Int Urol Nephrol (2012) 44:1039–1044
DOI 10.1007/s11255-012-0134-z
UROLOGY – ORIGINAL PAPER
Goserelin versus leuprolide in the chemical castration
of patients with prostate cancer
Élcio Dias Silva • Ubirajara Ferreira • Wagner Matheus • Eliney F. Faria •
Gustavo D. Silva • Minori Saito • Auro A. S. de Souza • Azuil Laranjo Jr. •
Otavio Clark • Luis Alberto Magna • Lı́sias Nogueira Castilho • Leonardo Oliveira Reis
Received: 2 November 2011 / Accepted: 23 January 2012 / Published online: 8 February 2012
Springer Science+Business Media, B.V. 2012
Abstract
Purpose To evaluate the relative efficiency of
leuprolide 3.75 mg, leuprolide 7.5 mg, and goserelin
3.6 mg in relation to the reduction in serum testosterone, regarding the levels of castration.
Materials and methods We evaluated prospectively
60 randomized patients with advanced prostate carcinoma, with indication for hormone blockade. The
patients were divided into 3 groups of 20: Group (1)
received leuprolide 3.75 mg; Group (2) received
leuprolide 7.5 mg; and Group (3) received goserelin
3.6 mg. All groups were treated with monthly application of the respective drugs. The patients’ levels of
serum testosterone were evaluated in two moments:
before the treatment and 3 months after the treatment.
Results The patients’ ages were similar within the
three groups, with a median of 72, 70, and 70 in groups
1, 2, and 3, respectively. Of the patients that received
leuprolide 3.75 mg, leuprolide 7.5 mg, and goserelin
3.6 mg, 26.3, 25, and 35%, respectively, did not reach
castration levels, considering a testosterone cutoff B
50 ng/dl. And 68.4, 30, and 45%, respectively, did not
reach castration levels, considering a testosterone
cutoff B 20 ng/dl.
É. D. Silva (&) U. Ferreira W. Matheus
E. F. Faria G. D. Silva M. Saito
A. A. S. de Souza A. Laranjo Jr. O. Clark
L. A. Magna L. N. Castilho L. O. Reis
Campinas, Brazil
e-mail: doutorelcio@terra.com.br
Conclusions There were no statistically significant
differences in the levels of castration when comparing
leuprolide 3.75 mg, leuprolide 7.5 mg, and goserelin
3.6 mg, altogether. When compared in groups of two,
there was a statistically significant difference between
leuprolide 3.75 mg and leuprolide 7.5 mg, the latter
presented better results in reaching castration levels,
cutoff B 20 ng/dl. The importance of this difference,
however, must be measured with caution, since the
comparison of the three groups simultaneously did not
reach the established significance level, even though it
came close.
Keywords Prostate cancer Testosterone
Level of castration GnRH agonist LHRH agonist
Introduction
Incidence of the disease in Brazil
Prostate cancer is the second greatest cause of death due
to malignant tumors in men, coming second only to lung
cancer. In 2010, there were an estimated 52,350 new
cases of prostate cancer in Brazil. These numbers
represent an estimated risk of 54 new cases to every 100
thousand men. The occurrence of prostate cancer is
greater than that of breast cancer in women [1].
The prevalence of this tumor and the cost of its
treatment should increase with the rising of the
population’s life expectancy rate and with the present
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tendency of expanding the early discovery of the
disease [2].
History of hormonal treatment for prostate cancer
In 1836, Cooper [3] observed that tumors varied in size
during the menstrual cycle, presenting a small size in
the beginning of the cycle and in menopause. As a
result, he established a correlation between the growth
of the tumor and the hormonal cycle.
Sixty years later, in 1896, Beatson reported the
regression of metastatic mammary cancer lesions after
bilateral oophorectomy in pre-menopausal women [4].
In 1941, Huggins reported that the majority of
patients with advanced prostate cancer presented
important clinical regressions after bilateral orchiectomy [5], which rendered him the Nobel Prize in
Medicine in 1966.
Androgen suppression is able to control the disease
in advanced stages in 80–90% of men and results
in a progression-free survival of approximately
12–33 months [6].
Several therapeutic approaches based on hormonal
or androgen suppression were described, and some are
widely used today in the treatment for advanced stages
of the disease [7] Table 1.
Table 1 Prostate cancer—commonly used drugs
LHRH analogs
Triptorelin
Buserelin
Goserelin
Leuprolide
LHRH antagonists
Abarelix
Cetrorelix
Degarelix
Antiandrogenics
Cyproterone acetate
Bicalutamide
Flutamide
Nilutamida
Estrogens
Diethylstilbestrol
Other drugs
Glucocorticoids
Ketoconazole
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Int Urol Nephrol (2012) 44:1039–1044
Although effective, the orchiectomy, which consists
of surgical hormonal suppression, is a traumatic and
mutilating approach, with a high impact on the patient’s
psychological condition. Subcapsular or total orchiectomies are equivalent in achieving low testosterone levels.
Some authors are performing the orchiectomy with
ultrasonic surgical aspirators, with good results [8–11].
Chemical suppression or hormonal blocking with
the use of luteinizing hormone-releasing hormone
(LHRH) agonists and antiandrogenics began in
the 80s and today represents an alternative to surgical
castration. Published data show that agonists, such as
goserelin and leuprolide, produce effects that are
similar to those of castration [2, 7].
Regarding these drugs, several studies are being
carried out for the purpose of determining the best
moment to initiate the use, the most effective combinations, and the best routes for administration [6, 12].
Ideal value of serum testosterone to obtain
chemical castration
The main purpose of any type of hormonal blocking is
to reach testosterone levels below 50 ng/dl, which is
considered castration level [13]. However, there are
controversies regarding the value of testosterone to
consider the level of castration and the necessary
dosage to reach such goal.
The 50 ng/dl value of testosterone as a cutoff level
for castration derives from the dosage method used in
the 60s and 70s, which was known as ‘‘isotopederivative dilution technique,’’ which considered 50 as
the lower limit for detection [14, 15].
The Food and Drug Administration (FDA) of
the United States considers a testosterone value of
50 ng/dl as the lower limit of castration for the purpose
of approving LHRH analogs. Several authors consider 20 ng/dl as the lower limit, since in the current
methods for dosing this hormone, radioimmunoassay,
and chemiluminescence, the expected values in
patients submitted to orchiectomy are, in average,
inferior to 20 ng/dl [16, 17].
Oefelein et al. obtained a testosterone average of
15 ng/dl in orchiectomized patients, and in 2005,
Tombal also referred to an average of 15 ng/dl in
orchiectomized patients [18, 19].
In Denmark, Rohl and Beuke [16] found 19.3 ng/dl
as an average testosterone value in orchiectomized
patients. They also emphasized the importance of
Int Urol Nephrol (2012) 44:1039–1044
dosing total testosterone (TT) and dihydrotestosterone
(DHT), since TT decreased 95%, while DHT
decreased 70% and the DHT/TT ratio increased
5–7 times after the orchiectomy, which can alter the
evolution of the prostate cancer.
The importance of the cost of treatment
In Brazil, the description leaflet for leuprolide contains conflicting information regarding the dosage
(3.75–7.5 mg per month or 22.5 mg every 3 months).
However, the dosage of goserelin is well established
(3.6 mg per month or 10.8 mg every 3 months).
In Brazil, there are significant differences related
to the cost of the medication: While the prices of
leuprolide 3.75 mg and goserelin 3.6 mg are equivalent, the use of leuprolide 7.5 mg would double
the cost of the treatment. In addition, the cost of
leuprolide 22.5 mg is also twice the price of goserelin
10.8 mg. The economic factor becomes even more
crucial if we consider that patients with advanced
prostate cancer can have a survival rate of more than
3 years [6].
Methods
Sixty randomized patients with advanced prostate
carcinoma were evaluated. They were divided into 3
groups of 20, based on a chronological order of arrival.
GROUP 1: patients who received leuprolide
3.7 mg. This group had one patient excluded from
the study due to a testosterone level of castration
before he received the medication.
GROUP 2: patients who received leuprolide 7.5 mg.
GROUP 3: patients who received goserelin 3.6 mg.
The patients were selected from the Uro-Oncology
service of Hospital Santa Marcelina in São Paulo and
from the Hospital do Câncer de Barretos. The patients
who received leuprolide 3.75 mg and goserelin
3.6 mg were from Hospital Santa Marcelina and those
who received leuprolide 7.5 mg were from the Hospital do Câncer de Barretos.
The patients included in the study had advanced
prostate cancer with indication for hormone blockade.
Patients who had previously undergone hormone
blockade treatments and patients who already
1041
presented castration testosterone levels were not
included in the study.
After reading and signing the study agreement, the
selected patients were submitted to total testosterone
tests and initiated the treatment with one of the three
drugs.
The drugs were administered once a month during
3 months. Total testosterone tests were carried out
before the treatment and 3 months of treatment. After
the conclusion of the proposed treatment, the patients
were followed in the respective services, with the
drugs that were appointed to the respective groups and
under the same rules of procedure for patients with
advanced prostate carcinoma.
The testosterone dosage was taken with microparticle enzyme immunoassay (MEIA) in the patients
of the groups that received leuprolide 3.75 mg
and goserelin 3.6 mg and with eletrochemiluminescence—Testosterone II (cobas) Elecsys and cobas
analyzers (Roche Diagnostics GmbH), in the group
that received leuprolide 7.5 mg.
The proportion of chemically castrated patients, for
cutoffs defined B 50 and B 20 ng/dl of testosterone,
was compared in the three groups (19 patients who
received leuprolide 3.75 mg, 20 patients who received
leuprolide 7.5 mg, and 20 patients who received
goserelin 3.6 mg) using the chi-square, considering a
significance level of 5% (p \ 0.05).
Results
Patients’ age
The ages of the patients who received leuprolide
3.75 mg, leuprolide 7.5 mg, and goserelin 3.6 mg
varied according to Table 2.
Table 2 Patients age
Patients age (in years)
Leuprolide
Leuprolide
Goserelin
3.75 mg
7.5 mg
3.6 mg
58–88
56–81
58–86
Median, 72
Median, 70
Median, 70
Average, 71.4
Average, 69.6
Average, 71.3
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Int Urol Nephrol (2012) 44:1039–1044
Patients who received leuprolide 3.75 mg
Five out of nineteen patients did not obtain castration
levels that corresponds to 26.3% (when considering a
cutoff B 50 ng/dl) and 13 patients did not obtain
castration levels, which corresponds to 68.4% (when
considering a cutoff B 20 ng/dl).
Patients who received leuprolide 7.5 mg
Five out of twenty patients did not obtain castration
levels that corresponds to 25% (when considering a
cutoff B 50 ng/dl) and 6 patients did not obtain
castration levels, which corresponds to 30% (when
considering a cutoff B 20 ng/dl).
For the castration cutoff B 20 ng/dl testosterone,
although the difference of proportion among the three
groups did not vary significantly (6/19 or 31.6%; 14/20
or 70%; and 11/20 or 55% respectively; p = 0.054),
we can identify a tendency toward difference, which is
due to the difference between the two groups treated
with leuprolide (p = 0.016), rather than the difference
between each one of those and the group treated with
goserelin (p = 0.140 and p = 0.327 respectively).
The importance of this difference, however, must be
measured with caution, since the comparison of the
three groups simultaneously did not reach the established significance level, even though it came close.
Discussion
Patients who received goserelin 3.6 mg
Seven out of twenty patients did not obtain castration
levels that corresponds to 35% (when considering a
cutoff B 50 ng/dl) and 9 patients did not obtain
castration levels, which corresponds to 45% (when
considering a cutoff B 20 ng/dl) Table 3.
Summary of the obtained results.
In total, 59 patients:
•
•
28.77% did not obtain levels B50 ng/dl.
47.80% did not obtain levels B20 ng/dl.
Statistical analysis of the data
For the castration cutoff B 50 ng/dl testosterone, 14 of
19 (73.7%) of the patients treated with 3.75 mg
leuprolide, 15 of 20 (75%) of those treated with
7.5 mg leuprolide, and 13 of 20 (65%) of those treated
with 3.6 mg of goserelin can be considered castrated,
while the difference of proportions among the three
groups cannot be considered significant (p = 0.751).
Table 3 Failure to obtain testosterone castration levels
Testosterone
Summary of the obtained results
Leuprolide
3.75
Leuprolide
7.5
Goserelin
3.6
26.3
25
35
68.4
30
45
Did not obtain
B50 ng/dl (%)
Did not obtain
B20 ng/dl (%)
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There are no randomized prospective studies that
adequately evaluate the effectiveness of leuprolide
3.75 and 7.5 mg in comparison with goserelin 3.6 mg,
regarding the achievement of testosterone values in
levels of castration.
The fact that a drug can be used with a determined
dosage and with double dosage, indistinctively, is
intriguing. The pharmaceutical industries responsible
for leuprolide state that either one of the dosages, 3.75
or 7.5 mg, is efficient in obtaining testosterone
castration levels for patients with advanced prostate
cancer. This motivated us to analyze the effectiveness
of these drugs, comparing them with goserelin, which
is one of the most widely used drugs in these cases.
Several authors have studied what would be an
ideal dosage of testosterone in order to consider a
castration. The analysis of the results of such dosages
in orchiectomized patients, with the current techniques
(radioimmunoassay and chemiluminescence), leads
to the conclusion that the level of castration should
be testosterone B 20 ng/dl, since this is the value
obtained with the removal of the testicles. However,
many authors still consider B 50 ng/dl values as
sufficient for ‘‘castration level,’’ due to the fact that
there is no difference in the follow-up of the patients
regarding the decrease in PSA and the evolution of
prostate cancer with either B 20 or B 50 ng/dl
testosterone values.
Esquena et al. [20], in the Hospital Vall d’Hebron,
in Barcelona, achieved a failure rate of 16.7% in
obtaining levels inferior to 50 ng/dl in 135 patients
treated with LHRH analogs, and they suggest that in
Int Urol Nephrol (2012) 44:1039–1044
these cases, the correct procedure is to perform an
orchiectomy. They also emphasize the importance of
always measuring and controlling the testosterone
levels in patients treated with such analogs.
Oefelein and Cornum [18], from Cleveland, found a
failure rate of 5% in obtaining castration level when
considering \50 ng/dl and 13% when considering
\20 ng/dl values. In these cases, they also advise
orchiectomy or complimentary treatment with antiandrogen and always recommend the control of the
testosterone levels in patients treated with LHRH
analogs.
Novara et al. [14], from the University of Padova, in
Italy, carried out a research of 20 authors that observed
the results of testosterone dosage in patients being
treated with LHRH analogs and, in general, did not
obtain castration level in 3.2% when considering less
than 50 ng/dl and 11.8% when considering less than
20 ng/dl.
A formal meta-analysis carried out by the Prostate
Cancer Trialists’ Collaborative Group (PCTCG),
involving 27 studies with 8,275 patients, which
corresponds to 98% of the randomized evidence in
the world, shows that there was a modest increase
in cancer-specific survival rate within 5 years with
maximum androgen blockage (around 2%). This
shows that even associating antiandrogens for patients
treated with androgen suppression, regardless of
whether they obtained castration level, we must not
expect promising results regarding cancer-specific
survival rates within 5 years [21, 22].
In our study, for castration level B 50 ng/dl of
testosterone, 14/19 (73.7%) of patients treated with
3.75 mg of leuprolide, 15/20 (75%) of those treated
with 7.5 mg of leuprolide, and 13/20 (65%) of those
treated with 3.6 mg of goserelin can be considered
castrated, while the difference of proportion between
the three groups cannot be considered significant
(p = 0.751).
For the castration level B 20 ng/dl of testosterone,
although the difference of proportion between the
three groups did not vary significantly (6/19 or 31.6%;
14/20 or 70%; and 11/20 or 55% respectively;
p = 0.054), we can identify a tendency toward
difference, which is due to the difference between
the two groups treated with leuprolide (p = 0.016),
rather than the difference between each one of those
and the group treated with goserelin (p = 0.140
e p = 0.327 respectively).
1043
The importance of this difference, however, must
be measured with caution, since the comparison of the
three groups simultaneously did not reach the established significance level, even though it came close.
Our rates of failure to obtain castration levels of
testosterone, in the treatment of patients with LHRH
analogs, were, in average, in the 3 groups, of 28.8%
when considering a value of 50 ng/dl and 47.8% when
considering a value of 20 ng/dl, therefore superior to
those described in the world literature. This makes us
wonder for what reasons the medication used in Brazil
does not produce the same results as the medication
used in other countries, especially in the United States
and in European countries.
Conclusion
There was no significant difference in obtaining
castration levels with leuprolide 3.75 mg, leuprolide
7.5 mg, and goserelin 3.6 mg, when comparing the
three substances altogether.
When compared in groups of two, there was a
statistically significant difference in the analysis of
leuprolide 3.75 mg with leuprolide 7.5 mg, with the
latter presenting a greater achievement of castration
levels, when considering the value of 20 ng/dl. The
importance of this difference, however, must be measured with caution, since the comparison of the three
groups simultaneously did not reach the established
significance level, even though it came close.
The results in obtaining castration levels were
below our expectations in relation to the studies
carried out in other centers.
Conflict of interest
of interest exists.
The authors have declared that no conflict
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