Download Improving the diagnosis and treatment of high‐risk localised or

PROSTATE diSEASE
26
Improving the diagnosis and
treatment of high-risk localised or
locally advanced prostate cancer
HEATHER PAYNE, VINCENT KHOO, NOEL CLARKE, MARK BERESFORD, CAROLINE MOORE, PHILIPPA ASLETT,
AMIT BAHL, RUPESH BHATT, GREG BOUSTEAD, SIMON BREWSTER AND ROGER KIRBY
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 this first article,
the authors look at ways in
which the diagnosis of the
disease could be improved
and discuss how to optimise
hormonal and radiotherapy.
The second article in the series
will evaluate surgical therapy.
Figure 1. Magnetic resonance image showing a stage T3b prostate tumour (arrowed)
ne of the most challenging areas of
prostate cancer is the management of
patients with high-risk localised or locally
advanced disease (stage T3-T4, Nx-N0, M0;
Figure 1). The problem with a single definition,
such as that of D’Amico,1 is that it does not
take into consideration the heterogeneity of
this group of patients whose post-surgical
pathological T stage can be higher or lower.2,3
O
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; Roger Kirby, Medical Director, The Prostate Centre, London
www.trendsinmenshealth.com
In addition, it does not consider indicators of
disease load, such as biopsy core involvement
or occult lymph node positivity, the latter
being as high as 40% in this group.4 Also, the
various guidelines relating to treatment of
high-risk disease do not provide a cohesive
therapeutic strategy. A number of studies
have reported the benefits of using a genomic
classifier, a 22-gene expression panel test, to
predict metastatic disease following surgery,
but further validation is required.5
RADIOLOGY
Radiological diagnosis of high-risk
prostate cancer
The radiological objective in high-risk
localised prostate cancer patients is to
detect those men with extraprostatic
disease, but without distant metastases,
who should be offered additional
multimodality therapy. The current NICE
recommendation for imaging in the UK is
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for men with biopsy-confirmed prostate
cancer who may be suitable for radical
curative therapy or active surveillance to
be considered for pelvic MRI, or CT scan
where MRI is contraindicated.6
There is growing interest in the use of
multiparametric MRI prior to biopsy.
This has two purposes: to be able to
direct the biopsy to maximise the
detection of higher risk disease,7 and
to provide accurate local staging
information, without the post-biopsy
artefact, which can lead to under- or
overstaging. While a number of centres
across the UK and beyond are adopting
this strategy, it is not yet standard practice.
In order to determine accurately whether
standard biopsy or MRI-targeted biopsy
is more accurate in the detection of higher
risk disease, a set of internationally agreed
reporting standards for MRI-targeted
biopsy studies has been developed (the
START criteria).8
Radiological staging of the prostate
MRI for prostate cancer was first
developed as a staging tool, using
anatomical sequences (T1- and T2weighted imaging) to assess for local
invasion and nodal disease. The addition
of functional parameters has allowed the
detection of areas of higher risk prostate
cancer within the gland, which can be used
to direct both biopsy and treatment. All
agreed that pictorial reporting of the MRI
to show the location of disease was a
critical component of the MRI report.
The European Society of Urogenital
Radiology guidelines give specific
criteria for their structured reporting
scale, which they call the Prostate
Imaging and Reporting Archiving Data
System (PI-RADS). This includes specific
criteria for the likelihood of extracapsular
disease, which include capsular abutment,
irregularity and loss of capsule, as well
as radiological criteria for the prediction
of seminal vesicle, distal sphincter and
bladder neck involvement.9
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Radiological assessment for
nodal disease
Size criteria are applied to define nodal
spread; a node is considered pathologic
when the minimal axial diameter is ≥10mm
or when the maximum axial diameter is
8–10mm and the ratio of the short to
long axis is >0.8 (a round node).10 These
measurements can be made on CT or
anatomical MRI images (T2-weighted).
The problems with using size criteria are
that they fail to detect metastases in
normal sized nodes and have difficulty in
distinguishing between large hyperplastic
(benign) nodes and malignant nodes.
The gold standard for diagnosis of lymph
node involvement remains extended
lymph node dissection; however, due
to the morbidity associated with this
procedure it is recommended only for
those more likely to have lymph node
involvement. In comparison to this gold
standard, CT and conventional MRI
have an average specificity of around
80%, and sensitivity of around 40%.11
The latest NICE guidelines recommend
use of pelvic CT for staging only when
MRI is contraindicated.6
Radiological assessment of distant
metastases
The standard approach to the detection of
bone metastases in men with high-risk
prostate cancer is 99Technetium (99Tc) bone
scintigraphy. While it has an established
high sensitivity for osteoblastic metastases,
early work shows that whole-body
diffusion-weighted (WB-DWI) MRI is able
to detect more malignant lesions per
patient and fewer benign lesions compared
with planar bone scans.12 A single WB-DWI
MRI scan to replace pelvic MRI and 99Tc
bone scan has been proposed.13 This would
streamline the patient pathway, using
MR scanning time at the expense of
nuclear medicine time. The standard
recommendations in the UK, Europe and
the USA are still for 99Tc bone scan for the
evaluation of distant metastases, with
MRI or CT for pelvic staging. Data on
both clinical utility in standard care and
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cost-effectiveness will be required to
change these recommendations.
RADIOTHERAPY AND HORMONAL
THERAPY
The National Comprehensive Cancer
Network recommendations for the
treatment of patients with clinically
localised high-risk prostate cancer are
shown in Table 1.14 Initial treatment
includes radiotherapy with or without
brachytherapy plus long-term androgen
deprivation therapy (ADT) or radical
prostatectomy with pelvic lymph node
dissection in selected patients.14
Radiotherapy
Key to the administration of radiotherapy
is three-dimensional (3D) treatment
planning with image guidance. Initial
studies with 3D conformal radiotherapy
(CRT) showed that individually shaping the
treatment fields to the patient’s prostate
gland can significantly reduce radiationinduced proctitis from 41% to 32% at
1 year (p=0.004).15 CRT became the new
standard as recommended by NICE in
2002.16 The possibility of reducing doselimiting radiation side-effects through the
3D CRT technique has been explored in
dose-escalation studies applying 64–68Gy
to 74–78Gy over 7–8 weeks.17,18 These have
reported an improvement in biochemical
PSA control rates, but unfortunately this
was also correlated with an increase in
both rectal and urinary side-effects.
Intensity-modulated radiation therapy
(IMRT) was subsequently introduced in
the late 1990s to overcome the limitations
of the CRT method and to provide safer
dose escalation. Using IMRT to deliver
a dose up to 81Gy in patients with highrisk prostate cancer, the group at the
Memorial Sloan-Kettering Cancer Center
reported biochemical progression-free
survival of 64% at 10 years with minimal
genitourinary toxicity.19
Another method of dose escalation
is using proton therapy as a boost to
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Patient group
Initial therapy
Adjuvant therapy
High risk
T3a OR
Gleason score 8–10 OR
PSA >20ng/ml
RT (3D-CRT/IMRT) + long-term neoadjuvant/
concomitant/adjuvant ADT (2–3 years) (category 1)
OR
RT (3D-CRT/IMRT) + brachytherapy +/– long-term
neoadjuvant/concomitant /adjuvant ADT (2–3 years)
OR
Radical prostatectomy + pelvic lymph node
dissection (selected patients with no fixation)
Adverse pathological features:
RT OR observation
Lymph node metastases:
ADT OR observation OR ADT + pelvic RT
(category 2B)
RT, radiotherapy; 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiation therapy; ADT, androgen
deprivation therapy.
Table 1. National Comprehensive Cancer Network recommendations for treatment of patients with clinically localised high-risk prostate
cancer14
standard external beam radiotherapy.
This has been evaluated in patients
with high-risk prostate cancer and
shown to improve local control in
patients with poorly differentiated
tumours but not overall survival or
recurrence-free survival.20 However,
increased late radiation sequelae
were recorded.
The addition of pelvic radiation to
prostate radiation has been evaluated
in a number of studies, with no
demonstration of an added benefit
but with increased toxicity.21,22 However,
the use of 3D conformal shaping
can provide a ‘surgical template’
for pelvic nodal irradiation and
IMRT can permit substantially higher
doses including boosts to be delivered
while maintaining small bowel dose
tolerances. This will underpin future
pelvic radiotherapy trials.
Conventional radiation schedules
range between 70 and 80Gy administered
over 7–8 weeks. Studies have evaluated
shorter radiation fractionation schedules
(hypofractionation) on the radiobiological
basis that the cellular sensitivity of
prostate cancer may respond better
to a larger dose per fraction than
the conventional 1.8–2.0Gy per
fraction with greater sparing of the
normal tissues.
www.trendsinmenshealth.com
Future directions in radiotherapy
Pelvic organ movement around the
prostate can be an issue in terms of
accurate delivery of daily radiotherapy and
it is known that a filled rectum or the
bladder, to a lesser degree, can affect the
location of the prostate.23 This issue could
be minimised with the use of image
guidance techniques that ensure reliable
and accurate delivery of radiation either
before or during treatment delivery.
Recent reports using image-guided
radiation therapy with IMRT have recorded
significantly improved biochemical PSA
control rates with less treatment toxicity,
and this may become the standard of care
in the future.24
Other methods are being investigated
to reduce radiation to dose-limiting
normal structures such as the rectum.
The insertion of ‘obturators’ or spacers
such as gel (Augmenix) or a biodegradable
balloon (ProSpace)25 is intended to
minimise rectal motion and/or displace
the rectum from the high-dose radiation
regions around the prostate.
Another strategy to improve patient
outcomes for localised high-risk prostate
cancer is to target the dominant nodule
within the prostate. There are many
different methods to locate the dominant
or functionally radioresistant nodule
using multiparametric MRI or magnetic
resonance spectroscopy, or 18F- or
C-choline positron emission tomography
(PET) scanning. By isolating the site of
potential relapse, this region can be
targeted and boosted with IMRT. Chang
and associates confirmed the feasibility of
IMRT dose painting using 11C-choline PET
scans in patients with localised prostate
cancer.26 This method has been modelled
to provide good tumour control while
minimising any late side-effects.
11
Hormonal therapy
Hormonal therapy has a major role in
combination with radiotherapy in high-risk
localised or locally advanced prostate
cancer. Neoadjuvant hormonal therapy
(NHT) given before definitive radiotherapy
treatment can reduce tumour bulk and
prostate volume; short-term therapy of
3–4 months was shown to reduce prostate
size by 25–30%.27 The administration of
NHT to reduce prostate gland size could
also allow the application of more focused
radiotherapy and potentially reduced
toxicity to the surrounding normal tissues.
Neoadjuvant hormonal therapy
plus radiotherapy
The role of NHT and adjuvant hormonal
therapy (AHT) plus radiotherapy has been
evaluated in depth by Payne et al.28 Overall,
the addition of NHT and/or AHT has been
shown to improve time to disease
progression and/or overall survival
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compared with radiotherapy alone in highrisk localised and locally advanced prostate
cancer. NHT is normally given as a short
course of therapy, either 3 or 6 months.
Reports indicate that intermediate-risk
patients may also gain survival benefits
from 4–6 months of hormonal therapy
before and during radiotherapy.29,30
The rationale for ADT alone as opposed
to therapy in combination with radical
radiation treatment has been investigated
in two important studies. The SPCG-7
study randomised men with locally
advanced prostate cancer to treatment
with 3 months of total androgen blockage
followed by continuous treatment with
an LHRH agonist or the same treatment
plus radiotherapy.32 Ten-year prostate
cancer-specific mortality was 23.9% in
the endocrine group and 11.9% in the
endocrine plus radiotherapy group. The
cumulative incidence at 10 years for PSA
recurrence was higher in men in the
endocrine-only group (74·7% versus
25.9%, p<0.0001). The MRC PR07/NCIC PC3
study reported by Warde et al. compared a
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RT (112 deaths)
90
RT + LHRH (80 deaths)
80
Overall survival (%)
Adjuvant hormonal therapy plus
radiotherapy
It has been established in a number of
studies that AHT plus radiotherapy
provides significant improvement in
10-year outcome. The seminal EORTC study
by Bolla et al. reported that in patients
with high-risk localised or locally advanced
prostate cancer, the addition of ADT
initiated at the start of radiotherapy
and continued for 3 years significantly
improved survival compared with
hormonal therapy given for disease
progression after radical radiotherapy
(Figure 2).31 The study demonstrated an
increase in 10-year overall survival from
39.8% to 58.1%. Other randomised phase 3
studies of adjuvant luteinising hormonereleasing hormone (LHRH) agonists have
demonstrated similar very positive results
and it is now standard practice to continue
with hormone therapy for 2–3 years after
radiotherapy.
100
70
60
50
40
30
20
10
0
0
Number at risk
RT
208
RT + LHRH 207
2
4
6
8
10
Years
12
14
16
178
185
123
154
82
113
56
77
41
51
22
26
9
11
3
2
18
Figure 2. Improved overall survival with luteinising hormone-releasing hormone (LHRH) and
radiotherapy (RT) in patients with high-risk localised or locally advanced prostate cancer31
similar regimen, using hormone
therapy/orchiectomy with and without
radiotherapy in men with T3/T4 N0/NX
or T2 and PSA >40ng/ml or T2 and PSA
>20ng/ml and Gleason score 8–10 prostate
cancer.33 This reported 7-year overall
survival rates of 66% for ADT alone versus
74% for combined treatment.
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.
Declarations of interest
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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