DOWN-STAGING OF EARLY STAGE PROSTATE

CANCER BEFORE RADICAL PROSTATECTOMY:

THE FIRST RANDOMIZED TRIAL OF
NEOADJUVANT COMBINATION THERAPY
WITH FLUTAMIDE AND A LUTEINIZlNG
HORMONE-RELEASING HORMONE AGONIST
FERNAND LABRIE, M.D., Ph.D.
HONEL CUSAN, M.D., Ph.D.
JOSt~-LUIS GOMEZ, M.D.
PIERRE DIAMOND, M.D., Ph.D.
RAUL SUBURU, M.D.
MARTIN LEMAY, M.D.
BERNARD TETU, M.D.
YVES FRADET, M.D.
BERNARD CANDAS, Ph.D.

From the Prostate Cancer Research Unit and Departments of Molecular Endocrinology,
Medicine, Radiology, Pathology, and Urology, CHUL (Centre Hospitalier of L'Universite
Laval) Research Center; Departments of Pathology and Urology,
H6tel-Dieu de Quebec,Quebec City, Canada

ABSTRACT--Objective. To assess the effect of neoadjuvant combination therapy with

the antiandrogen fiutamide and a luteinizing hormone-releasing hormone (LHRH) ago-
nist administered for 3 months before radical prostatectomy, compared with surgery
alone in early stage prostate cancer.
Methods. A sample of 161 randomly screened patients diagnosed as having stage B
(134 patients) or C (27 patients) prostate cancer were randomly assigned to radical
prostatectomy alone or to 3 months of neoadjuvant combination therapy with the
antiandrogen flutamide and an LHRH agonist before radical prostatectomy.
Results. Neoadjuvant combination therapy before radical prostatectomy decreased
cancer-positive surgical margins from 33.8% in the control group to only 7.8%, thus
leaving 92.2% of patients with negative margins at surgery. Although, on average, the
final stage determined by histopathologic examination of the surgical specimen was more
advanced than predicted at initial diagnosis in 33.8% of control patients, an opposite
observation was made in the group of men who received the 3-month neoadjuvant
combination therapy where the final stage, instead of being more advanced, was less
advanced than at diagnosis in an average of 21.1% of men for a net 54% improvement of
staging in favor of combination therapy. Organ-confined disease, on the other hand,
increased from 49.3% to 77.8% of patients after 3 months of combination therapy, for a
57.8% increase in the incidence of organ-confined disease. No cancer was found in 6
(6.7%) prostatectomy specimens from the treated group.
Conclusions. Although long-term follow-up of these patients is required to determine
the impact on survival, the marked influence of neoadjuvant combination on the stage of
the disease suggests the possibility of a major improvement in the morbidity and
mortality from prostate cancer.

UROLOGY SYMPOSIUM/ December 1994 / Volume 44, Number 6A 29


TABLE I. Distribution of the age of the patients
Median
Mean -+ SEM (limits)
Group (yr) (yr)
Group 1 (radical prosta-
tectomy alone) 62.7 -+ 0.6 60.0 (49-70)
Group 2 (combination
therapy before radical
prostatectomy) 62.5 _+ 0.5 59.6 (46-72)
Prostate cancer has become the most common
cancer in men and it ranks as the second most
frequent cause of cancer death in men in North
America. In fact, in 1994, it is predicted that
200,000 new cases of prostate cancer will be discov-
ered and that 38,000 men will die from this disease
in the United States alone. ~ Prostate cancer is thus a
major medical and social problem} which is increas-
ing further with today's longer life expectancy. 3
Although limited information is available on the
best choice of therapy for early stage prostate
cancer, 4 it is well recognized that the only opportu-
nity for a cure of prostate cancer is at an early stage
when the cancer is still localized to the prostate. 4-6
The main objective in the prostate cancer field
should thus be early diagnosis and treatment of
organ-confined disease, since it is known that such
patients treated by radical prostatectomy have a life
expectancy comparable to that of men having no
prostate cancer. 5,7
Unfortunately, not all men who are thought to
have organ-confined prostate cancer at diagnosis are
found to have organ-confined disease at surgery. In
fact, in 50-60% of cases, the pathologic analysis of
the specimen obtained at radical prostatectomy
shows that the cancer is more advanced than
originally predicted at diagnosis, s<4 Since the prog-
nosis for stage C or D1 prostate cancer is poor, the
risk that > 50% of prostate cancers expected to be
localized at diagnosis are found to be not curable at
surgery can easily explain the lack of enthusiasm for
radical prostatectomy and the controversies sur-
rounding the diagnosis and treatment of early stage
prostate cancer.
A possible means of improving the proportion of
patients with organ-confined disease and cancer-
negative margins at surgery was clearly suggested by
the observation that patients treated by combination
therapy using a pure antiandrogen associated with
medical or surgical castration for metastatic disease
show a much more rapid and marked regression of
the cancer in the prostatic area compared with
distant metastatic disease. ~5-~7 Moreover, it is well
recognized that when there is a recurrence of the
30
disease, progression of the cancer at the level of the
prostate is a rare event; instead, the bones are the
usual site of progression. Since prostate cancer
localized in the prostatic area is so highly sensitive to
androgen deprivation, it is logical to use combina-
tion therapy to down-stage prostate cancer in men
diagnosed as having localized prostate cancer before
performing radical surgical prostatectomy. '
Following an encouraging preliminary trial} 8 we
have conducted a prospective and randomized clini-
cal trial to assess precisely the potential advantages
of neoadjuvant combination therapy with the pure
antiandrogen flutamide and a luteinizing hormone-
releasing hormone (LHRH) agonist administered for
3 months before radical prostatectomy, compared
with surgery alone} 9 This report is an update of this
first randomized trial, which analyzes the data on
organ-confined disease, specimen-confined disease,
and compares the final stage at histopathologic
examination of the surgical specimen with the
clinical stage at diagnosis.
METHODS
PATIENTS
A total of 161 men ages 46-72 years (Table I) with
histopathologically proven adenocarcinoma of the
prostate took part in the study. M1 gave written
informed consent, had a life expectancy > 10 years,
and were diagnosed as having localized prostate
cancer in the first prospective study of screening for
prostate cancer performed in a randomly selected
population of men. This study was started in
November 1988 in the Quebec City area by the Laval
University Prostate Cancer Detection Program
(LUPCDP). 6
Six patients were classified at diagnosis as having
stage B0 disease, defined as 1 localized nodule at
digital rectal examination (DRE) and/or a transrectal
ultrasonography (TRUS) lesion <1.0 cm (mean
TRUS diameter); 82 had stage B1 disease, defined as
1 localized nodule at DRE and/or a TRUS lesion
between 1.0 and 1.5 cm (mean TRUS diameter)~ 46
had stage B2 disease, defined as > 1 palpable
nodule at DRE and/or TRUS lesion > 1.5 cm (mean
TRUS diameter); 15 had stage C1 disease, defined as
minimal palpable extracapsular extension and/or
invasion of the prostatic capsule seen by histopatho-
logic examination of biopsy specimen; and 12 had
stage C2 disease, defined as C1 but with, in
addition, invasion of seminal vesicles and/or neuro-
vascular bundle seen at histopathologic examination
of biopsy specimen. Complete clinical evaluation16
and TRUS of the prostate, including biopsy, 6'2° were
done for precise staging of prostate cancer; bone
scan, computed tomography scan of the pelvis and
UROLOGY SYMPOSIUM / December 1994 / Volume 44, Number 6A
abdomen, chest roentgenogram, and skeletal survey
TABLE II. Distribution of patients according
were done to rule out distant disease.
to initial stage*
ELIGIBILITYAND RANDOMIZATION B0 B1 B2 C1 C2 Total
After confirmation of eligibility, each patient was Control 3 39 17 7 5 71
informed about his possible participation in the Combination
therapy 3 43 29 8 7 90
randomized clinical trial. After receiving full informa-
tion and signing the agreement, the patients were *Test of Kolmogorov-Smirnov for difference between the two groups, p =
0.999.
randomly assigned to a group receiving radical
prostatectomy alone, done with minimal delay (con-
trol group), or to a group who received neoadjuvant
TABLE I11. Effectof 3-month neoadjuvant
combination therapy for 3 months before radical
prostatectomy. Because stage of disease (B0, B1, B2, combination therapy with the antiandrogen flutamide
C1, and C2) is a major prognostic factor, the and an LHRH agonist on positive margins at radical
randomization with permuted block was stratified prostatectomy in stages B and C prostate cancer
according to the stages to assign patients to the two Negative Positive
groups (Table II). The median and average ages of Group Margins Margins Total
the patients (Table I) as well as the distribution of Control 47 (66.2%) 24 (33.8%) 71
stages at diagnosis (Table II) showed no significant Combination
difference between the two groups. therapy 83 (92.2%) 7 (7.8%) 90
Among 30 patients who refused randomization, Total 161
26 (1 stage B0, 19 stage B1, 3 stage B2, and 3 stage Chi-square test: p < 0. O01.
C1) chose radical prostatectomy alone and 4 (2 stage
B1 and 2 stage B2) chose neoadjuvant combination
therapy for 3 months (leuprolide acetate [Lupron confined, including capsular penetration but with
Depot or (DTRP6, des-GlyNH21°)LHRI-I ethylamide], negative surgical margins, seminal vesicles, and
7.5 mg intramuscularly every 28 days or 250 Ixg lymph nodes; and (3) cancer-positive margins, or
subcutaneously daily plus flutamide [Eulexin, Eu- those that were not confined, including capsular
flex], 250 mg every 8 hours orally) before radical penetration with positive margins and/or seminal
prostatectomy. Therefore, a logistic regression analy- vesicles and/or tumor involving pelvic lymph nodes.
sis of randomized and nonrandomized patients, The preoperative clinical stage confirmed by biopsy
including covariates for treatment and important was in all cases compared with the final stage as
prognostic factors (age and stage), was done for each determined by the histopathologic data of the surgi-
group to assess and confirm the validity of the trial, cal specimen. The presence of perineural space
in which all eligible patients were studied, 21 includ- invasion was also assessed in radical prostatectomy
ing the 30 patients who refused randomization. specimens. Following radical prostatectomy, serum
Neither the homogeneity of distribution of stages in prostate-specific antigen (PSA) is measured in all
the control versus the treated groups nor the conclu- patients every 3 months for follow-up.
sion of the outcome of the study are affected by the
inclusion of these eligible patients in the analysis. All STATISTICALANALYSIS
patients had liver function tests on a monthly basis The chi-square test and the Kolmogorov-Smirnov
for 3 months, as described previously. 22 test were used to measure statistical significance of
the differences of distribution observed between the
RADICAL PROSTATECTOMY,HISTOLOGY,AND various treatment groups.
FOLLOW-UP
All subjects underwent radical retropubic prosta- RESULTS
tectomy after preoperative staging peMc lymphad- As shown in Table III, the incidence of cancer-
enectomy. 5,23 Specimens from the radical prostatec- positive surgical margins was reduced highly signifi-
tomies were fixed and radially sectioned in 0.57cm cantly to only 7.8% (7 of 90) in the group of patients
segments from the apex to the base and submitted in who received an LHRH superagonist and flutamide
their entirety for histopathologic examination. All for 3 months before radical prostatectomy, com-
surgical specimens were classified as described pared with 33.8% (24 of 71) in the group of men
previously. > In brief, pathologic stages were classi- who had no endocrine therapy before radical prosta-
fied into three main groups: (1) organ-confined, tectomy (chi-square test, p < 0.001). Figure 1 shows
those without capsular penetration; (2) specimen- that the decrease in cancer-positive surgical margins

U R O L O G Y SYMPOSIUM / December 1994 / Volume 44, Number 6A 31

 Effect of 3-month neoadjuvant
TABLE IV. It is, then, of particular interest to examine the
combination therapy with flutamide and leuprohde final staging at histopathologic examination of the
acetate on the final histopathologic stage at surgery specimen obtained at surgery compared with cliniCh[:
compared with the initial clinical stage at diagnosis staging at diagnosis and to determine the effect of
combination therapy at each stage of the diseasel
Final Histopathological Up-staging is particularly striking at stages B1 and:~
Original Stage at Surgery
B2 in the control untreated group. In fact, of 39'
Stage No. NC B0 B1 B2 C1 C2 D1
cancers originally classified as B 1, 21 showed a morel
A: Control, untreated
advanced stage at surgery, including five with Ci
B0 3 0 I 0 I I 0 0 and ten with C2 disease (Table IV). Similarly, of 1~
BI 39 0 7 11 6 5 10 0 cancers originally classified as B2 disease in the;
B2 17 0 0 3 I 3 8 2 control group, three became C1, eight became C2:i
CI 7 0 I I 2 3 0 0
and two became D1 disease. On the other handl ie
C2 5 0 0 0 I 0 I 3
can also be seen on Table IV that down-staging
B: 3-Month neoadjuvantcombinationtherapy following neoadjuvant combination therapy wa~:
frequent at all stages of the disease: in fact, in thei
BO 3 0 1 0 0 1 1 0 patients originally classified as having ]31 disease, i4!
B1 43 6 14 11 7 3 2 0
of 43 (32.5%) tumors originally classified as having al
B2 29 0 2 11 6 5 3 2
C1 8 0 2 1 3 1 1 ,0
mean diameter of 1.0-1.5 cm decreased to < 1!0
C2 7 0 1 2 2 1 0 1 cm, while no cancer was found in six patients aftei:
thorough examination of additional histologic se~
NC = no cancer
tions. Down-staging was seen in 13 of 29 (44.8%):~f~
patients originally classified as having stage g 2
is of major amplitude at all stages of the disease disease. Although the number of patients is smaIi~
except at stage B0 and C1. In fact, although cancer- the down-staging effect was particularly important {~
positive margins were found in the surgical speci- patients originally classified as having C1 disease~i
men in 25.5% of stage B1, 58.8% of stage B2, and diagnosis where 6 of 8 (75.0%) had down-stagidgi:
80% of stage C2 control patients, the incidence of and in patients originally classified at diagnosis ~.
positive margins decreased to 2.3% in stage B1, stage C2, where six of seven cancers (85.7°£) w ~
13.8% in stage B2, and 14.3% in stage C2 patients down-staged following neoadjuvant combinatio~
who received combination therapy for 3 months therapy.
before surgery. The final stage determined after histopatholog
% examination of the surgical specimen revealeci
POSITIVE MARGINS 50.0% (45 of 90) improvement of the stage
100 -
disease compared with the initial diagnostic evak
"'-]CONTROL
tion in patients who received neoadjuvant combil
75 B COMBINATION THERAPY tion therapy compared with only 21.1% (15 of 71) i
the control group (Table V). Worsening of the stag
(up-staging) at histopathologic analysis, on the o ~ i
50 hand, occurred in 54.9% (39 of 71) of patients wg!~
33%
underwent radical prostatectomy alone.
-- 25,6% Comparison of the initial clinical stage at diagni?i
25 sis with the final stage at histopathologic examina~i
13.8%
2.3% tion of the surgical specimen following radie{i
0 prostatectomy can be more easily seen in Figure 2i
The down-staging effect of combination therapy I~
STAGE AT DIAGNOSIS C2 t thus clearly seen at all stages of the disease, except ~t
stage B0 and C 1. The net advantages of combinatio~
FIGURE 1. Effect of 3-month neoadjuvant combination
therapy are best illustrated in Figure 3, where the
therapy with flutamide and an LHRH agonist on cancer-
positive surgical margins at radical prostatectomy according final stage at surgery was, on average, w orsened b~ i!!~
to the clinical stage at diagnosis. Data are expressed as 35.9% (14 of 39) in stage B1 disease, 58.8% (10 of
percentage of patients in each group. The number within the 17) in stage B2 disease, and 40% in stage C2 disease:
bars indicates the number of patients having cancer-positive in patients who had radical prostatectomy alola¢~i
margins in each group. whereas the final stage of the disease, on th~

32 U R O L O G Y SYMPOSIUM / December 1994 / Volume 44, Number 6/i

 TABLE V. Effectof 3-month neoadjuvant combination therapy with flutamide and an LHRH agonist on the
histopathologic stage at surgery of prostate cancer compared to clinical stage at diagnosis
Stage at Diagnosis
B0 B1 B2 C1 C2 Total
Stage at Surgery
Down-staging
Control 0% 0/3 17.9% 7/39 17.6% 3/17 57.1% 2/7 20% 1/5 21.1% 15/71
LHRH-A
+ flutamide 0% 0/3 46.5% 20/43 44.8% 13/29 75% 6/8 85.7% 6/7 50.0% 45/90
Up-staging
Control 66.7% 2/3 53.8% 21/39 76.5% 13/17 0% 0/7 60.0% 3/5 54.9% 39/71
LHRH-A
+flutamide 66.7% 2/3 27.9% 12/43 34.5% 10/29 12.5% 1/8 14.3% 1/7 28.9% 26/90
No change
Control 33.3% 1/3 28.2% 11/39 5.9% 1/17 42.9% 3/7 20% 1/5 23.9% 17/71
LHRH-A
+ flutamide 33.3% 1/3 25.6% 11/43 20.7% 6/29 12.5% 1/8 0% 0/7 21.1% 19/90
Net effect*
Control +66.7% 2/3 +35.9% 14/39 +58.8% 10/17 -57.1% - 4 / 7 +40.0% 2/5 +33.8% 24/71
LHRH-A
+ flutamide +66.7% 2/3 -18.6% -8/43 -10.3% -3/29 -62.5% - 5 / 8 -71.4% - 5 / 7 -21.1% 19/90
* + = upstaging; - = down-staging.

contrary, w a s improved following combination stage C1 disease, and from 20% (1 of 5) to 71.4%
therapy by 18.6% (8 of 43) in stage B1 disease, (5 of 7) in stage C2 disease. On the other hand,
10.3% (3 of 29) in stage B2 disease, 62.5% (5 of 8) specimen-confined disease or cancer-negative mar-
in stage C1 disease, and 71.4% (5 of 7) in stage C2 gins increased from 66.2% (47 of 71) in men who
patients.
After 3 months of combination therapy, average
up-staging decreased to 28.9% (26 of 90) in patients NET STAGING CHANGE
who received neoadjuvant combination therapy corn- ,-~ 15 -
pared with 54.9% (39 of 71) in the control group, ua
Thus, net up-staging (difference between the num- "~
bet of patients who had upstaging and the number ~ 10 -
n

of those who had down-staging) occurred, on aver-

age, in 33.8% of control patients whereas, in con- 5-
trast, 2 !. 1% of patients were down-staged at analysis
of the surgical specimen in the group of patients
who had combination therapy before surgery, for a ~ 0
net difference of 54.9% in favor of neoadjuvant zO
v

combination therapy (Fig. 4).

The net effect of neoadjuvant therapy on specimen- ~ 8-
confined margins and organ-confined disease can be <
clearly seen in Figure 5 and Table VI. Since organ- m 10-
confined disease has such an important prognostic
value, it is of major interest to see in Figure 5A that o
organ-confined disease increased from 49.3% (35 of " 15-
71) in the control group to 77.8% (70 of 90), for a Bo [ B1 ] B2 ] C1 02
57.8% improvement in the group of men who STAGE AT DIAGNOSIS
received neoadjuvant combination therapy. In fact, FIGURE 2. Effect of 3-month combination therapy with
organ-confined disease increased from 61.5% (24 of flutamide and an LHRH agonist on the final histopathologic
39) to 88.4% (38 of 43) in stage B1 disease, from stage at surgery versus the clinical staging at diagnosis. Data
23.5% (4 of 17) to 65.5% (19 of 29) in stage B2 are expressed as number of patients showing up-staging or
disease, from 57.1% (4 of 7) to 87.5% (7 of 8) in down-staging in each group.

UROLOGY SYMPOSIUM / December 1994 / Volume 44, Number 6A 33

 STAGING CHANGE NET S T A G I N G C H A N G E
40-
a 33.8%
---.~
LU 20
,,¢ 30-
I- (5
cO 15 Z
n
13/17
(3
,,¢ 2 0 -
I---
rj~ Ii DIFFERENCE = 54.9%
Q.
:D
10-

cO CONT
I-
a. 0 0 0
% 0
0
Z
5
(.9 1 0 -
Z
a (3
<~
10 I--
¢j-j
Z 20-
I-
cO 21.1%
Z O
15 a
0 30-
a
20 CONTROL: 39/71 (54.9%)~ UP: 15/71 (21.1%)= DOWN ]
Bo B1 B2 C1 C2 COMB. THER.: 26/90 (28.9 %) = UP: 45/90 (50%) = DOWN
J
STAGE AT DIAGNOSIS FIGURE 4. Net change of stage between initial staging;~
diagnosis and final staging at radical prostatectomy in iS~
FIGURE 3. Net changes of stage between clinical staging at
tients who had radical prostatectomy alone and those wl~d!
diagnosis and final staging following histopathologic examina-
received combination therapy for 3 months before radi!~at
tion of the specimen obtained at radical prostatectomy. The
prostatectomy. Data are expressed as percentage of patie~
data presented are the difference between the number of
in each group.
patients who had up-staging and those for whom the disease
was down-staged for each treatment group and according to
the stage at diagnosis. Data are expressed as number of
patients in each group. data show that prostat e androgen
volves cancer cell death or apopto:
relatively high rate in the prostate
had radical prostatectomy alone to 92.2% (83 of 90) influence of combination therapy, s
(p <0.001) in those who received neoadjuvant death leads to a relatively rapid dov<
combination therapy before radical prostatectomy disease. In fact, after only 3 months
(Fig. 5B). There is thus a 57.8% increase in the combination therapy with flutamide
incidence of organ-confined disease following 3 agonist, cancer-positive surgical mal
months of neoadjuvant combination endocrine from 33.8% to only 7.8%, whereas v-e,. . . . .
therapy compared with untreated men (Fig. 5A), disease increased from 49.3% to 77.8%.
and the incidence of cancer-positive margins is A serious drawback of radical prostatectomy f0{
4.3-fold higher in the group of control untreated the treatment of early stage prostate cancer has bee~
men (33.8% vs 7.8%; Fig. 5B). the lack of precision of the staging of prostate caned{
at diagnosis. In fact, although it is well recognize~
COMMENT that radical prostatectomy of organ-confined disease
The essential objective of treatment of early stage can cure the disease, 5,24 the best available staging
prostate cancer is complete removal or elimination and diagnostic procedures underestimate the stage
of cancer tissue. Although the long-term effects of of the disease in 50-60% of cases, s-> As shown i~
androgen deprivation achieved by neoadjuvant com- the present study where TRUS of the prostate and;
bination therapy on survival remain to be assessed TRUS-guided biopsy were used to assess the stage 0{
by long-term follow-up of the patients, the present the disease in all cases a t diagnosis, the stage of the

34 UROLOGY SYMPOSIUM / December 1994 / Volume 44 Number 6~

 ORGAN-CONFINED DISEASE NEGATIVE MARGINS
100 - loo- g 92.2%
A
7£8°/0
75- 75-
66.2%
47/71
49,3%
50- % 5o-
35/71 I

25- 25-

0 0 i I
C
CONTROL C' CONTROL I

F I G U R E 5. Effectof 3-month neoadjuvant combination therapy with flutamide and

an LHRH agonist on organ-confined disease (A) and specimen-confineddisease (B) in
stages B and C prostate cancer.

disease remained underestimated in; on average,
33.8% of cases, thus further illustrating the difficulty
of proper staging of prostate cancer at diagnosis. The
net result of understaging at diagnosis is that
organ-confined disease was present in only 49.3% of
control patients, and cancer-negative margins were
found in only 66.2% of control patients--thus
leaving cancer present after surgery in possibly 34%
of control men untreated by endocrine therapy
'before surgery. Thus, despite the improvements of
radical prostatectomy, which have led to reduced
blood loss, improved urinary continence, and better
preserved potency, 2<25 the risk of an incomplete
removal of the cancer in approximately 50% of
tive margins and/or tumor involving the seminal
vesicles and/or pelvic lymph nodes, 30% had dis-
tant metastases. 24
An important aspect of the present approach is the
use of a LHRH superagonist to block temporarily the
secretion of testicular androgens. 31,32 Although de-
creased libido and loss of sexual potency are ob-
served in about 75% of patients treated with a LHRH
superagonist, 16 their return is usually seen within a
few months after cessation of treatment) 8,33 The
LHRH superagonist also prevents any increase in
serum LH and testosterone that could occur using a
pure antiandrogen alone) 6,32
, Because the aim of neoadjuvant therapy is to cause

patients has a major negative impact on the accept-
ability of radical prostatectomy or any other curative
approach for the treatment of early stage prostate
cancer. The inaccuracy of staging of prostate cancer
at diagnosis, which leads to incomplete removal of
cancer at surgery in an important proportion of
patients, is largely responsible for the controversies
surrounding treatment and even diagnosis of early
stage prostate cancer. 26-3°
The importance of cancer-negative margins at
siargery is based on an associated more favorable
prognosis; on the other hand, finding cancer cells at
the margin of the surgical specimen indicates a high
risk of recurrence of cancer54 As an illustration of
the importance of cancer-negative margins, it was
found that in 586 patients with clinically localized
prostate cancer who had undergone radical prostatec-
tomy, the 5-year actuarial status showed an inci-
dence of 1% and 2% of distant metastases for
organ-confined and specimen-confined pathologic
stages, respectively; however, of patients with posi-
a maximal reduction in prostatic androgen levels to
induce maximal atrophy, apoptosis, and death of
prostate cancer cells, combination therapy using a
pure antiandrogen 6aSa6 in association with a LHRH
superagonist is the most logical approach. The use of
a LHRH superagonist alone, an antiandrogen alone,
or an inhibitor of androgen formation alone is not
recommended because partial blockade of andro-
gens is likely to induce the development of tumors
TABLE VI. Effect of 3-month neoadjuvant
combination therapy with flutamide and an LHRH
agonist on organ-confined disease at radical
prostatectomy in stages B and C prostate cancer
Nonorgan-
Groups Organ-Confined Confined Total
Control 32 (45.1%) 39 (54.9%) 71
Combination
therapy 66 (73.3%) 24 (26.7%) 90

UROLOGY SYMPOSIUM / December 1994 / Volume 44, Number 6A 35

resistant to androgen blockade. 33-35 This would be a
major concern to patients having incomplete re-
moval of the cancer or positive margins at surgery.
The success of the present approach relies, to a
large extent, on the availability of an efficient,
low-cost, and widely acceptable strategy to detect
early stage prostate cancer m the general population.
In the first study performed in a randomly selected
population, namely LUPCDP, the relative roles of
serum PSA, DRE, and TRUS were evaluated in 1002
men. 6 Extension of this study to 7350 men at first
visit has shown that prescreening with serum PSA
and DRE in a previously unscreened population
followed by TRUS only when PSA and/or DRE is
positive led to finding a 3.5% prevalence of prostate
cancer. 36 Most importantly, 70.2% of the cancers at
first visit were at stage B, 19.3% at stage C, and only
10.5% at stage D. At 5781 follow-up visits, the
incidence of prostate cancer was only 0.6%; but,
most importantly, 82.4% of the cancers thus de-
tected were at stage B, 17.6% at stage C, and none at
stage D.
As shown in the present study, down-staging o f
prostate cancer with 3-month combination therapy
dramatically improves the results of radical prostatec-
tomy, thus permitting 90% of patients found to have
prostate cancer at first visit to become candidates for
radical prostatectomy and nearly 100% of men at
follow-up visits to have access to the same poten-
tially curative treatment. However, to achieve such
results, the detection strategy mentioned above must
be followed. 6 Serum PSA must be used as prescreen-
ing technique with the addition of DRE when
possible at first visit; TRUS should be restricted to
patients with serum PSA levels > 3.0 Ixg/L and/or
positive DRE. 6,36We have, in fact, found that 88% of
cancers could be detected by serum PSA alone at
first visit, while 97% of cancers could be detected by
serum PSA at follow-up visits. If annual or biennial
serum PSA measurements are performed, it is ex-
pected that > 90% of the cancers detected will be
candidates for radical prostatectomy, thus making it
possible, as demonstrated in the present study, to
obtain cancer-negative surgical margins in 92% of
cases or in > 80% of the total population of men
who develop prostate cancer detectable by serum
PSA and/or DRE. This is a complete reversal of the
present situation, in which 7 5 % of the prostate
cancers are not confined to the prostate at diagnosis,
and only prolongation of life can be offered to the
patients.
Although the effects of the present approach on
Survival remain to be determined by long-term
follow-up, it is reasonable to expect that patients
with localized disease at final histopathologic stag-
36 UROLOGY SYMPOSIUM / December 1994 / Volume 44, Number 6A
ing following radical prostatectomy should have a
life expectancy similar to that of men of similar age
with no prostate cancer. 5,> It remains to be seen,
however, if cancer cell death or apoptosis induced
by combination therapy in the prostate area as
clearly demonstrated in the present study occurs to
the same extent at distant micrometastafic sites. The
answer to this important question will also be
provided by long-term follow-up of these patients,
Previous studies have shown that combination
endocrine therapy decreases the total volume of the
prostate and of the cancer, i8,33,37-42 The present data
show, in the first randomized study, that neoadju-
vant combination therapy leads not only to downsiz-
ing of the prostate and tumor but also to a true
down-staging of prostate cancer. Lee et al. 42 have
also clearly demonstrated that prostate_ cancer cell
death is induced by combination therapy in the
prostate area.
The present data show that neoadjuvant combina-
tion therapy eliminates the previous serious limita-
tion that 50% of men had a disease more advanced
than expected at diagnosis when the final and true
staging was obtained by histopathologic examina-
tion of the surgical specimen. Following only 3
months of Combination endocrine therapy, the stage
of the disease was, on average, decreased by 23%
compared to the initial staging at diagnosis. Such
histopathologic findings, which remain to be sup-
ported by long-term follow-up of the patients, offer
the hope of a m a j 0 r improvement in the morbidity
and mortality from prostate cancer.
Fernand Labrie, M.D.
Department of Medicine and Laboratory
of Molecular Endocrinology
CHUL Research Center
2705 Laurier Boulevard
Qulbec, G1V 4G2, Canada
REFERENCES
1. Boring CC, Squires TS, Tong T, and Montgomery S:
Cancer statistics 1994. CA CancerJ Clin 44: 7-26, 1994.
2. Brown ML, Fintor L, and Newman-Horm PA: The eco-
nomic burden of cancer, in Greenwald P, Kramer B, and Wed D
(Eds): The Science and Practice of Cancer Prevention and Contro!:
New York, Marcel Dekker, 1994.
3. Chisholm GD: Prostate cancer. Perspectives and pros-
pects. Recent Results Cancer Res 78: 173-184, 1981.
4. Kolata G: Prostate cancer consensus hampered by lack of
data. Science 236: 1626-1627, 1987.
5. Walsh PC, and Jewett HJ: Radical surgery for prostatic
cancer. Cancer 45: 1906-1911, 1980.
6. Labrie F, Dupont A, Suburu R, Cusan L, Tremblay M,
Gomez JL, and Emond J: Serum prostatic specific antigen as
pre-screening test for prostate cancer. J Urol 147: 846-851,
1992.
 7. Jewett HJ, Bridge RW, Gray GF Jr, and Shelley WM: The
palpable nodule of prostatic cancer. Results 15 years after radical
excision. JAMA 203: 403-406, 1968.
8. Brawer MK, and Lange PH: Adjuvant therapy after radical
prostatectomy. Probl Urol 4: 461-472, 1990.
9. Gibbons RP, Correa RJ Jr, Brannen GE, and Weissman
led: Total prostatectomy for clinically localized prostate cancer:
long-term results. J Urol 141: 564-566, 1989.
10. Lange PH, and Narayan P: Understaging and undergrad-
ing of prostate cancer. Argument for postoperative radiation as
adjuvant therapy. Urology 21:113-118, 1983.
11. Boxer RJ, KaufmanJj, and Goodwin WE: Radical prosta-
tectomy for carcinoma of the prostate: 1951-1976. A review of
329 patients.J Urol 117: 208-213, 1977.
12. Catalona wJ, and Stein AJ: Staging errors in clinically
localized prostatic cancer.J Urol 127: 452-456, 1982.
13. Veenema RJ, Gursel EO, and Lattimer JK: Radical
retropubic prostatectomy for cancer: a 20-year experience. J
Urol 117: 330-331, 1977.
14. Elder JS, Jewett HJ, and Walsh PC: Radical perineal
prostatectomy for clinical stage B2 carcinoma of the prostate. J
Urol 127: 704-706, 1982.
15. Labrie F, Dupont A, B41anger A, Cusan L, Lacourci~re Y,
Monfette G, Laberge JG, Emond JP, Fazekas AT, Raynaud JP,
and HussonJM: New hormonal therapy in prostatic carcinoma:
combined treatment with an LHRH agonist and an antiandro-
gen. Clin Invest Med 5: 267-275, 1982.
16. Labrie F, Dupont A, and B41angerA: Complete androgen
blockade for the treatment of prostate cancer, in de Vita VT,
Hellman S, and Rosenberg SA (Eds): Important Advances in
Ontology. Philadelphia, J.B. Lippincott, 1985, pp 193-217.
17. Labrie F, B41anger A, Dupont A, Luu-The V, Simard J,
and Labrie C: Science behind total androgen blockade: from
gene to combination therapy. Clin Invest Med 16: 475-492,
1993.
18. Monfette G, Dupont A, and Labrie F: Temporary combi-
nation therapy with flutamide and Tryptex as adjuvant to radical
prostatectomy for the treatment of early stage prostate cancer, in
Labile F, Lee F, and Dupont A (Eds): Early Stage Prostate Cancer:
Diagnosis and Choice of Therapy. New York, Excerpta Medica,
i989, pp 41-51.
19. Labrie F, Dupont A, Cusan L, Gomez J, Diamond P,
Koutsilieris M, Suburu R, Fradet Y, Lemay M, Tetu B, et al.:
Downstaging of localized prostate cancer by neoadjuvant therapy
with flutamide and lupron: the first controlled and randomized
trial. Clin Invest Med 16: 499-509, 1993.
20. Lee F, Torp-Pedersen ST, Siders DB, Littrup PJ, and
McLeary RD: Transrectal ultrasound in the diagnosis and staging
of prostatic carcinoma. Radiology 170: 609-615, 1989.
21. Olschewski M, Schumacher M, and Davis KB: Analysis of
randomized and non-randomized patients in clinical trials using
the comprehensive cohort follow-up study design, controlled.
Control Clin Trials 13: 226-239, 1992.
22. Gomez JL, Dupont A, Cusan L, Tremblay M, Suburu K
Lemay M, and Labrie F: Incidence of liver toxicity associated
with the use of flutamide in prostate cancer patients. Am J Med
5: 465-470, 1992.
23. Walsh PC: Radical retropubic prostatectomy in Walsh
PC, Beretik A, Stamey TA, and Vaughan ED Jr (Eds): Campbell's
Urology, 6th ed, vol 3. Philadelphia, WB Saunders, 1992, pp
2865-2886.
UROLOGY SYMPOSIUM / December 1994 / Volume 44, Number 614
24. Brendler CB, and Walsh PC: The role of radical prosmtec-
tomyin the treatment of prostate cancer. CA 42: 212-222, 1992.
25. Walsh PC, and Doker PJ: Impotence following radical
prostatectomy: insight into etiology and prevention. J Urol 128:
492-497, 1982.
26. Johansson JE, Adami HO, Andersson 50, Bergstrom R,
Holmberg L, and Krusemo UB: High 10-year survival rate in
patients with early, untreated prostatic cancer. JAMA 267:
2191-2196, 1992.
27. Lerner SP, Seale-Hawkins C, Carlton CEJr, and Scardino
PT: The risk of dying of prostate cancer in patients with clinically
localized disease.J Urol 146: 1040-1045, 1991.
28. Handley K Can- TW, Travis D, Powell PH, and Hall RPc
Deferred treatment for prostate cancer. BrJ Uro162: 249-253, 1988.
29. Epstein JI, Paull G, Eggleston JC, and Walsh PC:
Prognosis of untreated stage A1 prostatic carcinoma: a study of
94 cases with extended followup. J Urol 136: 837-839, 1986.
30. Whitmore WF Jr, Warner JA, and Thompson IM Jr:
Expectant management of localized prostatic cancer. Cancer 67:
1091-1096, 1991.
31. Labrie F, B41anger A, Cusan L, S4guin C, Pelletier G,
Kelly PA, Reeves JJ, Lefebvre FA, Lemay A, Gourdeau Y, and
Ranaud JP: Antifertility effects of LHRH agonists in the male. J
Androl 1: 209-228, 1980.
32. Labrie F, Dupont A, B41angerA, St-Arnaud R, Gigu~re M,
Lacourci~re Y, EmondJ, and Monfette G: Treatment of prostate
cancer with gonadotropin-releasing hormone agonists. Endocr
Rev 7: 67-74, 1986.
33. Labrie F: Endocrine therapy for prostate cancer. Endocri-
nol Metab Clin North Am 20: 845-872, 1991.
34. Labrie F, B41anger A, SimardJ, Labrie C, and Dupont A:
Combination therapy for prostate cancer: endocrine and biologi-
cal basis of its choice as new standard first line therapy. Cancer
71: 1059-1067, 1993.
35. Labrie F, Veilleux K and Foumier A: Maintenance of andro-
gen responsiveness by glucocorticoids in Shionogi mammary carci-
noma cells in culture.J Nat Cancer Inst 80: 966-970, 1988.
36. Labrie F, Dupont A, SimardJ, Luu-The V, and B41anger
A: Intracrinology: the basis for the rational design of endocrine
therapy at all stages of prostate cancer. Eur Urol 24 (Suppl 2):
94-105, 1993.
' 37. Solomon MH: Radical prostatectomy following androgen
blockade, in Lee F, and McLeary RL (Eds): 5th International
Symposium on Transrectal Ultrasound in the Diagnosis and
Management of Prostate Cancer. Chicago, 1990, pp i00.
38. Schulman CC, and Sassine AN: Neoadjuvant hormonal
deprivation before radical prostatectomy. Clin Invest Med 16:
523-531, 1993.
39. Fair WF, Aprikian AG, Cohen D, Sogani P, and Reuter V:
Use of neoadjuvant androgen deprivation therapy in clinical
localized prostate cancer. Clin Invest Med 16: 516-522, 1993.
40. Solomon MH, McHugh TA, Dorr RP, Lee F, and Siders
DB: Hormone ablation therapy as neoadjuvant treatment to
radical prostatectomy. Clin Invest Med 16: 532-538, 1993.
41. Andros EA, Danesghari F, and Crawford ED: Neoadju-
vant hormonal therapy in stage C adenocarcinoma of the
prostate. Clin Invest Med 16: 510-515, 1993.
42. Lee F, Siders DB, NewbyJE, McHugh TA, and Solomon
MH: The role of transrectal ultrasound-guided staging biopsy
and androgen ablation therapy prior to radical prostatectomy.
Clin Invest Med 16: 458-470, 1993.
37