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Salvage Brachytherapy After External-Beam Irradiation for Prostate Cancer

Salvage Brachytherapy After External-Beam Irradiation for Prostate Cancer

ABSTRACT: The options available for patients with recurrent prostate cancer are limited. Men who have failed external-beam irradiation as the primary treatment are rarely considered for potentially curative salvage therapy. Traditionally, only palliative treatments have been offered with hormonal intervention or simple observation. A significant percentage of these patients have only locally recurrent cancer and are thus candidates for curative salvage therapy. Permanent brachytherapy with iodine-125 or palladium-103 has been used in an attempt to eradicate the remaining prostate cancer and prevent the need for additional intervention. It is critical in this population to identify patients most likely to have distant metastases or who are unlikely to suffer death or morbidity from their recurrence, in order to avoid potential treatment morbidity in those unlikely to benefit from any intervention. Following salvage brachytherapy, up to 98% of these cancers may be locally controlled, and 5-year freedom from second relapse is approximately 50%. With careful case selection, relapse-free rates up to 83% may be achieved. A schema is presented, suggesting that it may be possible to identify the patients most likely to benefit from salvage treatment based on prostate-specific antigen (PSA) kinetics and other features. Such features include histologically confirmed local recurrence, clinical and radiologic evidence of no distant disease, adequate urinary function, age, and overall health indicative of at least a 5- to 10-year life expectancy, prolonged disease-free interval (> 2 years), slow PSA doubling time, Gleason sum ≤ 6, and PSA < 10 ng/mL.

Worldwide, the management
of cancer of the prostate remains
a difficult problem.
Each year close to 190,000 patients in
the United States alone are diagnosed
with prostate cancer.[1] The optimal
initial management of these patients
has been the subject of considerable
debate. Typically, treatment options
including radial prostatectomy, external-
beam irradiation, brachytherapy,
watchful waiting, or hormonal ablation
have been recommended. Individual
decisions are often guided by
consideration of the published and
well documented cancer control rates
and complication risks. Very little has
been published, however, to guide in
the management of locally recurrent
prostate cancer, despite the fact that
25% of patients will receive a secondary
cancer treatment.[2]

Epidemiologic Background

In 1988, roughly half of all newly
diagnosed prostate cancers were locally
advanced or metastatic. Today,
however, close to 80% of prostate cancer
patients present with clinically localized
disease[3] and are candidates
for potentially curative therapy. Recent
estimates from the National Cancer
Data Base[4] and the National Cancer
Institute's Surveillance, Epidemiology,
and End Results (SEER) program[
5] suggest that 30% of presenting
patients are managed initially with
external-beam irradiation. Yet 10% of
low-risk patients, and up to 50% of
high-risk patients, may be expected to
suffer a failure of primary treatment.
Assuming an average case mix, there
may therefore be up to 13,500 patients
presenting annually in the United
States with a recurrence following primary
irradiation.

For many men no further treatment is required, based on their advanced
age or failing health. For others, the
recurrent cancer might have a prolonged
indolent course and not require
further intervention. For those in
whom intervention is recommended,
92% of patients treated secondarily
after radiation failure are managed
with androgen deprivation.[2] However,
many of these patients have local
recurrence as a component of their
disease and might be considered for
further treatment to the prostate. A significant-
though not well documented-
percentage of these patients
can be expected to have only a local
recurrence with no distant disease.
While the number of patients who require
salvage therapy is thus greatly
reduced, it still represents a sizable
and growing group of men.

This review is intended to help address
this potentially significant patient
population and, in particular, to
frame the following important questions:

  • Can we identify patients who
    are most likely to require salvage
    treatment?
  • Can we identify patients who
    are most likely to respond to salvage
    treatment?
  • What is the expected morbidity
    of salvage brachytherapy?
  • What other options should be
    considered?

Can We Identify Patients
Who Are Most Likely to
Require Salvage Treatment?

An American Society for Therapeutic
Radiology and Oncology
(ASTRO) consensus panel acknowledged
in 1997 that some component
of local failure is common in radiotherapy-
treated patients with a rising
prostate-specific antigen (PSA)
level.[6] As a result of this statement,
they suggested a limited role for routine
rebiopsy in patients experiencing
a biochemical recurrence, unless further
local treatments are being contemplated.
Conservative therapy, with
observation or hormonal intervention,
is usually the treatment of choice for
this population, and histologic confirmation
offers little benefit. However,
for the occasional patient being considered
for a potentially aggressive
local therapy, it seems prudent to require
biopsy confirmation of prostatic
recurrence as a minimum requirement
for local intervention.

As with men evaluated for primary
treatment, the age and overall health
of the patient should be the first and
foremost factor in identifying appropriate
candidates for salvage therapy.
This requires an estimation of the
individual's likely mortality from
other causes, and the anticipated time
to symptomatic progression of the
cancer or death if left untreated. Unfortunately,
neither will be known
with any certainty. As with primary
treatment, one is unlikely to have
much beyond "good clinical judgment"
to guide this choice. With that
being said, there are some data to
serve as a guide.

A few authors have written about
the clinical course of recurrent disease
after radiation therapy. Kuban et al[7]
reported that local recurrence diminishes
the overall 5-year survival rate
from 89% to 66%. Unfortunately, no
PSA data were available during the
years of this report, and their relevance
in the PSA era is unclear.
D'Amico et al[8] studied survival following
PSA failure in radiotherapy
patients. They reported 10-year prostate
cancer-specific survival rates of
98%, 72%, and 44% in low-, intermediate-,
and high-risk groups, respectively.
For this patient population,
with a median age of 73 years, slightly
more than half of all deaths were from
causes other than prostate cancer.

Pound et al[9] addressed the natural
history of recurrent prostate cancer
following radical prostatectomy.
After PSA failure, the median time to
metastasis was 8 years, with death
occurring an average of 5 years thereafter.
The Gleason score, PSA doubling
time, and interval between surgery
and rising PSA were all significant
factors predicting for a more aggressive
disease course. Pound's study
represents a highly selected patient
population, and is perhaps not truly
indicative of the average patient failing
radiation therapy. The median age
was not stated, but based on usual surgical
criteria, might be expected to be
at least a full decade younger than the average radiation therapy cohort. Until
better data are available documenting
the time to metastasis (or death)
for radiation therapy populations, this
might be considered a best-case scenario,
expecting the average patient
to present with clinical progression
within 5 to 8 years after PSA failure.

The risk of cancer progression
must then be weighed against the individual
patient's life expectancy.
Death from unrelated causes, including
heart disease, other cancers, and
a host of other illnesses, remains the
leading cause of death in patients with
prostate cancer. Age-specific actuarial
life expectancy tables can be found for
populations, but never for individuals.
For older and sicker patients, intervention
targeting locally recurrent
prostate cancer will often be unnecessary.
In clinical practice, however,
one is often faced with relatively
young and healthy patients who must
be considered at risk for death or
morbidity from recurrent prostate cancer.
These patients would be candidates
for intervention if the cancer
were expected to progress within their
life expectancy.

Historically, most radiation therapy
practices have treated primary prostate
cancer patients who averaged over
70 years of age.[8,10] Consequently,
the typical patient showing a rising
PSA several years after irradiation
would generally not be a good candidate
for aggressive second-line
therapy. However, during the past decade,
there has been a dramatic rise
in the number of young prostate cancer
patients (45-70 years old),[11]
and almost a twofold increase in the
number of younger men being treated
with radiation. Even if only a minority
of the treated patients fail, many
men will still be young enough to reasonably
consider definitive salvage
treatment.

Local salvage treatment of any sort
only makes sense in patients without
distant disease. In the PSA era, however,
most failures now present with
only a rising PSA level. Radionuclide
bone scans, computed tomography
(CT), or magnetic resonance imaging
studies are still indicated but may miss
subclinical metastases. Nevertheless,
there is every reason to expect that the PSA may contain more information
and give some indication of the probability
of occult distant metastases at
the time of biochemical failure in
these patients. Both the level of PSA
elevation and time course of the
PSA findings since the primary
treatment contain potentially useful
information.

In men given radiation therapy for
local recurrence after radical prostatectomy,
both the absolute value of the
PSA at the time of second-line therapy
and the interval from initial treatment
to biochemical failure predict for freedom
from a second failure, and thus
are likely indicators of disease beyond
the pelvis. Schild et al[12] determined
that grade, dose, and PSA > 1.1 ng/mL
at the time of salvage irradiation independently
identify patients at high risk
of failing salvage therapy. Several
other series confirm that delaying
treatment after surgical failure may
more than halve the 5-year biochemical
freedom from failure rates, with
the critical PSA level ranging from 1.0
to 2.5 ng/mL.[13-15]

Less information is available regarding
the prognostic impact of the
PSA level after radiation therapy.
Given the nature of the treatments and
differences in the definition of PSA
failure between surgical and radiotherapy
patients, one would reasonably
expect that radiation patients
would likely have a higher average
PSA at the time of failure. Indeed,
using the ASTRO definition of failure,[
6] which requires three rising
PSA intervals, few patients are
likely to be identified as radiation
failures while PSA is still less than
2 ng/mL.

Tefilli et al[16] compared patients
at a single institution having salvage
radiotherapy following a radical prostatectomy
with men having salvage
prostatectomy following failed external-
beam irradiation and noted a significant
difference in serum PSA at
the time second-line therapy was instituted.
Patients having salvage radiation
after surgery had a mean PSA of
1.1 ng/mL, in contrast to 9.1 ng/mL
for salvage after radiotherapy. Salvage
treatment after radiation therapy was
more likely to be delayed, averaging
15.6 months from the time of recurrence, compared to 4.9 months for
patients receiving radiation therapy
after failing prostatectomy.

There are even fewer data addressing
the level of PSA at the time of salvage
brachytherapy following external-
beam irradiation. One report suggests
a PSA > 10 ng/mL as indicative
of a high risk of failure,[17] but other
levels were not addressed. It is not
clear if this dramatic difference in the
PSA cut-point following surgery and
radiation therapy is a reflection of a
biologic difference between these two
initial treatment modalities, a delay in
recognition of recurrence, or simply
a reflection of the paucity of studies
evaluating salvage brachytherapy.
Most likely all three of these possibilities
are to some extent true;
it seems reasonable, however, to
conclude that the risk of failing
second-line therapy rises with PSA
elevation.

The disease-free interval since
initial treatment has also been suggested
as an indicator of disease site.
Following radical prostatectomy, patients
who show signs of PSA failure
within the first 24 months have a
significantly increased risk of developing
distant metastases, whereas
those with a later PSA failure are more
likely to have only local failure.[9]
In addition, a post-initial therapy PSA
doubling time of less than 6 months
has been suggested as a strong predictor
of metastatic disease.[18]
Similar results have been reported
following radiation therapy, with
no clinical signs of progression seen
at 28 months in patients with a
PSA doubling time of more than
9 months.[19]

Guidelines
Thus, it appears that the patients
most likely to require additional local
therapy are those with

  • Pathologically documented local
    failure
  • Clinically and radiographically
    absent distant metastases
  • Life expectancy > 5-10 years
    based on age and health
  • Disease-free interval > 2 years
  • PSA < 10 ng/mL
  • Long PSA doubling time (ie,
    > 6-9 months).

Can We Identify Patients
Who Are Most Likely to
Respond to Salvage Treatment?

The concept of using brachytherapy
as a salvage treatment is not
new. Shortly after the introduction of
iodine-125 as a clinically useful isotope
for primary prostate cancer,
Goffinet et al[20] reported a small preliminary
series of patients treated with
retropubic implantation for recurrent
disease. Implanting 14 to 23 mCi they
delivered 9,000 to 22,500 cGy. Early
results were encouraging, with 11 of
14 patients locally controlled and 8
completely disease-free. This report
is unfortunately limited by use of the
now outdated retropubic technique,
lack of PSA results, and short followup.
Complications were modest, except
in the group implanted with high
activity (> 0.5 mCi) sources.

Wallner et al[21] reported a unique
series of 13 patients with locally recurrent
disease following retropubic
iodine-125 implantation who underwent
a second implant with a median
matched peripheral dose of 170 Gy.
A variety of techniques including retropubic
implantation, open perineal
placement, and fluoroscopic and CTguided
brachytherapy were used. A
5-year freedom from local progression
of 51% was achieved, although
10 of 13 patients developed distant
metastases, with 59% survival at the
5-year mark. By today's standards,
these were fairly advanced cancers.
The PSA assay was not yet available,
most had moderately or poorly differentiated
cancers, and all patients had
palpable tumors larger than 1.5 cm or
extraprostatic extension.

Loening and Turner reported on 31
patients treated with transperineal ultrasound-
guided gold-198 brachytherapy.[
22] Follow-up was short, and
no PSA information was presented.
They primarily reported biopsy results,
showing that 40% of biopsies
became negative while 33% showed cancer with radiation effect. Three
patients developed metastases, and the
5-year survival rate was 67% with
only two cancer-related deaths.

Taken together, it appears from
these early series that several conclusions
can be reasonably justified.
First, prior to the introduction of PSA,
it was difficult to select patients with
truly localized disease, and overall
survival of just over 50% at 5 years
could be expected. Local control was
generally in excess of 50% with salvage
brachytherapy, although it remains
difficult to accurately assess.
Complications were relatively modest
but frequent enough to discourage
widespread adoption of these
procedures.

During the past decade, there has
been a virtual revolution in prostate
brachytherapy with the introduction
of transperineal ultrasound-guided
techniques, improved dosimetry, and
general acceptance of the procedure
for early cancer. During the same years, the introduction of routine PSA
testing in screening, pretreatment selection,
and posttreatment evaluation
has brought about parallel changes in
our understanding of the disease and
in the stage of newly diagnosed cancers.
A few studies have now been
published addressing the use of salvage
brachytherapy in this more
modern era, taking advantage of these
advances in implantation and PSA
evaluation.

Grado et al[23] performed salvage
brachytherapy in 46 patients who had
developed a recurrence 2 to 5 years
following conventional external-beam
irradiation (median: 66 Gy) and in 3
patients with recurrence following an
iodine-125 implant. They implanted
a median of 31.76 mCi iodine-125 or
126 mCi palladium-103 to deliver a
median matched peripheral dose of
160 Gy and 120 Gy, respectively. All
implants were performed prior to the
introduction of TG-43 and NIST-1999
standards. (These conventions were
established within the physics community
in the late 1990s to correct
some discrepancies in implant radiation
dose calculations. As such, the
equivalent doses using today's calculation
methodologies would be approximately
144 Gy and 125 Gy for
iodine-125 and palladium-103, respectively.)
Local control of 98% was
reported, although no biopsy confirmation
was provided. Biochemical
disease-free survival rates of 48% and
34% were achieved at 3 and 5 years,
respectively, using a definition of failure
that required two rising PSA values.
Patients who reached a PSA nadir
< 0.5 ng/mL (47% in this report)
fared dramatically better than those
who did not. At 5 years, the biochemical
disease-free survival rate was 56%
for those who achieved this nadir, and
15% for those who failed to do so.

This series presents a mixed cohort
of adversely selected patients. Four
men had also previously undergone
radical prostatectomy and had grossly
palpable recurrence. A total of 11 cancers
were hormone-refractory, and 16
patients had previously undergone a
transurethral resection of the prostate.
It is highly unlikely that any patient
who has hormone-refractory disease
or has failed a prior prostatectomy and radiation therapy has only local failure
and can be controlled. It is encouraging,
however, to look at the subgroup
who achieved a PSA nadir
< 0.5 ng/mL. One might presume
that these patients were less likely to
have metastatic disease and did enjoy
a 5-year PSA-based tumor control
rate of 56%.

Our own preliminary results for
salvage brachytherapy (at Arizona
Oncology Services) were published
for the first 17 consecutively treated
patients.[17] Doses of 120 Gy prior
to TG-43 (or 110 Gy post-TG-43)
were used for iodine-125 and 90 Gy
for palladium-103, prior to NIST-99.
Slightly better overall results were
achieved with 53% biochemical disease-
free survival and 93% prostate
cancer-specific survival reported at 5
years. Gleason sum (< 7) and PSA
< 10 ng/mL at the time of salvage predicted
for low-risk patients and improved
outcomes, although not at a
statistically significant level. It is encouraging
to note that 83% of these
low-risk patients are still free of a second
recurrence 5 years following salvage
therapy.

With additional treated patients
and longer follow-up, a retrospective
review of our results confirms many
of these initial impressions.[24]
Currently, 30 patients have been followed
up to 125 months (median:
46 months). The biochemical diseasefree
survival is shown in Figure 1 for
the same risk groups; consisting of
PSA ≤ 10 ng/mL vs PSA > 10 ng/mL
(Figure 1A) and Gleason score 2-6
vs Gleason score 7-10 (Figure 1B).
As in the initial analysis, a lower break
point for PSA failed to discriminate
any better than PSA greater than or
less than 10 ng/mL, although the size
of the cohort remains too small to
make any statistically significant
claims.

As might be expected with more
than 5 years' follow-up, late prostate
cancer deaths have now been seen. At
10 years, the prostate cancer-specific
survival rate is 60%. Gleason score
and PSA both predict for survival, as
can be seen in Figure 2. No cancer
deaths have been seen in patients with
a Gleason score of 6 or less at the time
of salvage brachytherapy.

Guidelines
In conclusion, it appears that iodine-
125 doses in the 110- to 145-Gy
range (accounting for TG-43) are effective
as a second-line treatment for
patients failing initial radiation
therapy. Incorporating the recommendations
of NIST-99, palladium-103
doses of 100 to 115 Gy would be indicated.
Overall, approximately 50%
of patients should be locally controlled
clinically and demonstrate PSA control.
As with primary treatment, however,
the PSA and Gleason score at the
time of salvage can help select patients
with better prognoses. Those most
likely to respond are men with

  • PSA < 10 ng/mL
  • Gleason score < 7
  • PSA nadir < 0.5 ng/mL.

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