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european urology supplements 7 (2008) 400–405
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What is the Role of Surgery for Locally Advanced Disease?
Michel Soulié *
Committee of Cancerology of the French Urological Association, Service d’Urologie d’Andrologie et de Transplantation Rénale, CHU Rangueil - 1
avenue Jean Poulhès, 31403 Toulouse Cedex 4, France
Article info
Abstract
Keywords:
Combined treatments
Extended pelvic
lymphadenectomy
Locally advanced prostate
cancer
Radical prostatectomy
Among the optimal options recommended for locally advanced prostate
cancer, radical prostatectomy (RP) with or without adjuvant radiotherapy or hormone therapy is a possible but relatively infrequent option.
The role of radical prostatectomy in locally advanced prostate cancer is
still controversial and has not been extensively assessed despite numerous recent series provided by great US and European institutions. Nevertheless, in selected patients with cT3a tumours, surgery can provide
good oncologic results with 10-yr and 15-yr prostate cancer survival rates
of about 85% and 75%, respectively. Moreover, approximately 20–30% of
patients who initially present with cT3 tumours ultimately have organconfined disease on pathologic examination. RP for locally advanced
prostate cancer provides similar short-term biochemical-free survival
compared to the of combination radiotherapy and androgen ablation.
Morbidity of the procedure is similar to RP for organ-confined tumours.
The impact of radical prostatectomy on local progression and local
recurrence is also important in well-selected patients with low- or
intermediate-grade tumours. Preoperative analysis of clinical stage,
biopsy data, Gleason score, endorectal magnetic resonance imaging,
and nomograms may enhance the choice of the best option in young
and healthy patients with locally advanced prostate cancer. RP should be
considered as a viable alternative to radiotherapy and hormone therapy
in patients with long life expectancy presenting with cT3 prostate
cancer. Combined treatments with RP have to be prospectively evaluated
in terms of oncologic outcome and quality of life. This approach should
be investigated in clinical and comparative trials.
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1.
Introduction
Treatment of locally advanced prostate cancer is
complex and the optimal option remains to be
clearly defined. One of the main reasons is explained
by the heterogeneity of these T3–4 tumours char-
acterised by the extension of the disease beyond the
confines of the prostatic capsule. Despite dramatic
stage migration due to widespread prostate-specific
antigen (PSA) screening, many patients continue to
present with locally advanced disease and current
incidence is reported at about 15–20% in routine
1569-9056/$ – see front matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2007.12.006
european urology supplements 7 (2008) 400–405
urologic practice [1–4]. Nowadays, clinical stage T3
tumours (cT3) are diagnosed with lower tumour
volume than in the past, enhancing the opportunity
for radical prostatectomy (RP) indications in many
selected cases [5].
The goal of therapy in patients with locally
advanced prostate cancer includes prolongation of
survival but also control of local tumour progression
[6]. Local control is important, particularly in locally
advanced prostate cancer due to the increased risk
of symptomatic progression. Moreover, patients
with cT3 prostate cancer have a higher probability
of death from recurrent prostate cancer than from
other causes [6].
The most common local treatments for locally
advanced prostate cancer include external-beam
radiation therapy (EBRT) associated with hormone
therapy followed by RP alone or combined with
other modalities. When RP is indicated as local
treatment, the procedure should be adapted to the
situation. Usually, it is an extended RP, enlarged to
include periprostatic tissue and combined with an
extended lymphadenectomy because of the risk of
pelvic nodal involvement [7–9].
Oncologic and functional outcomes of RP for
locally advanced tumours reported in the literature
for 10 yr are sometimes difficult to analyse because
of the heterogeneity of non-comparative studies.
These series provided data issued from some great
monocentric US or European institutions. Despite
comparative and randomised studies, the results of
RP with or without adjuvant therapy in recent
publications are similar to those of radiotherapy
combined with hormone therapy in terms of
biochemical-free, specific, and overall survival [4–
6,10–13].
Moreover, the morbidity of the procedure seems
comparable to RP for localised prostate cancer,
when it is performed by experienced surgeons
[4,6,7,10–14].
Regarding the lack of data on the pathologic
outcome of RP compared to EBRT combined with
hormone therapy, it is up to the urology community
to start randomised trials including RP in combined
treatments of locally advanced prostate cancer.
2.
Definition of clinically advanced tumours
The usual definition of locally advanced prostate
cancer includes the tumours that have involved the
periprostatic tissue through the capsule, seminal
vesicles, urethra, and bladder neck without clinical
lymph node involvement or distant metastases (T3–
T4 N0 M0) [15].
401
In the TNM 2002 classification, cT3 is defined as a
palpable tumour extended beyond the prostatic
capsule: T3a extracapsular extension, T3b extension
to the seminal vesicles [16]. The term extraprostatic
extension was accepted by the Conference of
International Consensus [17].
Locally advanced prostate cancer includes heterogeneous tumours between localised and metastatic disease; 30–50% of the patients have a
potential risk of pelvic lymph node involvement
and 40% progress to a metastatic stage at 5 yr and
65% at 10 yr [18].
3.
Results of RP in locally advanced prostate
cancer
Until recently, RP alone was not adapted to cure
locally advanced tumours because of the tumour
volume and the high incidence of positive pelvic
lymph nodes. Poor long-term survival rates were
reported in several series with a 5-yr biochemical
recurrence of 70% [10,14,19]. However, RP alone can
be acceptable in well-selected tumours classified
T3a with low Gleason score (<8) on biopsies and an
initial PSA value of <15 ng/ml, in young patients or
in men with associated urinary obstruction disorders [5,6,10,14,20].
Moreover, in recent RP series for cT3 prostate
cancer clinical over-staging occurred in 20–30% of
the cases and presented as organ-confined tumours
(pT2) on pathologic examination, whereas 30–40% of
T2 tumours are ultimately pT3 [4–6,10,21].
Oncologic outcomes of RP in cT3 prostate cancer
reported in the literature are heterogeneous because
they rely on retrospective series and are often from
single institutions (Table 1). Moreover, it is not
mentioned if patients had adjuvant treatment by
radiation or hormone therapy [19–22]. A review of
eight international studies showed an overall
survival rate at 5 yr ranging from 64% to 86% and
at 10-yr from 36% to 70%; disease-specific survival
rates at 5-yr and 10 yr ranged from 83% to 92% and
72% to 82%, respectively [14].
In the largest surgical series of cT3 treated in a
single institution and reported to date, approximately
50% of patients had not developed a PSA recurrence at
15 yr after surgery and only 16% of patients died of
prostate cancer [4]. However, it is difficult to evaluate
the real impact of RP on survival in this series because
some patients received neoadjuvant hormone therapy or secondary treatments or both [4]. In another
cT3 series, previous RP was associated with a
significant decrease in the risk of death compared
to those who did not undergo RP [23].
402
european urology supplements 7 (2008) 400–405
Table 1 – Pathologic results of radical prostatectomy specimen in cT3 prostate cancer
Lerner et al [22]
Gerber et al [19]
Van den Ouden et al [14]
Van Poppel et al [10]
Ward et al [4]
Carver et al [6]
n
pT2
pN+
SV+
PSM
812
298
83
158
842
176
17%
9%
18%
13%
27%
30%
33%
31%
12%
11%
27%
19%
18%
11%
40%
16%
—
34%
—
—
66%
60%
56%
30%
Adj Tt
50%
40%
0%
30%
76%
36%
Oncologic results in cT3a: 47 patients from Van Poppel [10]
N+: 10%.
SV involved: 6%.
PSM rate: 53%.
SV+ = seminal vesicles involved; PSM = positive surgical margins; Adj Tt = adjuvant treatment.
Nevertheless, more recent surgical series of
selected patients with locally advanced prostate
cancer have reported comparable survival rates
with a combination of radiation therapy and
hormone treatment, which is the most common
therapeutic option in this stage of disease, with 5-yr,
10-yr, and 15-yr prostate cancer-specific survival
rates of 85–99%, 72–92%, and 76–84%, respectively
[3,5,6,10,24]. Bolla et al have previously shown that
EBRT with 3 yr of adjuvant hormone therapy
improves clinical disease-free survival and overall
survival rates with 5.5 yr follow-up of 74% versus
40% and 78% versus 62%, respectively [25].
Some authors proposed extensive indications of
RP with immediate adjuvant treatment. A recent
single-surgeon study showed excellent 7-yr overall
survival and cancer-specific survival rates (77% and
90.2%, respectively) in patients with T3–4, N0–1
disease who underwent RP and immediate adjuvant
treatment with radiotherapy or hormone therapy (in
89.5% of cases) [26]. A nonrandomised US study has
compared patients who underwent RP for cT4
prostate cancer to those receiving radiotherapy
alone, hormone therapy alone, or radiotherapy
combined with hormone therapy. A comparable
survival was found between the RP group and
combined treatment group [27].
4.
Surgical aspects
Surgical technique is usually an extended RP to
include surrounding periprostatic tissue and in most
of cases a non–nerve-sparing technique must be
used [5–7]. The success of RP for clinically advanced
cT3 prostate cancer relies on the removal of all local
tumour-bearing tissue [28]. The technique was
previously described with several detailed points
different from the standard technique for organconfined tumours [5,28,29]. In fact, the aim is to have
negative surgical margins [5,7,10,14,21,29]. The
majority of palpable tumours originate in the
peripheral zone and, consequently, they are more
likely to extend into the posterolateral and rectal
periprostatic soft tissue. In this way, the neurovascular bundles are usually resected widely on the side
of the cancer. Moreover, the posterior plane of
resection should be deep enough and must include
the complete excision of the two layers of Denonvilliers fascia to reduce the risk of positive surgical
margins [28].
Unilateral or bilateral nerve-sparing surgery is
feasible in very selected young patients with small
cT3a tumours who desire to keep the erectile
function despite the increased risk of positive
surgical margins and incomplete tumour excision
[12]. However, it cannot be a systematic procedure
because it is carried out more frequently in RP for
localised prostate cancer.
Regarding the increased risk of lymph node
involvement in locally advanced disease, standard
lymphadenectomy limited to the ilio-obturator fossa
is not sufficient to define accurately the lymph node
status [8,9,30,31]. Extended iliac lymphadenectomy
does not have an impact on survival, but it optimises
pathologic staging with an increased number of
lymph nodes removed and number of positive nodes
[9]. Moreover, a good staging based on an extended
lymphadenectomy will help to introduce adjuvant
hormone therapy when needed. Such treatment has
shown significant benefit on overall survival in
patients with positive lymph nodes after RP [32].
5.
Who are the ‘‘good candidates’’ for surgery
in locally advanced prostate cancer?
The European Association of Urology (EAU) 2007
guidelines on prostate cancer state that RP can be
proposed to selected healthy patients with locally
european urology supplements 7 (2008) 400–405
advanced tumours presenting these clinical parameters: PSA < 20 ng/ml, T3a, and biopsy Gleason
score 8 [33].
The clinical assessment of locally advanced
prostate cancer relies on several parameters
obtained by the digital rectal examination, PSA,
and biopsy analysis (number of positive biopsies,
tumour length, and total percentage of cancer). The
patient should be young and healthy with a life
expectancy >10 yr. MRI to detect local regional
extension is helpful to evaluate the lymph node
status (as well for the computed tomography scan)
and the presence or not of extracapsular extension.
Bone scintigraphy, in patients with a PSA value
>20 ng/ml is required to detect asymptomatic bone
metastasis [18,34,35]. The evaluation of tumour
volume can be improved by modern imaging
techniques using new endorectal MRI to assess
extracapsular extension, seminal vesicles extension, and nodal involvement [36]. Specificity and
sensibility of the new generations of MRI (3 Tesla)
are 75–95% and 60–70%, respectively [36,37]. Numerous nomograms available today are helpful to
improve the preoperative assessment of the
patients [38].
It is clear that healthy patients <70 yr old with
cT3a stage are the best candidates for surgery with a
reduced risk of positive surgical margins and pelvic
lymph node metastasis. It was shown that in select
men with cT3a, RP can result in very good long-term
cancer control. Moreover, 20–30% of men undergoing RP for cT3 tumours have pathologic organconfined disease [4,7,10,14,19].
6.2.
403
Adjuvant and salvage radiotherapy
Poorly differentiated tumours in cT3 prostate cancers are associated with increased clinical and
biochemical progression rates after RP [4]. In these
cases, patients may benefit from adjuvant therapy
following RP [6,14]. Similar approaches can be
developed when examination of the RP specimen
shows extensive and multifocal positive surgical
margins or lymph node involvement.
A benefit of adjuvant EBRT after RP for pT3
disease in prolonging overall survival has not been
shown despite the fact that this radiation therapy
(60–65 Gy) can prevent or delay biochemical and
local recurrence, as was demonstrated in randomised studies [44–46].
In case of presumptive locally recurrent prostate
cancer, salvage radiotherapy is also an effective
option to improve local control and disease-free
survival as long as the postoperative PSA value is
<1.5 ng/ml [47].
6.3.
Adjuvant hormonal therapy
6.
How to improve the oncologic outcomes of
RP in stage cT3 tumours?
In case of nodal involvement after RP, it was clearly
shown that immediate hormone therapy by luteinising hormone-releasing hormone (LHRH) agonists
was beneficial for overall survival (72.5% vs. 49%)
and for disease specific survival (87.2% vs. 56.9%)
compared to a different hormone therapy at
metastasis progression [32,48].
In the Early Prostate Cancer (EPC) trial, with a
mean follow-up of 5.4 yr, the risk of clinical and
biochemical progression in the group undergoing RP
for locally advanced tumours was reduced 25% by
bicalutamide 150 mg compared with placebo [49].
6.1.
6.4.
Neoadjuvant hormonal therapy
Neoadjuvant hormonal therapy before RP, even in
case of cT3 tumours, is not recommended in current
practice because no study showed a benefit on
survival. Previous studies have shown a 30% clinical
down-staging and a 25% pathologic down-staging in
men treated with neoadjuvant hormone therapy
(mean time 3 mo). But this treatment has not shown
any statistical difference in disease-free or overall
survival between men with or without neoadjuvant
therapy [39–42].
Neoadjuvant combination of chemotherapy and
hormone therapy before RP has been reported in
locally advanced prostate cancer and high-risk
tumours [43]. These new modalities can be effective
and used in the future to improve local oncologic
issues of local treatments.
Functional outcomes
With improvements in surgical techniques including the laparoscopic approach, the complication
rates are similar to RP for organ-confined tumours
[4–7]. The most common postoperative complications are urinary incontinence and sexual dysfunction, which occur immediately after surgery and
improve over time [7,12]. Increased overall surgical
experience leads to decreased operative morbidity
and improves the functional results [4,50].
7.
Conclusion
The treatment of clinically advanced prostate cancer
remains controversial. RP is an adequate technique
and an acceptable option to treat the small cT3a
404
european urology supplements 7 (2008) 400–405
tumour with high risk of local progression; however,
this alternative should be avoided in more advanced
disease with a high risk of lymph node involvement
and macroscopic residual tumour. In the absence of
randomised controlled studies, it is not possible to
recommend RP as equivalent to radiotherapy and
hormonal therapy that is the treatment of choice in
several countries even if a benefit has been shown in
several studies. However, with very well-selected
criteria, extended RP for locally advanced prostate
cancer should be presented as an alternative treatment for young patients. These patients should be
informed of possible adjuvant or salvage treatments,
when needed, by radiation therapy, hormone therapy, and, perhaps in the future, by chemohormonotherapy.
Although EBRT combined with adjuvant hormone
therapy remains the most common treatment for cT3
prostate cancer, RP provides an excellent therapeutic
procedure for well-selected patients with locally
advanced prostate cancer, with a disease-free survival at 10 yr of 85% in the main series from the United
States and Europe. These findings should be confirmed in well-conducted clinical trials and multicentre randomised prospective studies.
Conflicts of interest
The author has nothing to disclose.
Acknowledgements
The author thanks Joe Nohra, MD, for translation
assistance.
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