients with intermediateand
high-risk disease do. Although
most experts would agree on how to
define low risk (T1-2, Gleason score
[GS] < 6, and prostate-specific antigen
[PSA] values < 10-20 ng/mL), how to
define intermediate- and high-risk subgroups
remains controversial. Several
classification schemes are employed
by physicians across the country. The
rationale for using a risk-group classification
scheme is that it can help to
determine prognosis. Ideally, such a
scheme should help determine which
patients are appropriate candidates for
a particular type of therapy. Different
institutions subscribe to different riskgroup
stratification, but most of the
commonly used schemes do not provide
insights into how patients should
be selected for hormonal therapy. An
exception is the RTOG risk-group
scheme, so for the sake of simplicity,
the RTOG risk groups will be used as
a frame of reference.

Table 1 shows the RTOG riskgroup
classification system, which
was developed to predict overall and
disease-specific survival, and has been
validated to predict PSA failure in
contemporary cases.[6,7] Using this
risk-group scheme, the value of hormonal
therapy has been studied in a
meta-analysis. Based on the data, it
appears that low-risk patients did not
benefit from hormonal therapy. Intermediate-
risk patients appeared to benefit
from short-term hormonal therapy,
and high-risk patients (groups 3 and
4) were found to have an overall survival
benefit with the addition of longterm
hormonal therapy.

Is There a Biologic Interaction
Between Hormonal Therapy
and EBRT?

How exactly does hormonal therapy
affect EBRT? In theory, the major
issue in low-risk patients is local control
because such patients are at low
risk for regional disease and at very
low risk for distant disease. Intermediate-
risk patients might benefit from
local and regional control because they
have a significantly higher risk of
lymph node involvement. In contrast,
high-risk patients are at a substantially
greater risk for distant as well as
local regional failure and likely to benefit
from therapy that addresses distant
metastasis.

Mechanism of Interaction
The exact mechanism by which
EBRT and hormonal therapy interact
is not known. Based on assessments
of the prostate itself, it appears that
androgen deprivation induces apoptosis
and thereby reduces the number
of tumor cells. The technique shifts
cells that are actively dividing into
quiescence.[8] Using the Shionogi
mouse in vivo tumor system, Zietman
et al showed that the dose of radiation
to the tumor plus hormonal therapy
could be halved (Figure 1).[9] Their
study suggested that maximal androgen
suppression prior to radiation was
the most effective strategy for controlling
these implanted tumors.

Based on these in vivo data, most
radiation oncologists assumed that, in
humans, the most favorable interactions
between androgen deprivation
and radiation therapy would be
sequence dependent, with the greatest
response following maximal androgen
suppression. It was assumed
that local control might be achieved
with lower doses of radiation and that
there were synergistic interactions
between hormonal therapy and EBRT.
This concept was supported by the
initial reports of findings from RTOG
8610. However, in vitro data failed to
demonstrate evidence of synergistic
interactions between hormonal therapy
and EBRT. This observation challenged
the notion that we would see
improved local control.[10]

Similarly, recent data suggest that
biopsy status after hormonal therapy
and radiotherapy may not be reliable
end points for predicting outcomes when
neoadjuvant hormonal therapy is added
to EBRT. For example, although Laverdiere
et al[11,12] demonstrated that the
positive biopsy rate was reduced with
9 (vs 3) months of neoadjuvant and
concurrent hormonal therapy, longer
follow-up showed no difference in the
incidence of biochemical failure between
the two treatment arms.

According to other recent data, at
least one type of favorable interaction
between neoadjuvant hormonal
therapy and EBRT occurs in the lymph
nodes. It remains to be determined
whether this has something to do
with the shape of the radiation doseresponse
curve.

This hypothesis is well illustrated
in Figure 1, which shows a plateau of
local control at doses of approximately
80 Gy in animal models. It might be,
for example, that in humans the plateau
of the dose-response curve might
also actually occur at 80 Gy, such that
no additional benefit is seen when hormonal
therapy is added to doses above
this level. If this is the case, however,
a favorable interaction might be observed
in the lymph nodes because the
dose of radiation given is still on
the steep part of the radiation doseresponse
curve at 50 Gy.

An alternative (and the most provocative)
explanation of the apparent
benefits of pelvic radiotherapy is that it
is mediated via a combined hormonal
immunologic mechanism. Space limitations
do not allow this mechanism
to be elaborated on in detail, but suffice
it to say, there are compelling
preliminary supporting data (Roach,
personal communication, 2004).

Optimal Timing of
Hormonal Therapy

Should hormonal therapy be given
adjuvantly or neoadjuvantly? RTOG
9413 was the first phase III prospective
randomized trial to stratify patients
by PSA, Gleason score, and
TNM stage, and to use progressionfree
survival (biochemical failure and
clinical failure) as a primary end point.
Using hormonal therapy in the form
of androgen blockade, the trial randomized
patients to treatment arms
that included whole-pelvic radiotherapy
and neoadjuvant/concurrent
hormonal therapy, prostate-only radiotherapy
and neoadjuvant/concurrent
hormonal therapy, whole-pelvic
radiotherapy plus adjuvant hormonal
therapy, and prostate-only radiotherapy
plus adjuvant hormonal therapy.[
13] RTOG 9413 not only addressed
the timing of hormonal
therapy, it also demonstrated the importance
of whole-pelvic radiotherapy
when using hormonal therapy.

Prostate-only radiotherapy plus
neoadjuant/concurrent hormonal
therapy vs adjuvant hormonal therapy
plus prostate-only radiotherapy
did not show any difference in biologic
interaction, despite the 2-month
advantage in the adjuvant arm (as
time to failure was measured from
the randomization date). This finding
indicates that there is no difference
in the interaction between
neoadjuvant and adjuvant hormonal
therapy with prostate-only radiotherapy.
Whole-pelvic radiotherapy plus
neoadjuant/concurrent hormonal
therapy vs whole-pelvic radiotherapy
plus adjuvant hormonal therapy
also showed a 2-month bias in the
adjuvant arm, but the adjuvant arm
was inferior (Figure 2), proving that
there is a sequence-dependent interaction
that is occurring in the lymph
nodes and not in the prostate.

In Figure 3, with both neoadjuant/
concurrent hormonal therapy curves,
the bias is eliminated and the difference
in the curves is more apparent.
Evaluation of disease progression favored
whole-pelvic radiotherapy plus
neoadjuant/concurrent hormonal therapy.
Assessment of death and PSA
failure demonstrated a trend toward
overall survival benefit, but at this
time follow-up is too short to expect
differences to be apparent.

RTOG 9413 eliminates the freedom
from biologic failure bias seen
in other studies that have compared
patients receiving radiation to those
receiving radiation plus hormonal
therapy. Previously, an inherent bias
was seen in hormonal therapy arms
because there is a delay in the time for
a rise in PSA. In RTOG 9413, all
arms received a similar duration of
hormonal therapy, thereby avoiding
this bias discrepancy in the definition
of PSA failure.

Because of the impact that a rising
testosterone level has on PSA, the
American Society for Therapeutic
Radiology and Oncology (ASTRO)
consensus definition of three consecutive
increases is also problematic.
Of interest, the definition of PSA failure
for RTOG 9413 was very similar
to one of the four definitions shown
to have a higher sensitivity and specificity
than the ASTRO definition.[14]

Optimal Duration of
Hormonal Therapy

Prospective randomized trials such
as the "Bolla Study," RTOG 8531,
and RTOG 9202 demonstrated improved
overall survival using longterm
hormonal therapy in patients with
high-risk disease.[15] RTOG 8610
established the role of neoadjuvant
hormonal therapy in intermediate-risk
patients.[16]

A meta-analysis of RTOG trials[
17] suggested that neoadjuvant
hormonal therapy showed a benefit in
patients with GS7, T1/2 or GS6, T3.
Short-term neoadjuvant hormonal
therapy did not appear to benefit patients
with GS7, T3 or GS8-10; however,
this risk group benefited from
long-term adjuvant hormonal therapy.

Role of Hormonal Therapy With
Permanent Prostate Implants

Controversy surrounds what type
of radiation therapy is most beneficial
for treating prostate cancer, but permanent
prostate implants offer an excellent
strategy in this setting. A
number of earlier studies, including
those by D'Amico et al[18] and Beyer
and Brachman,[19] have concluded
that EBRT is better than permanent
prostate implants when treating intermediate-
or high-risk patients. A study
by King et al[20] compared permanent
prostate implants, radical prostatectomy,
and EBRT, and concluded
that permanent prostate implants and
radical prostatectomy produced superior
results when compared to
EBRT. However, the EBRT dose was
inadequate (66 Gy), and the EBRT
patients were worse candidates at
baseline, compared to patients receiving
the other modalities.

One of the difficulties in interpreting
these studies was the "PSA blip"
seen after permanent prostate implants.
This phenomenon was not well
recognized at the time these studies
were conducted, and many of these
cases may have been mistakenly considered
biochemical failures. First described
in 1997, the "blip" occurred
after brachytherapy in approximately
25% to 30% of patients.[21] That is,
patients were found to have a transient
rise in PSA followed by a decline
(Figure 4). Studies that have biopsied
patients with "PSA blips" have occasionally
found histologic evidence of
cancer on repeat biopsy.[22] However,
it has been well documented that
with further follow-up, positive biopsies
can become negative due to
slow cancer involution.[23]

Previous Retrospective Studies
Before 1995, hormonal therapy was
mostly used for cytoreduction. Investigators
from Memorial Sloan-Kettering
Cancer Center (MSKCC)[24] assessed
the prognostic significance of Gleason
score in patients treated with permanent
prostate implants. They made
treatment distinctions based on Gleason
score to ascertain who were appropriate
candidates for monotherapy
with permanent prostate implants. Patients
with GS 4+3 had significantly
lower 7-year biochemical freedom
from recurrence rates compared to
those with GS 3+4. Unfortunately,
what causes this difference is unclear.
This finding may suggest that with
increasing risk, permanent prostate
implants alone may be inadequate
therapy. Conflicting applicable data
suggest that there may or may not be
a significant benefit to a combination
of EBRT and permanent prostate implants.[
25,26] Perhaps, in theory, this
is a population that would benefit from
adjuvant hormonal therapy.

The MSKCC investigators also
assessed 263 patients between 1992
and 1997 who had prostates weighing
more than 60 g and were given
neoadjuvant hormonal therapy for
cytoreduction (Table 2). A retrospective
matched-pair analysis was unable
to show any benefit with neoadjuvant
hormonal therapy plus permanent
prostate implants, compared
with permanent prostate implants
alone.[27]

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