Download Improving the surgical treatment of high‐risk localised or locally

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Improving the surgical treatment
of high-risk localised or locally
advanced prostate cancer
ROGER KIRBY, HEATHER PAYNE, VINCENT KHOO, NOEL CLARKE, MARK BERESFORD, CAROLINE MOORE,
PHILIPPA ASLETT, AMIT BAHL, RUPESH BHATT, GREG BOUSTEAD AND SIMON BREWSTER
Radiologists, oncologists,
urologists and clinical nurse
specialists met to evaluate
how patients with high-risk
localised or locally advanced
prostate cancer might
be better diagnosed and
managed. In the first article
in this series, the authors
reviewed diagnosis and
hormonal and radiotherapy.1
In this second paper, they
evaluate findings from
the meeting relating to
the surgical management
of the disease and how this
might be optimised.
he management of patients with
high-risk localised or locally advanced
disease (stage T3-T4, Nx-N0, M0) is
considered one of the most perplexing areas
of prostate cancer. Issues relate to the
classification of the disease and the optimal
treatment decisions for these patients.
Current guidelines do not provide a
treatment strategy, which is clearly needed.
T
RADICAL PROSTATECTOMY
There is no consensus on the optimal
treatment of men with high-risk prostate
cancer; radical prostatectomy is an option
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Figure 1. 3T MRI showing a tumour (arrowed), which has invaded and
penetrated the capsule of the prostate
provided that the tumour is not fixed to
the pelvic wall, or that there is no invasion
of the urethral sphincter (Figure 1).2
The use of neoadjuvant hormones in
this setting is uncertain: the majority of
studies have shown a reduction in positive
margins but no survival advantage, and
research is ongoing in this area.3
Roger Kirby, Medical Director, The Prostate Centre, London; Heather Payne, Consultant in
Clinical Oncology, University College London Hospitals Trust; Vincent Khoo, Consultant in
Clinical Oncology, Royal Marsden Hospital, London; Noel Clarke, Consultant Urologist, The
Christie and Salford Royal Hospitals, Manchester; Mark Beresford, Consultant Oncologist,
Royal United Hospital, Bath; Caroline Moore, Consultant Urological Surgeon, University
College London Hospitals Trust; Philippa Aslett, Urology Nurse Specialist, Basingstoke and
North Hampshire Hospital; Amit Bahl, Consultant Oncologist, University Hospitals Bristol,
Bristol Haematology and Oncology Centre; Rupesh Bhatt, Consultant Urological Surgeon,
University Hospitals Birmingham, New Queen Elizabeth Hospital, Birmingham; Greg Boustead,
Consultant Urological Surgeon, Lister Hospital, Stevenage; Simon Brewster, Consultant
Urological Surgeon, Oxford University Hospitals
www.trendsinmenshealth.com
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Ghavamian et al. reported the combined
approach of orchiectomy (within 3 months
of radical prostatectomy) plus or
minus radical prostatectomy/pelvic
lymphadenectomy in a series of patients
with pTxN+ treated between 1966 and 1995.4
This matched-pair study reported an overall
survival advantage at 10 years for the
combined treatment approach (66% versus
28%; p<0.001) as well as for cause-specific
survival (79% versus 39%). However, it is
important to be cautious in interpreting nonrandomised case series data of this type.
Radical prostatectomy has been compared to
observation in a randomised study of men
with early prostate cancer (predominantly T2)
and shown to reduce disease-specific
mortality, overall mortality and the risk of
metastases and local progression for up to
10 years.5 This contrasts with the lack of
benefit at 12 years reported by Wilt et al.,
where a reduction in all-cause mortality was
reported only for men with a PSA >10ng/ml
and possibly for those with low- or high-risk
prostate cancer.6
Again, the difference in case mix needs to be
recognised in the two randomised studies:
cases in the first report were largely clinically
detected with proportionally higher stage
disease, while those in the Wilt study were
mainly screen detected with a high proportion
of men with low-risk characteristics.
The majority of the evidence currently
available is from published case series, with
all the caveats associated with data of this
type. Single-institute 10-year studies have
been reported for radical prostatectomy in
men with locally advanced prostate cancer,
showing that surgery for T3 disease can
achieve good cancer-specific survival with
morbidities similar to those reported for cT2
prostate cancer.7,8
A large-scale Danish study of radical
prostatectomy conducted in 6489 men
with localised prostate cancer, including
1818 men with high-risk disease, reported
good outcomes at 15 years (Table 1).9
www.trendsinmenshealth.com
5 years
Death from any cause
Low risk
Intermediate risk
High risk
Death from prostate
cancer
Low risk
Intermediate risk
High risk
% (95% CI)
10 years
15 years
4.9 (4.2–5.7)
2.8 (1.6–4)
5.4 (4.3–6.5)
6 (4.5–7.5)
1.3 (0.9–1.9)
15.4 (13.2–17.7)
8.4 (4.9–11.9)
12.6 (9.9–15.3)
21.6 (16.2–27.1)
6.6 (4.9–8.2)
33 (17.3–48.8)
19 (4.2–33.7)
18.1 (12.4–23.7)
41.9 (21.2–62.6)
20 (4.5–35.4)
0.4 (0–0.8)
0.8 (0.4–1.3)
2.7 (1.6–4.3)
2.2 (0–4.8)
3.6 (2.1–5.2)
15.4 (10.2–20.6)
8.9 (0–22.2)
5.1 (1.8–8.4)
29 (9.6–48.4)
Table 1. Cumulative incidence of death in men treated with radical prostatectomy.
Reproduced with permission from Røder et al. BJU Int 2014;113:541–79
Additional support for the use of radical
prostatectomy in high-risk prostate cancer
patients comes from the Cancer of the
Prostate Strategic Urologic Research
Endeavor (CAPSURE) registry of 7538
men.10 Results from the study indicated
that radical prostatectomy was associated
with a significant and substantial reduction
in mortality relative to radiation therapy
and to androgen deprivation therapy as
monotherapy. The absolute differences
between prostatectomy and radiation
therapy were small for men at low risk
but increased substantially for men at
intermediate and high risk.
There have been no randomised studies of
the relative effectiveness of radiotherapy
and surgery in this setting but there
are an increasing number of case series
reports suggesting that surgery can be
advantageous.11,12 Interpretation of these
must be with caution because of the
inevitable problems of case selection
and stage/grade migration. An example
of such series is the report of the effect
of radical prostatectomy compared with
external beam radiotherapy (EBRT) on the
rate of distant metastases in 2380 men
with localised disease, in a single-centre
study by Zelefsky et al.13 The 8-year
probability of freedom from metastatic
progression was 97% for radical
prostatectomy patients and 93% for EBRT
patients. The Kaplan-Meier probability of
prostate cancer death at 8 years for
low-, intermediate- and high-risk patients
was 0, 4.5 and 9.5%, respectively, for
radiotherapy patients, and 0, 1.9 and 3.8%,
respectively, for surgery patients. Multivariate
Cox regression analysis showed that the most
significant variable associated with metastatic
progression was risk group (high versus lower
risk group; p<0.0005) followed by treatment
(surgery versus radiotherapy; p<0.001).
Spahn et al. examined pre-treatment
outcome predictors in men with PSA
>20ng/ml treated with radical prostatectomy
in a European multi-institute study of 712
men.14 The strongest predictor of progression
and mortality was biopsy Gleason score; a
Gleason score ≤7 resulted in a 10-year
prostate-cancer-specific mortality rate
of 5% compared with 35% in men with a
Gleason score ≥8. Lymph node positivity in
patients with a Gleason score >7 was high
at around 30%.
Adjuvant treatment: lymphadenectomy
Extended lymphadenectomy is being
advocated more widely on the basis of
increased node-positive detection, although
the effect in relation to curative benefit
remains to be determined. A limited pelvic
lymph node dissection (PLND) has a lower
positive node detection rate than extended
lymphadenectomy (eLND). A number of
studies have reported the lymph node
invasion (LNI) according to the type
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of dissection conducted. Large-scale
studies on limited LND report LNI rates
of 2–3.7%,15–17 which compares with the
rate of 11–26% in ePLND studies.18–20 It is
generally accepted that the eLND provides
important staging information, but there
is no consensus regarding the absolute
indications for eLND.2
The European Association of Urology
guidelines recommend that eLND is not
necessary in low-risk localised prostate
cancer, where the risk of lymph node
involvement does not exceed 5%.2 However,
for intermediate- and high-risk prostate
cancer, they state that eLND should be
conducted, as the relative risk of lymph
node involvement is 5% and 15–40%,
respectively. It has been estimated that
the removal of ≤10 nodes provides a
<10% ability to detect LNI, while removing
28 nodes increases the ability to 90%;21
although, once again, there is no clear
evidence to support the notion that this
affects long-term outcome.
Nomograms to assist decision making based
on preoperative biochemical markers and
biopsies are available.17 These suggest that
patients with PSA <10ng/ml and biopsy
Gleason score <7 have a low risk of lymph
node metastasis. A caveat is that the majority
of nomograms are based on a limited eLND
and consequently they underestimate the
incidence of patients with positive nodes.22
In patients with PSA <10ng/ml and Gleason
score ≥7, the incidence of nodal involvement
has been reported as 25%.23
eLND increases the morbidity associated with
prostate cancer treatment: a number of
studies have reported a higher rate of
complications compared with limited LND,24–26
while others have reported no increase.18,27
Complications include lymphocoele,
lymphoedema, deep venous thrombosis and
a higher rate of pulmonary embolism.
The debate as to whether LND should
be conducted routinely at the time of
radical prostatectomy was addressed in a
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population-based cohort study that
examined the benefits of LND in 281 patients
and matched these against 41 case controls
who died of their prostate cancer within
10 years.28 A therapeutic benefit of LND
was reported in node-negative patients.
However, this study exemplifies the problem
of interpreting data of this type because of
selection bias and the inevitable ‘Will Rogers’
effect, which may have been responsible
itself for the difference in outcome in the
two cohorts.
Postoperative radiotherapy
Ten-year biochemical recurrence rates of
49–57% after radical prostatectomy in
patients with clinical T3 prostate cancer have
been reported.7,8,29 Multivariate analysis
shows that higher preoperative PSA, clinical
stage, estimated tumour volume and
pathological Gleason score were factors
associated with an increased risk of
biochemical recurrence.29 Postoperative
radiotherapy may be beneficial in the
situation when there are residual prostate
cancer cells limited to the prostate bed,
although current imaging techniques are
unable to identify these patients.
A number of retrospective studies show
improved biochemical progression-free
survival, but there is less convincing
evidence for a benefit in overall survival,
metastasis-free or prostate-cancer-specific
survival.30–32 As expected, there were more
side-effects in the adjuvant radiotherapy
groups, including rectal complications,
urethral strictures and incontinence,
although quality-of-life assessments were
similar or better after 2 years. There are not
yet any large published comparisons of
immediate adjuvant versus early salvage
radiotherapy to the prostate bed on
biochemical recurrence, but the UK
RADICALS trial will address this issue.
Acknowledgements
This paper is based on an advisory board
meeting sponsored by Ipsen Ltd. Medical
writing support was provided by
MedSciMedia Ltd, funded by Ipsen Ltd.
Declaration of interests
All authors received an honorarium from
Ipsen for attendance at the advisory board
meeting. H. Payne and G. Boustead act as
consultants for Ipsen.
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