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237
Effects of Endocrine Therapy on the Primary Lesion in
Patients with Prostate Carcinoma as Evaluated by
Endorectal Magnetic Resonance Imaging
Jun Nakashima, M.D.1
Yutaka Imai, M.D.2
Masaaki Tachibana, M.D.1
Shiro Baba, M.D.1
Kyoichi Hiramatsu, M.D.2
Masaru Murai, M.D.1
BACKGROUND. Little effort has been made at the quantitative and qualitative evaluation of patients with prostate carcinoma, including downsizing and downstaging
of the primary lesion, after conservative therapy. The current study was undertaken
1
Department of Urology, Keio University School
of Medicine, Tokyo, Japan.
2
Department of Diagnostic Radiology, Keio University School of Medicine, Tokyo, Japan.
to investigate the qualitative and quantitative effects of endocrine therapy on the
primary prostate carcinoma using magnetic resonance imaging (MRI).
METHODS. The primary prostate carcinoma was evaluated by endorectal MRI approximately 4 months after the initiation of endocrine therapy in 48 patients with
histologically confirmed prostate carcinoma detected by endorectal MRI before
therapy.
RESULTS. The volumes of the prostate gland, the carcinoma, and the noncarcinomatous components were reduced to 60.2 { 2.7%, 25.5 { 2.9%, and 83.2 { 6.3%
of their pretreatment volumes respectively after endocrine therapy, indicating that
the tumors are more susceptible to endocrine therapy than the nontumorous
components. The number of prostate carcinomas that demonstrated low signal
intensity compared with the normal peripheral zone on T2-weighted images decreased after endocrine therapy and the number of carcinomas with enhancement
of T1-weighted contrast-enhanced images increased after therapy. Seven of the 48
patients underwent downstaging after endocrine therapy, based on the endorectal
MRI evaluation.
CONCLUSIONS. The results of the current study suggest that downsizing and occasionally downstaging of the carcinoma may occur after endocrine therapy in patients with prostate carcinoma. In addition, the androgen sensitivity of the prostate
carcinoma tissue is relatively high compared with the residual noncancerous prostate gland. Cancer 1997;80:237–41. q 1997 American Cancer Society.
KEYWORDS: prostate neoplasms, endocrine therapy, magnetic resonance imaging,
tumor volume.
T
Supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science and Culture, Japan.
Address for reprints: Jun Nakashima, M.D., Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160,
Japan.
Received March 12, 1997; accepted March 19,
1997.
ransrectal ultrasonography has been considered to be the most
reliable method of measuring the total prostate volume. However,
it has been very difficult to analyze changes in tumorous tissues. In
recent years, magnetic resonance imaging (MRI) with an endorectal
surface coil (endorectal MRI) has been shown to be of great value in
imaging the prostate. Schnall et al. reported that they were able to
identify a low signal intensity region in the peripheral zone, in the
region that demonstrated positive biopsy findings in all cases evaluated.1 It has been reported that endorectal MRI was 82% accurate in
the differentiation of Stage B from Stage C disease (Jewett-Whitmore
staging classification), because endorectal MRI has improved visualization of the prostate capsule and neurovascular bundle.2 Chen et
al. have attempted to evaluate the effect of androgen deprivation
q 1997 American Cancer Society
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CANCER July 15, 1997 / Volume 80 / Number 2
FIGURE 1.
Prostate gland volume estimated by endorectal magnetic
resonance imaging (MRI) before and after endocrine therapy (Tx). The
prostate gland volume estimated by endorectal MRI after the endocrine
therapy (23.1 { 1.9 mL; n Å 48) was significantly smaller than that before
therapy (38.4 { 2.6 mL) (P õ 0.05).
therapy on the MRI findings of the prostate gland and
prostate carcinoma in patients treated by means of
hormonal ablation before radical prostatectomy.3
However, fewer efforts have been aimed at the quantitative and qualitative evaluation (including downsizing and downstaging of the primary lesion of prostate
carcinoma after conservative therapy) because it has
been quite difficult to quantitatively evaluate primary
lesions and bone lesions in response to endocrine
therapy, utilizing imaging techniques, in patients with
advanced disease. In recent years, it has been anticipated that MRI would permit a practical in vivo measurement of the volumes of prostate carcinomas.4 In
fact, a significant correlation has been reported between carcinoma volume calculated with MRI and that
of the pathologic specimens.5 The current study was
undertaken to investigate the qualitative and quantitative effects of endocrine therapy on the primary lesion
of prostate carcinoma using endorectal MRI, which
is believed to be the most reliable method currently
available.
MATERIALS AND METHODS
In untreated patients with prostate carcinoma histologically confirmed by core needle biopsy, endorectal
MRI combined with phased array coil (ATD-III; MEDRAD, Pittsburgh, PA) was used for the purpose of
local staging. The authors retrospectively selected 48
patients with focal lesions detected on endorectal MRI
before therapy that were believed to be consistent with
the positive results of core needle biopsy. In contrast,
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FIGURE 2. Carcinoma volume estimated by endorectal magnetic resonance imaging (MRI) before and after endocrine therapy (Tx). The carcinoma volume estimated by endorectal MRI after the endocrine therapy
(4.7 { 0.8 mL; n Å 48) was significantly smaller than that before the
therapy (18.3 { 2.7 mL) (P õ 0.05).
patients whose histologically confirmed prostate carcinomas were not detected by endorectal MRI were not
included in the current study. Eight patients had well
differentiated, 31 had moderately differentiated, and
9 had poorly differentiated adenocarcinoma.
In all 48 patients, endorectal MRI was performed
before endocrine therapy (21 { 3 days after biopsy)
and 120 { 5.8 days after endocrine therapy. Serum
levels of prostate specific antigen (PSA) and prostatic
acid phosphatase (PAP) were also assayed by enzyme
immunoassay (E-Test Tosoh II PA, and E-Test Tosoh II
PAP; Tosoh, Tokyo, Japan) before and after endocrine
therapy. The endorectal coil is placed inside an inflatable latex balloon, which is positioned in the rectum.
The coil is placed immediately posterior to the prostate gland by inflating the balloon. The internal architecture of the prostate is compared in the T1- and
T2-weighted images taken before and after treatment.
Informed consent was obtained from all subjects for
the MRI examinations performed in this study. Invasion beyond the confines of the prostate involving the
periprostatic soft tissue or seminal vesicles was identified by direct tumor extension beyond the prostate, as
well as decreased signal intensity beyond the bulge of
the capsule near the tumor. T categorization of the
primary tumor by endorectal MRI was as follows6: T2:
tumor confined within the prostate; T3: tumor extending through the prostate capsule or involving the
seminal vesicles; and T4: tumor fixed or invading adjacent structures other than the seminal vesicles. The
W: Cancer
Endocrine Effects on Prostate Carcinoma/Nakashima et al.
maximum linear dimensions of the prostate gland and
the carcinoma were obtained in three axes (width: D1;
height: D2; and length: D3). The volume was determined using the formula for an ellipsoid object (V Å
0.52 1 D1 1 D2 1 D3).3 The carcinoma volume was
presumed to be zero when the lesion disappeared
from the endorectal MRI during the follow-up period.
Reductions in prostate gland volume and prostate carcinoma volume were calculated as volume before
treatment-volume after treatment. Changes in prostate gland and carcinoma volumes were calculated as
volume after treatment/volume before treatment.
The staging procedures included a clinical examination, intravenous pyelography, endorectal MRI,
bone scanning, and computed tomographic scan and/
or ultrasonography and/or MRI of the abdomen and
pelvic cavity. The TNM classification was given for
each patient and was translated into the clinical stage
as reported previously.6 The staging evaluation revealed Stage II in 8 patients, Stage III in 12 patients,
and Stage IV in 28 patients. All patients were placed
on endocrine therapy in the form of an luteinizing
hormone-releasing hormone (LH-RH) analogue alone
(n Å 36) or in combination with an antiandrogen (n
Å 12).
The results of the current study are presented as
means { standard errors. Variables of different groups
were compared using the Student’s t test for paired
data. Linear correlations were evaluated by simple regression analysis. Two different sets of categoric data
were analyzed by the chi-square test. P õ 0.05 was
considered statistically significant.
RESULTS
The serum PSA levels in patients with Stage II, III, and
IV disease before endocrine therapy were 53.7 { 37.5
ng/mL, 59.4 { 12.2 ng/mL, and 1016.0 { 400.6 ng/
mL, respectively, and decreased to 1.8 { 0.8 ng/mL,
5.8 { 1.6 ng/mL, and 18.9 { 7.5 ng/mL, respectively,
after therapy. The serum PAP levels in patients with
Stage II, III, and IV disease before endocrine therapy
were 2.8 { 1.6 ng/mL, 6.3 { 2.0 ng/mL, and 434.0 {
209.5 ng/mL, respectively, and decreased to 0.6 { 0.1
ng/mL, 1.0 { 0.4 ng/mL, and 9.7 { 5.6 ng/mL, respectively, after therapy.
The volumes of the prostate gland and the carcinoma estimated by endorectal MRI after endocrine
therapy (23.1 { 1.9 mL [n Å 48] and 4.7 { 0.8 mL [n
Å 48], respectively) were significantly smaller than the
pretreatment values (38.4 { 2.6 mL and 18.3 { 2.7 mL,
respectively) (P õ 0.05) (Figs. 1 and 2). The reductions
in volume of the prostate gland, carcinoma, and noncarcinomatous components achieved with endocrine
therapy were 16.5 { 1.5 mL, 13.7 { 2.2 mL, and 2.8
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239
TABLE 1
Comparison of Volume before and after Endocrine Therapy
Prostate gland volume
Carcinoma volume
Nontumorous volume
Reduction in
volume (mL)
Changes in
volume (%)
16.5 { 1.5
13.7 { 2.2
2.8 { 1.6
60.2 { 2.7
25.5 { 2.9
83.2 { 6.3
TABLE 2
Signal Intensity of Carcinoma before and after Endocrine Therapy on
T2-Weighted Images
Before therapy
Slightly low
Low
intensity
intensity
After therapy
Slightly low intensity
Low intensity
3
1
13
31
{ 1.6 mL, respectively (Table 1). The volumes of the
prostate gland, carcinoma, and noncarcinomatous
component were reduced to 60.2 { 2.7%, 25.5 { 2.9%,
and 83.2 { 6.3% of the pretreatment values, respectively (Table 1), after endocrine therapy, indicating
that carcinomas are more susceptible to endocrine
therapy than noncarcinomatous components. The
volumes of the prostate gland, carcinoma, and noncarcinomatous component estimated by endorectal MRI
were reduced to 57.5 { 3.1%, 25.3 { 3.3%, and 83.3 {
8.2% of the pretreatment values, respectively, in patients treated with an LH-RH analogue alone, and to
68.3 { 5.4%, 25.8 { 6.5%, and 81.6 { 6.2%, respectively, in patients treated with an LH-RH analogue plus
an antiandrogen. There was no significant difference
in the reduction of each component between the two
treatment groups.
Forty-four of the 48 carcinomas had an area showing low signal intensity compared with the normal
peripheral zone on T2-weighted images before therapy, whereas 32 of the 48 carcinomas had an area
showing low signal intensity on T2-weighted images
after therapy (Table 2). Thus, the number of prostate
carcinomas that demonstrated low signal intensity
compared with the normal peripheral zone on T2weighted images decreased after endocrine therapy,
and low signal intensity of the focal lesion tended to
become slightly lower after therapy. In addition, the
number of prostate carcinomas that demonstrated enhancement on T1-weighted contrast-enhanced images after intravenous administration of gadoliniumdiethylenetriaminepentaacetic acid (Gd-DTPA) was 21
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240
CANCER July 15, 1997 / Volume 80 / Number 2
TABLE 3
Enhancement of the Carcinoma on T1-Weighted Contrast-Enhanced
Image before and after Endocrine Therapy
Before therapy
After therapy
No
Yes
No
Yes
4
23
1
20
TABLE 4
Local Staging Evaluated by Endorectal MRI before and after
Endocrine Therapy
After therapy
T2
T3
T4
T2
Before therapy
T3
T4
8
0
0
7
32
0
0
0
1
MRI: magnetic resonance imaging.
before endocrine therapy, but increased to 43 after
therapy (Table 3).
Local staging of the primary lesion evaluated by
endorectal MRI before endocrine therapy was T2 in 8
cases, T3 in 39 cases, and T4 in 1 case. These numbers
became 15 T2 cases, 32 T3 cases, and 1 T4 case after
treatment. Seven of the 39 cases with T3 tumors had
downstaging after endocrine therapy based on the endorectal MRI evaluation (Table 4).
DISCUSSION
The effects of hormonal therapy on prostate gland size
and carcinoma volume have been evaluated by digital
rectal examination and transrectal sonography.7 However, there was no standard of reference for assessing
changes in tumor size by imaging in previous reports,
and the clinical and imaging reports describing decreases in carcinoma volume and carcinoma staging
after endocrine therapy have lacked a gold standard.3
However, a significant correlation was reported between carcinoma volume calculated with MRI and that
of pathologic specimens.5 In the current study, the
authors retrospectively selected patients with focal lesions detected on endorectal MRI that were thought
to be consistent with the positive results of core needle
biopsy, and investigated the qualitative and quantitative effects of endocrine therapy on the primary lesion
in patients with prostate carcinoma using endorectal
MRI.
Kojima et al. have reported that a minimal prostate volume was attained 4 months after endocrine
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therapy and decreases in prostate volume ranged from
17 – 42% (mean, 35%).8 Other studies have reported
that the overall decrease in prostate volume after endocrine therapy was 10 – 52%.7,9 – 11 In agreement with
these reports, the current study showed a 40% decrease in prostate volume after endocrine therapy for
a median duration of 4 months.
Okihara et al. reported that the volume reduction
time of a focal hypoechoic lesion (FHL) on transrectal
ultrasonography, which they believed to be a section
of the carcinoma nodule, was remarkably shorter than
that of the volume not indicating the FHL, suggesting
that the reactive velocity of the cancerous nodule to
androgen ablation therapy was much faster than that
of normal prostatic tissue.12 Pinault et al. have reported that after endocrine therapy for a median duration of 3 months, all patients showed a significant reduction in tumor volume with a median reduction of
81% (range, 20 – 91%).7 Changes in tumor volume were
estimated by MRI after hormonal ablation and a mean
reduction of 61% was reported.3 The current study
demonstrated a 75% reduction in tumor size after endocrine therapy for a median duration of 4 months,
which is similar to previously reported results.3,7 It has
also been reported that LH-RH analogues efficiently
ameliorate symptoms in elderly patients with benign
prostatic hyperplasia.13,14 An average 30% reduction in
prostate volume has been reported in patients with
benign prostatic hyperplasia after 3 months of endocrine therapy.15 In the current study, the noncarcinomatous component was reduced by 17% after endocrine therapy. As reported previously,7 the current
study suggests that prostate carcinoma tissue has relatively high androgen sensitivity compared with the residual nontumorous prostate gland.
It is possible that biopsy-related changes may account for some discrepancies. Based on the author
experience, hemorrhage in the tumor after core needle
biopsy does not appear to extend diffusely. In addition, the time interval between the biopsy and endorectal MRI is known and the age of the hemorrhage can
therefore be easily calculated and its signal intensity
pattern can be anticipated. Accordingly, one can recognize biopsy sites on T1-weighted images by identifying high signal intensity and using this information
to review corresponding T2-weighted images to differentiate between hemorrhage and tumor, as described
previously.16
The peripheral zone contains more glandular acini
and a less densely packed stroma. Basically, the relatively high signal intensity of the prostate on T2weighted images is likely to be due to the increased
water content of the gland and the less compact
stroma. Therefore, the normal peripheral zone is a
W: Cancer
Endocrine Effects on Prostate Carcinoma/Nakashima et al.
high signal intensity crescent on the posterior and lateral aspects of the prostate and the central and transition zones have lower signal intensities. Conversely, it
is possible for the stroma to be enhanced by Gd-DTPA
on T1-weighted images whereas glandular acini may
not be enhanced. In the current study, the number
of prostate carcinomas that demonstrated low signal
intensity compared with the normal peripheral zone
on T2-weighted images decreased after endocrine
therapy and the number of prostate carcinomas showing enhancement of T1-weighted contrast-enhanced
images after the administration of Gd-DTPA increased
after treatment. These findings appear to be consistent
with the known pathologic finding of increases in intraglandular connective tissue and subsequent reduction in gland density in hormonally treated prostate
carcinoma.17
Peeling et al. have reported that downstaging on
ultrasound occurred in 7 of 50 patients receiving endocrine therapy.18 Andros et al. have reported that downstaging on endorectal MRI occurred in 5 of 7 patients
with Stage C disease 4 months after the initiation of
endocrine therapy.10 Conversely, Oesterling et al. believed neoadjuvant treatment to artificially lower PSA
without downstaging the carcinoma, but rather downsizing only the prostate gland.19 In the current study,
7 of the 48 cases had downstaging after endocrine
therapy based on the endorectal MRI evaluation. The
rate of clinical downstaging in the current study may
be lower than those of some previous reports, partly
because the majority of patients had advanced stage
disease and had a relatively large primary tumor and
partly because a more sophisticated technology, endorectal MRI, was used to evaluate clinical downstaging. Because the limitations of MRI findings as well as
sonographic findings should be acknowledged and the
results of downsizing and downstaging viewed with
caution3 and also because it is impossible to evaluate
pathologic downstaging in individual cases, large, prospective, randomized studies comparing radical prostatectomy versus radical prostatectomy with neoadjuvant endocrine therapy in patients with locally advanced prostate carcinoma should be undertaken to
assess the clinical implications of downstaging.
The results of the current study suggest that tumor
downsizing and occasionally tumor downstaging may
occur in response to endocrine therapy in patients
with prostate carcinoma and that prostate carcinoma
tissue has a relatively high androgen sensitivity compared with the residual nontumorous prostate gland.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
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