Primary Hormonal Treatment in Localized and Locally

ORIGINAL ARTICLE
Primary Hormonal Treatment in Localized and Locally
Advanced Prostate Cancer: Effectiveness and Survival
Predictive Factors
Nugroho B. Utomo, Chaidir A. Mochtar, Rainy Umbas
Department of Urology, Faculty of Medicine, University of Indonesia - dr. Cipto Mangunkusumo Hospital.
Jl. Diponegoro no. 71, Jakarta Pusat 10430, Indonesia. Correspondence mail: [email protected];
[email protected]
ABSTRAK
Tujuan: mengevaluasi efektivitas terapi hormonal primer pada kanker prostat lokal dan lokal lanjut, serta
faktor prediksi terhadap kesintasan. Metode: penderita kanker prostat lokal (T1,T2N0M0) dan lokal lanjut
(T3,T4N0M0) yang mendapatkan terapi hormonal primer, selama Januari 1995-Desember 2009, diteliti secara
retrospektif berdasarkan catatan medik khusus di Departemen Urologi RSCM dan RSKD. Hasil: sebanyak 79
(29,9%) dari 264 pasien kanker prostat lokal dan lokal lanjut mendapat terapi hormonal primer. Pada kelompok
kanker prostat lokal, rerata kesintasan adalah 58,3 bulan (rentang: 1,87–170,78 bulan), dengan angka kesintasan
5 tahun 77,3%. Sedangkan pada kelompok kanker prostat lokal lanjut, rerata kesintasan adalah 40,87 bulan
(rentang 7,29-115,29 bulan), dengan angka kesintasan 5 tahun 22,7%. Pada kelompok kanker prostat lokal
lanjut, semakin lanjut usia atau semakin rendah kadar hemoglobin (Hb) semakin rendah angka kesintasan.
Kesimpulan: tidak terdapat perbedaan yang bermakna secara statistik antara rerata kesintasan maupun angka
kesintasan 5 tahun, antara kelompok kanker prostat lokal dan lokal lanjut yang mendapat terapi hormonal
primer. Faktor usia dan kadar Hb menjadi prediktor kesintasan pada kelompok kanker prostat lokal lanjut.
Kata kunci: survival, agonis LHRH, orkidektomi, androgen deprivation.
ABSTRACT
Aim: to evaluate the effectiveness of primary hormonal treatment on localized and locally advanced prostate
cancer, including the analysis on the survival predictive factors. Methods: patients with localized (T1,T2N0M0)
and locally advanced (T3, T4N0M0) prostate cancer who had received primary hormonal treatment between
January 1995 and December 2009 were evaluated retrospectively based on their specific medical records at
Department of Urology in Cipto Mangunkusumo Hospital (RSCM) and Dharmais Cancer Hospital (RSKD).
Results: about 79 (29.9%) of 264 patients with localized and advanced local prostate cancer received primary
hormonal treatment. In the localized prostate cancer group, mean survival was 58.3 months (range: 1.87-170.78)
and 5-year survival was 77.3%; while in locally advanced prostate cancer patients, mean survival was 40.87
months (range 7.29-115.29) and 5-year survival was only 22.7%. Hemoglobin level was a significant clinical
parameter of survival predictive factors for both localized and locally advanced prostate cancer groups. The
lower the hemoglobin level, the survival will be shorter. Conclusion: there were no significant differences between
mean survival and 5-year survival rate, between localized and locally advanced prostate cancer patients who
had received primary hormonal treatment. Hemoglobin level is survival predictive factors for localized and
locally advanced prostate cancer patients.
Key words: survival, LHRH agonist, orchidectomy, androgen deprivation.
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Acta Medica Indonesiana - The Indonesian Journal of Internal Medicine
Vol 44 • Number 1 • January 2012
Primary Hormonal Treatment in Localized and Locally Advanced Prostate
INTRODUCTION
Hormonal treatment in prostate cancer has
been developed since Huggins and Hodges1
reported that castration and estrogen treatment
are effective in advanced prostate cancer.
Although radical prostatectomy is still the gold
standard treatment for localized prostate cancer
and certain cases of locally advanced prostate
cancer2,3, the primary hormonal treatment may be
considered as an alternative option for patients
who are not suitable for radical prostatectomy
due to their unfavorable general condition for
surgical treatment.3
Recently, primary hormonal treatment in
localized and locally advanced prostate cancer
has been more common.4,5 Moreover, it has been
more frequently used after the Early Prostate
Cancer Program has provided evidence that
antiandrogen treatment is effective for localized
and locally advanced prostate cancer.6,7 Five and
10-year follow up by Akaza et al, in Japan show
that primary hormonal treatment may slow down
the progression of localized and locally advanced
prostate cancer.3,4
The present study was aimed to evaluate the
effectiveness of primary hormonal treatment on
localized and locally advanced prostate cancer,
including the analysis on the survival predictive
factors. We expect that the study may become
the first referral study exploring the effectiveness
of primary hormonal treatment on localized and
locally advanced prostate cancer.
METHODS
Patients with localized (T1,T2) and locally
advanced (T3,T4) prostate cancer who had
primary hormonal treatment (LHRH agonist
[Leuprolide or Goserelin], either as continuous
or intermittent androgen deprivation and
orchidectomy), between January 1995 and
December 2009, were studied retrospectively
based on specific medical records at Department
of Urology in Cipto Mangunkusumo Hospital
(RSCM) and Dharmais Cancer Hospital (RSKD).
Patients were being followed up until December
2010, both through direct visit and contact by
phone. Patients who had been followed up
over 12 months were included in the analysis.
Data on age, Prostate Specific Antigen (PSA),
tumor grade and stage, hemoglobin level (Hb),
serum ureum and creatinine level, and the
presence/absence of retention were analyzed
as survival predictive factors. Tumor grade was
determined based on WHO classification; while
tumor staging was established according to
American Joint Committee on Cancer (AJCC)
recommendation.9
Statistical analysis was performed using
Mann-Whitney test for mean survival rate of both
localized and locally advanced prostate cancer
group; while 5-year survival rate among both
groups was analyzed using Chi-square test and p
<0.05 was considered as statistically significant.
Survival rate was analyzed using Kaplan-Meier
curve; while survival predictive factors were
determined by using multivariate Cox regression
model.
RESULTS
Between January 1995 and December 2009,
there were 789 patients with prostate cancer
in both hospitals; among them, 264 patients
had localized and locally advanced prostate
cancer. About 79 patients, i.e. 51 patients with
localized prostate cancer and 28 patients with
locally advanced prostate cancer had received
primary hormonal treatment. The mean age of
the patients with localized and locally advanced
prostate cancer were 74 years (median: 74 years)
and 68.07 years (median: 67 years), respectively.
The mean and median value of PSA in locally
advanced prostate cancer group was higher than
localized prostate cancer group. All patients with
localized prostate cancer had stage 2 tumor (T2);
while most patients in locally advanced group had
stage 4 (T4), as summarized in Table 1.
During follow up until December 2010, 18
patients died in each group of both localized
and locally advanced prostate cancer. The mean
survival rate of the dead patients was 48.73
months in localized prostate cancer group and
42.56 months in locally advanced prostate cancer.
Mean survival rate in localized prostate
cancer group was 58.3 months (range: 1.87–
170.78 months); while the mean survival rate in
locally advanced prostate cancer group was 40.87
months (range: 7.29-115.29 months). Although
there was different survival rate among both
groups, yet statistically the difference was not
significant. (p=0.124).
The 5-year survival rate in localized prostate
cancer may reach 77.3%; while in locally
11
Nugroho B. Utomo
Acta Med Indones-Indones J Intern Med
Table 1. Subject characteristics of patients with prostate
cancer who received primary hormonal treatment
Locally Advanced
Prostate Cancer
(n=28)
74.00 (57-84)
68.07 (50-92)
74.00
67.00
Mean
78.35
108.34
Median
32.66
75.47
-- Grade 1 (%)
6 (11.8)
1 (3.6)
-- Grade 2 (%)
20 (39.2)
7 (25.0)
-- Grade 3 (%)
23 (45.1)
20 (71.4)
-- T1
0
0
-- T2
51 (100)
0
-- T3
0
13 (46.4)
-- T4
0
15 (53.6)
-- Mean
58.30
40.87
-- Median
50.14
37.09
17 (77.3)
5 (22.7)
Age
Mean(range)
(years)
Median
0.8
survival probability
Localized
Prostate
Cancer (n=51)
Tumor
localized
locally advanced
localized-censored
locally advancedcensored
1.0
0.6
0.4
PSA (ng/mL)
a
Tumor Gradingb
0.0
Tumor Staging (T)
Survival (months)
-- Survival > 5
years (%)
-- Survival < 5
years (%)
0.00
24 (61.5)
15 (38.5)
Four patients with localized prostate cancer and two
patients with locally advanced prostate cancer did not
have data on PSA.
b
Two patients with localized prostate cancer did not
have data on tumor grading.
c
Ten patients with localized prostate cancer and eight
patients with locally advanced prostate cancer had
been lost for follow up.
advanced prostate cancer group was only 22.7%.
However, statistically, there was insignificant
difference between both groups (p=0.209).
The comparison of survival period of time
between both groups could be observed in
Figure 1.
The correlation between parameters including
age, PSA, tumor grading, staging, hemoglobin
level, serum ureum and creatinine level, and the
presence of retention on survival could be seen in
Table 2. After performing multivariate analysis,
we found that hemoglobin level was a significant
clinical parameter for survival predictive factors,
both in localized and locally advanced prostate
cancer groups.
100.00
50.00
150.00
survival time (months)
Figure 1. Survival rate of patients with prostate cancer who
had received primary hormonal therapy
Table 2. Correlation between parameters of age, PSA,
tumor grading, tumor staging, Hb level, serum ureum
and creatinine level, as well as the presence of retention
on survival rate
c
a
12
0.2
Localized
Prostate cancer
(p)
Locally Advanced
Prostate cancer
(p)
Age
0.962
0.019
PSA
0.835
0.393
Tumor Grading
0.501
0.072
Tumor Staging
a
0.627
Hb
0.059
0.001
Ureum
0.798
0.411
Creatinine
0.80
0.496
Retention/not
0.261
0.191
a All patients with localized prostate cancer had stage
2 tumor; therefore, we could not analyze the correlation
between tumor staging and survival rate
DISCUSSION
In the present study, there were approximately
thirty percent (29.9%) of 264 patients with
localized and locally advanced prostate cancer had
received primary hormonal treatment. Moreover,
the percentage of patients with localized prostate
cancer who received primary hormonal treatment
was 23.7%. In the United States, an observational
study, CaPSURE, showed increased percentage
of primary hormonal treatment for localized and
locally advanced prostate cancer, from 4.6%
into 14.2% for low-risk group; 8.9% into 19.7%
for moderate-risk group; and 32.8% into 48.2%
for high-risk group.5 Another study by Nara
Uro-oncological Research Group Registration
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Primary Hormonal Treatment in Localized and Locally Advanced Prostate
in Japan found that 38% of 1699 patients with
localized prostate cancer and 58% of 604 patients
with locally advanced prostate cancer had
received primary hormonal treatment.11
Until now, no study has been conducted
randomly comparing the effectiveness of three
modalities of treatment for localized prostate
cancer, i.e. radical prostatectomy, radiotherapy
and hormonal treatment. Data from the Agency
for Healthcare Research and Quality, Department
of Health of the United States, based on the
results of systematic review on 18 Randomized
Controlled Trials (RCT) and 473 observational
studies revealed that there is no evidence
concluding that one is better than the other
modalities of treatment. Therefore, patient’s
preference and clinical consideration on patients’
age and predictive/biological characteristics of
prostate cancer is very important to determine
the treatment of choice in patients with localized
prostate cancer.3,5,10-12
In addition to the patient’s preference,
Cooperberg et al found that the rationale of
clinicians in selecting primary hormonal treatment
for localized prostate cancer was based on patient’s
consideration, including low-risk group of patients
with prostate cancer, short life expectancy rate,
and radical treatment, which is assumed to bring
little clinical improvement for the patients.13,14
Schymura et al added that aging, normal results of
digital rectal examination, PSA >20 ng/mL, low
Gleason Score and other comorbidities are the
rationales in selecting primary hormonal treatment
over radical treatment for patients with localized
prostate cancer.15
The overall 5-year survival rate in the present
study was 77.3%; while Akaza et al. in Japan
found similar results, i.e. 72%.3 However, on
the 10-year follow up by Akaza et al. they found
that the overall survival rate was only 41% with
specific survival rate of 78%.4 A study in our
institution in 2010 reported 5-year survival rate of
the patients with prostate cancer who had received
radical treatment, prostatectomy or radiotherapy
was 68.4% and 69.2%, respectively.16
Nevertheless, Lu-Yao et al. found different
results revealing that primary hormonal treatment
was not associated with survival rate in patients
with localized prostate cancer and elder age
compared to patients who had undergone
radical prostatectomy or radiotherapy.17 Another
study by Wong et al demonstrated that primary
hormonal treatment did not improve the survival
rate in patients with localized prostate cancer
and even provide worse outcome compared to
patients with localized prostate cancer who had
only been treated with observation.18
Although primary hormonal treatment has
become an alternative for localized and locally
advanced prostate cancer, its effectiveness is
still controversial. Moreover, the side effect of
hormonal treatment, including hypogonadism
should be considered. Hypogonadism may cause
loss of libido, metabolic syndrome including
increased serum lipoprotein level, reduced insulin
sensitivity and obesity; and all of them may
increase the risk of cardiovascular disease.19-22
Reduced bone mass up to the resulting
fracture,19,21,22 and the development of psychocognitive impairment, which are known as
Androgen Deprivation Syndrome,23,24 are also
the effect of hypogonadism due to hormonal
treatment. Testosterone replacement therapy,
which is usually used for hypogonadism due to
aging factor, is contraindicated in patients with
localized prostate cancer who have not or did not
received radical treatment as well as for patients
with advanced prostate cancer who still show
responses with hormonal treatment.25
Among all of the side effects, we should
consider that in such treatment, besides it may
reduce survival rate, it may also reduce the
patient’s quality of life; therefore, appropriate
thought which is consistent with indication and
the characteristic of prostate cancer for each
patients should be considered before suggesting
primary hormonal treatment as an alternative
treatment option for patients with localized and
locally advanced prostate cancer.
In the present study, hemoglobin levels
were a significant clinical parameter as survival
predictive factors, both in localized and locally
advanced prostate cancer group who had
received primary hormonal treatment; while
PSA, tumor grading and staging did not show
any significance. It explains that the survival
rate of patients with prostate cancer is possibly
determined not only by PSA, tumor grading or
staging, but also by other comorbidities. Such
results are consistent with the results in the study
by Schymura et al reporting that comorbidities
do have effect on 5-year survival rate.15
Irregular medical visits by patients with
prostate cancer has caused a number of patients
13
Nugroho B. Utomo
to be lost to follow up; therefore, we could
not have any data about the confirmed cause
of death. Thus, the survival rate found in our
study is overall survival rate instead of specific
survival rate for prostate cancer. Both issues are
the limitations of our study. However, to our
knowledge, the present study is the first study
in Indonesia reporting on the role of primary
hormonal treatment in localized and locally
advanced prostate cancer.
CONCLUSION
There were 29.9% patients with localized
and locally advanced prostate cancer who had
received primary hormonal treatment between
January 1995 and December 2009. There are no
significant statistic differences regarding mean
survival rate and 5-year survival rate between the
localized and locally advanced prostate cancer
group.
Hemoglobin level is a significant clinical
parameter of survival predictive factors, both in
localized and locally advanced prostate cancer
group, i.e. the lower the hemoglobin level, the
lower the survival rate.
Considering a significant number of side
effects of hormonal treatment that may reduce
the patient’s quality of life, hormonal therapy
as primary treatment in patients with localized
and locally advanced prostate cancer should be
applied according to the indications.
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