Urol Clin N Am 30 (2003) 751–763
Recurrent prostate cancer following external beam
radiotherapy: Follow-up strategies and management
Charles Catton, MD, FRCPC*, Michael Milosevic, MD, FRCPC,
Padraig Warde, MD, FRCPC, Andrew Bayley, MD, FRCPC,
Juanita Crook, MD, FRCPC, Robert Bristow, MD, PhD, FRCPC,
Mary Gospodarowicz, MD, FRCPC
Department of Radiation Oncology, University of Toronto, Princess Margaret Hospital, 610 University Avenue,
Toronto, Ontario M5G 2M9, Canada
Patients with early-stage prostate cancer who
are treated with radical radiotherapy (RT) have
an excellent prognosis, and although long-term
survival is expected, many patients fail and will
require further interventions. The optimal followup strategies to detect treatment failure and the
optimal timing of further treatment are the subject
of ongoing prospective trials. A well-designed
follow-up strategy is part of an optimal management policy, and early detection of tumor recurrence also may improve the chance of re-treatment
and salvage of a local or systemic relapse.
The availability and eﬃcacy of additional
treatment govern the timing, frequency, and selection of follow-up investigations. This requires
an understanding of the natural history of treated
prostate cancer and the cost-eﬀectiveness of
therapy. There is no beneﬁt in an intensive
follow-up program if early intervention is not
recommended and treatment is introduced only
when recurrent disease is clinically apparent and
symptomatic [1]. This article reviews the information on the follow-up strategies including detection and treatment of relapse of prostate cancer
following radical external beam RT (EBRT)
(Figs. 1 and 2).
Identiﬁcation of local relapse
Because the prostate gland remains in situ after
radical EBRT, the prostate-speciﬁc antigen (PSA)
does not fall to undetectable levels as is seen after
radical prostatectomy (RP). Rising PSA is the
most common sign of recurrence after EBRT, but
it may reﬂect local, regional, or distant failure, or
a combination of the sites of failure. Digital rectal examination (DRE) with PSA determination
are employed in post-EBRT follow-up, although
Johnstone et al [2] determined that new information was provided by post-RT DRE in only 30%
of abnormal examinations, and in 75% of these
cases the ﬁndings were related to EBRT-induced
rectal bleeding rather than to tumor recurrence.
The measurement of PSA levels following EBRT
is the most widely employed method of evaluating
post-EBRT outcome in patients with localized
prostate cancer, but the sensitivity and speciﬁcity
of the method for predicting a clinically relevant
outcome is less than perfect and is open to
criticism [3,4]. Other follow-up tests, such as
posttreatment biopsy of the prostate and functional imaging, may be used to supplement DRE
and PSA in determining post-RT disease status,
and these are discussed below.
Serial PSA determinations
* Corresponding author.
E-mail address: [email protected]
(C. Catton).
The serum PSA level is correlated to total
tumor burden and the PSA level after treatment
is a widely used surrogate endpoint of response
0094-0143/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved.
doi:10.1016/S0094-0143(03)00051-X
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C. Catton et al / Urol Clin N Am 30 (2003) 751–763
Fig. 1. (acrobat ﬁgure 030J). Follow-up ﬂow chart for men treated with radical EBRT for prostate cancer.
in prostate cancer. The value of PSA response
has been documented in a number of studies
[5–9], although the use of adjuvant hormone
therapy makes the interpretation of PSA levels
after RT unreliable because the PSA production
is under hormonal control and the value of PSA
may not reﬂect directly the presence or absence
of tumor. The decline of PSA following RT is
slow and normally takes 6 to 24 months or more,
and the deﬁnition of response or failure based on
the PSA levels following treatment is referred to
as ‘‘biochemical response or failure.’’ Biochemical response may be deﬁned as ‘‘PSA nadir’’ or
‘‘PSA failure.’’ In 1997, the American Society for
Therapeutic Radiology and Oncology (ASTRO)
consensus panel published a consensus statement
on the deﬁnition of PSA failure [10]. The
ASTRO consensus panel agreed on four guidelines [10]:
1. Biochemical failure is not equivalent to
clinical failure.
2. Three consecutive increases in PSA is a reasonable deﬁnition of biochemical failure, with
the date of failure reported as the midpoint
of the nadir PSA and the ﬁrst of the three
consecutive rises. Three consecutive rises were
adopted to prevent classiﬁcation of patients
with ﬂuctuating PSA from being classiﬁed as
treatment failures.
Fig. 2. (acrobat ﬁgure 031J). Flow diagram for the management of clinical local failure or biochemical failure of
localized prostate cancer following radical EBRT.
C. Catton et al / Urol Clin N Am 30 (2003) 751–763
3. No deﬁnition of PSA failure has been shown
unequivocally to be a surrogate for clinical
progression or survival.
4. Although nadir PSA is a useful factor, no
absolute level is a valid cutoﬀ point in
deciding successful or unsuccessful treatment
outcome.
Although these criteria generally correlate well
with clinical outcome [8,11], they have many
limitations. Taylor et al [12] reported that the
speciﬁcity and sensitivity of a rising PSA to
predict a clinically meaningful failure such as
a local recurrence, distant recurrence, or initiation
of unplanned hormone therapy or RP is related to
the proportional magnitude of the PSA rise above
nadir levels and the steepness of the slope of the
rise (the PSA doubling time [PSADT]). For
example, proportionally small consecutive rises
measured over a short interval may have a benign
cause and be misclassiﬁed as biochemical disease
progression. In another scenario, any gradually
progressing tumor may have a slowly rising PSA
trend that is obscured by occasional decreases in
PSA levels, thus resulting in a much-delayed
recognition of treatment failure.
PSA nadir
The PSA nadir is the lowest level of PSA
measured after RT. A PSA nadir predicts a subsequent biochemical and clinical failure [7], but
the nadir level is not in itself an indicator of
disease remission or relapse. Longer interval from
treatment to PSA nadir positively correlates with
freedom from metastatic disease [6,7], and PSA
progression immediately following RT is a strong
indicator of the presence of systemic metastases,
presumably because in this situation PSA production continues unimpeded during and immediately after EBRT.
PSA bounce
A PSA bounce has been deﬁned as an initial
posttreatment increase in PSA of greater than 0.4
ng/mL or greater than or equal to 15% of the
previous value over a 6-month period within 60
months of therapy that subsequently decreases to
prebounce baseline levels [13–15] or lower. A PSA
bounce has been identiﬁed in 12% to 33% of
patients treated with EBRT [14,15], and the mean
time to PSA bounce was found to be as long as 9
months [15]. The cause has not been deﬁned, but is
speculated as possibly being due to ejaculation or
753
instrumentation [13]. A PSA bounce is not predictive of future biochemical failure and should
not be used as a sole indicator of relapse, although
the risk of relapse is higher in patients who exhibit
multiple episodes of PSA ﬂuctuation [14].
Post-RT prostate biopsy
Crook et al [16] proposed that routine, systematic, transrectal, ultrasound-guided prostate biopsies might be an eﬀective way of determining
post-RT local tumor control. They observed that
sequential positive biopsies often converted to
negative over time, and recommended that the
optimal time to biopsy was 24 to 30 months postRT [17]. Several other reports of EBRT for
localized prostate cancer have included post-RT
biopsies with the outcome assessment [18–20].
Despite the attractiveness of using post-RT biopsies to determine local control, and the demonstrated interest in this procedure, experience has
shown that correctly identifying viable tumor in
biopsies of irradiated prostate is not straightforward. In addition to the problem of correctly
timing the biopsies after treatment, the diagnosis
of complete response is diﬃcult, with 3% to 40%
of post-RT biopsies remaining as indeterminate,
even with expert evaluation [9,21,22]. Furthermore, there is signiﬁcant interobserver variability
in reporting positive post-RT biopsies among
expert uropathologists, and poor agreement of
expert pathologists with nonexpert pathologists
[21]. Immunohistochemical tumor staining for
PSA, high—molecular-weight keratin, and proliferative cell nuclear antigen have been reported to
improve the sensitivity and speciﬁcity of reporting
positive post-RT biopsies [23], as does correlation
of biopsy status with the post-RT PSA nadir [24].
However, in spite of the limitations, posttreatment biopsy remains a valuable tool for selecting
patients for local salvage therapy. In fact, retreatment with a local ablative procedure should
not be considered without a positive prostate rebiopsy. A wider experience with the technique is
required, and the criteria for the diagnosis of
carcinoma in post-RT biopsies need to be reﬁned
further and applied uniformly before re-biopsy can
be adopted as a routine method for assessing
treatment response [21,25].
Imaging
Although the assessment of the response to
treatment and early detection of recurrence in
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C. Catton et al / Urol Clin N Am 30 (2003) 751–763
prostate cancer are driven completely by serial
serum PSA measurements, the site of recurrence
cannot be determined by PSA and should be
assessed by clinical examination and imaging,
recognizing that standard imaging is likely to be
negative and should not be done unless the patient
has a Gleason score greater than 7 or a PSA
greater than 50 ng/mL [26].
Radioisotope bone scans
Skeletal imaging using 99mtechnetium-labeled
diphosphonate is the most widely used technique
for the detection and surveillance of prostate
cancer to the bones [27]. Because a PSA rise
usually antedates the detection of bone metastases
in patients with prostate cancer, routine bone
scans are not recommended as part of follow-up
[28,29]. The bone scan should be used to help
diﬀerentiate local recurrence from metastatic
spread in patients with a rising PSA [27], although
it has been demonstrated that for a PSA of less
than 20 ng/mL and a Gleason score greater than
7, or for a PSA of less than 50 ng/mL and
a Gleason score less than 8, a bone scan has less
than 10% likelihood of being positive [26].
Because they are not useful, bone scans should
not be performed in patients with very low PSA
levels.
imaging is not recommended as part of routine
follow-up. For the investigation of a patient with
a rising PSA after EBRT, preliminary evidence
suggests that the technique is more sensitive and
speciﬁc than is CT or MRI in identifying patients
with nodal metastases. The very limited experience with capromab pendetide imaging for restaging patients treated with EBRT has shown
it to be of value in making management decisions
[32,33], but wider availability and more experience with the technique will be required before
capromab pendetide imaging can be considered as a substitute for these standard staging
investigations.
Positron emission tomography
[18F]ﬂuorodeoxyglucose positron emission tomography (FDG PET) is a common method for
imaging the metabolic activity of cancer. FDG
PET scanning is valuable for the identiﬁcation of
metastases in a variety of tumors, although the
low cellular uptake rate of FDG in prostate
cancer has limited the usefulness of the technique
for staging and follow-up for adenocarcinoma of
the prostate [34,35]. More eﬀective radiotracers
such as [18F]ﬂurocholine are under investigation
and may improve the ability of PET to detect
prostate cancer metastases [34,36], but at present
PET scanning should not be used routinely for
prostate cancer staging or follow-up.
Capromab pendetide (ProstaScint) imaging
Capromab pendetide (ProstaScint) is the conjugated form of a murine immununoglobulin G1
monoclonal antibody directed against prostatespeciﬁc membrane antigen (PSMA). 111Indium
capromab pendetide is capable of identifying bone
and soft tissue disease in patients with known
metastases [30], and it is approved only for
imaging of soft-tissue disease. A recent comparison of capromab pendetide imaging to CT or
MRI for the diagnostic assessment of prostate
cancer in 51 surgically explored patients demonstrated that capromab pendetide had a sensitivity
of 75% in detecting nodal involvement compared
with 20% for CT or MRI. Speciﬁcity and positive
predictive value for capromab pendetide imaging
was 86% and 79%, respectively, compared with
a speciﬁcity and positive predictive value of 68%
and 31% for CT or MRI imaging [31]. Imaging
with capromab pendetide is challenging technically, and requires speciﬁc training to read the
images [31], and routine capromab pendetide
Treatment of relapse
Salvage local therapy
Hormonal ablative therapy has a long history
of eﬀectiveness in the management of relapsed
prostate cancer and in a recent patterns of practice
report [37], 93% of patients who received secondary therapy after EBRT were treated with
hormonal ablative therapy. The numerous reasons for the popularity of this approach include
the high response rate to therapy, the ease of
access to treatment, the relative lack of associated
serious toxicity, and patient preference. In addition, clinical factors such as advanced patient age
at relapse and advanced disease extent at presentation or at relapse may make other, more
aggressive approaches to salvage therapy less
suitable. Clearly, there also is a role for curative
local salvage treatment in selected individuals,
although this use remains controversial, due
largely to many unresolved issues in the natural
C. Catton et al / Urol Clin N Am 30 (2003) 751–763
history of disease progression in these patients,
and especially in accurately deﬁning those patients
who have a high likelihood of having an isolated
local recurrence of disease.
Patients with locally recurrent disease may be
candidates for RP, cryosurgery, and brachytherapy, but these treatments are being used infrequently and it is diﬃcult to compare the
outcomes in these case series with the outcomes
following conservative management. These series
tend to have carefully selected patients and include
only a small proportion of men who relapse after
RT. Even so, only 35% to 50% of these patients
will have prolonged biochemical disease-free
survival [38,39]. The curative potential of these
salvage local therapies is poorly documented.
Who should be considered for salvage
local therapy after RT?
The individual most likely to beneﬁt from
ablative local treatment after failure of radical RT
will have an anticipated life span of 10 years or
more, a proven local recurrence, and a low
probability of harboring micrometastatic disease.
Because biochemical failure after RT can be due
to local recurrence, distant recurrence, or both,
biopsy proof of a local recurrence is essential, and
restaging investigations looking for nodal or bone
metastasis should be negative. The likelihood of
success for local salvage therapy is dependent on
the same risk factors as is the success of RT. A
patient with a low pre-RT Gleason score, low
PSA, and low initial clinical stage is least likely to
fail because of the low risk of micrometastases,
and therefore is most likely to beneﬁt from
a second attempt at a cure.
In addition to the pre-RT risk factors, the
timing of biochemical relapse after RT and
PSADT both have been shown to be useful in
predicting the pattern of failure after RT [40–42].
Sartor et al [42] reported the outcome of 400
patients with localized prostate cancer treated
with radical RT between 1987 and 1994. With
a median follow-up of 3 years, 234 patients
(58.6%) had rising PSA values, 38 patients
(9.7%) developed local failure, and 23 (5.8%)
developed distant failure. On multivariate analysis, rapid PSADT was found to predict for
metastatic rather than for local failure. Thirtyseven patients had a PSADT of less than 6 months
and 17 (46%) of these patients developed distant
metastasis as compared with only 4 (8%) who
developed local relapse. Patients with a PSADT of
755
less than 6 months had an 8.5 fold increased odds
of distant failure as opposed to local failure
compared with patients with a doubling time of
6 to 12 months. Lee et al [41] reported on the
pattern of failure after deﬁnitive RT in 459
patients with localized disease and found that
PSADT (<12 months) and a short interval from
the end of treatment to PSA elevation (<12
months) were signiﬁcant independent predictors
of distant metastases. Given the potential for
signiﬁcant local side eﬀects of re-treatment, local
salvage therapy should likely be considered only
for patients with a long life expectancy who would
prefer the option of a potentially curative
treatment to the option of surveillance or longterm hormonal ablation. Patients most likely to
respond to re-treatment will have clinical stage
T1/T2 at initial presentation and at relapse,
PSADT of greater than 6 months, and an interval
between primary treatment and relapse of greater
than 1 year. In addition, the serum PSA presalvage treatment should be less than 10 ng/mL and
the initial Gleason score should be 7 or less.
Salvage RP
RP has not been accepted widely as salvage
therapy for local recurrence after radiation
therapy because of the morbidity and high recurrence rates. Reports from the pre-PSA era
show a 40% to 50% incidence of postsurgery
incontinence, 100% impotence, and a substantial
incidence of serious bowel and rectal injury [43–
46]. In the modern era, with relapse being detected
earlier based on rising PSA, a number of series
reported more favorable outcomes. Pisters et al
[47] reported on 13 patients treated with salvage
RP between 1995 and 1999. All received a continent catheterizable reconstruction to prevent
urinary incontinence, and 9 of 13 remain disease-free 6 to 48 months after surgery. Gheiler
et al [48] reported results in 30 patients treated
with salvage RP between 1992 and 1997 at Wayne
State University. With a mean follow-up of 36
months, 15 patients (50%) had no evidence of
biochemical disease progression. Only 15 patients
(50%) were continent; mild incontinence was
present in 8 patients (26%) and severe incontinence was seen in 7 patients (23%). Vaidya and
Soloway [49] reported the outcome of six patients
who underwent salvage RP at the University of
Miami between 1995 and 2000. Androgen deprivation therapy was given preoperatively in ﬁve
of these patients. With a mean follow-up of
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C. Catton et al / Urol Clin N Am 30 (2003) 751–763
27 months, biochemical failure has occurred in
only one patient. All six patients are impotent, ﬁve
are continent, and one patient has mild stress
incontinence.
Although these results may be encouraging, it
is impossible to generalize them, given the degree
of patient selection in these series. Patients
choosing RP as salvage local therapy should be
informed of the potential morbidity, particularly
the risk of clinically signiﬁcant incontinence, and
surgery optimally should be performed in a center
that has experience with this approach.
a posttreatment America Urological Association
symptom score greater than 20. Overall satisfaction with cryotherapy was reported by only 33% of
patients.
Cryosurgery has been approved by the Centers
for Medicare and Medicaid Services as the only
treatment speciﬁcally approved for the indication
of recurrent local cancer after radiation. However,
the signiﬁcant complication rates after treatment
and the lack of proven eﬃcacy have limited its use
largely to specialized centers.
Interstitial brachytherapy
Salvage cryotherapy
Initial results of cryotherapy as salvage therapy
after failure of RT were disappointing. Control
rates were less than 25% and signiﬁcant incontinence was seen in more than 40% of patients
[50]. Advances in cryosurgical technique have
improved these results with long-term incontinence rates now being reported as less than 10%
[51–53]. Biochemical disease-free survival rates are
in the 30% to 40% range, with better results seen
in patients with low-grade T1/T2 disease and PSA
less than 10 ng/mL before treatment [51,54] Chin
et al [51] reported results in 118 patients treated
between 1994 and 1999. With a median follow-up
of 19 months, the biochemical no evidence of
disease rate at 4 years was 34%. Severe incontinence was noted in eight patients (6.7%) and
rectourethral ﬁstula occurred in four patients
(3.3%). In a recent update of the MD Anderson
data, Izawa et al [54] reported a 5-year disease-free
survival of 40% in 131 patients treated between
1992 and 1995 (median follow-up = 4.8 years).
As in other series, patients with a precryotherapy
Gleason score greater than 9, PSA greater than 10
ng/mL, and advanced clinical stage did poorly. In
addition, patients with androgen-independent
local progression did worse compared with those
with androgen-dependent disease [54].
Quality of life is compromised after cryotherapy in a substantial number of patients. In a
patient-based questionnaire administered to 150 patients (112 questionnaires returned, 74%) at MD
Anderson Cancer Center, 72% of patients reported
some degree of dribbling or leakage when asked to
describe bladder control [55]. Forty-four percent of
patients reported problems with perineal pain, and
pain interfered with normal daily activity in 38%
of patients. Treatment without an eﬀective urethral
warming catheter was associated with urinary
incontinence, perineal pain, tissue sloughing, and
Grado [56] and Grado et al [57] reported on
a series of 49 men treated with salvage brachytherapy, using either iodine 125 or palladium 103
for full-dose permanent transperineal seed implants. Median follow-up was 64 months. Initial
RT dose was 66 Gy (range 20–70 Gy) completed
at a median interval of 41.7 months previously.
Patients were not rigorously selected for having
a high chance of successful local salvage. Seventyone percent had presented with an initial stage B2C tumor. Moderately diﬀerentiated tumors had
been documented in 53% and poorly diﬀerentiated tumors had been documented in 34%. Only
half had baseline PSA levels available from the
time of initial diagnosis; the median value was
26.4 ng/mL. Despite the high-risk proﬁle of the
population, the actuarial, biochemical, diseasefree survival at 3 and 5 years following salvage
brachytherapy was 48% and 34%, respectively.
More importantly, the results of these studies
[56,57] demonstrate the feasibility of salvage
brachytherapy in terms of toxicity. Posttreatment
irritative and obstructive urinary symptoms were
self-limited and managed with alpha-blockers.
Transurethral resection of the prostate (TURP)
was performed in 14%, 4% experienced persistent
gross hematuria, 6% experienced penile dysuria,
and 4% had rectal ulcers. One of these latter
patients required colostomy after aggressive rectal
biopsies. Incontinence (at least one pad per day
more than 6 months after the procedure) was
documented in 6%, all of who had a postbrachytherapy TURP. Only one patient who previously
was potent reported diminished sexual function.
The authors [56,57] now recommend avoidance of
TURP and management of irritative and obstructive urinary symptoms with alpha-blockers and
intermittent self-catheterization. Beyer [58] reported on 17 patients treated with salvage
permanent seed prostate brachytherapy. Those
C. Catton et al / Urol Clin N Am 30 (2003) 751–763
patients with a low-grade tumor at the time of
salvage had 83% freedom from second relapse as
compared with 30% for those patients with highgrade tumors. Salvage brachytherapy compares
favorably with other potentially curative salvage
options for locally recurrent prostate cancer after
conventional-dose RT. There is no experience
with its use after modern external RT techniques
that employ prostate doses greater than 70 Gy
[57], and the potential for increased rectal and
urinary toxicity exists with re-treatment following
high-dose EBRT. The ideal patient for retreatment with brachytherapy should have presented
originally with a tumor likely to be conﬁned to the
prostate (T1c/T2a, Gleason 6, PSA<10 ng/mL),
and should have biopsy evidence of residual lowgrade prostate carcinoma with minimal radiation
eﬀect [24]. Because early biochemical failure is
likely to be associated with a distant component,
a disease-free interval of at least 12 months and
preferably 24 months is more likely to be associated with purely local recurrence [6]. Finally,
good tolerance of the initial RT with an
absence of rectal or urinary toxicity is advisable.
Hormonal therapy for progression following RT
It has been known for many years that prostate
cancer is a hormonally responsive disease and
that withdrawal of testosterone leads to rapid
regression of disease [59]. The mechanisms underlying the dramatic response to androgen
withdrawal that frequently is seen clinically are
complex and interrelated, and include increased
apoptosis, inhibition of angiogenesis, and altered
expression of hormonally responsive genes. Most
men who recur following RT for prostate cancer
will, at some point in their disease, require
treatment with androgen suppression. Historically, the diagnosis of recurrence was most likely
to be made on the basis of new urinary symptoms,
due to progressive local disease or musculoskeletal
pain from bone metastases. However, rising PSA
in the absence of symptoms now provides an early
sign of recurrence following RT and precedes
clinical evidence of failure by many years. Many
men at the time of PSA progression are not
candidates for potentially curative salvage treatments, but may nevertheless live long, productive
lives with slowly progressive disease. Therefore,
management recommendations at the time of
recurrence must focus on extending the symptom-free interval and improving survival, while
maintaining a high quality of life.
757
Surgical or medical castration produces a high
likelihood of prolonged PSA control in the
majority of men. The combination of a nonsteroidal antiandrogen and castration to produce ‘‘total
androgen blockade’’ [60] yields only minimal
improvement in survival compared with castration alone [61–63]. Furthermore, increased cost,
more frequent and bothersome side eﬀects, and
a general reduction in quality of life may overshadow the small beneﬁt. Short-course neoadjuvant androgen suppression, which is commonly
prescribed before RT, does not compromise the
response to subsequent salvage hormonal treatment administered for disease progression [64].
The type and severity of the side eﬀects from
androgen suppressive therapy vary depending on
the speciﬁc treatment and its mechanism of
action, but commonly include vasomotor hot
ﬂashes, loss of libido, erectile dysfunction, breast
pain and gynecomastia, mood swings and anxiety,
anemia, osteoporosis that predisposes to fractures, loss of muscle mass, and altered glucose
and lipid metabolism. Vasomotor symptoms
and impaired sexual performance aﬀect a large
proportion of men treated with a luteinizing
hormone-releasing hormone (LHRH) agonist.
Nonsteroidal antiandrogens—particularly bicalutamide—may preserve erectile function at the
expense of a higher incidence of breast symptoms
[65]. The implications of long-term androgen
ablation on bone, lipid, and glucose metabolism,
although minimal in the setting of known
metastatic disease in which survival is limited,
are potentially much greater in otherwise healthy
men who begin treatment for a rising PSA
following RT and are expected to live for many
years.
Timing of hormonal therapy
Men who develop clinical local progression or
metastases following RT for prostate cancer require immediate androgen suppression by orchiectomy or with an LHRH agonist. In the case
of the latter, pretreatment with an antiandrogen is
required to prevent tumor ﬂare and worsening of
symptoms. However, this is now a rarely seen
presentation of relapse. The majority of patients
is followed with serial PSA measurements and
develops PSA failure with no evidence of clinical
disease. The optimal time to begin hormonal
therapy in an asymptomatic man with PSA failure
alone is not know, but, in practice, most men in
North America opt for earlier rather than later
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C. Catton et al / Urol Clin N Am 30 (2003) 751–763
treatment. The choice may diﬀer from individual
to individual depending on how each weighs the
potential beneﬁts versus the side eﬀects. Some men
or their families experience considerable anxiety
and emotional distress knowing that a rising PSA
represents progressive cancer and demand active
treatment immediately upon diagnosis of recurrence. Others prefer to defer treatment and
exposure to possible side eﬀects for as long as
possible.
There is increasing evidence from clinical
studies that ‘‘early’’ intervention with hormonal
therapy is beneﬁcial, compared with later treatment at the time of symptom development. This is
likely due to an eﬀect of hormonal treatment on
gene expression in prostate cancer, with delayed
emergence of clinically aggressive and metastatic
phenotypes. Messing et al [66] demonstrated a
survival advantage to immediate medical or
surgical castration in men with node-positive
prostate cancer identiﬁed at the time of radical
prostatectomy compared with initial observation.
Bolla et al [67,68] described improved survival in
patients with locally advanced or high-grade
prostate cancer treated with RT and hormonal
ablation for 3 years, compared with RT initially
and hormonal treatment at the time of disease
progression.
The UK Medical Research Council Prostate
Cancer Working Party Investigators Group [69]
studied 934 asymptomatic men with previously
untreated locally advanced or metastatic prostate
cancer, and randomized them to receive either
immediate surgical or medical castration or initial
observation and the same treatment at the time
of symptomatic progression. Men who received
immediate treatment had a signiﬁcantly lower
risk of developing urethral obstruction, metastatic
disease, pain due to bone metastases, pathologic
fracture, or spinal cord compression. There also
was an advantage of immediate treatment with
respect to both overall and disease-speciﬁc survival, especially in men without metastases. This
study has been criticized because PSA follow-up
was not available (given that the study was
initiated in 1985 before the routine use of PSA),
clinical follow-up of patients was erratic, and
a small proportion of patients on the delayedtreatment arm died of progressive prostate cancer
without receiving hormonal treatment. Nevertheless, it provides strong support for early hormonal
treatment in men with recurrent prostate cancer
after RT who are anxious to obtain the maximal
beneﬁt of this treatment, and are not bothered by
the attendant side eﬀects and potential reduction
in quality of life.
The deﬁnition of ‘‘early treatment’’ in the
context of modern medical practice, where progression after RT most commonly is diagnosed on
the basis of serial rises in PSA, is ill deﬁned. It is
likely that men participating in the MRC study had
a broad spectrum of locally advanced and occult
metastatic disease and, extrapolating from more
recent experience, a correspondingly broad range
of PSAs ranging from minimally abnormal to very
high values that would now be viewed as a clear
indication for immediate treatment. In contrast,
men with progression following RT frequently
have normal or minimally elevated PSAs that
increase very slowly over time. It is not known
whether beginning hormonal treatment immediately at PSA progression oﬀers any advantage
compared with careful follow-up and later initiation of treatment at some ‘‘trigger’’ point before the
development of symptoms. This is particularly
important in light of the young age of many patients
undergoing RT, their long anticipated survival,
and the side eﬀects of hormonal treatment. The
European Organization for Research and Treatment of Cancer (EORTC) 30943 study, which is
randomizing men with a rising PSA to immediate
versus delayed hormonal treatment, should help to
answer this question. Currently, the most frequent
indication for beginning hormonal treatment in
men who fail RT is the rate of PSA rise. Short
PSADTs predict metastatic disease and a shorter
interval to the development of symptoms [70,71].
Sylvester et al [60] surveyed urologists and radiation oncologists who treat prostate cancer and
found that 65% to 70% used a short PSADT as the
main indication for hormonal therapy following RT. Most used a threshold doubling time of
6 months or less, although almost 25% recommended treatment at a threshold doubling time
of 12 months or less. The remaining 30% to 35%
relied on either the absolute PSA value, or used
the ASTRO deﬁnition of failure to recommend
treatment.
Intermittent hormonal therapy
The development of hormone-refractory disease remains a major problem in the management
of men with prostate cancer. Although the rate of
response to initial hormone treatment is high, most
men develop progressive disease despite continued
antiandrogen therapy at a median interval of
about 2 years from the start of treatment [62,63].
The duration of hormone responsiveness may be
C. Catton et al / Urol Clin N Am 30 (2003) 751–763
longer in men who have small-bulk disease when
treatment is initiated. Once hormone refractory
disease becomes clinically evident on the basis of
a rising PSA or the development of new symptoms,
the management options for patients are limited.
Changes in the type of hormone treatment may
produce secondary responses, but the duration of
response usually is short lived. Therefore, treatment strategies that prolong the interval of
hormone dependence have the potential also to
prolong survival and improve quality of life.
There is preliminary evidence that intermittent
androgen suppression—which involves sequential
periods of androgen suppression followed by withdrawal of treatment and androgen recovery—
has the potential to delay the molecular and
genetic changes that lead to hormone resistance,
extend the duration of response to hormone
therapy, and reduce side eﬀects. Several, small,
phase 2 clinical studies now have been reported,
most of which used PSA as the indication for
starting and stopping treatment with an LHRH
agonist [72–74] Treatment and oﬀ-treatment
intervals in these studies have been approximately
equal, typically ranging from 6 to 9 months in
duration [72–74]. Testosterone recovery occurred
in the majority of men while oﬀ treatment, and
was associated with improved libido and sexual
capacity in those who were potent before beginning treatment, as well as an overall improvement
in quality of life. There was a suggestion of
delayed development of hormone resistance relative to continuous androgen suppression. However, the results in this regard are very diﬃcult
to interpret, given diﬀerences in patient selection
and the multitude of factors that can aﬀect the
duration of hormonal response, including the
extent of disease at the time that treatment is
initiated.
Intermittent androgen suppression may be
particularly well suited to men with PSA progression alone following EBRT, who may survive
10 years or more with slowly progressive disease.
It has the potential to extend the clinical progression-free interval with minimal side eﬀects and
cost. However, there is insuﬃcient evidence at
present to recommend intermittent therapy as
routine treatment. Prolonged hormone responsiveness has not been documented rigorously in
the clinical domain, and the eﬀect on survival is
not known. Furthermore, intermittent hormone
therapy may lead to repeated swings in symptoms,
libido, sexual capacity, and general quality of life
that some men may ﬁnd intolerable compared
759
with the predictable steady-state of continuous
treatment. The National Cancer Institute of
Canada with the collaboration of Intergroup is
conducting a phase 3 randomized trial of intermittent versus continuous androgen ablation
for asymptomatic men with a rising PSA following RT and no clinical or radiographic evidence of
metastatic disease that will provide answers to
these important questions.
Antiandrogen monotherapy
Although most men who require androgen
suppression for prostate cancer undergo either
surgical or medical castration as a component
of their treatment, there is interest in exploring
alternate treatments that produce a more acceptable side-eﬀect proﬁle and therefore greater longterm tolerance and compliance. Treatment with
a nonsteroidal antiandrogen alone, particularly
bicalutamide, has the potential to maintain potency at the expense of an increased likelihood
of gynecomastia and breast pain [65,75–77], a
trade-oﬀ that many men would accept. There
also is increasing clinical evidence to indicate that
bicalutamide alone may preserve bone density
relative to castration [78,79]. However, antiandrogens may yield inferior long-term disease
control in some circumstances relative to castration because of secondary elevation of serum
testosterone levels that overcomes the competitive
blockade of androgen receptors.
Several randomized clinical studies [75–77]
have evaluated treatment with bicalutamide alone
as a single agent relative to castration. A bicalutamide dose of 150 mg daily was used in many of
the studies. In general, the results have shown the
survival of men with metastatic disease to be
inferior with bicalutamide compared with castration. However, the results in men with locally
advanced, nonmetastatic disease have been equivalent. The pooled results of three, large, randomized studies of bicalutamide 150 mg daily
comprising over 8000 patients showed that 80%
to 90% of men developed breast toxicity within
6 months of beginning bicalutamide, and that 15%
of men abandoned treatment because of intolerable breast symptoms. Breast pain resolved within
1 year in the majority of men stopping bicalutamide.
However, resolution of gynecomastia was less
predictable and inversely inﬂuenced by the duration of prior treatment. There was a low incidence
of impotency compared with controls, and a low
incidence of vasomotor symptoms [65].
760
C. Catton et al / Urol Clin N Am 30 (2003) 751–763
There have been no completed randomized
studies of single-agent bicalutamide in men with
a rising PSA following RT for prostate cancer.
Nevertheless, the available evidence suggests that
this may be appropriate treatment in those who
wish to maintain potency and can tolerate the
breast side eﬀects.
Summary
All patients who undergo curative therapy for
prostate cancer should be followed for a prolonged
period of time to determine tumor control and
treatment toxicity for quality assurance purposes.
Follow-up duties may be reasonably shared
between the oncologist and the family doctor or
urologist; however, it is probable that some
follow-up information speciﬁc to the irradiated
patient will be lost unless the oncologist maintains
regular contact with the patient, especially in the
ﬁrst 5 years of follow-up when late radiation
eﬀects are most likely to appear. There is no strong
evidence that patients stop being at risk for
recurrence at any time after treatment, and
because PSA testing is an accurate, simple, and
inexpensive method of determining post-RT tumor status, it is recommended that periodic PSA
measurements be continued for life. In the absence
of a rising PSA, all other tests and visits are unnecessary to determine post-RT tumor control.
Because DRE has been shown to be of limited
utility in follow-up of irradiated patients, it should
be possible to eﬀectively follow patients remotely.
This could be done by asking patients to have PSA
tests done, forward the results to their physicians,
and report treatment toxicity when it occurs. Only
abnormal results would trigger an oﬃce visit. This
strategy is being evaluated in clinical trials. The
alternative is to delegate the follow-up to the
primary-care physician with guidelines as to when
referral back is required. Follow-up frequency,
and the most beneﬁcial follow-up investigations
vary from scenario to scenario, and are inﬂuenced
by the likelihood of relapse, time to relapse, and
planned intervention. These decisions are inﬂuenced in turn by the initial presentation—either
with high or low risk factors—and by the patientÕs
general state of health at completion of EBRT.
Eﬀective follow-up also requires active patient
cooperation that only can be achieved after discussion of the goals of follow-up with the patient and with the patientÕs full understanding of
the process. The follow-up strategy proposed in
Fig. 1 is most suitable for a ﬁt patient with low or
intermediate risk factors who wishes to consider all
salvage options should he relapse, or for the highrisk individual in situations in which the probability of systemic relapse is of major concern.
Young patients with very adverse risk factors may
beneﬁt from even closer follow-up in the early
years after EBRT and the elderly or frail may
require only occasional visits to record or treat
treatment toxicity and to ensure clinical nonprogression.
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