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european urology supplements 7 (2008) 410–415
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What Does Failure After Surgery or Radiation Mean?
Noel W. Clarke *
Christie and Salford Royal Hospitals, Manchester, UK
Article info
Abstract
Keywords:
Prostate cancer
Rising PSA
ASTRO 2006 definition
Postprostatectomy failure
Radiation failure
Objective: The accurate definition of what constitutes treatment failure
after surgery and radiotherapy for localised prostate cancer is critical to
patient management. The current post-radiotherapy (post-RT) standard
is the 2006 ASTRO definition of an increase of 2 ng/ml above the nadir
level. After radical prostatectomy (RP) one definition is the detection of
prostate-specific antigen (PSA) at or above 0.2 ng/ml following surgery,
although some might argue that any detectable PSA is a sign of treatment
failure.
Diagnosis and Treatment: The localisation of the origin of the PSA rise is
difficult, and imaging and/or biopsy is often unhelpful. Postsurgical
recurrence is present in the pelvis in a significant proportion of patients.
Prostate/seminal vesical biopsy can be helpful in the post-irradiation
setting, but the utility of cross-sectional imaging of the primary site is
limited. PSA kinetics can be helpful in identifying aggressive disease, but
PSA bounce must be considered, particularly after brachytherapy and
high dose RT. Treatment responses are seen in patients, particularly
when the PSA is <0.2 ng/ml and the interval to PSA failure is >18 months,
but side effects can be significant.
Conclusions: The natural history of progression after failure is often
prolonged. Most importantly, a significant number of men who fail
treatment will not die of prostate cancer. This should be borne in mind
when considering salvage therapy to the primary with interventional
procedures, or systemic treatment with adjuvant hormonal and/or other
therapies. Treatment can help some patients, but there is considerable
associated morbidity in many cases. In the post-treatment failure scenario, it is critically important to consider the risk–benefit ratio for
individual patients.
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1.
Defining treatment failure
The critical answer to the question lies in the
definition of treatment failure, because subsequent
management of patients is predicated on this. It is
therefore of fundamental importance that clear
definitions are established to plan therapy and to
interpret the outcomes of salvage treatment. Only
1569-9056/$ – see front matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2008.01.017
european urology supplements 7 (2008) 410–415
when the treatment failure has been defined and the
nature of that failure determined as accurately as
possible it is possible to direct therapy appropriately
and safely.
1.1.
Biochemical failure after RT
Prostate cancer is usually a slowly progressive
disease. In this specific patient population, there
are various competing causes of death, and
biochemical failure per se is not always associated
with clinical symptoms or cancer-specific mortality. Many attempts have been made to define
biochemical failure after radical prostatectomy
(RP) or radiation therapy (RT). Whilst this approach
is a useful aid to clinical decision making, it has
proved difficult in practical terms to define
treatment failure precisely and universally, particularly in the early stages of prostate cancer
progression. The reason for this difficulty lies in
the differing effects of surgery and RT on posttreatment PSA levels and the idiosyncratic effects
of the PSA after different types of RT, notably the
‘‘PSA bounce’’ effect after brachytherapy and high
dose RT.
The old definition of PSA failure followed the
American Society for Therapeutic Radiology and
Oncology (ASTRO) consensus conference of 1996, in
which it was agreed that failure was defined as
three consecutive rises in PSA after a nadir, with the
date of failure being the point half way between the
nadir date and the first rise, or any rise great enough
to provoke initiation of salvage therapy. Because of
problems with this definition, particularly the noncomparability of survival estimates based on different follow-up periods and a failure to link the
criteria to clinical outcomes, a second ASTRO
consensus conference re-defined biochemical failure following RT, publishing the ‘‘Phoenix definition’’ [1]. This definition defines failure after
external beam RT as ‘‘an increase of 2 ng/ml or
more above the nadir PSA (ie, the lowest PSA
reached following treatment). The data used to
arrive at this definition suggest that there is a
sensitivity and specificity of 66% and 77%, respectively for predicting clinical failure at 10 yr. Patients
who undergo salvage therapies without meeting the
PSA failure definition should also be counted as
failures at the time of positive biopsy or salvage
treatment, whichever is first. A further recommendation is that control rates are quoted 2 yr before the
median follow-up to avoid the reporting artefacts.
Ongoing research and treatment protocols have
now adopted this definition as the standard for
post-RT treatment failure after external beam RT.
1.2.
411
Defining failure after surgery
The definition of PSA failure after radical prostatectomy differs by virtue of the fact that the prostate
is removed; theoretically, there should be no
residual PSA in the absence of local residue/
recurrence or metastatic disease. In a recent review
of the published definitions of biochemical recurrence after surgery and RT by the American
Urological Association (AUA) guideline panel [2],
recommendations for a standard definition in
patients treated with RP were suggested. This review
followed the realisation that there was no clearly
agreed definition of biochemical recurrence after
surgery. Of 436 papers dealing with clinically
localised T1–2 disease that were analysed, 145
papers contained 53 different definitions of biochemical recurrence following RP. The AUA panel
recommended defining biochemical recurrence as
an initial serum PSA 0.2 ng/ml, with a second
confirmatory level of PSA > 0.2 ng/ml. Although this
definition has been adopted by the AUA, it is not
universally recognised at the present time.
2.
Differentiating local recurrence from
metastatic disease
In the setting of a rising PSA following treatment, it
is often difficult to be sure whether the rise in the
tumour marker is a consequence of local or distant
failure. In the case of RT, it is possible to biopsy the
prostate; this approach has proven to be of value in
some circumstances, both in directing treatment
and in ascertaining prognosis [3]. However, after RP,
local biopsy is of limited value. The positivity rate
can be as high as >50% in some reports [4], but most
practitioners do not find this procedure to be
helpful, because a negative biopsy creates uncertainty, usually resulting in treatment and a positive
biopsy would trigger a decision to treat in any case.
Post-RP treatment with RT is therefore directed to
the pelvis on the basis that it is the most likely
source of the measured PSA. Long-term follow-up of
the Southwest Oncology Group (SWOG) 8794 study
bears out this approach to a degree: 10-yr follow-up
confirms the relatively high rate of biochemical
control in patients with a PSA below 0.2 ng/ml [5].
One of the more helpful predictors enabling
prediction of the location of the cancer is the
interval to biochemical failure after RP. A study of
post-RP patients with PSA failure showed that an
interval to biochemical failure (IBF) of <18 mo was
the only predictor of prostate cancer-specific mortality (PCSM) [6]. In this report, the actuarial 5-yr
412
european urology supplements 7 (2008) 410–415
disease mortality rate for an IBF of <18 versus 18
mo was 52% versus 20%, and the actuarial PCSM rate
was 36% versus 6%, respectively. The authors
concluded that the IBF is an important discriminator
of PSA kinetics after RT in identifying local versus
distant disease.
3.
Implications of PSA kinetics and PSA
bounce
PSA doubling time (PSADT) has been reported to be
an important post-treatment predictor of distant
disease [7] and prostate cancer death; this parameter is thought to reflect the biology of the prostate
cancer. There is a gathering body of literature
on this subject. In a recent review [8] of all articles
on PSADT published after 2000 that looked at
this situation, six studies with the largest and
best-documented cohorts of patients treated
with surgery or irradiation were analysed. The
results showed that PSADT was the most effective
parameter for identifying patients at significant
risk for mortality specific to prostate cancer,
and that PSADT was a reliable predictor of
prognosis. However, it is accepted that prospective
validation is needed to optimise its use and to
determine specific cut points in determining
prognosis.
One effect that can mimic an adverse PSADT or
that may be considered PSA relapse according to the
current ASTRO criteria is PSA ‘‘bounce.’’ This term
refers to the phenomenon whereby the PSA exhibits
a transient and often late rise, usually in association
with brachytherapy or high dose RT. In a recent
study of 295 patients treated with brachytherapy,
49% exhibited a transient PSA rise of >0.2 ng/ml; the
mean time to ‘‘bounce’’ was 18 mo [9]. This finding
emphasises the need for cautious interpretation of
PSA kinetics in this population.
4.
The natural history of progression after PSA
recurrence
The first important paper studying PSA recurrence
[10] showed that men who had PSA relapse after
prostatectomy and had no additional intervention
had a mean actuarial time of 8 yr to the development
of metastasis and, thereafter, a period of 5 yr to
death. The natural history of the disease, therefore,
is relatively long for many men in this age
category. Further study of this phenomenon is
facilitated by additional data from this and other
US groups looking at the actual outcomes in
patients undergoing RP [11–13]. These case series
show that not all of the patients undergoing surgery
and developing subsequent PSA relapse go on to
manifest clinical problems or die from their disease.
In the first study [11], the number of men who
developed PSA relapse and/or metastasis at 5 yr was
16% and 4%, respectively; only 1% suffered a
prostate cancer death. At 10 yr the PSA failure
and metastasis rate were 26% and 10%, respectively,
with only 4% going on to die specifically of the
disease. In the second series [12], which looked at
an earlier cohort of patients, the 10-yr PSA,
metastasis, and cancer-specific death figures were
48%, 18%, and 10%, respectively. Similar data
have also been reported by another large US
group [13], who found that in patients undergoing
RP the 5-yr PSA failure rate was 41%, but clinical
failure was seen in only 16%. It is clear from these
data that, in the 10 yr following prostatectomy and
PSA relapse, about 35% will develop metastases, but
only about 20% will die specifically of their prostate
cancer.
The published figures for failure following RT are
difficult to compare with those seen with surgery
because of the inevitable differences in clinical and
pathological staging and the more widespread use
of neo- and adjuvant hormonal therapy. The
results for RT tend to have the appearance of being
slightly worse stage for stage compared with those
RP; whether these results are true is uncertain. In a
report studying treatment failure in patients
treated under the aegis of the Radiation Therapy
Oncology Group (RTOG) 86-10 study [14], the
overall 5-yr freedom from failure and overall
survival rates after RT were 69% and 90%, respectively. In patients with locally advanced disease,
results for biochemical failure, development of
metastases, and cancer-specific death at 8 yr for RT
alone and RT plus 4-mo androgen-deprivation
therapy (ADT) were 90% and 76%, 45% and 34%,
and 31% and 23%, respectively [15], confirming
the facts from the surgical series that PSA relapse
does not necessarily equate to metastasis and
cancer-specific death in many of the patients. The
median time to PSA relapse in this series is
between 20 to 24 mo, with death occurring about
5 yr from the time of PSA failure. It is important
to be aware that figures quoted from all these
series are from an older cohort, and in some
cases, from practice carried out in the pre- or earlyPSA era. The current day actuality may be even
lower in more recent practice when the lead
time effects on natural history arising as a consequence of screening and early detection is
considered [16].
european urology supplements 7 (2008) 410–415
5.
Salvage therapy following primary
radiation failure
A full review of the various salvage therapies is
beyond the scope of this article; however, there is a
worrying lack of level 1 evidence from randomised
trials in this field.
Salvage radical prostatectomy is an option for
selected patients; the authors of some expert groups
consider the morbidity profile to be ‘‘acceptable’’
[17], although scrutiny of the results confirms
a relatively high complication rate. Similarly, salvage cryotherapy is successful in establishing
biochemical control, especially in recurrent lowrisk patients, but success measured as patient
survival is very disappointing, being as low as 11%
in high-risk groups. The morbidity of the procedure
is significant, with 13% incontinence, 4% chronic
perineal pain, and a small but significant rectal
fistula rate [18].
Whatever salvage therapy considered, the morbidity associated with treatment is considerable. A
review of all series of post-RT therapies, including
salvage prostatectomy, cryosurgery, and brachytherapy from 1990 onwards [19], confirmed this
morbidity unequivocally. Urinary incontinence was
greater after salvage prostatectomy (41%) or cryosurgery (36%) than after brachytherapy (6%), but 17%
of brachytherapy patients had a risk of grade 3 or 4
genitourinary complications. Furthermore, the rectal fistula risk averaged 3.4% across all series.
Rightly, the authors conclude that ‘‘prospective
randomized studies are needed to determine the
relative efficacy of the 3 major local salvage
modalities’’ and that this parameter should be allied
to an estimation of the risk–benefit ratio.
6.
The case for immediate versus early
salvage treatment post-RP
The current management of patients with PSA
failure or high-risk features after RP is uncertain,
as exemplified by the variation in practice in this
clinical scenario. In two separate clinical surveys,
there were widespread differences in practice.
Amongst urological oncologists, 51% did and 49%
did not recommend adjuvant RT for pT3 marginpositive cases [20], whilst a survey of oncologists and
urologists showed differences in the use of adjuvant
RT as well as the mode, timing, and duration of
hormone therapy [21].
The most common scheme of treatment currently used is RT to the prostatic bed when there is
evidence of PSA failure. However, it is important to
413
note that only two randomised controlled trials of
adjuvant RT are currently in the international
literature. The European Organization for Research
and Treatment of Cancer (EORTC) 22911 study
randomised patients with pT3 disease post-RP
between observation and adjuvant RT [22]. A
significant advantage for freedom from biochemical
and clinical progression was seen for adjuvant RT
(hazard ratio, 0.48) at 5 yr. An advantage was also
reported for adjuvant RT in terms of clinical
progression-free survival (HR, 0.69; 98% confidence
interval, 0.43, 0.87; p = 0.004) with 87% and 77% PFS
event-free at 5 yr, but there was no evidence of a
difference in overall survival.
The second randomised controlled trial [23] of 425
men with pT3 disease (SWOG 8794/National Cancer
Institute of Canada Clinical Trials Group protocol 2
[NCIC CTG PR-2]) randomised patients with pT3
disease to observation or prostate bed RT. Again,
adjuvant RT improved biochemical control (HR, 0.43)
and was associated with a trend towards better
metastasis-free and overall survival.
Since the design of these studies’ standard
practice has changed to the extent that patients
with a previously undetectable postoperative PSA
level have their static and dynamic PSA changes
measured at a much earlier stage with more
sensitive PSA assays. It is distinctly possible that
these patients will have a lower risk of relapse than
in the past, and there is a good rationale for
randomised trials in this setting. However, there
are few trials addressing this subject. A number of
studies, such as EORTC 30094, address the use of
adjuvant RT with or without additional treatment
(mainly hormones) in high-risk disease, but few deal
with the question of treatment combinations and
the timing of therapy in the residual or rising PSA
setting postsurgery. One trial [24] recently initiated
is the UK (NCRI) and Canadian (NCIC) RADICALS trial
of early/delayed RT with or without short- or longterm hormones post-RP; this trial will test the timing
of treatment and the use of hormones in this setting.
7.
PSA failure and adjuvant/early hormone
therapy
There are currently a limited number of randomised
controlled trials addressing the role of hormone
therapy in men receiving postoperative RT or for
men failing surgery. Three retrospective nonrandomised studies have compared the outcome of
salvage RT alone versus salvage RT plus short-term
(4–6 mo) hormone therapy. All of these have
observed improved biochemical control rates with
414
european urology supplements 7 (2008) 410–415
the addition of hormone therapy [25–27]. The RTOG
96-01 trial [28] recruited 840 patients with PSA failure
after radical prostatectomy and randomised them to
early salvage RT versus early salvage RT plus 2-yr
hormone therapy. The first outcome data are not
expected until 2008. There is, however, a gathering
body of evidence regarding the adverse effects of
ADT in early prostate cancer, and timing of ADT in
the setting of PSA failure after local treatment is very
uncertain. This finding is of particular importance in
the setting of PSA failure in screen-detected and
low-risk prostate cancer, whose natural history is
long and whose overall cancer-specific survival is
good. In the large Astra-Zeneca–based Early Prostate
Cancer Trial (EPC) using Casodex [29,30], there was a
small increase in mortality in patients with relatively early localised disease. There are also
increases in the risk of hitherto unrecognised
side-effects including weight gain, fatigue, anaemia
[31,32], bone loss [30,33,34] cardiovascular disease,
insulin resistance, lipid disorders, and loss of
cognitive function. The critical issue therefore is
when to start ADT in the event of PSA failure. The
goal of starting ADT in these patients is the
avoidance of distressing symptoms in the long
term. There is little point in using ADT if it is
associated with a number of side-effects that offset
its palliative merit. This issue is to be addressed in
two newly planned trials run by the Trans-Tasman
Group (the TOAD trial) and the Canadian Urology
Oncology group (the Early vs. Late Androgen Ablation Trial [ELAAT]), but there is a need for other
groups to join these initiatives to determine more
accurately the best form of intervention with the
minimum morbidity in this patient group.
8.
Conclusions
PSA is critically important as a marker of disease
progression in men who have undergone primary
treatment for prostate cancer. However, its use can
create uncertainty for the clinician when interpreting the significance of a PSA rise, particularly with
regard to the necessity and timing of further
treatment in individual patients. Although evidence
suggests that a number of the existing salvage
therapeutic modalities appear to offer significant
numbers of men a benefit in terms of prevention of
PSA progression, their effect on prostate cancerspecific and overall survival in all cases is less clear.
For the future, it is the responsibility of the
urological community to examine these important
clinical questions in randomised trials when possible and, when it is not, to record and report
accurately the results of treatment both in terms
of its therapeutic effect and its morbidity. In all of
this it is necessary to ensure that the benefit-risk
ratio for the patient is on the side of the former,
without too great an exposure to the latter.
Conflicts of interest
The author has nothing to disclose.
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