Download Management of locally advanced prostate cancer

PROSTATE DISEASE
35
Management of locally
advanced prostate cancer
REENA DAVDA, DANNY BLOOMFIELD AND HEATHER PAYNE
The management of locally
advanced or high-risk prostate
cancer is challenging –
involving the patient and
multidisciplinary team in
decision-making is essential
so that treatment is tailored
to the individual.
he management of prostate cancer
involves the consideration of a number of
clinical, biological and patient factors in
order to determine the most appropriate
treatment. These include the clinical stage
of the tumour, the presence or absence of
high-risk features, and individual patient
factors such as comorbidities and
performance status. There is then careful
discussion between the patient and the
multidisciplinary team regarding treatment
options and their potential risks and benefits
(Figure 1).
T
Clinical stage is defined using the American
Joint Committee on Cancer staging system.1
Locally advanced prostate cancer includes
T3 and T4 disease (where tumour extends
beyond the prostate capsule and may invade
Disease stage/risk –
appropriate treatment
options
• Efficacy: overall survival,
disease-free survival,
progression-free survival
• Reduction in symptoms
Side-effects
• Impact on quality of life
• Importance of: sexual,
bowel and urinary changes,
physical strength, bone
strength, level of anxiety
local structures) and any tumour that has
metastasised to local lymph nodes.
However, TNM staging alone does not
provide sufficient prognostic information in
selecting out patients with apparent organconfined tumours but with significant risk
of extraprostatic invasion and undetectable
micrometastases. Additional parameters
of Gleason score (denoting the degree
of differentiation of cancer cells) and
pre-treatment prostate-specific antigen
(PSA) were used by D’Amico and colleagues
to describe three prognostic groups in
non-metastatic disease (Box 1).2
The management of patients with locally
advanced disease and those with high-risk
features often involves local treatment of
the primary disease and systemic treatment
BOX 1. Prognostic groups for non-metastatic prostate
cancer2
LOW RISK
If all of the following are met:
G T1–T2a primary G PSA <10
G Gleason score ≤6
INTERMEDIATE RISK
If any of the following are met:
G T2b–c primary
G PSA 10–20 G Gleason score 7
HIGH RISK
If any of the following are met:
G T3 or T4 primary G PSA >20
G Gleason score ≥8
Figure 1. A risk–benefit decision is required for each patient
Dr R. Davda, MB BS, MRCP, FRCR, Specialist Registrar in Clinical Oncology, University
College Hospital, London; Dr D. Bloomfield, MA, BM BCh, MRCP, FRCR, Specialist Registrar
in Clinical Oncology, Royal Surrey County Hospital, Guildford; Dr H. Payne, MB BS, FRCP,
FRCR, Consultant in Clinical Oncology, University College Hospital, London
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for potential micrometastases. The
therapeutic options for these patients are
discussed below.
IMMEDIATE OR DELAYED HORMONE
THERAPY ALONE
Watchful waiting involves monitoring a
patient for symptoms (such as bone pain)
and/or a PSA rise, with hormone treatment
initiated at the time of progressive disease.
This strategy serves to avoid or delay the
morbidity of immediate treatment. Hormone
therapy may involve castration, which is
achieved medically with luteinising
hormone-releasing hormone (LHRH)
agonists such as goserelin, or surgically with
bilateral orchidectomy. Alternatively,
antiandrogens such as bicalutamide, which
block the effects of endogenous hormones,
may be used.
‘
A Medical Research Council study
randomised patients with locally advanced
or asymptomatic metastatic prostate cancer
to immediate castration-based treatment
or treatment upon clinical progression.3
Progression from locally advanced to
metastatic disease and the development of
metastatic pain occurred more rapidly in
patients who received deferred hormone
therapy. In addition, complications from
metastatic disease, such as pathological
fractures, spinal cord compression and
ureteric obstruction, were twice as common
in deferred patients. This study suggested
that early hormone therapy reduces disease
progression and the complications due to
progression.
RADICAL PROSTATECTOMY
Patients with locally advanced disease or
high-risk features have not traditionally been
treated with radical surgery, as they are likely
to require additional treatment. A proportion
of patients with clinically organ-confined
disease preoperatively are found to have
more extensive or aggressive disease at the
time of surgery, with pathological T3 cancer,
positive surgical margins, a high Gleason
score or even lymph node metastases.
Adjuvant treatments for these patients
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include radiotherapy, hormonal therapy or
both combined. Studies investigating the
timing of postoperative radiotherapy in
patients found to have T3 disease suggest
radiotherapy can reduce the risk of PSA and
clinical failure,4,5 and possibly increase
metastases-free and overall survival. The
optimal timing of radiotherapy and duration
of concomitant hormone therapy in
postoperative patients is being investigated
in the RADICALS study.6
RADIOTHERAPY
Radiotherapy entails targeted delivery of
high-energy X-rays, which cause doublestrand DNA breaks and subsequent tumour
cell death. Individualised radiotherapy plans
deliver a high dose to the tumour volume
while minimising irradiation of normal tissues
such as the bladder and rectum.
The benefit of the addition
of radiotherapy to hormonal
treatment has also been
investigated
’
Technological advances in radiotherapy
planning have enabled a shift from twodimensional to three-dimensional CT-based
conformal planning, and more recently
sophisticated dose distributions can be
achieved with intensity-modulated
radiotherapy. More precise delivery of
radiotherapy to the target volume has
allowed dose escalation to the tumour while
ensuring normal structures are within
tolerance levels. This has been shown to
improve local tumour control. A UK study
found an improved five-year biochemical
progression-free survival rate of 71 per cent
when treating to an increased radiotherapy
dose of 74Gy, compared with 60 per cent in
men randomised to receive 64Gy.7 This dose
of 74Gy has been adopted as standard UK
practice. Radiotherapy is currently delivered
in small daily fractions, Monday to Friday,
continuously for 7.5 weeks. Early side-effects
include cystitis, faecal frequency and
urgency, proctitis and rectal bleeding. Late
complications occurring three months or
later after treatment include erectile
dysfunction, bleeding, proctitis and
diarrhoea.
The dose may be further escalated with
high-dose-rate brachytherapy, which entails
insertion of a radioactive iridium source
temporarily into the prostate gland. This may
be used in combination with external beam
radiotherapy.
RADIOTHERAPY WITH CONCOMITANT
HORMONE THERAPY
Patients with locally advanced or high-risk
disease carry a risk of micrometastases,
which needs to be addressed for optimal
treatment. Neoadjuvant hormone therapy
commenced before radiotherapy reduces
tumour bulk and prostate volume, reducing
the size of the required radiotherapy fields
and potential toxicity to the surrounding
normal tissues. Hormone therapy may also
sensitise tumour cells to the radiotherapy
treatment.
An early study, which randomised
patients between radical radiotherapy
with or without four months of neoadjuvant
hormone therapy (goserelin and flutamide),
has demonstrated significant improvements
with combined treatments. The 10-year
disease-specific mortality was significantly
lower in the hormone-treated group
(23 versus 36 per cent), as was distant
metastasis (35 versus 47 per cent),
disease-free survival (11 versus 3 per
cent) and biochemical failure (65 versus
80 per cent).8
Adjuvant hormone treatment immediately
after radical radiotherapy has shown
a significant improvement in overall
survival, progression-free survival, local
control and risk of distant metastases
in several large, international, phase 3
randomised trials.
In one such study, Bolla and colleagues
randomised high-risk patients between
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radiotherapy alone with hormones on
progression and radiotherapy with three
years of adjuvant goserelin.9 At five-year
follow-up, overall survival in those
treated with immediate hormones was
significantly superior (78 versus 62 per
cent), as was disease-free survival (74
versus 40 per cent; Figure 2). Further
benefit in overall survival was seen at 10
years (39.8 versus 58.1 per cent).10 There
were similar very significant improvements
in progression-free survival and clinical or
PSA relapse.
The large, Early Prostate Cancer study
included a subgroup of patients with locally
advanced disease treated with radiotherapy,
who were randomised between additional
adjuvant bicalutamide 150mg once daily and
placebo.11 The addition of bicalutamide
significantly improved overall survival
(hazard ratio 0.65) and reduced the risk of
prostate-cancer-related death compared
with placebo.
Given this demonstrated efficacy of
hormones, the benefit of the addition of
radiotherapy to hormonal treatment has also
been investigated.12 Patients treated with
hormones alone were found to have a
10-year prostate-cancer-specific mortality
of 23.9 per cent compared with 11.9 per
cent in those who received hormones plus
KEY POINTS
• Factors considered in selecting the appropriate management of non-metastatic
prostate cancer include clinical TNM stage, presenting PSA, Gleason sum score,
patient comorbid factors and patient preference
• Current treatment options for locally advanced disease include immediate or
delayed hormone monotherapy, radical radiotherapy in combination with hormone
therapy, or radical prostatectomy with or without further adjuvant treatments
• Several studies have demonstrated a significant improvement in overall survival
when radiotherapy is combined with hormonal therapy
• Standard UK practice for locally advanced or high-risk prostate cancer is
treatment with hormonal therapy both before and after radiotherapy, for a
total of two to three years
• Luteinising hormone-releasing hormone agonists and the antiandrogen
bicalutamide 150mg have both shown positive results in this setting with
different side-effect profiles, allowing patients a choice in hormone therapies
radiotherapy. There was an acceptable risk
of side-effects in the radiotherapy group.
Although trials of radiotherapy and hormone
therapy have used different hormone agents,
varying the timing and duration, there is
strong evidence for benefits in overall and
disease-free survival when radiotherapy
is used in combination with hormonal
treatment. This combined modality approach
is therefore standard to achieve optimal
outcomes in locally advanced and high-risk
prostate cancer.
100
Radiotherapy + androgen
deprivation therapy
Overall survival (%)
80
60
40
Radiotherapy alone
20
Log-rank test p<0.001
HR = 0.51 (95% Cl 0.36–0.73)
0
0
1
2
3
4
5
6
Time since randomisation (years)
7
8
HR: hazard ratio; CI: confidence interval.
Figure 2. Kaplan–Meier estimates of overall survival by treatment
group in EORTC trial 22863 by Bolla et al.9
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CONCLUSION
The management of locally advanced or
high-risk prostate cancer is challenging.
Optimal patient care is dependent upon
discussion and collaboration between
radiologists, pathologists, oncologists,
urologists and specialist nurses to
recommend the most appropriate options
for an individual patient.
Declaration of interests
Heather Payne has received honoraria and
expenses for consultancy and involvement in
educational projects for Astra Zeneca.
REFERENCES
1 American Joint Committee on Cancer.
Prostate. AJCC Cancer Staging Manual. New
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2 D'Amico AV, Whittington R, Malkowicz SB,
et al. Biochemical outcome after radical
prostatectomy, external beam radiation
therapy, or interstitial radiation therapy for
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1998;280:969–74.
3 Medical Research Council. Immediate versus
deferred treatment for advanced prostatic
cancer: initial results of the Medical Research
Council Trial. The Medical Research Council
Prostate Cancer Working Party Investigators
Group. Br J Urol 1997;79:235–46.
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4 Bolla M, van Poppel H, Collette L, et al.
European Organization for Research and
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