Download 20year survival after radical prostatectomy as initial treatment for cT3

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20-year survival after radical prostatectomy as
initial treatment for cT3 prostate cancer
BJU INTERNATIONAL
Christopher R. Mitchell, Stephen A. Boorjian, Eric C. Umbreit,
Laureano J. Rangel*, Rachel E. Carlson* and R. Jeffrey Karnes
Departments of Urology and *Health Sciences Research, Mayo Medical School and Mayo Clinic, Rochester, MN,
USA
Accepted for publication 19 April 2012
Study Type – Therapy (case series)
Level of Evidence 4
OBJECTIVE
• To present long-term survival outcomes
after radical prostatectomy (RP) for
patients with cT3 prostate cancer, as the
optimal treatment for patients with clinical
T3 prostate cancer is debated.
PATIENTS AND METHODS
• We identified 843 men who underwent
RP for cT3 tumours between 1987 and
1997.
• Survival was estimated using the
Kaplan–Meier method.
• Cox proportional hazards regression
models were used to evaluate the
association of clinicopathological features
with outcome
RESULTS
• The median (range) postoperative
follow-up was 14.3 (0.1–23.5) years.
• Down-staging to pT2 disease occurred in
26% (223/843) at surgery.
INTRODUCTION
A significant stage migration has occurred
with the introduction of routine PSA
screening for prostate cancer. Accordingly,
most newly-diagnosed tumours are now
organ-confined (cT2), with only a small
subset of patients presenting with locally
advanced (cT3) disease [1]. As a result, the
optimal treatment for these patients
©
What’s known on the subject? and What does the study add?
Despite a lack of randomised controlled trials, most men with locally advanced
prostate cancer are recommended to undergo external beam radiotherapy (EBRT), often
combined with long-term androgen-deprivation therapy (ADT). Many of these men are
not offered radical prostatectomy (RP) by their treating urologist. Additionally, it is
know that EBRT with long-term ADT does provide good cancer control (88% at 10
years). We have previously published intermediate-term follow-up of a large series of
men treatment with RP for cT3 prostate cancer.
We report long-term follow-up of a large series of men treated with RP as primary
treatment for cT3 prostate cancer. Our study shows that with long-term follow-up RP
provides excellent oncological outcomes even at 20 years. While most men do require
a multimodal treatment approach, many men can be managed successfully with RP
alone.
• Local recurrence-free, systemic
progression-free and cancer-specific
survival for men with cT3 prostate cancer
after RP was 76%, 72%, and 81%,
respectively, at 20 years.
• On multivariate analysis, increasing RP
Gleason score (hazard ratio [HR] 1.8; P =
0.01), non-diploid chromatin content (HR
1.8; P = 0.01), positive surgical margins (HR
2.1; P = 0.007), and seminal vesicle
invasion (HR 2.1; P = 0.005) were
associated with a significant risk of
prostate cancer death, while a more recent
year of surgery was associated with a
decreased risk of cancer-specific mortality
(HR 0.88; P = 0.01)
CONCLUSIONS
remains unclear and highly controversial.
Interestingly, despite a lack of prospective
randomised clinical trials comparing
treatment methods for men with high-risk
prostate cancer, these patients have been
found to be significantly less likely to
undergo surgery [2,3].
associated with 5-year cancer-specific
survival (CSS) rates of 94% for men with
locally advanced prostate cancer, and in fact
has become a preferred treatment in this
setting [4]. The use of concomitant
long-term androgen-deprivation therapy
(ADT) has been found to be critical in
optimising outcomes for high-risk tumours
treated with EBRT, as results from the EORTC
Phase III trial 22961 found a 10-year
Indeed, external beam radiotherapy (EBRT)
combined with hormonal therapy has been
• RP affords accurate pathological staging
and may be associated with durable cancer
control for cT3 prostate cancer, with 20
years of follow-up presented here.
• RP as part of a multimodal treatment
strategy therefore remains a viable
treatment option for patients with cT3
tumours.
KEYWORDS
clinical T3, prostate cancer, radical
prostatectomy, extraprostatic extension,
seminal vesicle invasion
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MITCHELL ET AL.
prostate cancer mortality rate of 31% for
patients treated with EBRT alone, vs 11.2%
after EBRT combined with long-term ADT
[5].
Radical prostatectomy (RP) has been
evaluated for patients with cT3 in several
single-institution series to date, including a
previous report from our centre [1,6–8].
Data from these studies suggest that RP
may afford long-term cancer control for cT3
tumours. However, these studies have
largely contained relatively few patient and/
or short-term follow-up, and have variously
included patients treated with adjuvant
therapies. Here, then, we provide long-term
follow-up from a large cohort of men who
underwent RP for cT3 prostate cancer.
PATIENTS AND METHODS
After Institutional Review Board approval
was obtained, we reviewed our
Prostatectomy Registry to identify 7883
consecutive patients who underwent RP at
Mayo Clinic between 1987 and 1997. This
era was chosen to allow for reporting of
extended follow-up. Of these patients, 4812
(61%) patients had cT2 and 843 (15%)
presented with cT3 disease, which was
determined based on DRE. RP was
performed by various surgeons using
standard techniques. All patients included
here underwent an open retropubic
approach. The Mayo Clinic protocol for
preparing and reporting serially sectioned
prostates has been previously reported [9].
Postoperative assessments, including
physical examinations and serum PSA
measurements, were done quarterly for the
initial 2 years, semi-annually for an
additional 2 years, and annually thereafter.
Adjuvant therapy was defined as treatment
received ≤90 days of RP, and was given at
the discretion of the treating physician.
Biochemical recurrence was defined as a
PSA level of ≥0.4 ng/mL [10,11]. Local
recurrence was defined as cancer on biopsy
of the prostatic bed or clinically evident
disease within the prostatic fossa on
physical examination or imaging studies.
Systemic progression involved demonstrable
metastasis on radionuclide bone scan or on
biopsies outside the prostatic bed. Vital
status was identified from death certificates
or physician correspondence. For patients
followed elsewhere, the Mayo Clinic
1 71 0
Variable
Median (IQR):
Age at RP, years
Preoperative PSA level, ng/mL
Body mass index, kg/m2
N (%):
Biopsy Gleason score:
6
7
8–10
Receipt of neoadjuvant ADT
RP Gleason score:
6
7
8–10
Pathological stage:
T2N0
T3a
T3b
T4
TxN1
Positive surgical margin
Median (IQR) tumour volume, mL3
Ploidy, n (%)
Diploid
Tetraploid
Aneuploid
Prostatectomy Registry prospectively
monitors outcomes annually by
correspondence.
The primary endpoints were local
recurrence-free survival, systemic
progression-free survival, CSS, and overall
survival. Postoperative survival was
estimated using Kaplan–Meier method.
Patients were censored at last follow-up or
death if the end point of interest was not
attained. Univariate and multivariate
analysis of features associated with
outcomes were conducted using Cox
proportional hazards regression models.
All tests were two-sided, with P ≤ 0.05
considered to indicate statistical
significance.
RESULTS
Clinical and pathological demographics of
the study population are shown in Table 1.
The median age was 65 years and median
body mass index was 27.2 kg/m2. The
median preoperative PSA level and tumour
TABLE 1
Clinicopathological
demographics of patients
with cT3 tumours treated
with RP
Value
65.0 (60–69)
10.2 (4.7–23.7)
27.2 (25.1–29.6)
201 (45)
161 (36)
84 (19)
198 (24)
305 (41)
305 (41)
128 (17)
223 (26)
191 (22.7)
199 (23.6)
3 (0.4)
227 (27)
472 (56)
5.2 (2.3–11)
421 (52)
285 (35)
112 (14)
IQR, interquartile range .
volume were 10.2 ng/mL and 5.2 mL3,
respectively. Interestingly, as can be seen,
clinical over-staging occurred in 26%
(223/843) of patients, as these men were in
fact found to have organ-confined (pT2)
disease at RP. In all, 198 (24%) of the men
with cT3 prostate cancer received
neoadjuvant hormonal therapy. A total of
344 (40.8%) men received adjuvant
hormonal therapy, while 109 (12.9%) were
treated with adjuvant radiation. As such,
356 (42%) men in the cT3 cohort were
treated with RP without neoadjuvant or
adjuvant therapy.
The median (range) postoperative follow-up
was 14.3 (0–23.5) years. During this time,
501 (59%) men had biochemical recurrence,
156 (19%) developed local recurrence, and
197 (23%) had systemic progression. In all,
454 (54%) had died at last follow-up, with
126 (15%) dying from prostate cancer
(Table 2). The resulting survival estimates at
20 years after RP, then were 76%, 72%,
81%, and 36% for local recurrence-free,
systemic progression-free, prostate CSS, and
overall survival, respectively (Figs 1–4).
Overall, 170 (20.2%) patients received
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20-YEAR SURVIVAL AFTER RP FOR CT3 PROSTATE CANCER
FIG. 1. Postoperative local recurrence-free survival
for men with cT3 prostate cancer.
Freedom from Local
Recurrence, %
Local Recurrence Free Survival
100
90
80
70
60
50
40
30
20
10
0
0
5
10
15
20
Time, Years
Survival Estimate (Number at Risk)
100(843) 92(690) 83(527) 80(325) 76(55)
Prostate Cancer Specific Survival
100
90
80
70
60
50
40
30
20
10
0
0
10
15
20
Time, Years
Survival Estimate (Number at Risk)
100(843) 95(743) 90(609) 83(386) 81(65)
5
FIG. 4. Postoperative overall survival for men with
cT3 prostate cancer.
Overall Survival
Systemic Progression Free Survival
100
90
80
70
60
50
40
30
20
10
0
0
Free of All Cause
Death, %
Freedom from Systemic
Progression, %
FIG. 2. Postoperative systemic progression-free
survival for men with cT3 prostate cancer.
FIG. 3. Postoperative CSS for men with cT3 prostate
cancer.
Free of Prostate Cancer
Death, %
Clinical endpoint, n
Biochemical recurrence
Clinical local recurrence
Systemic progression
Clinical local recurrence or systemic progression
Death from prostate cancer
Death from any cause
TABLE 2
Summary of clinical
endpoints after RP for cT3
disease
cT3 patients
(N = 843)
501
156
197
273
126
454
5
10
15
20
Time, Years
Survival Estimate (Number at Risk)
100(843) 90(704) 82(564) 75(355) 72(61)
100
90
80
70
60
50
40
30
20
10
0
0
5
10
15
20
Time, Years
Survival Estimate (Number at Risk)
100(843) 90(743) 76(609) 57(386) 36(65)
TABLE 3 Multivariate analysis of variables associated with death from prostate cancer and all-cause
mortality after RP for men with cT3 prostate cancer
Variable
Year of surgery
Gleason score (ref = 6)
Preoperative PSA level
Tumour ploidy (non-diploid)
Positive surgical margin
Seminal vesicle invasion
Positive lymph nodes
Adjuvant hormonal therapy
©
Prostate cancer death
HR (95% CI)
0.88 (0.79–0.97)
1.79 (1.07–2.99)
1.09 (0.94–1.27)
1.81 (1.16–2.82)
2.14 (1.23–3.72)
2.05 (1.24–3.38)
1.10 (0.58–2.07)
0.80 (0.43–1.48)
P
0.011
0.026
0.238
0.010
0.007
0.005
0.778
0.472
All-cause mortality
HR (95% CI)
0.96 (0.91–1.01)
1.25 (0.99–1.58)
1.11 (1.02–1.20)
1.19 (0.96–1.48)
1.12 (0.88–1.42)
1.55 (1.22–1.98)
0.92 (0.66–1.29)
0.89 (0.65–1.21)
P
0.091
0.061
0.011
0.117
0.368
<0.001
0.639
0.441
salvage radiotherapy for biochemical
recurrence, while 319 (37.8%) patients were
treated with salvage ADT during clinical
follow-up.
We next evaluated variables associated with
death from prostate cancer among men
with cT3 disease undergoing RP. On
multivariate analysis (Table 3), we found
that increasing RP Gleason score (hazard
ratio [HR] 1.8; P = 0.01), non-diploid
chromatin content (HR 1.8; P = 0.01),
positive surgical margin (HR 2.1; P = 0.007),
and seminal vesicle invasion (HR 2.1; P =
0.005) were associated with a significantly
increased risk of prostate cancer death. On
the other hand, more recent year of surgery
(HR 0.88; P = 0.01) was associated with a
decreased risk of prostate-cancer mortality.
DISCUSSION
For men with cT3 prostate cancer, RP offers
durable oncological outcomes, with
long-term follow-up, now up to 20 years.
Additionally, over-staging of cT3 disease was
26%, suggesting that while most patients
with cT3 tumours will probably require a
multimodal treatment strategy, more than a
quarter of patients may be able to be
managed with RP alone, thereby delaying if
not avoiding the costs and toxicities of
secondary therapies. This series represents,
what is to our knowledge, the largest single
institution series reported to date, with the
longest postoperative follow-up, for patients
with cT3 prostate cancer treated with RP.
While routine PSA screening has resulted in
a significant stage migration of prostate
cancer, a small percentage of men continue
to be diagnosed with locally advanced
tumours. The optimal treatment approach
for men with high-risk/locally advanced
disease remains unknown and continues to
be the subject of much debate. The
long-term postoperative CSS for men with
cT3 disease in the present study (90% at 10
years) compares favourably with the
reported rates achieved with EBRT combined
with long-term ADT in the EORTC phase III
trial 22961 (88% at 10 years) [5]. The
present study further shows that RP
continues to achieve durable oncological
outcomes, with a CSS of 81% at 20 years
(≈1%/year after 10 years). One potential
benefit from RP for patients with cT3
disease is the ability to obtain pathological
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MITCHELL ET AL.
staging, as >25% of these men were found
to be clinically over-staged. As such, the
pathological staging information from RP
may guide a more selective application of
secondary therapies, including ADT, which
carries significant adverse consequences on
health-related quality of life and non-cancer
morbidity [12,13]. Although the exact
association remains unclear and has recently
been questioned [14], there is recent
increased awareness of the potential for
increased risk of cardiac death in men
receiving ADT as well [15].
Others have examined the impact of RP for
locally advanced prostate cancer. Carver
et al. [6] reported on 176 men with cT3
cancer treated with RP. One third of patients
received neoadjuvant while none received
adjuvant therapy. The 15-year probability of
death from prostate cancer in that series
was low (24%); however, follow-up was
short (median 6.4 years). In another series
from Johns Hopkins of cT3a only, Freedland
et al. [7] reported on 61 patients with a
median follow-up of 10.3 years. Estimated
15-year survival was 84% with no men
having received adjuvant therapies.
Meanwhile, Hsu et al. [16] reported on a
series of 235 men with cT3 prostate cancer
treated with RP. Of these men, 22% received
adjuvant and 34% received salvage
treatments. Nonetheless, with a relatively
short follow-up (5.8 years), actuarial 10-year
prostate cancer survival was 91.6%.
In the present series, despite nodal
metastases in ≈25%, 28% of men with cT3
prostate cancer did not receive any form of
ADT during treatment or follow-up, while
48% did not receive any form of adjuvant
therapy. Thus, a significant percentage of
men with cT3 tumours may achieve durable
oncological outcomes with RP alone.
Nevertheless, it is important to note that RP
for cT3 prostate cancer is often part of a
multimodal treatment strategy. Interestingly,
for the impact of the sequence of
treatments in such a multimodal approach,
initial treatment with RP followed by
salvage radiation has been associated with
improved health-related quality of life
outcomes, particularly for erectile
dysfunction and urinary incontinence, than
initial treatment with radiation therapy
followed by salvage RP [17].
While no prospective randomised trials have
been conducted for RP vs radiation therapy
1 71 2
in men with high-risk prostate cancer,
several retrospective series have examined
this issue. When controlling for case mix,
these series have noted a significantly
increased risk of mortality among patients
treated with EBRT vs RP [18,19]. It has been
postulated that this finding may be related
in part to a potential increased risk of
cardiac death, particularly in men with
coronary artery disease, receiving ADT
together with EBRT [15]. However, the need
remains for prospective clinical trials to
define the optimal multimodal management
approach for patients with high-risk
prostate cancer.
We recognise the present study is limited by
its retrospective and non-randomised
design. As such, administration of secondary
cancer treatments with regard to the choice,
timing, and duration of therapy was subject
to individual physician discretion. In
addition, the present series represents a
historical cohort of patients, largely treated
before the stage migration that has
occurred as a result of aggressive PSA
screening. As increasing year of surgery was
significantly associated with a decreased risk
of prostate cancer death, it is unclear
whether these results will continue to be
applicable in contemporary cT3 patients.
Moreover, it remains to be seen how
increased use of preoperative MRI for more
accurate staging of high-risk patients will
affect the rates of over-staging seen in the
present study [20,21]. While the present
study is devoid of a control group for
comparison, nonetheless we feel that RP as
part of a multimodal treatment strategy for
patients with cT3 disease offers durable
cancer control and survival rates 20 years
after RP and compares favourably with the
outcomes that have been reported after
EBRT + ADT for locally advanced tumours.
In conclusion, although patients with cT3
prostate cancer may have additional adverse
pathological features, RP affords accurate
pathological staging and identifies a
substantial proportion of patients who in
fact have organ-confined tumours, and may
thereby be spared the toxicities and cost of
adjuvant therapy. Moreover, RP may be
associated with durable cancer control,
frequently as part of a multimodal
treatment strategy, for patients with locally
advanced disease, and should therefore
remain a viable treatment option for such
patients.
CONFLICT OF INTEREST
None declared.
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Correspondence: R. Jeffrey Karnes,
Department of Urology, Mayo Clinic, 200
First Street SW, Rochester, MN 55905, USA.
e-mail: [email protected]
Abbreviations: ADT, androgen-deprivation
therapy; CSS, cancer-specific survival; EBRT,
external beam radiotherapy; HR, hazard
ratio; RP, radical prostatectomy.
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