Download The role of surgery in high‐risk localised prostate cancer

R EVI E W A R T IC L E
The role of surgery in high-risk
localised prostate cancer
BJUI
BJU INTERNATIONAL
Vincent J. Gnanapragasam, Malcolm D. Mason*,
Greg L. Shaw† and David E. Neal†
Translational Prostate Cancer Group, Department of Oncology, Hutchison/MRC research
centre and †Cambridge Research Institute, University of Cambridge, Cambridge,
*Department of Oncology, Cardiff University, Velindre Hospital, Cardiff, UK
Accepted for publication 10 June 2011
• The optimal management of high-risk localised prostate cancer is a major challenge for
urologists and oncologists. It is clear that multimodal therapy including radical local
treatment is needed in these men to achieve the best outcomes.
• External beam radiotherapy (EBRT) is an essential component of therapy either as a
primary or adjuvant treatment. However, the role of radical prostatectomy (RP) is more
controversial. Both methods are currently valid therapy options.
• There have been many individual studies of EBRT and RP in high-risk disease, but no good
quality large prospective randomized trials.
• In EBRT, combination with neoadjuvant plus long-term adjuvant androgen-deprivation
therapy (ADT) has been conclusively shown to improve outcomes and is widely considered
the standard of care.
• However, the role of RP has achieved recent prominence with several important studies.
Published data from prospective randomized trials in patients after RP have shown that in
men with adverse pathological features at surgery, the addition of adjuvant RT improves
biochemical-free and progression-free survival.
• More recently, studies from large-volume centres comparing EBRT and RP have provided
intriguing suggestions of better outcomes with RP as the primary treatment.
• An important question therefore, is which of the two methods provides the best
outcome in men with localised high-risk disease. Crucially, does the combination of RP
and selective adjuvant EBRT provide clinically significant better outcomes compared with
EBRT alone?
• In this review we discuss the current evidence for the role of RP for high-risk localised
prostate cancer and define the parameters and urgent need for a prospective trial to test the
role of surgery for this group of patients.
KEYWORDS
INTRODUCTION
648
high-risk prostate cancer, radical prostatectomy, radical radiotherapy
Men presenting with high-risk prostate cancer represent a significant proportion of patients
treated by radical therapy either by external beam radiotherapy (EBRT) or radical
prostatectomy (RP). In a review of 2380 men treated by EBRT or RP in the Memorial
Sloan Kettering Cancer Centre in the USA, 17% were classed as having high-risk disease [1].
In the UK, contemporary surgical series from tertiary centres have identified that up to 13%
of men will have high-grade disease [2]. In published UK and USA EBRT series, high-risk
disease has been reported in 17–19% of men [3,4]. In our own institution a recent review
identified 10% of men treated by RP and 16% of men treated by EBRT have high-risk
disease ([5] and unpublished data). Men with high-risk disease have the highest incidence of
treatment failure from radical therapy and disease progression and mortality [6,7]. These
factors implicate high-risk prostate cancer as a key priority for improving prostate cancer
outcomes.
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ROLE OF SURGERY IN HIGH-RISK LOCALISED PROSTATE CANCER
The most widely accepted definition of
high-risk disease is based on D’Amico’s risk
classifications and is used in several national
guidelines including those published by the
AUA, European Association of Urology (EAU)
and the UK National Institute for Health and
Clinical Excellence [8–10]. These include a
Gleason sum score of ≥8, or at least T2c
clinical stage or a presenting PSA level of
≥20 ng/mL. High-risk disease is increasingly
being defined by a high PSA level and
high-grade disease as there is evidence of
stage migration as a consequence of
screening programmes or serendipitous PSA
testing. In the pre-PSA era, organ-confined
prostate cancer was found in ≈67% of men
in the USA, while in 2000 this figure was up
to 80% [8]. This pattern is also rapidly
emerging in the UK and many men are
presenting with more localised disease [11].
An increasingly relevant clinical question
therefore is the role of surgery and RT in the
treatment of high risk apparently localised
disease at the point of presentation.
RP is an effective treatment for men with
localised low- and intermediate-risk prostate
cancer. However, its role in the management
of high-risk disease remains keenly debated.
RP for high-risk localised prostate cancer
is an attractive therapy option. It is the
only method that provides definitive
histopathological information as well as
providing excellent loco-regional control. In
addition, it allows for early detection of
treatment failure when the PSA level fails to
become undetectable or starts to rise. RP for
localised high-risk disease in expert hands
offers a high probability of delivering
long-term control without the need for
prolonged adjuvant systemic therapy. In
men who do need additional therapy,
adjuvant EBRT has been shown to provide
an excellent chance of long-term control
[12]. However, surgery does carry risks of
mortality and morbidity as well as
troublesome side-effects. Wide non-nerve
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sparing dissections, and extended lymph
node (LN) removal can also add to the
surgical morbidity and complications. The
important question therefore is whether
surgery offers a benefit over primary EBRT
for this group of men. In this review we
discuss the evidence for surgery in localised
prostate cancer as a primary therapy for
high-risk disease and define the need and
issues for a randomized trial comparing RP
with EBRT in this context.
OUTCOMES OF RADIOTHERAPY (RT) FOR
HIGH-RISK PROSTATE CANCER
after RT in particular seems advantageous;
although whether all patients should be on
long-term ADT, and for how long, is an area
of current debate [24–26]. Currently, both
the AUA and EAU prostate cancer guidelines
advocate RT with neoadjuvant and adjuvant
ADT for at least 2 years [8,9]. An on-going
uncertainty until recently has been the
relative contribution of EBRT and ADT in
achieving the results in RT trials. The recent
Scandinavian Prostate Cancer Group
(SPCG)-7 and National Cancer Institute of
Canada Clinical Trials Group (NCIC CTG) PR3/
MRC PR-07 studies have now shown that it
is the addition of RT to ADT that confers the
best survival advantage [27,28].
Radical RT is currently the most common
Most EBRT trials have been composed of
treatment offered for men with high-risk
mixed cohorts with a relative preponderance
prostate cancer [6,13]. In locally advanced
of men with locally advanced disease. The
disease it is considered the standard of care
[9]. There is clear
evidence that EBRT
combined with
‘Radical RT is currently the most common
neoadjuvant and
treatment offered for men with high-risk
adjuvant androgenprostate cancer’
deprivation therapy
(ADT) is superior to
RT alone [14–16]. There have been reports of specific results in organ-confined tumours
are less well defined, as few studies have
5- and 10-year biochemical-free outcomes
reported outcomes solely in localised
of up to 84% and 74.1%, respectively
[17–21]. Bolla et al. [22] in 2010 reported on disease. D’Amico et al. [17] in 2000 reported
on a retrospective analysis of 1586 men
the 10-year follow-up of a randomized
with clinically localised disease (T1c–T2c)
study (n = 415) comparing EBRT or EBRT
treated with EBRT or EBRT with ADT. The
with 3 years of ADT in men with high-grade
study groups were stratified by risk criteria.
T1–2 disease or T3–4 of any grade. The
That study identified that while outcomes
10-year disease-specific mortality was 30%
were similar in men with low-risk disease,
in the RT group alone compared with only
those with intermediate- and high-risk
10% in the combined therapy group. Similar
organ-confined disease had better 5-year
benefits were also seen in overall survival
biochemical relapse outcomes after
(OS) rates. The Radiation Therapy Oncology
Group (RTOG)-8610 trial reported on 10-year combined EBRT and ADT. In a follow on
randomized study, the same authors
outcomes in 2008 comparing EBRT with
reported on outcomes from 206 men who
EBRT and neoadjuvant ADT [23]. In that
were treated with either EBRT or EBRT with
study the combined treatment group had
6 months of ADT. At a median of 4.5 years
shown improvements in all parameters of
follow-up, the combined treatment group
disease-specific mortality, distant metastasis
had better outcomes compared with the
and biochemical failure rates. Adjuvant ADT
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GNANAPRAGASAM ET AL.
RT-alone group for freedom from salvage
ADT and prostate cancer-specific mortality
(82% vs 57% and 88% vs 78% respectively)
[18]. More recently, Heymann et al. [19] in
2007 reported comparable results using a
9-month course of ADT in men with
intermediate- or high-risk localised disease.
These results and that of studies in locally
advanced disease provide a rationale for
EBRT as a primary therapy for localised
disease in the absence of randomized
comparisons with other radical local
treatments. Moreover, the benefits of this
combined approach seem to be most
apparent in men with high-risk disease.
Despite good results from EBRT a significant
minority of men will develop disease
progression. A key problem in EBRT failure is
the lack of effective second-line local
therapy. Local
salvage therapies
‘Despite good results from EBRT a
such as surgery,
high-intensity
significant minority of men will develop
focused ultrasound
disease progression’
and cryotherapy all
carry significant
risks of morbidity and complications, with
most studies reporting 5-year biochemical
relapse-free survivals of ≈50% [29,30]. Thus,
when EBRT fails there are few proven
effective local therapy options and many
men are managed primarily by long-term
ADT.
OUTCOMES OF RP FOR HIGH-RISK
LOCALISED PROSTATE CANCER
Surgical case series reporting on outcomes
for high-risk disease have included men
with high PSA levels, high Gleason grades
and advanced stage or combinations of
these risk factors. These studies have been
well reviewed elsewhere [31–33]. Good
outcomes have been reported from several
different centres. In a series of 175 high-risk
cancers from the John Hopkins Institute in
the USA, Loeb et al. [34] reported a 10-year
ADT-free rate of 71% and a 92% cancerspecific survival (CSS) rate. Similar results
were reported in Germany by Spahn et al.
[35]; in a series of 375 men with high-risk
disease treated by RP and stage-dependent
adjuvant ADT, the 5- and 10-year CSS was
91.3% and 87.2% respectively. Koupparis
et al [36] reported on 299 men with
high-risk disease treated at the Vancouver
Prostate Centre, Canada. At a median of 4.7
650
years follow-up, 70% of men were free of
biochemical relapse and the disease-specific
survival (DSS) was 99%. Hsu et al. [37]
reviewed outcomes of 200 men with initial
clinical stage T3a disease who were treated
by RP. At 10 years the progression-free
survival (PFS), DSS and OS were 85.4%,
91.6% and 77%, respectively. Positive
margins and high tumour volume were
important indicators of a poor outcome.
Importantly, one in five tumours were
pathologically down-staged to pT2 at the
time of surgery. It is highly likely that similar
down-staging would be contained within
EBRT series (although conversely it may be
balanced by T2 cases that are upstaged).
Ploussard et al. [38] reported on a cohort of
110 men with high-risk disease managed by
laparoscopic RP. The median follow-up was
relatively short at just over 36 months and
key determinants of relapse were adverse
tumour stage (extracapsular extension/
seminal vesical involvement) and positive
margins. In men who had pathological
organ-confined cancer at surgery, none
relapsed during follow-up.
Defining outcomes in men with high-risk
but clinically localised disease is more
difficult. Studies which report on outcome
from surgery in cohorts selected based on
high Gleason grade, however, do provide
important insights. Mian et al. [39] in 2002
reported on 188 men with Gleason score ≥8
disease and who did not receive any
adjuvant therapy. Disease-free survival rates
for the entire cohort were 71% and 55% at
the 5- and 7-year follow-up. Patients with
pathologically confined disease, however, did
much better with disease-free survival rates
of 84%. An earlier study by Oefelein et al.
[40] also reported similar findings. In a
series of high-grade tumours (n = 116), the
10-year DSS was 96% for stage ≤pT2c
tumours but 78% for higher stage tumours.
Another important aspect is tumour
down-grading at surgery. Donohue et al.
[41] reviewed 238 men with initial Gleason
8–10 disease on diagnostic biopsies. The
incidence of tumour down-grading was 45%
in the final RP specimen. Men who were
down-graded also had significantly better
outcomes in terms of biochemical
recurrence-free survival (58% vs 27%).
Again, it is highly likely that similar
down-grading would be contained within an
EBRT series. In this study an important
finding was that tumours that were organ
confined were the most likely to be
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ROLE OF SURGERY IN HIGH-RISK LOCALISED PROSTATE CANCER
down-graded compared with locally
advanced tumours. Similar findings were
reported by Walz et al. [42] in 2011. In a
multi-institutional cohort of high-grade
cancers the lowest incidence of favourable
pathology at RP (organ-confined, negative
margin and Gleason <7) was in men with
initial clinical T3 disease. This study also
showed that men with only one high-risk
feature had much better biochemical
relapse-free outcomes compared with those
with two or more features. These studies
show that the outcomes from surgery are
not uniform in men with high-risk disease.
Importantly, many men may be downgraded and down-staged at the time of RP
and this translates into more favourable
outcomes.
ADJUVANT RT AFTER RP
An important aspect of RP in high-risk
disease is the risk of adverse pathological
features at surgery (more extensive disease
or a positive margin). The role and benefit of
adjuvant RT in this context has been clearly
shown with the recent reporting of three
seminal trials. In the European Organization
for Research and Treatment of Cancer
(EORTC)-22911 trial men with positive
margins, seminal vesicle invasion or
extracapsular extension were randomized to
receive adjuvant RT or conservative
management [43]. In this trial, men who had
adjuvant RT had improved biochemical-free
survival and PFS when compared with a
conservatively managed control group (74%
vs 52.6% and 87% vs 78%, respectively). The
German Intergroup trial (ARO 96-02/AUO AP
09/95) randomized patients to receive
adjuvant RT or observation only [44]. The
study reported biochemical-free survival
rates of 72% vs 54% in the treatment and
non-treatment groups, respectively. The
Southwest Oncology Group (SWOG) 8794
trial also reported very similar results [45];
at the 5-year follow-up biochemical
relapse-free survival rates were 73% and
44% for the adjuvant and conservative
treatment group, respectively. In addition, in
the SWOG trial there was a significant
increase in the recurrence-free survival
interval as well as a reduced incidence of
the need for hormonal therapy in an
updated report on the study. These trials
compared immediate adjuvant vs late
salvage RT and at present the timing and
optimal regime for adjuvant EBRT remains
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investigated adjuvant therapy after RP
keenly debated. The currently open
[51–53]. Messing et al. [51] randomized men
Radiotherapy and Androgen Deprivation in
with positive LNs at RP to observation and
Combination after Local Surgery (RADICALS)
deferred treatment or immediate ADT. At a
trial is actively seeking to address this
median follow-up of 11 years there was a
aspect [46]. These studies, however, do show
significant improvement in OS and DSS as
evidence that in men with pathologically
well as PFS in the ADT group. In a separate
unfavourable disease, the addition of
study, Wirth et al. [53] also reported an
adjuvant RT after
surgery confers a
significant benefit
‘ADT appears to confer a benefit on men
in tumour control
found to have LN-positive disease at surgery’
[12]. In men who
present with
high-risk but apparently localised disease,
improvement in PFS with immediate ADT in
however, many may not need adjuvant
this group of patients. There was, however,
therapy and will do well from surgery alone.
no difference in OS or DSS in this study.
Therefore currently, ADT appears to confer a
benefit on men found to have LN-positive
disease at surgery. Although untested it is
ADT IN RP-TREATED HIGH-RISK
possible that this benefit will also apply to
PROSTATE CANCER
men with local disease but who are at high
risk of microscopic metastatic spread. There
Numerous studies have reported on
has been to date, no neoadjuvant plus
neoadjuvant ADT trials in surgery, although
none have specifically investigated men with adjuvant ADT surgical trial, which is the
combination that has shown most efficacy
high-risk disease. Aus et al. [47] at 7 years
follow-up found no difference in DSS in 126 in men treated by RT for high-risk disease.
men recruited into a randomized trial of
surgery or surgery with 3 months of
neoadjuvant ADT. Soloway et al. [48]
NEOADJUVANT CHEMOTHERAPY IN RP
recruited 282 men with ≤T2b disease in a
TREATED HIGH-RISK PROSTATE CANCER
multicentre study comparing RP and RP
with 3 months of leuprolide. After 5 years of Early trials using different chemotherapy
follow-up there was no difference in the
regimens before surgery in high-risk men
biochemical recurrence rate. Klotz et al. [49]
have also failed to show convincing
2003 similarly reported no difference in OS
evidence of long-term benefit. Clarke et al.
in their study with up to 6 years follow-up.
[54] reported on an early Phase II trial of
Interestingly, the authors did report a
neoadjuvant estramustine and etoposide
significant benefit in biochemical diseasebefore RP in 16 men with locally advanced
free survival in the subgroup of men with
disease. Nine men achieved undetectable
high-risk disease. Schulman et al. [50]
PSA levels before surgery, but all had
reported the outcomes from a European
residual tumour in the resected specimen.
prospective randomized study of
Pettaway et al. [55] administered
neoadjuvant ADT. Men who received
ketoconazole and doxorubicin alternating
neoadjuvant ADT had significant clinical and
with vinblastine and estramustine together
pathological down-staging as well as
with ADT to 33 men with high-risk disease
reduced positive margin rates. There was,
before RP. Although all men achieved
however, no difference seen in PSA
undetectable PSA levels after surgery, the
progression rates after surgery. In all these
study endpoint of achieving a 20% pT0 rate
studies a consistent finding was that ADT
was not achieved.
decreased positive margin rates but did not
change biochemical survival or DSS.
In 2004, docetaxel (Taxotere) became the
Neoadjuvant ADT is therefore not currently
first cytotoxic agent to show a survival
recommended for patients undergoing
benefit in men with metastatic castratesurgery for high-risk disease [8,9]. As these
refractory prostate cancer [56,57]. The
trials were not focused on high-risk men,
survival benefit that taxanes exhibited in
however, this is arguably based on absence
advanced prostate cancer raised the
of high quality evidence, rather than
possibility that they may be effective in men
convincing proof of absence of effect. There
with lower disease burdens. Several studies
are few randomized trials that have
have explored the use of taxanes combined
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with RP. Dreicer et al. [58] trialled the use of
six cycles of docetaxel before RP. In their
initial report, 79% of men experienced a fall
in PSA level after chemotherapy. In a
follow-up paper published in 2007, only
43% of the study cohort was disease free at
a median follow-up of 49.5 months [59]. A
parallel immunohistochemical study in the
ex vivo prostate failed to find any significant
biological changes associated with therapy.
A separate study using single agent
docetaxel reported early findings in 2005
[60]. In that study the PSA level fell by 50%
in half the cohort with chemotherapy and
interval MRI showed a 25% reduction in
tumour size in 89% of patients. In all, 16
men completed the regime but only seven
of these had an undetectable PSA level at a
mean follow-up of 26 months. Garzotto
et al. [61] reported a trial of mitoxantrone
and docetaxel given over 16 weeks before
RP. Here a PSA level reduction was seen in
95% of men as well
as a higher than
‘numerous studies of neoadjuvant chemotherapy expected negative
surgical margin
and indeed ADT have therefore so far failed to rate. The data was
suggest that they have a convincing role in
too immature to
comment on
improving outcomes from RP’
biochemical or
survival outcomes.
More recently Vuky et al. [62] in 2009
conducted a trial of docetaxel and gefitinib
for 2 months before RP in 31 men with
high-risk prostate cancer. In this study no
complete pathological responses were seen
although the combination was well
tolerated.
Docetaxel has also been evaluated combined
with ADT. One of the earliest combination
trials involved chemo-hormonal therapy and
was reported by Prayer-Galetti et al. [63] in
2006. In this study, LHRH analogues were
used in addition to estramustine and
docetaxel in 21 men. Only 42% of men
remained disease free at a mean follow-up
of 4 years. A more aggressive regime was
used by Konety et al. [64] with men with
PSA levels of >20 ng/mL or T3–4 disease
receiving ADT in conjunction with four
cycles of paclitaxel, carboplatin and
estramustine. At a median follow-up of 29
months, however, 55% of men had
developed biochemical relapse. The current
largest study investigating dual neoadjuvant
chemotherapy is being conducted by the
Cancer and Leukemia Group B group
(90203) [65]. The study intends to randomize
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to either RP alone vs LHRH analogue plus
six cycles of docetaxel before RP. The
intention is to accrue >700 high-risk men
with the primary study endpoint to decrease
5-year recurrence rates. No interim results
from this study have so far been published.
In all these studies a common thread is a
lack of complete responders at the time of
surgery. Furthermore, in medium-term
analysis chemotherapy whether alone or
combined with ADT has not been shown to
improve biochemical-free recurrence.
Evidence from the numerous studies of
neoadjuvant chemotherapy and indeed ADT
have therefore so far failed to suggest that
they have a convincing role in improving
outcomes from RP and cannot currently be
recommended in standard practice.
COMPARISONS BETWEEN RP AND
EBRT OUTCOMES FOR HIGH-RISK
PROSTATE CANCER
There are no good quality data that has
directly compared RP and EBRT for high-risk
prostate cancer and none that has focused
on clinically organ-confined disease. The
primary sources of comparisons have been
from observational studies and casematched series. Abdollah et al. [66] in 2010
reviewed the comparative treatment
outcomes of 404 604 USA men with
clinically localised prostate cancer in a
retrospective observational study. In the
whole cohort, the disease-specific mortality
was lowest in the men treated by RP (3.6%)
compared with either EBRT (6.5%) or
observation (10.8%). When stratified by risk
category, men aged <69 years with high-risk
disease also did best when treated by RP.
However, in men aged >70 years both EBRT
and RP had equivalent outcomes. In another
observational study involving the Cancer of
the Prostate Strategic Urologic Research
Endeavor (CaPSURE) registry, Cooperberg
et al. [67] compared the risk adjustedmortality outcomes in 7538 men treated by
RP, EBRT or ADT. In that study there was a
significant survival benefit in men treated by
RP compared with either EBRT or ADT.
Zelefsky et al. [1] published metastatic
progression outcomes comparing 2380 men
treated by either EBRT or RP and using
competing risk regression analysis. Men in
the RP group had pelvic LN dissection
(PLND) and only a small percentage (6%)
received adjuvant or salvage adjuvant EBRT.
In the EBRT group half the cohort received
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neoadjuvant and concurrent ADT. At a
median of 8 years follow-up, RP was
associated with a lower risk of progression
to metastasis and prostate cancer-specific
mortality. Crucially, the difference in rates of
metastatic progression was most noticeable
in men with high-risk disease (7.8%
difference between the groups). In a study
by Tewari et al. [68] in 2007, 453 men
with Gleason 8 disease were treated by
observation, EBRT or RP and followed for a
median of >50 months. In that study the
risk of cancer-specific death was 13.4% in
RP group, 16.8% RT group and 43% with
conservative treatment. Boorjian et al. [69]
undertook a retrospective review focusing
on high-risk men from the Mayo clinic
treated by either RP or EBRT. At a median
follow-up of 10 years for RP (n = 1238) and
6 years for EBRT plus ADT (n = 609), the
10-year CSS rates were identical at 92%.
There was also no difference in the rates of
disease progression or disease-specific
mortality when comparing the two
treatments. The only finding was that men
who had RP had better OS rates (77%)
compared with men treated by EBRT and
ADT (62%) or EBRT alone (52%).
These retrospective studies while very
informative, suffer from the common
shortfall of being non-randomized and
involving different patient populations with
the confounding influence of different
treatment regimens (e.g. RT doses, adjuvant
or neoadjuvant hormones). Nevertheless,
these studies strongly justify further
investigation to determine whether these
differences are due to the superiority of
surgery, or to case selection. The only
published prospective randomized trial
comparing RP and EBRT is a multicentre
study conducted across five sites in Japan
published in 2006 [70]. The study involved
95 patients treated for T2b–3N0M0 disease.
All patients had 8 weeks of neoadjuvant
diethylstilboestrol (300 mg) taken once daily
before randomization. RP patients (n = 46)
had concurrent PLND, with RT patients (n =
49) treated with 40–50 Gy to the pelvis
followed by a 20 Gy boost to the prostate.
The two groups were matched for patient
and disease criteria. The median follow-up
was 102 months. Here there was no
significant difference between biochemical
relapse, clinical progression or DSS.
Contemporary EBRT regimes and the few
cases in this study, however, make any
meaningful conclusions difficult to draw.
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ROLE OF LN THERAPY IN HIGH-RISK
PROSTATE CANCER
The most accurate diagnostic and staging
technique for pelvic LNs is the extended
template dissection [71]. This involves
removal of the LNs in the obturator fossa,
along the external and internal iliac chains
and along the common iliac vessels up to
the crossing of the ureters. Data from
surgical series have shown that the
combination of RP and extended PLNDs can
improve biochemical-free progression and
potentially DSS [72,73]. There is also known
to be a direct relationship between the
number of LNs removed at surgery and PFS
and CSS whether or not they harbour
obvious metastatic disease [74,75]. In a
recent study of 614 men by Schiavina et al.
[76] in 2010, those who had ≥10 LNs
removed had better biochemical relapse-free
survival compared with those had fewer LNs
removed. Masterson et al. [77] reported that
in men without nodal involvement, the
number of negative LNs removed was
positively associated with freedom from
biochemical relapse.
The primary benefit of extended PLNDs is
therefore most evident in men with
intermediate- and high-risk disease [86,87].
It is therefore justifiable to consider that
optimal surgical therapy for high-risk
disease should include an extended PLND.
Indeed this is currently recommended by the
EAU guidelines for surgery in high-risk
prostate cancer. In RT, pelvic LN irradiation
was part of the treatment protocol in many
landmark trials of high-risk prostate cancer
[14,21,23]. In 2009, the RTOG genitourinary
group published a consensus statement on
the extent of pelvic LNs that should be
treated in high-risk prostate cancer [88].
This recommends treatment to the distal
common iliac, pre-sacral, external iliac,
internal iliac and obturator fossa LNs and is
a very comparable template to the surgical
extended PLND.
OPTIMAL DESIGN FOR A POTENTIAL
COMPARATIVE RP AND EBRT TRIAL IN
HIGH-RISK PROSTATE CANCER
In the presence of two comparable therapies
there is a clear need for a prospective
randomized trial to assess which provides
the better outcome. In high-risk disease this
is most apparent in the management of
localised high-risk disease particularly as
surgical outcomes appear better in this
context compared with locally advanced
disease. Recent evidence also confirms that
men who have adjuvant RT after surgery do
better than with surgery alone in the
Even in the presence of positive LNs,
outcomes from RP are very encouraging. A
review of 507 men with LN-positive disease
had a 10-year DSS of 86% with 56% free of
biochemical relapse [78]. Daneshmand et al.
[79] reported an even longer follow-up
of 235 men with positive LNs at RP.
Recurrence-free survival was 65% at 10
years and 58% at
15 years. The
incidence of
‘Even in the presence of positive LNs, outcomes
positive LNs
from RP are very encouraging’
increases with
higher risk disease
[71]. In men with Gleason 8 disease, 55–80% context of positive margins, seminal vesicle
involvement and extracapsular invasion [12].
have been found to have positive LNs at
EBRT is therefore clearly an essential
surgery. By contrast, studies of low-risk
modality in the management of high-risk
prostate cancer have failed to show
localised prostate cancer. The key question is
convincing evidence of a benefit of PLND
whether a policy of surgery with selective
[80]. Using the D’Amico criteria definition
adjuvant RT offers an advantage when
of low-risk disease, the incidence of LN
compared with EBRT plus ADT. In essence,
involvement has been shown to be low in
does surgery offer an incremental benefit
men undergoing limited PLNDs [81–83].
for these men? Another important issue is
Extended PLND in these men have yielded
the role of ADT in conjunction with radical
higher rates of detection although
therapy. Evidence from EBRT studies
commonly only between 3% to 10% [84,85].
suggests that men with high-risk organBecause of these low yields and the
confined disease benefit most from a
potential morbidity associated with PLND,
combined EBRT and ADT approach. However,
current guidelines do not recommend
in surgery this issue remains an open
extended PLNDs in men with low-risk
question. There have been no focused
prostate cancer undergoing RP.
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GNANAPRAGASAM ET AL.
FIG. 1. Proposed format of a trial comparing RP and ERBT for men with high-risk localised prostate cancer
and suitable for either treatment. SVI, seminal vesicle invasion; ECE, extracapsular extension; SMDT,
Specialist Multi Disciplinary Team.
High risk localised prostate cancer
SMDT review
Suitable for Radical Radiotherapy or Radical Surgery
Equipoise counselling
Randomisation
Group 1
Radical Radiotherapy
with neo-adjuvant and
adjuvant AD therapy
Group 2
Radical Prostatectomy
Common
assessment of
health scores
e.g. quality of
life, urinary
symptoms,
sexual function,
radiation toxicity
Extended lymph node
dissection
Pelvic node
irradiation
Adjuvant radiotherapy based on positive
margins/SVI/ECE
Primary outcomes of improved disease free and overall survival
studies in men with high-risk disease and
no study that has used a combination of
neoadjuvant plus adjuvant approach as is
routine in EBRT regimes. A further important
aspect is the role of LN therapy. There is
good evidence in surgical studies that
extended PLNDs are beneficial. In EBRT, LN
therapy is increasingly being recognised as
an important aspect of treatment. A trial
soon to open in the UK, PIVOTAL (Prostate
and pelvIs Versus prOsTate Alone treatment
for Locally advanced prostate cancer), is
seeking to address this issue and will
randomize men between RT to prostate only
and prostate with pelvic nodal intensity
modulated RT in patients with locally
advanced prostate cancer. However, in the
context of a trial comparing RP and EBRT in
high-risk disease, it is reasonable to consider
nodal therapy as a standard for both
methods. This should include an extended
PLND in surgery and for parity, a comparable
template for irradiation in the RT cohort. A
potential trial proposal is outlined in Fig. 1.
An important aspect is the comparative
side-effects of each treatment regime for
patients. A prospective trial will allow a
unique opportunity for a comparison
between the two methods with assessment
of multiple domains including health-related
quality of life, urinary symptoms, erectile
function and radiation effects from the
baseline, through therapy and in follow-up.
654
This would be an essential tool to define the
potential toxicity of combined therapy
relative to any oncological benefit.
CONCLUSION
Men with high-risk localised prostate
cancers are at the highest risk of disease
relapse regardless of the primary therapy.
Multimodal therapy is crucial in these men
either by RP and selective adjuvant EBRT or
primary EBRT combined with ADT. There is
no doubt that EBRT is an important method
for these patients either as a primary or
adjuvant therapy. However, RP offers an
attractive opportunity for tumour excision
either as definitive management (where
there is tumour down-staging and
down-grading at surgery) or as a first step
in multimodal therapy. There are emerging
indications in observational studies that RP
may offer benefits over EBRT in DFS and OS.
However, there is no good Level 1 evidence
to support this notion and this is needed
before RP can be considered as a preferred
therapy for these patients. In this
uncertainty there is a critical need for a
well-designed randomized study comparing
these two treatments in this group of
patients. This should involve optimal delivery
of both methods and parity for LN
treatment. It is clear that recruitment to
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such a trial will be challenging and will
require large numbers. As a first stage it is
likely that a feasibility study will be needed
to address if patients might agree to
randomization and indeed the best way to
achieve equipoise and optimise recruitment.
However, this will be the only way to answer
the on-going debate on the role of RP in
high-risk localised prostate cancer. In
particular, should RP remain a therapeutic
option or in fact be an essential component
of optimal (multimodal) treatment for this
group of patients.
7
8
9
CONFLICT OF INTEREST
None declared.
10
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Correspondence: Vincent J Gnanapragasam,
Translational Prostate Cancer Group,
Department of Oncology, Hutchison/MRC
research centre, University of Cambridge,
Hills Road, CB1 0XZ, Cambridge, UK.
e-mail: [email protected]
Abbreviations: (EB)RT, (external beam)
radiotherapy; RP, radical prostatectomy;
EAU, European Association of Urology; ADT,
androgen-deprivation therapy; RTOG,
Radiation Therapy Oncology Group; SPCG,
Scandinavian Prostatic Cancer Group; CSS,
cancer-specific survival; NCIC CTG, National
Cancer Institute of Canada Clinical Trials
Group; PFS, progression-free survival; DSS,
disease-specific survival; OS, overall survival;
EORTC, European Organization for Research
and Treatment of Cancer; SWOG, the
Southwest Oncology Group; RADICALS,
Radiotherapy and Androgen Deprivation in
Combination after Local Surgery; LN, lymph
node; PLND, pelvic LN dissection.
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