Treatment of local progression following radiotherapy.

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Treatment of local progression following radiotherapy
Theo M. de Reijkea, Thomas Wiegelb
aAcademic Medical Center, Amsterdam, The Netherlands
bUniversit¨ atsklinikum Ulm, Ulm, Germany
Introduction
The outcome of radiotherapy for localised prostate
cancer has improved over past years due to improved
radiation techniques resulting in the possibility of
delivering higher doses to the prostate and, secondly,
due to more precise patient selection. However, there
are still many men in follow-up that have been
treated with radiotherapy doses which are nowadays
considered as insufficient. Although improved staging
and patient selection is possible, it is estimated
that following surgery or radiotherapy for localised
prostate cancer, approximately 40% of men will fail
and present with a prostate specific antigen (PSA)
relapse (biochemical recurrence) [1].
Since published results of phase III trials, randomis-
ing patients with high-risk prostate cancer between
radiotherapy alone or radiotherapy plus neo- or
adjuvant androgen deprivation therapy, have reported
improved survival for the combined approach, these
high-risk patients are, in most instances, now treated
in first-line with this combination for a period of time
up to 3 years [2,3]. Although improved survival rates
were accomplished with this combined treatment, a
considerable number of patients will still experience a
biochemical relapse. The most important issue in case
of a demonstrated PSA relapse is the determination of
local disease only or distant failure, which has to be
approached in a different way.
Following radical prostatectomy, several factors
are helpful in defining patients at risk for local
recurrence or metastatic disease e.g. time between
surgery and PSA relapse, PSA doubling time, and
pathological stage and grade [4]. For radiotherapy,
these discriminative, predictive factors have not been
identified.
PSA evaluation
Definition of PSA relapse
Following radical prostatectomy, the definition of PSA
relapse is rather simple since the organ responsible
for the majority of PSA production has been removed,
although sometimes benign glands can be left behind
due to a nerve sparing procedure [5]. The PSA
level for recurrence following radical prostatectomy
is defined as 0.2ng/mL followed by a subsequent
rise [6]. Recently, however, there were proposals to
increase the PSA level to 0.4ng/mL, because this level
better explained the development of distant metastases
after controlling for clinical variables and use of
secondary treatments [7,8]. Some laboratories provide
ultrasensitive methods to determine PSA levels, which
could detect PSA relapse at a much earlier stage, but
in clinical trials these very low levels have never been
confirmed as useful in the definition of biochemical
failure (or they have never been used or reported).
In 1997, the American Society for Therapeutic
Radiology and Oncology (ASTRO) agreed that PSA
recurrence is an appropriate early endpoint for clinical
trials. Biochemical failure after radiation therapy was
defined as three consecutive increases in PSA. For
clinical trials the date of failure should be the midpoint
between post-irradiation PSA nadir and the first of
the three consecutive increases [9]. This ASTRO
definition was not linked to clinical progression or sur-
vival and it performed poorly in patients undergoing
androgen deprivation therapy, and backdating biased
the Kaplan-Meier estimates of event-free survival.
A second Consensus Conference was sponsored by
ASTRO and the Radiation Therapy Oncology Group
in Phoenix to revise the ASTRO definition [10]. The
panel recommended that a rise of 2ng/mL or more
above the nadir PSA be considered the standard
definition for biochemical failure after external beam
radiotherapy (EBRT) with or without short-term
hormone therapy. Nowadays, the two definitions are
often reported in most publications.
PSA response and bounce
Following radiotherapy the PSA decline is different
compared to radical prostatectomy where an almost
immediate disappearance can be observed according
to the PSA half-life if radical surgical resection has
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Treatment of local progression following radiotherapy
141
been accomplished. Following radiotherapy, a PSA
increase can first be observed due to cellular necrosis,
inflammatory changes and disruption of the cellular
membrane. Later, a rapid decline can be seen, followed
by a slower, but more sustained, decrease.
The reason why three, rather than two, consecutive
PSA values were proposed in the original ASTRO
recommendation for PSA progression was due to
the risk of ‘bouncing’. This phenomenon results
when, during follow-up, one or two increases in PSA
are observed followed by a sustained decrease. The
effect of PSA ‘bounce’ was reported following EBRT
and also post-brachytherapy for prostate cancer. It
seems that the incidence of the ‘bounce’ is higher
following brachytherapy compared to EBRT (40%
versus 12%) [11–14].
The magnitude of PSA increase and the occurrence
of PSA ‘bounce’ were evaluated in several series with
respect to subsequent failure. Mitchell and colleagues
found a lower rate of subsequent biochemical failure
in a prospectively collected database where PSA
‘bounce’ was defined as a rise of 0.2ng/mL above
an initial PSA nadir with subsequent decline to or
below that nadir without treatment. The patients who
received neo-adjuvant or adjuvant hormone manipu-
lation were excluded. Biochemical failure was deter-
mined using both the ASTRO consensus and Phoenix
definitions [15]. Horwitz and colleagues found an
increased risk of biochemical failure in patients with
a PSA ‘bounce’ following EBRT, while Crook and
colleagues found no relationship with PSA ‘bounce’
and subsequent biochemical failure following 125-I
prostate brachytherapy [13,16]. The reasons for these
different findings are not completely understood, but
definition and perhaps the use of different PSA kits
could be an explanation.
The PSA ‘bounce’ was independent of age, race,
pre-treatment PSA, clinical T-stage, Gleason score
and radiation dose although Hanlon and colleagues
concluded that ‘bouncing’ was associated with a
lower radiation dose and higher pre-treatment PSA
levels [17]. The median time of occurrence for this
phenomenon was 9 to 18 months from the time of
therapy and the majority of ‘bounces’ were observed
within 36 months. This phenomenon should of course
be fully understood by all doctors following patients
after radiotherapy for prostate cancer in order to re-
assure the patient.
PSA levels and nomograms
The initial PSA level is a determining factor for
eventual success of radiotherapy. 5-year biochemical
relapse rates were reported in 32%, 49% and 69%
of patients with an initial PSA of 10−20ng/mL,
20−30ng/mL and 30ng/mL or greater, respectively
[18]. The PSA nadir was also a strong prognostic
factor, with PSA recurrence-free survival rates of 83%,
68%, 56% and 28% if the PSA nadirs were 0.5ng/mL
or less, 0.6−0.9ng/mL, 1.0−1.9ng/mL and 2.0ng/mL
or greater, respectively.
The initially developed nomograms could help to
predict the risk of recurrence for EBRT and different
forms of brachytherapy by including different baseline
characteristics e.g. pre-treatment PSA, Gleason score
on biopsies and clinical T-stage. Since an increasing
number of patients were treated with combination
treatments (neo- and/or adjuvant hormonal therapy
for shorter or longer duration), the more recent
nomograms also included this as a baseline factor in
order to determine the risk of PSA recurrence [19–
22]. However, there are so many variables in treatment
techniques, durations and schemes of neo- and/or
adjuvant treatment that it is questionable if these
nomograms are very helpful for the individual pa-
tient.
Investigations in case of PSA recurrence
Physical examination
In case of a PSA only relapse, a physical examination,
and especially a digital rectal examination (DRE), is
usually not helpful in determining the site of relapse.
Due to the radiation the prostate has undergone
changes and can be displaced, which usually makes a
proper digital evaluation not possible. Only in the case
of a high-risk patient and a very early PSA relapse or
in the case of local symptoms can a local progression
be identified by DRE.
Transrectal ultrasound and biopsies
Transrectal ultrasound (TRUS) examination following
radiation therapy of the prostate is also not very help-
ful and certainly no better than DRE. No exact data
exist on the sensitivity, specificity, and positive pre-
dictive value in case of follow-up after radiotherapy,
but these figures will not differ significantly from the
data for the initial work-up in case there is suspicion of
prostate cancer, approximately 32−85%, 41−89%, and
20−76%, respectively [23]. In the field of TRUS many
new developments (e.g. Doppler sonography, contrast-
enhanced TRUS, elastography) are now being evalu-
ated in the initial work-up of patients with elevated

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T.M. de Reijke, T. Wiegel
PSA. Some of these improved sonographic investiga-
tions have already shown promising results but, in the
field of evaluation of PSA recurrence following radi-
ation treatment, no data are available yet [24–26].
Following radiation therapy there is no role for
routine follow-up prostate biopsies. It is known that it
takes up to 3 years for biopsies to convert to negative,
so there is no role for taking routine prostate biopsies
before 3 year follow-up unless there are other clinical
reasons [27].
In case local recurrence is suspected and the
demonstration of local recurrence has clinical con-
sequences, prostate biopsies are indicated. However,
no prospective data exist on the number and location
of the biopsies, but it would be recommendable to
target the biopsies to the previously positive location of
the biopsies, although this information will frequently
be lacking. The number of biopsies should not differ
from that of the initial work-up of an elevated PSA,
i.e. 12 biopsies. The interpretation of post-irradiation
biopsies should be done with great care, especially
if radiation was combined with hormonal therapy,
because morphological changes may be present that
resemble prostate cancer, but in fact these may just be
radiation-induced changes [28].
Bone scintigraphy
Bone scans are indicated in the initial work-up in
the following cases: PSA is greater than 20ng/mL,
higher clinical stage or Gleason grade. In the situation
of a demonstrated PSA relapse following radiation
therapy, a rapid slope or a PSA greater than 40ng/mL
are indications to perform bone scintigraphy [29,30].
However, in case a second local therapy is considered,
distant metastases should be excluded, and certainly
if the PSA relapse occurs early following radiation
therapy. In cases of salvage therapy, a complete work-
up will usually be performed, including a bone scan.
Computer tomography (CT)-scan
In spite of improvements in imaging techniques, a CT-
scan is not the most sensitive technique for identifying
prostate cancer or excluding the presence of metastatic
disease. The diagnostic accuracy ranges between 50
and 60%. Johnstone and colleagues concluded that
only in the case of a rapidly increasing PSA could a
CT-scan be of any value [30].
Magnetic resonance imaging (MRI)
Thanks to the technical improvements and introduction
of the endorectal coil, the diagnostic accuracy of MRI
increased, compared to CT-scans, to 60−70%. MR-
spectroscopy is evaluating metabolism properties of
different areas in the prostate, choline/citrate ranges,
which can increase the diagnostic accuracy again to
70−90%. However, these data are obtained in the
initial work-up of patients suspected for the presence
of prostate cancer; if these figures are also to apply for
patients presenting with PSA relapse, further research
is needed. For the evaluation of lymphogenous spread,
ultrasmall superparamagnetic iron oxide (USPIO)-
enhanced MRI seems very promising with a detection
limit for lymph node metastases of 4mm [31].
Positron emission tomography (PET)-scan
The role of PET-scan is not clearly defined at this
moment due to conflicting reports on the accuracy of
demonstrating local and/or distant recurrences. Differ-
ent techniques are being used at this moment which
makes interpretation of the published data difficult.
[18]fluorocholine PET/CT can be performed to
exclude distant metastases in patients with PSA levels
greater than 4ng/mL and 11C-choline PET/CT seems
a valuable tool to demonstrate recurrent prostate can-
cer, but the limited positive predictive value warrants
careful interpretation of these data [32,33]. Further
studies using these techniques have to be awaited
before PET-scans can be introduced in the work-up
of patients who are candidates for salvage treatment
following radiation treatment.
Timing of salvage treatment
Once a PSA relapse has been demonstrated the most
important question is if the patient is a candidate for
salvage treatment with curative intent or not. It has to
be realised that combination treatment also implies a
higher risk of morbidity.
In order to discuss salvage treatment the patient
should have a good performance status, the morbidity
of the initial radiotherapy should have been minimal,
the metastatic work-up should be negative and the life
expectancy should be at least 10 years.
In case of a biochemical relapse following radical
prostatectomy, it has been shown that it takes at
least 8 years before metastatic disease is demonstrated
without any treatment and another 5 years until
patients die [34]. In the survival analysis, time to
PSA recurrence, Gleason score and PSA doubling time
were predictive factors of the probability and time
to metastatic disease. Whether the same is true for
PSA relapse following radiotherapy is not known, but
these facts should be taken into consideration when
counselling a patient for a salvage procedure.

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143
Salvage treatments
In early publications it was reported that salvage
treatments had a poor outcome, due to the observation
that many patients had marginal positive disease
and/or lymph node metastases in the pathological
specimen. Also, an increase in Gleason score and ane-
uploid tumours was found and this resulted in a poor
outcome [35,36]. However, due to the introduction of
PSA, radio-recurrent disease can be detected earlier
and patients treated initially have been better staged
and possibly had lower prostate cancer volume; these
factors could result in better outcomes for patients
once treated with a salvage treatment.
Salvage radical prostatectomy
Apart from a biochemical recurrence the reason for
salvage radical prostatectomy could also be indicated
if there is severe toxicity, e.g. incontinence, radiation
cystitis or a contracted bladder. The proposed indi-
cations for salvage surgery are a PSA <10ng/mL,
PSA doubling time >12 months, ?T3a stage and
N0M0 [37].
The series of salvage surgery reported in the
literature comprise only small numbers of patients;
the oncological outcome with a median follow-
up of 2−92 months showed a 5-year failure-free
survival of 31−83% [38]. The reported morbidity was
considerable: urinary incontinence: 17−67%, rectal
injury: 4−8%, erectile dysfunction: 100%, bladder
neck stricture: 0−41%, and mortality: 0−4%. These
data have to be interpreted with great care because
of patient selection, the small number of patients and
short follow-up.
Following interstitial radiotherapy, only small series
have been reported, but the outcome does not seem
different from patients treated following EBRT [39].
Salvage radical prostatectomy is nowadays also
feasible via the laparoscopic approach [40].. It is clear
that these salvage procedures should be performed
in centres of excellence and the data should be
collected prospectively in order to obtain conclusions
on which patients are best suitable for salvage radical
prostatectomy.
Salvage radiation treatment
Since many patients that are in follow-up have been
treated with doses that are nowadays considered
insufficient, there could be room for salvage radiation
treatment. Different scenarios are possible in this
case: patients treated with EBRT could be treated
with salvage EBRT or brachytherapy and vice versa.
Of course, patients qualifying for salvage radiation
therapy should not have radiation-induced toxicity
from the initial treatment.
The series on salvage brachytherapy reported are
again small; oncological outcome with a median
follow-up of 19−64 months showed a 5-year failure-
free survival rate ranging from 20−89%. The mor-
bidity was considerable: urinary incontinence: 0−31%,
rectal grade 3−4 toxicity: 0−24%, genito-urinary
grade 3−4 toxicity: 0−47%, and prostatic-rectal fistula:
0−12% [38]. The series are difficult to compare since
different forms of brachytherapy were used (palla-
dium, iodine and iridium). Salvage brachytherapy
and salvage EBRT following initial brachytherapy are
incidentally reported and no clear recommendations
can be made from these small, highly selected
series [41].
Salvage cryotherapy
The technique for cryotherapy has been improved con-
siderably in recent years, especially the introduction
of the transperineal ultrasound-guided implantation
technique using thin needles which has reduced
toxicity and improved outcome for the treatment of
primary diagnosed prostate cancer [42].
The technique has now also been introduced for
salvage procedures because it has the theoretical
advantage of no radiation being used and the formation
of the ice ball can be monitored accurately. The
median follow-up of the series reported in the litera-
ture ranges from 12−82 months. Different cryotherapy
techniques were used in these series resulting in a
failure-free survival rate of 18−77%. Different PSA
criteria were used for defining success, which makes
comparison difficult. The reported percentages for
morbidity were: urinary incontinence 4−96%, tissue
sloughing 0−55%, bladder neck stricture 0−55%, and
fistula 0−11% [38]. In a recent series using up-
to-date equipment the 5-year biochemical relapse-
free survival was 73%, 45%, and 11% for low-
, intermediate-, and high-risk patients, respectively,
with a median follow-up of 33.5 months [43]. The
reported morbidity figures were: urinary incontinence
13%, erectile dysfunction 86%, lower urinary tract
symptoms 16%, and fistula 1%.
New minimally invasive salvage procedures
High intensity focused ultrasound (HIFU)
HIFU is a relatively new technique combining an
imaging and treatment modality using ultrasound.

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T.M. de Reijke, T. Wiegel
It destroys tissue with rapid heat elevation, which
essentially “cooks” the tissue. Ultrasound energy is
focused when transrectal ultrasound is guided at a
specific location and at that focal point the temperature
rises to 90ºC in a matter of seconds. This technique
is applied in some centres for the primary treatment
of localised prostate cancer. Long-term data are still
lacking, but the technique seems feasible. Recently, a
retrospective analysis was published on the application
of HIFU in radio-recurrent disease [44].
Local cancer control with negative biopsies was
achieved in 122/167 patients (73%) with a short
median follow-up (18.1 months). Urinary incontinence
rates were considerable (49.5%) and in 18 patients an
artificial urinary sphincter prosthesis was implanted.
Five patients developed a recto-urethral fistula. This
technique should not be applied in patients that present
with a PSA relapse following brachytherapy with
permanent seed implants, because the recto-urethral
fistula rate is then increased, probably due to impaired
blood supply near the rectum or HIFU-associated near-
field heating of the rectal wall [45].
Vascular targeted photodynamic therapy
Photodynamic therapy for prostate cancer has only
been used in a small cohort of patients and only
early reports have been published on this new tech-
nique. This technique applies photosensitisers that
are activated on different wavelengths. Several agents
have been explored in phase I/II studies and showed
minimal morbidity. Following a phase I trial exploring
photosensitiser and light doses, Trachtenberg and
colleagues reported on 28 patients treated with this
technique [46,47]. In this series, avascular areas could
be created based on MRI images and the tumour
burden could be decreased based on the outcome of
6-month biopsies. This is an evolving technique that
should be explored in well-defined studies in order
to demonstrate reproducibility and to produce long-
term outcome data. The treatment can be given in an
outpatient setting and the authors concluded that the
morbidity of this salvage therapy was low, although
two recto-urethral fistulas were seen.
Focal therapy
Since the follow-up of patients with localised prostate
cancer treated with potential curative intent is more
stringent and early relapses are diagnosed at an earlier
stage, the question arises if salvage treatment should
entail the whole prostate once PSA only recurrence has
been demonstrated. Due to improvements in imaging
modalities, recurrent tumour areas within the prostate
can possibly be identified and, hopefully in the near
future, the dominant tumour area within the prostate
can also be identified using new molecular techniques.
The possible advantages of focal therapy are the
reduction of toxicities using subsequent treatment
modalities because that is still a matter of great
concern with all existing salvage treatment modalities.
In fact, all the described techniques can be used for
focal therapy and in the literature the first reports have
appeared for using focal therapy as initial treatment or
salvage therapy [48–50].
Hormonal therapy
In case of metastatic disease androgen deprivation
therapy is indicated, but based on the outcome of
several phase III trials there is also a role for the
combination of hormonal therapy with EBRT for
specific high-risk patient groups. However, if only
biochemical recurrence is found, the role of androgen
deprivation has not been clearly defined until now. The
important question is if early hormonal therapy is as
good as delayed hormonal therapy. Some studies have
appeared randomising patients between immediate
and delayed hormonal therapy as initial therapy,
showing conflicting results. The Medical Research
Council (MRC) initially reported that patients with
M0 disease as well as M+ disease benefited from
early hormonal therapy, but in a later, not published,
report it was said that this benefit was only apparent
for patients with M0 disease [51,52]. The European
Organisation for Research and Treatment of Cancer
Genito-Urinary (EORTC GU) group also investigated
the role of immediate versus delayed therapy in
approximately 1000 patients that were not candidates
for primary treatment with curative intent. The trigger
to start hormonal therapy in the delayed arm was
symptomatic progression and not PSA progression
only. It was demonstrated that immediate androgen
deprivation resulted in a modest but statistically
significant increase in overall survival but no sig-
nificant difference in prostate cancer mortality or
symptom-free survival [53]. In a further analysis of
this trial, risk groups for progression in the delayed
treatment arm were identified: patients with a baseline
PSA greater than 50ng/mL and/or a PSA doubling
time less than 12 months were at increased risk of
dying from prostate cancer and might have benefited
from immediate androgen deprivation therapy, whereas
patients with a baseline PSA less than 50ng/mL and
a slow PSA doubling time (>12 months) were likely

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Treatment of local progression following radiotherapy
145
to die of causes unrelated to prostate cancer, and thus
could be spared the burden of immediate androgen
deprivation [54]. These data do not directly apply to
biochemical recurrence following radiation therapy,
but this group of patients can be considered to have
advanced disease and the criteria identified in this
EORTC GU group study could be used to counsel the
patient on the timing of hormonal therapy. A specific
problem can be the group of patients that have been
treated with a period of neo- or adjuvant hormonal
therapy and who develop biochemical recurrence. The
androgen deprivation treatment could have modified
the androgen receptor and this could result in a
worse outcome of starting hormonal therapy again.
Hormonal therapy in the trials mentioned was given
in the form of a chemical (LHRH analogue) or
surgical castration. This treatment induces short-term
and long-term side effects, which have to be taken into
account when discussing immediate therapy, especially
if treatment is started at the time of first demonstration
of PSA relapse, where most patients will receive
androgen deprivation therapy for a (very) long period
of time. The recently identified metabolic syndrome
and high chance of osteoporosis is especially a risk
for this older patient group [55,56]. Because of these
issues other forms of hormonal manipulation have
been explored, e.g anti-androgen monotherapy, inter-
mittent androgen deprivation and 5-alpha reductase
inhibitors alone or in combination. These treatments
are all investigational in this setting and no strong
recommendations can be made on their role for PSA
relapse following radiation treatment.
Conclusion
The treatment of biochemical relapse only following
radiation treatment is still controversial and the
optimal treatment and timing of treatment are not
known. The patient is concerned with the fact that,
following unsuccessful initial treatment with curative
intent, salvage treatment might induce considerable
morbidity, which will have an impact on his quality of
life. Based on clinical data and new evolving imaging
modalities, local or systemic recurrence can nowadays
be predicted in a better, but still not optimal way. In
case of local recurrence a salvage treatment can be
discussed, although the best modality is not yet known
and it is clear from the scarce literature that the salvage
procedure will add to the already present toxicity. The
patient opting for salvage treatment should have a
good life expectancy and a good performance status,
but it remains a matter of discussion between the
doctor and the patient to decide which treatment is best
in each individual case. New developments are being
explored and although these are called ‘minimally
invasive’, the morbidity can still be significant in a
salvage approach. Well designed clinical trials are
necessary in order to define which patients will benefit
most from salvage treatment and which technique is
the best. Follow-up procedures should be defined and
evaluation of outcome parameters of salvage strategies
determined, because the used parameters have not
been tested in this setting. Besides the evaluation of
new imaging procedures and the described salvage
techniques, collaboration with molecular biologists,
pathologists and others is essential in order to de-
termine which recurrent tumours are at risk, based
on molecular/genetic/metabolomic profiles, and need
a salvage procedure.
Conflict of interest statement
None declared.
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