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Special Article
Arch. Esp. Urol. 2013; 66 (3): 259-273
CURRENT ROLE OF SURGERY FOR HIGH RISK PROSTATE CANCER
Steven Joniau1*, Kathy Van der Eeckt1*, Alberto Briganti2, Paolo Gontero3, Siska Van
Bruwaene1, R Jeffrey Karnes4, Martin Spahn5 and Hein Van Poppel1.
For the European Multicenter Prostate Cancer Clinical and Translational research Group (EMPaCT).
Urology, Department of Development and Regeneration. University Hospitals of Leuven. Leuven. Belgium.
Department of Urology. Vita-Salute San Raffaele Hospital. Milan. Italy.
3
Department of Urology. University of Turin. Turin. Italy.
4
Department of Urology. Mayo Clinic. Rochester. United States.
5
Department of Urology. Inselspital. Bern. Switzerland.
*Both authors contributed equally to the manuscript.
1
2
Summary.- In this review, the role of surgery in patients with adverse tumor characteristics and a high risk
of tumor progression are discussed. In the current PSA
era the proportion of patients presenting with high risk
prostate cancer (PCa) is estimated to be between 15%
and 25% with a 10-year cancer specific survival in the
range of 80-90% for those receiving active local treatment. The treatment of high risk prostate cancer is a contemporary challenge. Surgery in this group is gaining
popularity since 10-year cancer specific survival data
of over 90% has been described. Radical prostatectomy
should be combined with extended lymphadenectomy.
Adjuvant or salvage therapies may be needed in more
than half of patients, guided by pathologic findings and
@
CORRESPONDENCE
Steven Joniau, MD, PhD
Urology, Department of Development and
Regeneration
University Hospitals Leuven
Herestraat 49, 3000 Leuven (Belgium)
Accepted for publication: January 22nd, 2013
postoperative PSA. Unfortunately there are no randomized controlled trials comparing radical prostatectomy to
radiotherapy and no single treatment can be universally
recommended. This group of high risk prostate cancer
patients should be considered a multi-disciplinary challenge; however, for the properly selected patient, radical prostatectomy either as initial or as the only therapy
can be considered an excellent treatment.
Keywords: High-risk prostate cancer. Multimodality approach. Radical prostatectomy. Extended
lymphadenectomy. Adjuvant treatment. Salvage
treatment.
Resumen.- En esta revisión se discute el papel de
la cirugía en los pacientes con tumor de características adversas y alto riesgo de progresión tumoral. En
la actual era del PSA, la proporción de pacientes que
presentan cáncer de próstata (CaP) de alto riesgo se
estima que es entre el 15% y 25%, con una supervivencia de 10 años cáncer-específica en el rango de
80-90% de los que recibieron tratamiento local activo.
El tratamiento del cáncer de próstata de alto riesgo es
un reto contemporáneo. La cirugía en este grupo está
ganando popularidad, dado que se han publicado datos de 10 años de supervivencia cáncer-específica del
90%. La prostatectomía radical se debe combinar con
linfadenectomía extendida. Los tratamientos adyuvantes
o de rescate pueden ser necesarios en más de la mitad
de los pacientes, basándose en los hallazgos anatomopatológicos y el PSA postoperatorio. Lamentablemente
no hay ensayos aleatorios controlados que comparen la
260
S. Joniau, K. Van der Eeckt, A. Briganti, et al.
prostatectomía radical y la radioterapia y no hay ningún
tratamiento que pueda ser recomendado universalmente. Este grupo de pacientes de cáncer de próstata de
alto riesgo debería ser considerado como un desafío
multidisciplinario; sin embargo, la prostatectomía radical, para el paciente adecuadamente seleccionado, ya
sea como primer o como único tratamiento puede ser
considerada un tratamiento excelente.
Palabras clave: Cáncer de próstata de alto riesgo. Estrategia multimodal. Prostatectomía radical.
Linfadenectomía extendida. Tratamiento adyuvante.
Tratamiento de rescate.
INTRODUCTION AND BACKGROUND
Epidemiology and definition of high-risk prostate
cancer
Prostate cancer (PCa) constitutes a major
health problem and poses specific challenges in the
male population. World wide, PCa is the second
most frequent cancer with an estimated 903,500
new cases in 2008. It was the sixth most frequent
cause of cancer death in the same year, resulting in
258,400 estimated deaths. In developed countries,
PCa is the most prevalent cancer with 648,400 new
cases, taking third place in cancer mortality with an
estimated 136,500 deaths in 2008 (1).
In the US, approximately 241,740 men will
be diagnosed with PCa and 28,170 will die of their
disease this year. PCa is second only to lung cancer
as a cause of cancer mortality among men in the US
(2).
In the EU, the number of newly diagnosed
cases increased from 145,000 in 1996 to 345,000
in 2006 (3). PCa represents the third cause of cancerrelated death in men in Europe; in 2006, 171,900
(26.3%), 74,500 (11.4%) and 67,800 (10.4%)
cancer deaths were attributable to lung, colorectal
and PCa, respectively (3). Despite the dramatic
increase in diagnosis, the number of deaths attributed
to the disease over the same time period remained
almost unchanged (75,000 in 1996 vs. 67,800 in
2006) (3,4).
Thus, advances in screening and diagnostic
techniques have resulted in detection of PCa at
progressively earlier stages and lower levels of
prognostic risk. In many men, PCa will have a
prolonged natural history, while some will rapidly
progress to metastatic stage and die of their disease.
The challenge faced daily by the physician is to
identify men with clinically localized PCa who are at
risk of suffering or dying from their disease, without
over-treating men who are likely to die of another
cause. The current inability to accurately distinguish
risk of life-threatening, aggressive PCa from indolent
cases contributes to the dilemma.
The outcome of PCa is strongly related to
its TNM (Tumor Node Metastasis) clinical stage,
biopsy Gleason score (GS) -which determines cancer
aggressiveness- and pretreatment serum prostatespecific antigen (PSA) levels. The TNM classification
recognizes four stages of local tumor growth, from
T1 (incidental) to T4 (invasion ofadjacent organs),
with each stage describing the state of pathological
development of the tumor (5). The nodal stage (NX,
N0, N1) and the metastatic stage (MX, M0, M1AC) reflect the clinical spread of the disease to lymph
nodes (LN) and distant sites.
It is widely accepted that patients with
localized PCa who are at elevated risk of dying
from the disease are those with clinical stage T3 or
T4 disease (cT3 or cT4; i.e. patients whose tumor
extends through the capsule or invades the seminal
vesicles (T3) or invades adjacent structures other than
the seminal vesicles (T4)). However, some patients
with cT2c disease (i.e. palpable disease that has
spread to both lobes) also fall within this high-risk
group. Indeed, once the pathological assessment has
shown that the tumor has grown through the capsule
(pathological T3a; pT3a) or into the seminal vesicles
(pT3b) or has invaded organs nearby (pT4), outcome
and progression-free survival are dramatically
decreased indicating that pathological stage of the
tumor is an important predictor of PCa progression.
This is supported by the findings of Epstein and coworkers who investigated the percentage of patients
with PCa who remained progression-free (defined as
postoperative PSA ≤0.2 ng/mL, no evidence of local
recurrence and no radiological evidence of distant
metastases) after radical prostatectomy (RP) (6).
After 10 years, the proportion of patients who were
progression-free was significantly different between
men with localized disease (pT2) and focal capsular
penetration (pT3a) (84.7 vs. 67.7, respectively;
p≤0.0001), and between men with focal and
established capsular penetration (67.7 vs. 58.4%,
respectively; p=0.001). Of the men with seminal
vesicle invasion (pT3b), 27% were progression-free,
and all men with LN metastases or adjacent organ
invasion progressed (pT4 / N+).
The Gleason grading system, which is based
on the degree of loss of normal glandular tissue
architecture of the prostate, assigns a grade to each
of the two largest areas of the tumor biopsy sample.
CURRENT ROLE OF SURGERY FOR HIGH RISK PROSTATE CANCER
A GS of 2 to 4 is considered to be low grade; 5 to
7, intermediate grade; and 8 to 10, high grade (7).
Patients with a GS of 8, 9 or 10 typically have a
markedly higher PCa death rate compared with those
patients with a lower score (8,9). In a retrospective
analysis of 751 men with non-metastatic PCa treated
with RP, the cumulative incidence of PCa death within
20 years was 36-43% for men with GS of 8 to 10
compared with 10-13%, 15-19% and 29-35%, for
men with scores of 5, 6 and 7, respectively (9).
PSA alone is not a good predictor of highrisk PCa patients. However, a study conducted by
D’Amico and co-workers suggested that the rate of
increase in PSA levels in the year before diagnosis
may be an important predictor of outcome. In this
study in 1,095 men with localized PCa, patients with
a PSA velocity >2 ng/mL/year had a significantly
shorter time to death from PCa (p<0.001) and death
from any cause (p=0.01) despite RP compared with
those patients who had a PSA velocity of ≤2 ng/mL/
year (10).
Although TNM stage, biopsy GS and
pretreatment PSA relate directly to outcome, no single
criterion is able to adequately identify all patients
with localized PCa who have a high likelihood of
progression after therapy. In an attempt to address
this, nomograms such as the Partin tables and the
Kattan nomogram have been developed which use a
combination of these three tumor parameters (11,12).
Furthermore, in 1998, D’Amico et al. proposed a risk
group stratification based on the known prognostic
factors: PSA level, biopsy GS, and T-stage. These
risk groups were derived to predict a patient’s risk
to biochemical recurrence (BCR) after RP, radiation
therapy (RT) or brachytherapy for clinically localized
disease. The proposed classification defines three
risk groups: “low-risk” with <25% probability of PSA
failure at 5 years (≤T2a and GS ≤6 and PSA <10
ng/mL), “intermediate-risk”with 25-50% probability
of PSA failure at 5 years (T2b or GS 7 or PSA 10-20
ng/mL) and“high-risk” with >50% probability of PSA
failure at 5 years (T2c or GS 8-10 orPSA >20 ng/mL)
(13). By using these pretreatment risk groups, D’Amico
and coworker shave also shown that it is possible to
predict the probability of PCa-specific mortality after
RP or RT. In a study of 7,316 patients with localized
PCa, the relative risk of PCa-related mortality following
RP for high- and intermediate-risk (vs. low-risk) PCa
was 14.2 (95% CI: 5.0-23.4; p<0.0001) and 4.9
(95% CI: 1.7-8.1; p=0.0037), respectively. For RT the
relative risk was 14.3 (95% CI: 5.2-24.0; p<0.0001)
for high-risk and 5.6 (95% CI: 2.0-9.3; p=0.0012)
for intermediate-risk patients (14). Together these
findings confirm that a considerable number of RT- or
RP-managed patients in the high-risk group will die
261
from PCa despite having clinically localized disease.
Interestingly, there is no definitive consensus on the
definition of high-risk PCa. For example, D’Amico
et al. define high-risk localized PCa as stage cT2c,
or PSA>20 ng/mL, or GS 8-10, while the European
Association of Urology (EAU) guidelines and the
National Comprehensive Cancer Network (NCCN)
guidelines define high-risk PCa asstage ≥cT3a or
PSA >20 ng/mL or GS 8-10 (15,16). Trials exploring
the feasibility of (neo)adjuvant chemotherapy have
also each used different criteria to enroll patients
with high-risk PCa (17). Furthermore, not all patients
diagnosed with high-risk PCa have an invariably poor
prognosis. Several reports indicate heterogeneous
outcomes for the group of high-risk PCa patients. For
example, Yossepowitch et al. have compared eight
different definitions of high-risk PCa to classify 4,708
men treated with RP (18). Depending on the definition
of high-risk PCa used, the 5-year biochemical
progression-free survival (BPFS) after RP ranged from
49% to 80%. Of the tumors classified as high-risk,
22% to 63% were actually confined to the prostate. In
a similar study using the same criteria it was shown that
the risk of secondary therapy, metastatic progression
and PCa-specific mortality were also depending on
the definition of high-risk PCa used (19). This means
that there is a substantial proportion of high-risk
patients that remains free from additional therapy or
metastatic disease after surgery. Considering these
results, patients with currently classified high-risk PCa
should not be categorically disqualified from having
surgical therapy with curative intent despite their
increased risk of treatment failure. Interestingly, both
Yossepowitch et al. (18) and Stephenson et al. (20),
have shown that patients with either PSA ≥20 ng/mL
or biopsy GS of 8-10 or cT3 PCa had the highest
PCa-specific mortality. These high-risk PCa factors
are now widely accepted and recommended by the
NCCN and EAU guidelines (15,16). Both guidelines
also define very high-risk PCa as cT3b-T4 N0 or any
T with N1.
Despite an extensive awareness on PSA
screening and early detection of PCa, a fair proportion
of patients still present at diagnosis with high-risk
PCa. Indeed, Cooperberg et al. evaluated the trend
in high-risk PCa in the US between 1990-2007. They
revealed an evolution in the number of patients with
high-risk PCa, defined by the NCCN definition, from
27.4% in 1990-1994 to 21.7% in 1995-1999, to
26.3% in 2000-2003 and to 13.7% between 20042007 (21). Furthermore, in the recently published
European Randomized Study of Screening for PCa
(ERSPC), 9.8% of the patients had T3/T4 tumors and
8.8% had GS >7 in the screening arm, while in the
control arm, these figures were 15.8% and 19.5%,
respectively (22).
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S. Joniau, K. Van der Eeckt, A. Briganti, et al.
The natural evolution of high-risk PCa
RP for high-risk PCa
Albertsen et al. reported in 2005 the 20-year
outcome of patients with localized PCa managed by
observation or androgen deprivation therapy (ADT)
alone (8). They concluded that patients with highgrade PCa have a high probability of dying from
PCa within 10 years of diagnosis (GS 8-10, 121
deaths per 1,000 person-years, 95% CI: 90-156). At
20 years, the estimated risk of dying from PCa was
60-90% (depending on the age of the patient) when
managed expectantly or hormonal therapy alone. A
Swedish study by Akre et al. evaluated the mortality in
a large cohort of men (12,184 patients) with locally
advanced PCa (cT3 or cT4 or cT2 with PSA between
50 and 99 ng/mL) managed with non-curative intent.
They described a PCa-specific mortality at 8 years of
follow-up of 52% in patients with biopsy GS 8 and
64% in those with biopsy GS 9-10 PCa (23).
• RP for GS 8-10 PCa
RP for locally advanced, high-risk PCa
The management of locally advanced
and high-risk PCa is one of the most compelling
contemporary challenges. In the absence of a
randomized trial comparing the true benefit of
currently available treatment modalities (i.e., surgery,
RT, ADT or a combination of these), it is very
difficult to properly counsel patients on the optimal
treatment. Cooperberg et al. recently published the
local variation and time trends in primary treatment
of localized PCa (24). Data were analyzed from 36
clinical sites that contributed data to the Cancer of
the Prostate Strategic Urologic Research Endeavor
(CaPSURE) registry. PCa risk was assessed using the
D’Amico risk groups. Of the11,892 patients, 1,790
patients (15.1%) had high-risk PCa. Of those, 3.2%
opted for active surveillance, 7.5% for brachytherapy,
18.1% for external RT, 32.8% for hormonaltherapy,
6.1% underwent cryotherapy and 32.2% underwent
RP.
RP combined with an extended pelvic lymph
node dissection (PLND) is a valid strategy accepted by
international guidelines (15,16). The putative benefits
of RP as first-line treatment are to achieve tumor volume
reduction and optimal local control. Furthermore,
pathologic examination of the resection specimen
and postoperative PSA allow for better treatment
individualization by carefully selecting patients that
require adjuvant treatment. Indeed, in high-risk PCa,
RP must often be combined with adjuvant RT or ADT.
Prospective randomized controled trials have been
conducted in that setting to provide clues on the
indication of each of these strategies, yet definitive
cure is far from being achieved in each of the patients
(25-29).
The biopsy GS is a significant predictor of
pathologic outcomes, as well as one of the key predictors
of clinical outcomes after RP (30,31). Furthermore,
GS on needle biopsy may be used to determine
therapeutic choices, the extent of neurovascular bundle
resection, or performing a PLND (15). As GS has been
successfully incorporated into predictive tools that have
been designed for PCa, the accurate and reproducible
application of this system is clinically meaningful (11,
12, 20). One of the reasons to opt for surgery is the
high rate of downgrading between the biopsy GS and
the GS of the resected specimen. Indeed, Donohue et
al.(32) reported a 45% downgrading to GS ≤7 in the
RP specimen in men with biopsy GS8-10. Downgraded
patients had an improved BPFS probability (56% vs.
27%). Moreover, patients with a biopsy GS 8 and a
cT1c were more likely to be downgraded and thus had
a better BPFS probability (33). Of these patients, 64%
were free of biochemical or clinical recurrence during
further follow-up. Several other studies corroborated
these observations and concluded that one third of
patients with a biopsy GS 8 are downgraded (3436). These men in particular may benefit most from
potentially curative resection.
Indeed, several studies have demonstrated
good outcomes after RP in the context of a multimodal
approach for patients with a biopsy GS of ≥8. BPFS
at 5- and 10-year follow-up ranged from 35-51% and
24-39%, respectively, while cancer-specific survival
(CSS) at 5-, 10- and 15-year follow-up was 96%, 8488% and 66%, respectively (Table I).
• RP for PCa with a PSA >20 ng/mL
Initial PSA has long been recognized as an
important risk indicator (38). Several articles report
that men considered to have high-risk PCa based upon
preoperative PSA >20 ng/mL have good outcomes
after surgery. Even in more extreme PSA ranges (PSA
above 50 ng/mL), Inman et al. (39) presented the
outcomes of RP with adjuvant therapy when needed.
BPFS at 10-year follow-up in the groups with a PSA
level 50-99 ng/mL and >100 ng/mL were 43% and
36%, respectively. Estimated CSS of the whole group
was 87% at 10 years. Even though patients with a
PSA ≥50 ng/mL may be considered as having very
high-risk PCa, 10-year survival outcomes remained
excellent. These observations provide support for an
aggressive local management of these cases.
Recent reports in patients with a PSA >20
ng/mL who underwent surgery as initial therapy
CURRENT ROLE OF SURGERY FOR HIGH RISK PROSTATE CANCER
within a multimodal approach, demonstrated a BPFS
at 5-, 10- and 15-year follow-up ranging between 4063%, 25-48% and 25% respectively. CSS at 5, 10
and 15 year ranges between 93-97%, 83-91% and
71-78% respectively (Table I).
263
• RP for patients with cT3b-T4 PCa
organs (bladder, rectum, pelvic floor, sphincter).
When seminal vesicle involvement is suspected,
most urologists will consider the patient inoperable
and opt for a combination of RT and ADT (15,16).
Nevertheless, according to international guidelines, RP
is considered optional in highly selected very high-risk
PCa patients strictly in the context of a multimodality
treatment approach (15,16). Very high-risk PCa
patients present two specific challenges. There is
a need for local control as well as a need to treat
any microscopic metastases, likely to be present but
undetectable until disease progression. The optimal
treatment approach will therefore often necessitate
multiple modalities. The exact combinations, timing
and intensity of treatment continues to be strongly
debated (15). A recent population-based study used
data from the Surveillance, Epidemiology and End
Results (SEER) database to determine the likelihood
of having pathologically non-organ-confined disease
in patients who were staged clinically as having T3T4 disease (48). A total of 235 cT3b and 57 cT4
patients were included in the analysis. Of patients
staged cT3b, 4.7% had organ-confined disease,
12.4% had extracapsular extension, 66.8% were
pathologically confirmed to have pT3b disease, while
2.6% had pT4 disease and 13.6% had positive LN.
Of those presenting with cT4 disease, 15.8% had
organ-confined disease, 7.1% had extracapsular
extension, 7% had seminal vesicle invasion, 50.9%
were pT4 and 19.3% had positive LN. These data
show that in very high-risk disease, clinical staging is
highly accurate in predicting extraprostatic disease.
Gontero et al. compared the results of RP in very highrisk PCa with those having localized PCa. There were
no significant differences in surgical morbidity except
for blood transfusion, operative time and lymphoceles.
The OS and CSS at 7 years were 76.7% and 90.2% in
the advanced disease group and 88.4% and 99.3%
in the organ confined disease group, respectively
(49). Another study by Johnstone et al., also using the
SEER database, showed that patients who underwent
RP for cT4 PCa had a better survival than those who
received ADT alone or RT alone and had a survival
comparable with that of patients who received RTplus
ADT (50). Joniau et al. described single-center results
of RP in 51 patients presenting with cT3b or cT4
PCa. Intriguingly, over-staging in this group was still
substantial, with roughly one third of patients having
organ-confined disease (7.8%) or capsular perforation
only (29.4%). Over-staged patients were often cured
by surgery alone, as 35.3% of the whole group did
not receive any form of (neo)adjuvant treatment and
21.6% remained free of additional therapies at a
median follow-up of 108 months.
T3b PCa invades the seminal vesicles. T4
PCa is defined as cancer extending into neighboring
In the 2 latter studies, describing oncological
outcomes of RP in cT3b-T4 PCa, 5- and 10-year CSS
• RP for cT3a PCa
Stage T3a PCa is defined as a tumor that
has perforated the prostatic capsule. Extraprostatic
extension (pT3a) represents an adverse disease
characteristic (6). Despite the lack of randomized
prospective trials and large observational series
comparing alternative treatment methods for highrisk PCa patients, about two thirds of the patients will
receive non-surgical management when they show
unfavorable clinical characteristics (24). Nevertheless,
RP can provide an acceptable treatment option for
well-selected patients with stage T3a PCa (43,44). In
a recent study of 200 patients with clinically locally
advanced PCa (cT3a) who underwent RP, the 10year BPFS for patients with pT3a disease was not
significantly different from that for patients with pT2
disease; however, patients with pT3b or pT4 PCa
fared significantly worse in terms of BPFS (44). It
should be noted, however, that more than half of the
patients included in this study also received adjuvant
or salvage treatment when necessary.
Recent studies demonstrate 5-, 10- and 15year BPFS to range between 45-62%,43-51% and
38-49%, respectively. RP may provide excellent tumor
control in selected patients with cT3 disease, with 5-,
10- and 15-year CSS ranging between 90-99%, 8592% and 62-84%, respectively. Even though more
than half of the patients received adjuvant hormonal
therapy and/or RT in most of the presented studies,
the high CSS suggests that local cancer control
remains especially important in men with locally
advanced disease. Five- and 10-year overall survival
(OS) ranged from 90-96% and 76-77%, respectively
(Table I).
It appears that in well-selected patients,
RP combined with adjuvant or salvage treatment
when needed may result in better outcomes than RT
alone, while published outcomes are similar to the
combination of RT plus adjuvant ADT. However, these
findings should ideally be confirmed in randomized,
prospective studies (33).
RP for very high-risk PCa
220
246
pts
No of
BJU Int 201
Gontero et al. (42)
BJU Int 2010
Walz et al. (37)
J Clin Oncol 2009
Stephenson et al.(20)
(19)Eur Urol 2008
Yossepowitch et al.
J Urol 2007
Magheli et al.(41)
Eur Urol 2007
Zwergel et al.(40)
BJU Int 2010
Walz et al. (37)
J Clin Oncol 2009
Stephenson et al.(20)
Eur Urol 2008
712
370
726
441
265
275
269
702
Yossepowitch et al. (19) 401
Cancer 2006
Bastian et al. (35)
J Urol 2006
Donohue et al. (32)
Author
1987-2005
1987-2005
1987-2005
1985-2005
1984-2005
1986-2005
1987-2005
1987-2005
1985-2005
1982-2004
1983-2004
Time span
90
-
-
-
-
87
-
-
-
-
-
5
73
-
-
-
-
70
-
-
-
-
-
10
OS
5
10
-
-
-
-
-
-
-
96
-
-
84
88
-
95
-
-
97
-
93
89
-
90
91
-
83
PSA >20 ng/mL
58
-
-
-
-
GS 8-10 at biopsy
-
15
CSS
-
-
78
-
-
71
-
66
-
-
-
15
63
40
-
-
47
53
35
-
-
40
51
5
48
26
-
-
33
25
24
-
-
27
39
10
BPFS
-
-
-
-
-
25
-
-
-
-
-
15
82
-
-
89
-
-
-
-
85
-
-
5
71
-
-
82
-
-
-
-
76
-
-
10
CPFS
-
-
-
-
-
-
-
-
-
-
15
Table I. Recent reports of overall (OS), cancer-specific survival (CSS), biochemical progression-free survival (BPFS) and clinical progression-free survival (CPFS) for
high-risk PCa.
264
S. Joniau, K. Van der Eeckt, A. Briganti, et al.
44
52
-
-
BJU Int 2010
Walz et al. (37)
J Clin Oncol 2009
293
1987-2005
-
-
1987-2005
254
Stephenson et al.(20)
BJU Int 2009
Although the incidence
of LN metastasis has
dramatically decreased
in the PSA era, LN
invasion is still diagnosed
in up to 40% of patients
submitted to extended
PLND (52). Historically,
patients with LN invasion
were considered to be
affected by systemic and
non-curable disease.
-
85
90
Xylinas et al. (47)
Eur Urol 2008
100
1995-2005
-
-
96
Yossepowitch et al. (19) 243
Cancer 2007
Freedland et al. (46)
Eur Urol 2007
62
1985-2005
-
-
-
-
89
-
49
91
98
1987-2003
-
-
62
45
-
72
85
-
73
80
49
90
62
84
85
51
92
77
Hsu et al. (44)
J Urol 2006
200
1987-2004
96
-
94
Carver et al.(45)
BJU Int 2005
176
1983-2003
76
Ward et al. (43)
pts
841
1987-1997
90
-
53
99
85
44
-
96
60
-
76
86
48
76
67
73
38
43
90
cT3a
95
15
10
10
5
10
5
15
85
58
79
15
10
• RP for patients with any
T, N1 PCa
5
5
was 88-92% and 92%,
respectively. Five- and
10-year OS was 73-88%
and 71%, respectively
(Table II).
15
CPFS
BPFS
CSS
OS
265
These results suggests that
RP may be a reasonable
step in the context of a
multimodality treatment
approach in selected
patients with cT3b-T4
PCa, provided that the
tumor is not fixed to the
pelvic wall or invaded
in the urethral sphincter.
Nevertheless,
data
describing outcomes after
surgery in very high-risk
PCa are extremely scarce
and further studies are
urgently needed in this
domain.
Time span
No of
Author
Table I. Recent reports of overall (OS), cancer-specific survival (CSS), biochemical progression-free survival (BPFS) and clinical progression-free survival (CPFS) for
high-risk PCa.
CURRENT ROLE OF SURGERY FOR HIGH RISK PROSTATE CANCER
They were traditionally
not considered suitable
for a surgical approach.
However, recent studies
described
excellent
survival outcomes after
surgery, with 5-, 10- and
15-year CSS ranging
from 84-95%, 51-86%
and 45%, respectively.
OS at 5, 10 and 15
years ranged from 7985%, 36-69% and 42%,
respectively (Table II). Two
studies (56,57) compared
lymphadenectomy with
completed vs. aborted
36
55*
71
-
10
Eur Urol 2011
Briganti et al. (51)
BJU Int 2011
Steuber et al. (57)
Eur Urol 2010
Engel et al. (56)
Eur Urol 2009
Da pozzo et al. (55)
Eur Urol 2008
364
108
688
250
1988-2003
1992-2004
1988-2007
1988-2002
85
79
84
-
60
69
64
-
52
83
88
73
5
OS
Schumacher et al. (54)
1989-2007
1988-1993
1989-2004
1995-2001
Time span
(11.5 yr)
122
98
51
72
pts
No of
(*with vs without ADT)
Lancet Oncol 2006
Messing et al. (53)
2012
Scand J Urol Nephrol
Joniau et al. (51)
Cancer 2006
Johnstone et al. (50)
Author
-
-
-
-
42
-
-
15
90
84
95
89
85
92
-
10
75
81
86
80
60
(11.5 yr)
51
85*
Any T and N1
92
88
cT3b-T4
5
CSS
-
-
-
-
45
-
-
15
-
-
-
72
14
53
-
5
-
-
-
53
3
(11.5 yr)
14
53*
46
-
10
BPFS
-
-
-
-
-
-
-
15
-
71
-
-
-
78
-
5
-
61
-
-
-
(11.5 yr)
25
60*
73
-
10
CPFS
-
-
-
-
-
-
-
15
Table II.Recent reports of overall (OS), cancer-specific survival (CSS), biochemical progression-free survival (BPFS) and clinical progression-free survival (CPFS) veryhigh-risk PCa following RP.
266
S. Joniau, K. Van der Eeckt, A. Briganti, et al.
CURRENT ROLE OF SURGERY FOR HIGH RISK PROSTATE CANCER
RP for patients with positive LN. Both showed very
significant survival differences in favor of completed
prostatectomy. This obvious advantage should
encourage urologists to complete RP, regardless of
pelvic LN status. Briganti et al. (58) demonstrated
that patients with up to 2 positive nodes experienced
excellent CSS, which was significantly higher
compared with patients with >2 positive nodes,
regardless of adjuvant treatment administration. CSS
at 15-year follow-up was 84% vs. 62%, respectively
(p<0.001).
These results on the one hand suggest that
some patients with limited LN invasion may benefit
from extended PLND, while on the other hand the
primary tumor needs to be optimally controlled.
Surgery may provide a first and important step to
achieve both these goals. Admittedly, surgery as sole
therapy is not likely to achieve cure in such patients,
and adjuvant treatment strategies will be necessary in
most of them.
Multimodality treatment for localized PCa at high risk
of relapse
It is clear that although some patients with
high-risk PCa can benefit from RP alone, this approach
will result in biochemical relapse in a high proportion
of patients, necessitating multimodality therapy. For
instance, in a large retrospective analysis conducted
by the Mayo Clinic, 78% of 842 patients with T3 PCa
were not controlled by surgery alone and required
either adjuvant or salvage RT or hormonal therapy
or a combination of both (43). The above mentioned
available data suggest that multimodality treatment
starting with RP in patients with high-risk disease is
associated with convincing CSS rates. Prospective,
randomized trials have been conducted in this area.
Below, the most important findings from those studies
are listed.
• Adjuvant or salvage RT
The eradication of microscopic residual
disease within the prostate bed after RP can potentially
be achieved with the use of RT by two distinct
strategies: in the adjuvant setting shortly after surgery,
but in the absence of any measurable disease, or
in the salvage setting at the time of BCR or later at
clinical recurrence. The lack of randomized trials
comparing adjuvant vs. salvage RT has created a long
standing dilemma: which one is best? RP followed by
immediate RT was compared with RP alone in patients
with positive surgical margin or pT3 PCa in three
randomized trials, EORTC 22911 (25), ARO 96-02
(27), and SWOG-S8794 (26). All three trials showed
a benefit in BPFS for the adjuvant RT group of at least
267
15% at 5 years. Whereas the largest (EORTC 22911,
n=1,005) and the smallest (ARO 96-02, n=307)
trials were powered to detect a benefit in BPFS, the
SWOG-S8794 with 431 randomized patients had
as primary end point metastasis-free survival. The
inclusion criteria were similar with the exception that
in the EORTC trial also pT2 with positive resection
margins patients could be included and in the other
two trials only pT3 cancers with or without a positive
resection margin. pN1 patients were excluded in all
three trials. The presence of patients with a positive
surgical margin was relatively high in all three trials
ranging from 63% to 68%. Of note is the fact that
the randomized population differed with respect to
the postoperative PSA level prior to randomization for
adjuvant RT between the three trials. In the German
ARO 96-02 trial only men with a PSA <0.1 ng/
mL were eligible for randomization whereas in the
EORTC trial 11% had a PSA level >0.2 ng/mL prior
to randomization. In the SWOG trial this percentage
was even higher (34%). This indicates that in the
EORTC and SWOG trial a substantial number of
patients received “salvage” RT for a non-normalized
PSA rather than adjuvant RT. In a subanalysis of the
SWOG trial, Swanson et al. (59) showed that men
in all categories of post-RP PSA level (<0.2,0.2-1.0,
>1.0 ng/mL) showed improvement of metastasis-free
survival suggesting that although less effective, also
salvage RT may be beneficial to improve metastasisfree survival. The relatively high number of men with a
non-normalized PSA after surgery (PSA >0.2 ng/mL)
may however result in an under estimation of the true
value of adjuvant RT. More recently, the SWOG trial
data have been updated. With a median follow-up of
152 months this is the trial with the longest follow-up.
Although in the initial publication at a median followup of 130 months no significant OS advantage was
observed (26), in the most recent update a significant
hazard ratio (HR) of 0.72 for adjuvant RT was found
(60). This translates into an estimated 10-year OS of
74% for adjuvant RT vs. 66% for the non-adjuvant
arm. A recent Cochrane analysis reviewed the three
afore mentioned trials (61). From this meta-analysis,
it was concluded that there was no OS benefit at 5
years for men treated with adjuvant RT (p=0.95). At
10 years however, adjuvant RT significantly improved
survival (p=0.02). PCa-specific mortality at 5 years
was not improved by adjuvant RT. Five-year metastasisfree survival was not improved by adjuvant RT, but10year CSS was significantly improved. Adjuvant RT
decreased local recurrence at 5 years (p<0.00001)
and at 10 years (p=0.00001). BPFS was decreased
by adjuvant RT at 5 years and 10 years. Although
the results seem to show superiority of BPFS in favor
of adjuvant RT compared with the wait and see arm,
the definition of what constituted biochemical relapse
differed in the included studies. Two recent studies have
268
S. Joniau, K. Van der Eeckt, A. Briganti, et al.
attempted to compare adjuvant vs. salvage RT using
a matched-control study design. Ost et al. matched
178 patients (62). In the whole group comparisons,
the 5-year BPFS survival of 84% favored the adjuvant
treatment group vs. 68% for salvage treatment group
(p= 0.04). Nevertheless, no difference was seen
between adjuvant and early salvage RT. Briganti et al.
studied 390 (43.8%) and 500 (56.2%) patients who
were treated with adjuvant RT and initial observation,
respectively. Within the latter group, 225 (45.0%)
patients experienced BCR and underwent early
salvage RT. In the post-propensity-matched cohort,
the 2- and 5-yr BPFS survival rates were 91.4% and
78.4% in the adjuvant RT versus 92.8% and 81.8%
in the initial observation and early salvage RT groups,
respectively (p=0.9). No differences BPFS was found,
even when patients were stratified according to pT3
substage and surgical margin status (all p ≥ 0.4).
These findings were also confirmed in multivariable
analyses (p=0.6).(63). These two studies concluded
that early salvage RT at PSA relapse (with PSA
≤0.5 ng/ml) equals the results of adjuvant RT, while
avoiding unnecessary treatment in roughly half of the
patients.
Three ongoing clinical trials which compare
adjuvant RT with observation and early salvage RT
(NCT00667069; RADICALS (ISRCTN40814031);
RAVES (NCT00860652)) will hopefully provide us
with an answer to the lingering dilemma whether
observation and early salvage RT is equally as good
as adjuvant RT. Furthermore, these trials may clarify
uncertainties related to differences in early and late
toxicity between adjuvant vs. early salvage RT.
• Adjuvant ADT
RT alone for locally advanced PCa is
associated with a 5-year OS rate of 62%; however,
this can be improved by the addition of longterm (3 years) adjuvant ADT (64). Immediate ADT
(goserelin 3.6 mg subcutaneously every 4 weeks plus
cyproterone150 mg/day) plus RT was associated
with a significant improvement in 5-year OS (79%,
95% CI: 72-86 vs. 62%, 95% CI: 52-72, p=0.001)
and a significant increase in the proportion of
patients who were disease-free at 5 years (85%,
95% CI: 78-92 vs. 48%, 95% CI: 38-58, p<0.001)
compared with RT alone. There are currently no data
available to suggest that the use of adjuvant ADT after
surgery for locally advanced PCa is associated with
a significant survival benefit. In the Early PCa (EPC)
trial program, the administration of oral bicalutamide
150 mg/day to surgically-treated patients with locally
advanced disease (T3-T4) was not associated with an
improvement in OS (65). However, early ADT has
been reported to provide asurvival benefit in patients
with nodal metastases. In an assessment of 98
patients with nodal metastases who had undergone
prostatectomy and lymphadenectomy, immediate
ADT was associated with a significant improvement
in OS (HR 1.84, 95%CI: 1.01-3.35, p=0.04), CSS
(HR 4.09, 95% CI: 1.76-9.49, p=0.0004) and
CPFS (HR 3.42,95% CI: 1.96-5.98, p<0.0001)
compared with deferred ADT (53). Nevertheless, this
was a small study including patients before the PSA
era with large cancer volumes, a high proportion of
seminal vesicle invasion, positive margins and bulky
nodal disease.Patients were either given immediate
adjuvant ADT or late ADT at the appearance of
symptoms. Nowadays, patients usually present
with lower stage/lower volume disease and mostly
present with low-burden nodal disease. Furthermore,
PSA is an extremely useful parameter during followup, allowing early salvage ADT. Thus, it is unclear
whether the conclusions drawn from this study are still
valid at present. Recently, Dorff et al. described the
results of the SWOG-S9921 study (29). This study
was designed to investigate the effectiveness of 2
years of adjuvant ADT alone or in combination with
mitoxantrone chemotherapy after RP for high-risk
PCa (GS≥8; preoperative PSA ≥15 ng/mL; pT3b,
pT4, or pN1 or N1 disease; or GS of 7 with either
preoperative PSA >10 ng/mL or a positive margin).
The authors reported on the results in the ADT-alone
control arm with a median follow-up of 4.4 years. Of
the 481 men, 61% presented with stage ≥T3 disease,
53% had high-grade tumors (GS8-10) and 16%
node-positive disease. BPFS at 5 years was 92.5%.
Only 27 deaths occurred (13 were disease-specific),
which translated to 96% OS at 5 years and 88% at
8 years. These numbers hold across risk groups that
were defined. Although the data on adjuvant RT in
this study are limited, the BPFS and OS results are not
changed when those receiving RT were excluded from
the analysis, with a 5-year freedom from biochemical
failure estimated at 92.7% compared with 92.5%
for the whole group. The authors concluded that 2
years of ADT after RP resulted in an extremely low
rate of disease recurrence and PCa-related death for
high-risk PCa patients in SWOG-S9921. These data
support the consideration of adjuvant ADT in patients
with high-risk PCa after RP.
• Chemotherapy
It is likely that some patients with highrisk localized PCa have occult micrometastases at
diagnosis, which would explain that they are unlikely
to be cured by local therapy alone. In analogy
with other types of carcinoma (e.g. breast, colon,
lung), neoadjuvant or adjuvant chemotherapy are
being explored in phase 2 and 3 trials with the
hope to help improve the curative rate of definitive
CURRENT ROLE OF SURGERY FOR HIGH RISK PROSTATE CANCER
therapies. Two prospective phase 3 trials for men with
metastatic castration-resistant PCa(CRPC) helped to
establish docetaxel and prednisone as the preferred
chemotherapy regimen. SWOG 9916, a prospective
trial randomizing 674 men with CRPC, compared
survival outcomes and toxicity profiles in a head-tohead comparison of docetaxel plus estramustine vs.
mitoxantrone. The docetaxel-containing regimens
demonstrated a significant increase in OS of nearly
2 months; however, there was also an increase
in side effects, including neutropenic fever and
cardiovascular events (66). The second pivotal study
was the TAX 327 trial which compared docetaxel
and mitoxantrone; prednisone was also administered
in both regimens. Docetaxel was given in a weekly
or in a 3-weekly schedule. Patients in the 3-weekly
docetaxel arm demonstrated an improved median
survival of 2.5 months with a 24% reduction in risk
of death (67). These studies in metastatic castrationrefractory patients helped lay the groundwork for
phase 2 and 3 trials of docetaxel and other agents
as part of the primary treatment for high-risk and
locally advanced PCa patients. The rationale of
using chemotherapy and other systemic agents in the
adjuvant setting is that micrometastatic disease as well
as androgen-resistant clones will encounter cytotoxic
treatment earlier. Recently, the role of chemotherapy
in conjunction with RP has been examined. In this
randomized phase 3 trial (SWOG 9921), 983
patients with high-risk features were randomized to
receive adjuvant ADT with or without mitoxantrone in
the post-RPsetting. Unfortunately, the study prematurely
closed the chemotherapy plus ADT arm due to the
development of acute myelogenous leukemias. This
study underlined the importance of prospective trials
to assess potential safety issues for patients. In this
particular case, the risk of secondary malignancies
associated with a mitoxantrone containing adjuvant
chemotherapy regimen was an unexpected problem
(68). Importantly, in 2011 Dorff et al. reported
preliminary data from the SWOG-S9921 study
because of the potential implications for future
prospective trial design. As mentioned in the former
paragraph, 5-year OS was as high as 95.9%. In light
of the favorable outcomes achieved with adjuvant
ADT post-RP, this study highlights the difficulty in
demonstrating that the addition of chemotherapy can
improve upon currently available therapies (29). Of
note, the cancer and leukemia group B has initiated
an ongoing phase 3 trial (CALGB 90203) in highrisk patients randomizing them to be treated with
neoadjuvant estramustine and docetaxel followed by
surgery or surgery alone (69).
Recently, interesting progress has been
made in the treatment of CRPC following docetaxelfailure. Better understanding of the biology of CRPC
269
has demonstrated two important mechanisms: (1) the
androgen receptor is over expressed in many of the
CRPC tumor cells and (2) PCa cells are capable of
producing steroids, activating the androgen receptor
(70,71). These observations clearly demonstrate that
the androgen receptor is still the key therapeutic target.
Two molecules have been developed and tested in
phase 3 clinical trials in the CRPC post-docetaxel
setting: abiraterone acetate (AA) and MDV3100.
Briefly, AA is a potent and selective irreversible
androgen biosynthesis inhibitor of the cytochrome
P450 c17 (CYP17) enzyme blocking 17alphahydroxylation and C17,20-lyase activity. This results
in blocking the androgen synthesis by the adrenal
glands and testes and within the prostate tumor. A
recently published phase 3 study (COU-AA-301)
randomized 1,195 docetaxel-treated CRPC patients
to receive 1,000 mg AA along with 5 mg prednisone
twice daily (797 patients) vs. placebo and the same
dose of prednisone (398 patients). The study met its
primary endpoint, demonstrating an improved OS
with AA and prednisone compared with placebo
and prednisone (14.8 vs. 10.9 months, HR 0.646,
p<0.001) (72). MDV3100 is an androgen receptor
antagonist that blocks androgens from binding to the
androgen receptor and prevents nuclear translocation
and co-activator recruitment of the ligand-receptor
complex. It also induces tumor cell apoptosis, and has
no agonist activity. Encouraging antitumor activity
had been shown in a phase 1-2 clinical trial with
MDV3100 in patients with CRPC (73). Recently, the
results of a phase 3 trial (AFFIRM) were published,
demonstrating a 4.8-month OS benefit for MDV3100
compared with placebo in post-docetaxel CRPC
patients (74). It is at the moment unclear whether these
new molecules could play a role in a multimodality
treatment approach of high-risk PCa. Such role will
have to be defined in future clinical trials.
CONCLUSIONS
In the high-risk PCa group, patient outcome
will be largely dependent on cancer characteristics
and the intensity of treatment, and less on age and
co-morbidities. Thus, these patients need a proactive,
multimodality treatment approach, consisting of the
combination of external beam RT and hormonal
deprivation, or initial radical surgery with adjuvant
RT or ADT when appropriate. The current role of RP in
patients with high-risk disease remains controversial.
Recent studies in patients with high-risk disease
show convincing CSS and OS. However, in order to
achieve complete eradication of local disease and to
improve outcomes, multimodality treatment is often
recommended.
270
S. Joniau, K. Van der Eeckt, A. Briganti, et al.
High-risk
PCa is still ill defined and
constitutes an extremely heterogeneous patient group.
Pathological stage varies from localized disease (pT2)
to cancers that have grown into neighboring organs
(pT4) or have affected nearby LN (N1). Therefore,
cancer-related outcomes which may be achieved with
surgery may vary from cure in patients with organconfined disease or with limited extracapsular extension
and negative section margins, to rapid progression
and death from the disease in patients with pT4 PCa,
massive nodal invasion and micrometastatic disease,
even when applying adjuvant RT and ADT. Patients
with favorable pathologic characteristics at RP will
obtain the greatest benefit from surgery alone (54).
Indeed, the EMPaCT group has recently published a
nomogram predicting specimen confined PCa (pT23a N0, margin negative). Of all 1366 high-risk PCa
patients who underwent RP, 505 (37%) had specimen
confined disease at histopathology. The latter patients
had excellent 10-yr CSS of 98.2%, vs. 87.6% for
those with non-specimen confined PCa (p<0.001).
Moreover, only 16.8% of patients with specimenconfined PCa received any form of adjuvant treatment
(any form), versus 66.4% in those with non-specimen
confined disease (p<0.001) (75).
Furthermore, because of the lack of a uniform
definition of high-risk PCa and the lack of specificity
of the definitions used, studies evaluating high-risk
PCa include heterogeneous populations and report
a large variance in outcomes after initial therapy.
Therefore, there is an urgent need to produce a
subclassification of patients into different prognosis
categories. Improved ability to stratify patients from
the heterogeneous high-risk group into demarcated
subgroups would enable better patient counseling
before treatment and would allow better comparison
between different treatment strategies.
Finally, such substratification may prove to
be extremely useful in future trial development. The
only way to avoid extensive trials powered to detect
minimal differences in endpoints over a long period
of time is to revisit our classification system and focus
our research activities to the group with the worst
prognosis.
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