Prostate Cancer and Prostatic Diseases (2004) 7, 343–349
& 2004 Nature Publishing Group All rights reserved 1365-7852/04 $30.00
www.nature.com/pcan
Comparison of external radiation
therapy vs radical prostatectomy
in lymph node positive prostate
cancer patients
R Kuefer1, BG Volkmer1, M Loeffler1, RL Shen2, L Kempf3,
AS Merseburger4, JE Gschwend1, RE Hautmann1, HM Sandler3,6
& MA Rubin5,6*
1
Department of Urology, University of Ulm, Ulm, Germany; 2Department of Pathology,
University of Michigan, School of Medicine, Ann Arbor, Michigan, USA; 3Department
of Radio-Oncology, University of Michigan, School of Medicine, Ann Arbor, Michigan,
USA; 4Department of Urology, University of Tuebingen, Tuebingen, Germany; and
5
Department of Pathology, Brigham & Women’s Hospital, Boston, Massachusetts, USA
Introduction: Treatment options for lymph node positive prostate cancer are
limited. We retrospectively compared patients who underwent external
radiotherapy (ERT) to patients treated by radical prostatectomy (RPX).
Materials and Methods: A total of 102 lymph node positive patients from the RPX
series at Ulm University were evaluated. In all, 76 patients received adjuvant
androgen withdrawal as part of their primary treatment. In the ERT group, 44
patients were treated at the University of Michigan using a fractionated regimen.
Of these, 21 patients received early adjuvant hormonal therapy. Patients with
neoadjuvant therapy before RPX or ERT were excluded.
Results: In the RPX group, PSA nadir (nadirp0.2 vs 40.2 ng/ml) showed a strong
association with outcome. In the ERT group, pretreatment PSA was an
independent predictor of outcome (P ¼ 0.04) and patients with adjuvant hormonal
therapy had a significant longer recurrence-free interval compared to patients
without adjuvant therapy (P ¼ 0.004). Comparing only patients with adjuvant
hormonal treatment after cancer-specific therapy, the ERT-treated patients had a
borderline longer PSA recurrence-free survival time compared to the RPX-treated
patients (P ¼ 0.05).
Conclusions: In case of positive lymph nodes, RPX and ERT might be considered
and need to be explained to the patient. For future treatment decisions, the
presented findings and a potential survival benefit need to be evaluated in a larger
prospective setting.
Prostate Cancer and Prostatic Diseases (2004) 7, 343–349. doi:10.1038/sj.pcan.4500751
Published online 7 September 2004
Keywords: external beam radiation therapy; radical prostatectomy; lymph node
positive; outcome
Introduction
Prostate cancer is a leading cause of male cancer-related
deaths in the United States.1 Currently, there is no
*Correspondence: MA Rubin, Pathology, Brigham & Women’s
Hospital, 75 Francis Street, Boston, MA 02115, USA.
E-mail: marubin@partners.org
6
These authors contributed equally to this work.
Received 7 April 2004; revised 26 May 2004; accepted 21 June 2004;
published online 7 September 2004
standard approach for treating clinically confined and
locally advanced prostate cancer. Patients and clinicians
deliberate between radical prostatectomy, radiation
therapy, and watchful waiting. One recent study provides evidence that men with clinically localized prostate
cancer may benefit from radical prostatectomy when
compared to watchful waiting due to reduced cancerspecific death and development of metastatic disease in
the surgical cohort.2 For men with locally advanced
prostate cancer disease (ie, localized prostate cancer with
Radiation or surgery in advanced prostate cancer
R Kuefer et al
344
spread to pelvic or regional lymph nodes but no
evidence of distant metastatic disease), one may anticipate that treatment decision is easier as it is documented
that patients receiving no therapy at all will have a very
poor prognosis.3–5 Yet, only limited comparative data are
available concerning different therapeutic options.6
The goal of the current study was to compare external
radiation therapy (ERT) and radical prostatectomy (RPX)
in the setting of locally advanced prostate cancer using
biochemical failure as the endpoint.
Material and methods
Patient population
At the University of Ulm, Germany, more than 1400
patients underwent RPX since 1984.
A total of 177 patients had RPX despite the identification of metastatic disease to pelvic lymph nodes during
the course of surgery or metastatic spread was identified
on the final review of pathology following surgery.
Extended lymphadenectomy was carried out and all
cases were staged using the TNM classification.7 Histopathology was re-evaluated by the study pathologist
(MAR), who assigned a Gleason score.8 Patients were
grouped according to PSA nadir with a cutoff at 0.2 ng/
ml, those with a PSA o0.2 ng/ml were considered as
cases with best local control of tumor. Progression was
defined as either an elevation of the PSA level (increase
of 40.2 ng/ml compared to PSA nadir) or clinical
detectable progress. Follow-up was carried out according
to a standardized protocol (physical examination and
PSA every 3 months for 2 y after RPX, then twice a year;
chest X-ray and bone scan once a year or if suspected).
Patients who had received neoadjuvant treatment were
excluded. There were 102 men treated by RPX, who fell
in this group.
At the University of Michigan, USA, 62 patients
received ERT for lymph node positive prostate cancer
between 1986 and 2001. For analysis, the following
clinical parameters were required: clinical TNM classification, biopsy Gleason score, pretreatment PSA levels,
type of adjuvant therapy, treatment duration and total
dose of radiation, and standardized follow-up including
evaluation of post-treatment PSA levels. In 45 patients
(72.6%), attempted radical prostatectomy was abrogated
due to histologically confirmed lymph node metastases.
The other 27.4% were diagnosed by enlarged lymph
nodes without resection, potentially resulting in a higher
tumor burden at time of referral to treatment. ERT was
carried out using a fractionated, 3D conformal regimen
with an average total dose of 69 Gy (range 45–77 Gy)
applied onto the prostate within 54 days (range 32–76
days). Failure was defined according to the ASTRO
criteria as three consecutive PSA rises compared to
nadir.9 The study population of the ERT group consisted
of 44 cases. Detailed demographics are given in Table 1.
Table 1 Demographics of the two treatment modalities: radical prostatectomy (RPE) and external radiation therapy (EBRT)
Radical prostatectomy
Patient cohort
Radiation dose (Gy)
Radiation duration (days)
Clinical T1
Clinical T2
Clinical T3
Clinical T4
T stage not assigned
3 (6.8)
Pathological T1
Pathological T2
Pathological T3
Pathological T4
N1
N2
PSA median (ng/ml)
Gleason sum
6
7
8
9
10
Gleason score not assigned
PSA nadir median (ng/ml)
PSA nadir o0.2
PSA nadir X0.2
Adjuvant treatment
Hormonal monotherapy
Complete suppression
Follow-up median (y)
Biochemical failure
Time till failure median (y)
102 (100%)
2 (2%)
47 (46%)
51 (50%)
2 (2%)
0 (0%)
5 (5%)
90 (88%)
7 (7%)
65 (64%)
37 (36%)
26.1 (3.5–414 range)
RPE specimen
4 (4%)
24 (24%)
54 (53%)
18 (18%)
2 (2%)
0.0
64
38
76
54
22
1.9
60
0.6
N1 ¼ one affected lymph node; N2 ¼ two or more positive lymph nodes.
Prostate Cancer and Prostatic Diseases
(0.0–3.1 range)
(62.7%)
(37.3%)
(75%)
(53%)
(22%)
(0.1–12.4 range)
(59%)
(0.1–10.7 range)
Radiation therapy
44 (100%)
Mean 69 (45–77 range)
Mean 54 (32–76 range)
2 (5%)
18 (41%)
17 (39%)
4 (9%)
23 (52%)
21 (48%)
19.9 (2.9–3100 range)
Biopsy
5 (11%)
19 (43%)
9 (21%)
2 (5%)
0 (0%)
9 (21%)
0.1 (0.0–6.6 range)
21
9
12
2.1
27
1.5
(48%)
(21%)
(27%)
(0.5–14.1 range)
(61%)
(0.5–7.5 range)
Radiation or surgery in advanced prostate cancer
R Kuefer et al
Data analysis
Statistical analysis was performed by a bio-statistician
(RLS) applying standard approaches such as the T-test to
test for significant difference between the study populations and the Kaplan–Meier analysis to estimate survival.
Univariate, unmatched comparisons of survival were
performed using the log rank test. The Wald test was
used for Cox hazards regression analysis in a multivariate model.
Results
Analysis of the RPX study population
All 102 patients of the RPX group underwent surgery
with the intention of a surgical cure. The majority of
cases had microscopic proven metastases identified in
the review of the permanent pathology sections after
surgery. Average age at surgery was 64.7 y (range 49.3–
79.1 y). The median PSA level before surgery was
26.1 ng/ml (range 3.5–414 ng/ml). Two (2%) cases were
classified as clinical T1 tumors, 47 (46%) cases as T2, 51
(50%) as T3 and two (2%) cases as clinical T4 tumors.
Pathologic evaluation demonstrated that tumor classification was underestimated by the clinical T stage as most
of the cases proved to be in the pathology report pT3 (90
patients; 88%). Only five (5%) patients were pT2 and
seven (7%) cases T4. In all, 64% of the patients had one
positive lymph node after final review of the pathology.
All tumors were Gleason score X6. In 64 (62.7%)
patients, PSA after surgery dropped o0.2ng/ml, in 38
(37.3%) patients nadir was X0.2 ng/ml. A total of 76
(74.5%) patients received early adjuvant hormonal
treatment, 54 patients as monotherapy and 22 patients
complete androgen withdrawal. Mean time of follow-up
was 2.9 y (range 0.1–12.4 y; 40 (39%) follow-up 43 y). Of
the 102 patients, 60 experienced biochemical failure.
Median time till failure was 0.6 y (mean 1.5 y; range
0.1–10.7 y). All patients experiencing local or distant
recurrence had prior biochemical relapse. Detailed
clinical data are given in Table 1 and a graphical
presentation of the PSA recurrence-free survival of the
102 RPX cases is given in Figure 1a.
To test for associations between clinical parameters
and outcome in the RPX group, univariate Cox regression analyses were performed. None of the clinical
parameters including age at diagnosis, clinical or
pathological tumor stage, lymph node burden, Gleason
sum, WHO tumor grade of the prostatectomy specimen,
preoperative PSA (numeric value, categorized or logarithmic value) or type of adjuvant hormone treatment
demonstrated a statistically significant association with
outcome defined as biochemical failure. The only
parameter with significant association with outcome
was PSA nadir following surgery (Po0.0001, 95%
confidence interval (CI) 1.7–4.9) (Figure 1b). The best
multivariate model for the RPX group eliminated in a
stepwise backward procedure all of the clinical parameters mentioned above, calculating a P-value of
o0.0001 for PSA nadir (CI 1.7–5.0; hazard risk 2.9).
There was no statistically significant difference in
recurrence-free survival time based on type of adjuvant
treatment (log rank P ¼ 0.46). Only if stratified for PSA
nadir, those patients reaching a nadir of PSAo0.2 ng/ml
and receiving complete hormonal withdrawal had a
longer time of recurrence-free survival compared to
those patients receiving mono-therapy (log rank
P ¼ 0.03). In the group of patients with a nadir
PSAX0.2 ng/ml, there was no association between type
of treatment and recurrence-free survival (log rank
P ¼ 0.3).
345
Analysis of the ERT study population
Since 1986, 44 patients were treated by ERT for lymph
node positive prostate cancer at the University of
Michigan. Median PSA level before radiotherapy was
19.9 ng/ml (range 2.9–3100 ng/ml). Two (4.5%) patients
had clinical stage T1, 18 (40.9%) patients T2, 17 (38.6%)
T3 and four (9.1%) patients T4. Three (6.8%) patients
were not assigned a clinical T stage. In all, 52.3% of the
patients had one positive lymph node. Five (11.4%) cases
had a Gleason sum of 6. A total of 30 (68.2%) patients had
a Gleason score of X7 (Gleason ¼ 7, 43.2%; Gleason ¼ 8,
Figure 1 (a) Kaplan–Meier analysis showing the recurrence-free survival for the group of patients with lymph node positive disease treated by radical
prostatectomy. (b) Patients treated by prostatectomy stratified for postoperative prostate-specific antigen nadir o0.2 ng/ml vs X0.2 ng/ml (log rank
Po0.0001).
Prostate Cancer and Prostatic Diseases
Radiation or surgery in advanced prostate cancer
R Kuefer et al
346
20.5%; Gleason ¼ 9, 4.5%). For nine biopsies, a Gleason
score was not available for analysis. Median nadir was a
PSA of 0.1 ng/ml (0.0–8.8 ng/ml). In all, 21 (47.8%)
patients received adjuvant treatment, nine (20.5%)
patients monotherapy and 12 (27.3%) patients complete
androgen deprivation. Median follow-up time was 2.1 y
(range 0.5–14.1 y; mean 3.2 y; 15 (34%) follow-up 43 y).
Of the 44 patients, 27 (61.4%) had biochemical failure.
Median time to failure was 1.5 y (range 0.5–7.5 y). A
graphical presentation of the recurrence-free survival
data of the 44 ERT treated cases is given in Figure 2a.
Of all clinical parameters, tumor stage (Cox regression
P ¼ 0.005, CI 1.4–7.4) and pretreatment PSA (P ¼ 0.007, CI
95% 1.3–4.3) had a strong association with outcome on
the univariate level. In the ERT group, there is a
significant higher percentage of patients with freedom
from recurrence if adjuvantly treated by any type of early
hormonal withdrawal (P ¼ 0.004) (Figure 2b). There was
statistically no difference if treated with monotherapy or
complete hormonal withdrawal (log rank P ¼ 0.38). The
multivariate model calculated a P-value of 0.001 for
pretreatment PSA if categorized into three groups
PSAo10 ng/ml, PSA410 and o20 ng/ml and
PSA420 ng/ml (CI 2.2–19.6). In this setting, adjuvant
hormonal therapy had the strongest association with
PSA recurrence-free survival in patients treated with
ERT (Po0.001; CI 0.01–0.2).
Comparison of the two treatment modalities:
RPX and ERT
For comparison of the two treatment options, we first
looked at patients who had received some kind of
adjuvant hormonal therapy. With this approach, it is
taken into consideration that adjuvant treatment had a
significant influence on outcome in the ERT group. In the
RPX group, independent of nadir, there was no strong
association between type of adjuvant hormone therapy
and outcome as described above. The RPX group
consisted of 76 patients. In all, 45 patients experienced
biochemical failure during follow-up; median follow-up
was 1.6 y (mean 3.1 y; range 0.1–12.4 y). The ERT group
consisted of 21 cases of which seven had PSA relapse
during follow-up; median follow-up was 2.3 y (mean
3.3 y; range 0.5–10.6 y). There was no significant difference in the pretreatment clinical parameters between
these two groups including tumor stage (T-test P ¼ 0.6),
lymph node burden (P ¼ 0.7) and PSA (P ¼ 0.06).
As demonstrated in Figure 3a, the Kaplan–Meier
survival curve revealed a borderline significant difference in PSA recurrence-free survival rate between these
two groups (log rank P ¼ 0.053). Interestingly, the ERT
group reached a plateau at about 50% PSA recurrencefree survival, starting at a follow-up time of 4 y. In
contrast to that, in the RPX group, the survival curve of
the patients receiving some sort of adjuvant hormonal
therapy, does not reach a plateau up to 12 y after RPX.
Complete hormonal withdrawal has, in both treatment
groups, some, but not a statistically significant, benefit
compared to monotherapy (RPX log rank P ¼ 0.36; ERT
log rank P ¼ 0.38). As demonstrated in Figure 3b, when
comparing only patients with complete hormonal withdrawal after cancer-specific therapy, there is no difference in PSA recurrence-free survival between the RPX
and the ERT group (log rank P ¼ 0.37). In this comparison, all patients independent of nadir were included in
the RPX group, as postsurgical nadir cannot be used as a
parameter to preselect patients for RPX.
Discussion
Currently for men diagnosed with clinically localized
and locally advanced prostate cancer, there is no
definitive single ‘best’ treatment option. Some guidelines
have been developed to evaluate men on watchful
waiting protocols.10 A recent study provides evidence
that in clinically localized prostate cancer, radical
prostatectomy may reduce the cancer-specific but not
the overall mortality compared to watchful waiting.2 At
first glance, the debate regarding treatment seems easier
in locally advanced disease, as it is known that patients
with node positive disease, receiving no therapy will die
due to prostate cancer within a short period of time.11
But in these cases, the question is what type of therapy is
of most long-term benefit to the majority of patients?
Figure 2 (a) Kaplan–Meier analysis showing the recurrence-free survival for the group of patients with lymph node positive disease treated by ERT.
(b) Freedom from recurrence of patients after radiation stratified for type of adjuvant hormonal treatment. Patients receiving no adjuvant hormonal therapy
vs patients with adjuvant androgen withdrawal (log rank P ¼ 0.014).
Prostate Cancer and Prostatic Diseases
Radiation or surgery in advanced prostate cancer
R Kuefer et al
347
Figure 3 (a) Kaplan–Meier analysis comparing the recurrence-free survival of patients treated by radical prostatectomy vs patients who underwent
external radiation therapy. Both groups received adjuvant hormonal treatment either by monotherapy or complete hormonal withdrawal (log rank
P ¼ 0.05). (b) Comparison of the recurrence-free survival of patients who received complete hormonal withdrawal after radical prostatectomy or ERT.
Radiation therapy as an option in the treatment for
prostate cancer goes back to the 1960 s. Technical
advances and application of field techniques have helped
reduce complications and only in the minority of cases
do patients report moderate urinary and bowel symptoms.12,13 In prostate cancer, the gross disease requires
radiation doses of at least 70 Gy applied in a fractionated
regimen. The median dose in this study was 69 Gy and
thus is quite low. Such low doses are likely suboptimal
for treatment. In fact, there is evidence that increased
doses are associated with reduced risk of biochemical
failure, distant metastasis and even overall survival.14–16
Controversy exists if there is a benefit to irradiation of
the pelvic lymph nodes with a total dose of about 45 Gy.
A study conducted by the RTOG failed to show a benefit
in treating lymph nodes and prostate compared to
prostate alone in prostate cancer A2 and B tumors.17
This observation is supported by another study including lymph node positive prostate cancer patients.18 No
clear benefit is described in the literature from prophylactic pelvic nodal irradiation compared to prostate-only
radiation. Yet, according to the RTOG 9413 study, there is
a benefit of whole pelvic radiotherapy if combined with
neoadjuvant and concurrent hormonal therapy compared to radiotherapy of the prostate-only with any type
of hormonal withdrawal.19
Radical prostatectomy combined with adjuvant hormonal therapy is considered a valuable treatment option
in high-risk prostate cancer patients.20 In the presence of
positive lymph nodes, it has been demonstrated that
immediate antiandrogen therapy reduces the risk of
recurrence and improves survival compared to observation.21 Surgery often is stopped once positive lymph
nodes are discovered during lymphadenectomy. Still
some benefit through surgery and adjuvant hormonal
treatment in these advanced cases is reported.5,11,22 In
fact, there is evidence that radical prostatectomy with
early adjuvant androgen deprivation provides a significant advantage compared to androgen suppression alone
as goes for overall and disease-specific survival.23
Presently, less advanced cases are diagnosed due to
increasing awareness of the population and the merit of
PSA as a screening tool. On the other hand, a recent
series from Europe shows minute lymph node metas-
tases in about 40% of all cases including cases with a low
pathological tumor stage. In this study, examination of
iliac lymph nodes from the external and internal region
was examined.24 These findings suggest that at least
some published outcome results after RPX had a
significant number of cases with lymph node positive
disease, included as pN0 disease.
A critical issue in comparing the results of two
treatment modalities in this or any study is the choice
of exclusion criteria and the definition of outcome.
In this study, all patients with any kind of neoadjuvant
treatment have been excluded. For patients treated with
RPX, neoadjuvant hormonal therapy is still considered
controversial and not generally recommended.25,26 For
patients treated with ERT, neoadjuvant therapy is
promising to have an influence even on disease-free
and overall survival.27 Adjuvant treatment has been
grouped the RPX and the ERT patients into three
categories, no adjuvant treatment, monotherapy and
complete androgen deprivation. Although it has been
suggested in previous studies that early adjuvant
androgen deprivation is beneficial for patients with node
positive disease treated by RPX,21,28,29 surprisingly a
considerable number of patients did not receive adjuvant
hormonal therapy. The same is true for the ERT group. In
accordance with the findings in this study and supported
by in vitro and in vivo experiments,30 early adjuvant
hormonal treatment has been shown to be beneficial in
bulky tumors.31–34
Crucial for comparison of the results is the choice of
endpoint. In the current series, there have not been
enough disease-specific deaths, that is, three in the ERT
group, for comparative statistical analysis. This points
out the importance of even longer follow-up times. The
endpoint was defined as biochemical failure measured
by PSA. For all interpretations in this setting, it has to be
kept in mind that the most common, but still different
definitions of failure, have been applied for the two
treatment options. It cannot be ruled out that the
differences seen might be only related to the calculation
of PSA failure or the expected kinetics after specific
therapy. For radiation therapy, there is significant
controversy about definition of the appropriate nadir. It
is known that after radiation therapy, PSA levels decline
Prostate Cancer and Prostatic Diseases
Radiation or surgery in advanced prostate cancer
R Kuefer et al
348
over a period of several years. It is unclear if the time till
nadir is associated with risk of biochemical failure but, in
one study, it was demonstrated that a nadir of less than
1 ng/ml is an independent predictor of biochemical
outcome.35 In the current study, we applied to the ERT
group the ASTRO criteria,9 although variations in results
due to different criteria and potential improvements of
the ASTRO criteria have been described.36,37 For the RPX
group, biochemical failure was defined as a PSA increase
over 0.2 ng/ml compared to nadir. For comparison with
the ERT group, those patients not reaching undetectable
PSA levels after RPX were not excluded, although these
cases obviously represent unsatisfactory surgical control
and might be defined as failures at day zero in other
studies. So not surprisingly, there was a strong association between nadir and biochemical failure in the RPX
group. This is a post-treatment parameter and thus cannot be taken into consideration for treatment decision.
Analysis of the RPX group demonstrated that an optimal
surgical result is mandatory for an additional significant
positive effect of adjuvant hormonal deprivation.
As described in detail above, patients treated by ERT
and adjuvant hormonal therapy had statistically a
borderline significant better outcome than patients after
RPX and adjuvant hormonal therapy. This difference
diminishes if best surgical condition was achieved
reflected by a PSA nadir of o0.2 ng/ml. In this case,
patients treated by RPX and receiving some adjuvant
hormonal treatment do as well as patients treated by ERT
and adjuvant hormonal treatment (log rank 0.47).
Obviously, there is no possibility to predict a PSA nadir
of o0.2 ng/ml after RPX. Therefore, we believe that the
rationale for the comparison between these two treatment groups of men with locally advanced prostate
cancer is appropriate. On the other hand, analysis
demonstrated that a patient reaching a PSA nadir of
o0.2 ng/ml and receiving complete hormonal withdrawal has almost a 80% chance not to experience
biochemical failure within 10 y after surgery (data not
shown). Furthermore, one may state that patients treated
by RPX and not reaching a PSA nadir of o0.2 ng/ml will
need some other sort of adjuvant therapy as hormonal
withdrawal does not seem to have a major influence. In
this group, ERT might be a very good option of adjuvant
treatment after RPX.38
Our data also suggest that in patients treated with ERT,
adjuvant therapy by the means of hormonal withdrawal,
is beneficial. The different mechanisms represented by
radiotherapy and hormonal deprivation concerning
control or killing of malignant cells suggest a rationale
for their combined use. In the RPX group, it is
demonstrated that long-term success primarily depends
on a perfect local control and thus surgical success. In
this setting, hormonal therapy shows an additive effect
on PSA recurrence-free survival.
Conclusions
Acknowledging the fact that morbidity and mortality of
both treatment options, RPX and ERT, have been
significantly decreasing due to technical improvements,
both therapy modalities have to be considered and
explained to the patient in case of positive lymph nodes.
Prostate Cancer and Prostatic Diseases
If a PSA nadir of o0.2 ng/ml is not reached after RPX,
additional therapy (ie ERT) is indicated as hormonal
withdrawal is not sufficient.
Acknowledgements
This study was supported by the Specialized Program of
Research Excellence for Prostate Cancer (S.P.O.R.E.) NCI
Grant no. P50CA69568.
References
1 Jemal A et al. Cancer statistics, 2002. CA Cancer J Clin 2002; 52:
23–47.
2 Holmberg L et al. A randomized trial comparing radical
prostatectomy with watchful waiting in early prostate cancer.
N Engl J Med 2002; 347: 781–789.
3 Davidson PJ et al. Progression in untreated carcinoma of the
prostate metastatic to regional lymph nodes (stage t0 to 4,N1 to
3.M0,D1). European Organization for Research and Treatment of
Cancer Genitourinary Group. J Urol 1995; 154: 2118–2122.
4 Seay TM, Blute ML, Zincke H. Long-term outcome in patients
with pTxN+adenocarcinoma of prostate treated with radical
prostatectomy and early androgen ablation. J Urol 1998; 159:
357–364.
5 Zwergel U et al. Lymph node positive prostate cancer: long-term
survival data after radical prostatectomy. J Urol 2004; 171:
1128–1131.
6 Pollack A, Horwitz EM, Movsas B. Treatment of prostate cancer
with regional lymph node (N1) metastasis. Semin Radiat Oncol
2003; 13: 121–129.
7 Fleming ID, Cancer AJCo, (U.S.) NCI. AJCC Cancer Staging
Manual, 5th ed., Philadelphia: Lippincott-Raven, 1997.
8 Gleason DF. Classification of prostatic carcinomas. Cancer
Chemother Rep 1966; 50: 125–128.
9 American Society for Therapeutic Radiology aOCP. Consensus
Statement: Guidlines for PSA following radiation therapy. Int
J Radiat Oncol Biol Phys 1997; 37: 1035–1041.
10 Choo R et al. Feasibility study: watchful waiting for localized
low to intermediate grade prostate carcinoma with selective
delayed intervention based on prostate specific antigen, histological and/or clinical progression. J Urol 2002; 167: 1664–1669.
11 Seay TM, Blute MC, Zincke H. Radical prostatectomy and early
adjuvant hormonal therapy for pTxN+ adenocarcinoma of the
prostate. Urology 1997; 50: 833–837.
12 Sandler HM et al. Three dimensional conformal radiotherapy for
the treatment of prostate cancer: low risk of chronic rectal
morbidity observed in a large series of patients. Int J Radiat Oncol
Biol Phys 1995; 33: 797–801.
13 Fukunaga-Johnson N et al. Results of 3D conformal radiotherapy
in the treatment of localized prostate cancer. Int J Radiat Oncol
Biol Phys 1997; 38: 311–317.
14 Michalski JM et al. Preliminary report of toxicity following 3D
radiation therapy for prostate cancer on 3DOG/RTOG 9406. Int
J Radiat Oncol Biol Phys 2000; 46: 391–402.
15 Ryu JK et al. Interim report of toxicity from 3D conformal
radiation therapy (3D-CRT) for prostate cancer on 3DOG/RTOG
9406, level III (79.2 gy). Int J Radiat Oncol Biol Phys 2002; 54:
1036–1046.
16 Jacob R et al. The relationship of increasing radiotherapy dose to
reduced distant metastases and mortality in men with prostate
cancer. Cancer 2004; 100: 538–543.
17 Asbell SO et al. Elective pelvic irradiation in stage A2, B
carcinoma of the prostate: analysis of RTOG 77-06. Int J Radiat
Oncol Biol Phys 1988; 15: 1307–1316.
18 Leibel SA et al. The effects of local and regional treatment
on the metastatic outcome in prostatic carcinoma with pelvic
Radiation or surgery in advanced prostate cancer
R Kuefer et al
19
20
21
22
23
24
25
26
27
28
lymph node involvement. Int J Radiat Oncol Biol Phys 1994; 28:
7–16.
Roach III M et al. Phase III trial comparing whole-pelvic vs
prostate-only radiotherapy and neoadjuvant vs adjuvant combined androgen suppression: Radiation Therapy Oncology
Group 9413. J Clin Oncol 2003; 21: 1904–1911.
Vaishampayan U, Hussain M. The evolving role of systemic
therapy in high risk prostate cancer: strategies for cure in the
21st century. Crit Rev Oncol Hematol 2002; 42: 179–188.
Messing EM et al. Immediate hormonal therapy compared with
observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl
J Med 1999; 341: 1781–1788.
Samson D-J et al. Systematic review and meta-analysis of
monotherapy compared with combined androgen blockade for
patients with advanced prostate carcinoma. Cancer 2002; 95:
361–376.
Ghavamian R et al. Radical retropubic prostatectomy plus
orchiectomy vs orchiectomy alone for pTxN+prostate cancer: a
matched comparison. J Urol 1999; 161: 1223–1227, discussion
1227–1228.
Heidenreich A, Varga Z, Von-Knobloch R. Extended pelvic
lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis. J Urol 2002; 167:
1681–1686.
Wieder JA, Soloway MS. Incidence, etiology, location, prevention
and treatment of positive surgical margins after radical
prostatectomy for prostate cancer. J Urol 1998; 160: 299–315.
Gleave ME et al. Long-term neoadjuvant hormone therapy prior
to radical prostatectomy: evaluation of risk for biochemical
recurrence at 5-year follow-up. Urology 2000; 56: 289–294.
Bolla M et al. Improved survival in patients with locally
advanced prostate cancer treated with radiotherapy and
goserelin. N Engl J Med 1997; 337: 295–300.
Zincke H et al. Stage D1 prostate cancer treated by radical
prostatectomy and adjuvant hormonal treatment. Evidence for
29
30
31
32
33
34
35
36
37
38
favorable survival in patients with DNA diploid tumors. Cancer
1992; 70 (1 Suppl): 311–323.
Frohmuller HG et al. Survival and quality of life of patients with
stage D1 (T1-3 pN1-2 M0) prostate cancer. Radical prostatectomy
plus androgen deprivation vs androgen deprivation alone. Eur
Urol 1995; 27: 202–206.
Zietman AL et al. The effect of androgen deprivation and
radiation therapy on an androgen-sensitive murine tumor: an
in vitro and in vivo study. Cancer J Sci Am 1997; 3: 31–36.
Pilepich MV et al. Phase III radiation therapy oncology
group (RTOG) trial 86-10 of androgen deprivation adjuvant to
definitive radiotherapy in locally advanced carcinoma of the
prostate. Int J Radiat Oncol Biol Phys 2001; 50: 1243–1252.
Whittington R et al. The use of combined radiation therapy
and hormonal therapy in the management of lymph nodepositive prostate cancer. Int J Radiat Oncol Biol Phys 1997; 39:
673–680.
Sands ME, Pollack A, Zagars GK. Influence of radiotherapy on
node-positive prostate cancer treated with androgen ablation. Int
J Radiat Oncol Biol Phys 1995; 31: 13–19.
Zagars GK, Pollack A, von-Eschenbach AC. Addition of
radiation therapy to androgen ablation improves outcome for
subclinically node-positive prostate cancer. Urology 2001; 58:
233–239.
Zelefsky MJ et al. Significance of normal serum prostate-specific
antigen in the follow-up period after definitive radiation therapy
for prostatic cancer. J Clin Oncol 1995; 13: 459–463.
Cherullo EE et al. Variable definitions influence the reporting of
biochemical failure rates. Prostate Cancer and Prostatic Disease
2002; 5: 54–58.
Taylor JM, Griffith KA, Sandler HM. Definitions of biochemical
failure in prostate cancer following radiation therapy. Int J Radiat
Oncol Biol Phys 2001; 50: 1212–1219.
Kalapurakal JA et al. Biochemical disease-free survival following
adjuvant and salvage irradiation after radical prostatectomy. Int
J Radiat Oncol Biol Phys 2002; 54: 1047–1054.
349
Prostate Cancer and Prostatic Diseases