Results of antiandrogen and biphosphonate therapy in treatment of bone metastatic prostate cancer in 108 Military Central Hospital

Journal of military pharmaco-medicine no1-2019

RESULTS OF ANTIANDROGEN AND BIPHOSPHONATE THERAPY
IN TREATMENT OF BONE METASTATIC PROSTATE CANCER
IN 108 MILITARY CENTRAL HOSPITAL
La Van Truong1; Tran Van Ton2
SUMMARY
Objectives: To evaluate the results of antiandrogen and bisphosphonate therapy in treatment
of bone metastatic prostate cancer. Subjects and methods: A prospective clinical interventive
study on 44 newly diagnosed bone metastatic prostate cancer patients at the 108 Military
Central Hospital from July 2010 to July 2018. Results: 31.1% of the study patients was
65 years old, 27.7% had combined disease, 45.5% had severe urinary disorders, 50% had bone
pain and 38.6% had systemic condition at 1 - 2 points. At the time of diagnosis: 86.4% had PSA
≥ 20 ng/mL, 52.3% had Gleason ≥ 8 points, 43.2% cT4, 77.3% had only bone metastases,
22.7% had bone metastases and nodal metastases or organ metastases. Spinal and pelvic
bones were the two most frequent metastases (88.6% and 77.3%); 95.4% of patients had
testicular cut, 95.4% had PSA response, 67.6% had PSA nadir ≤ 4 ng/mL; median non-progressive
survival and median overall survival were 20.54 months and 38.6 months. Conclusions:
Most patients with bone metastatic prostate cancer had testicular cut and PSA response in
antiandrogen and pamisol therapy, however, the median non-progressive survival was short.
* Keywords: Prostate cancer; Bone metastases; Antiandrogen; Bisphosphonate.

INTRODUCTION
Prostate cancer is one of the common
cancers. According to Globocan 2012,
the rate of prostate cancer is the second
highest in the world and the 10th in Vietnam.
As with most cancers, the treatment strategy
for prostate cancer is multidisciplinary
treatment, combining several therapies:
surgery,

radiation,
antiandrogen,
chemotherapy, and treatment. The specific
treatment options are based on the stage
of the disease, the risk level, the prognostic
factors, the expectation of survival, the

condition of the patient. Antiandrogen
therapy is the standard treatment for
prostate cancer [11].
Although at the time of diagnosis,
only about 5% of prostate cancer has
metastatic distances, approximately 90%
of distant metastatic patients have bone
metastases. Bone metastasis is a bad
prognosis factor. Some studies have shown
that bisphosphonate and antiandrogen
therapy prolongs development time in
patients with bone metastatic prostate
cancer. In Vietnam, there are very few
published data on this patient group.

1. 108 Military Central Hospital
2. 103 Military Hospital
Correspoding author: La Van Truong ()
Date received: 20/10/2018
Date accepted: 04/12/2018

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Journal of military pharmaco-medicine no1-2019
We conducted the study with the aim of:
Evaluation of the results of antiandrogen
and bisphosphonate therapy in treatment
of bone metastatic prostate cancer.
SUBJECTS AND METHODS
1. Subjects.
44 patients newly diagnosed bone
metastatic prostate cancer at the
108 Military Central Hospital from July
2010 to July 2018.
* Criteria for selecting patients:
- Diagnosis of prostate cancer based
on tissue biopsy.
- Diagnosis of bone metastases based
on clinical and bone scans and/or MRI:
bone metastases are diagnosed based
on clinical symptoms and bone scans.
If patient has painful, but bone scan is
unclear will be given MRI scan for diagnosis.
- New diagnosis, no treatment.
- Systemic condition 0 - 2 points.
- There are no contraindications to zoladex,
diphereline, casodex and pamisol.
* Exclusion criteria:
- Patients with prostate cancer without
bone metastases.
- Patients with bone metastatic prostate
cancer treated before.

- Systemic condition > 2 points.
- Failure to fully implement the research
plan.
- Do not agree to participate in research.
2. Methods.
A prospective clinical interventive study.
* Study process:
- Pre-assessment of patients: Clinical
examination, complete routine tests,

PSA tests, computerized tomography or
MRI of the abdomen, bone scans, MRI
scans clinical case and bone skeletal
suspicion.
- Treatment: Antiandrogen + pamisol
therapy. As follows:
+ Casodex 50 mg/day + pamisol
90 mg/month or LHRH agonist (zoladex;
diphereline)/28 days + casodex 50 mg/day +
pamisol 90 mg/month.
Follow-up during treatment: Clinical
examination every 4 weeks; PSA testing
every 4 weeks or on suspected development;
bone scintigraphy every 12 weeks or on
suspected development; CT/MRI every
12 weeks or on suspected development.
* Some criterias for evaluating treatment
results:
- Criterias for scrotal ablation: Blood
testosterone < 20 ng/dL (1.7 nmol/L).

- PSA response:
+ Partial response: Decrease ≥ 50%
compared to pre-treatment (after 12 weeks).
+ No response: Not meet standard
(after 12 weeks).
PSA nadir (lowest): The lowest PSA
level achieved during treatment.
Non-progressive survival: From the
onset of treatment, treatment progresses
until the disease progresses. Identify
progressive disease when PSA progresses
after treatment response ≥ 4 ng/mL and
continuous increase > 25% for 3 consecutive
intervals of 1 week apart.
- Overall survival: From test to death.
Data were processed by SPSS
software. 20.0. Estimated survival time by
Kaplan-Mayer method.
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Journal of military pharmaco-medicine no1-2019
RESULTS AND DISCUSSION
Table 1: Clinical characteristics of patients.
Characteristics

Age

Number

Rate (%)

< 65

14

31.1

65 - 75

20

44.1

10

22.1

0 - 7 points

12

27.3

8 - 19 points

12

27.3

20 - 35 points

20

45.5

0 points

22

50.0

1 - 4 points

8

18.2

5 - 7 points

12

27.3

8 - 10 points

2

4.5

0 points

27

61.4

1 points

15

34.1

2 points

2

4.5

No

34

72.3

Yes

10

27.7

Cardiovascular

8

18.2

Diabetes

6

13.6

Respiratory

3

6.8

Other

1

2.3

> 75

IPSS*

Bone pain

Systemic condition

Combined disease

(* IPSS: International Prostate Symptom Score)

Of the 44 patients studied, only 31.1% were < 65 years old. Nearly 30% of patients
had combined disease, of which 18.2% had cardiovascular disease, and 13.6%
had diabetes. There were 17 patients (38.6%) with systemic condition 1 - 2 points.
Eberhard Varenhorst et al studied 915 patients with bone metastatic prostate cancer
with 47.4% of patients 65 - 74 years olds, 38% of patients age 75 or older, 10.4% with
cardiovascular disease and 45.5% of patients had systemic condition 1 - 3 points.
Thus, about two thirds of patients with metastatic bone cancer are of old age, while
about one-third had combined disease and nearly half have poor systemic condition.
Patients with old age, combined disease, poor systemic condition will have difficulty in
having antiandrogen therapy.
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Journal of military pharmaco-medicine no1-2019
Lower urinary tract symptoms (difficulty urinating, frequent urination, etc) and bone
pain are common symptoms in prostate cancer patients. In our study, 50% of patients
had bone pain, of which 27.3% had moderate pain and 4.5% had severe pain. There
were 27.3% showing mild degree of urinary disorders, 27.3% moderate and 45.5%
severe. Also in the study by Eberhard Varenhorst et al, 58.6% of the 915 patients had
bone pain. Natsuo Tomita et al (2015) studied 216 patients with stage prostate cancer,
124 patients (57.4%), mild (70.4%), morderate 70 patients (32.4%); 22 patients
(10.2%) had severe disorders [9]. The severity of patients with severe dyslipidemia in
our study was higher than Natsuo Tomita's study, probably because the patients in our
study were stage IV, with distant metastasis. Bone pain and dysmenorrhoea affect the

quality of life of the patient.
Table 2: Clinical characteristics of patients.
Characteristics
PSA pre-treatment

Number

Rate (%)

1

2.3

5

11.4

≥ 20

38

86.4

< 10
10 - < 20

Gleason

cT

N
M

Bone injury

Distant metastasis

≤6

9

20.5

3+4

6

13.6

4+3

6

13.6

8

13

29.6

9 + 10

10

22.7

T1

2

4.5

T2

6

13.6

T3

17

38.7

T4

19

43.2

N0

34

77.3

N1

10

22.7

M1b

34

77.3

M1c

10

22.7

Spine

39

88.6

Pelvis

34

77.3

Other bone

32

72.7

Low volume disease

13

29.5

High volume disease

31

70.5

Nodal

3

6.8

Lung

4

9.0

Liver

2

4.5

Other position

2

4.5

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Journal of military pharmaco-medicine no1-2019
PSA is a biomarker of cancer value
screening, risk level, evaluation of treatment
response and development tracking. In our
study, 86.4% of patients had PSA ≥ 20 ng/mL
at the time of diagnosis. Giorgio Gandagliaa
et al analyzed SEER data from 1991 - 2009,
in 3,093 patients with bone metastatic

prostate cancer, at the time of diagnosis
79.8% of patients had PSA ≥ 20 ng/mL,
442 patients had both metastatic metastases
with 84.4% PSA ≥ 20 ng/mL [6]. Bone
metastatic prostate cancer usually has PSA
≥ 20 ng/mL.
Kazuhiro Nagao et al (2016) studied
100 patients with bone metastatic prostate
cancer, 6 patients (6%) had Gleason
≤ 6 points, 28 patients (28%) Gleason =
7 points, 66 patients (66%) Gleason ≥ 8
[7]. About half of patients with bone
metastatic prostate cancer have Gleason
score ≥ 8.
In our study, the majority of patients
with cT3 and cT4 (81.9%), however, 4.5%
had cTl and 13.6% had cT2. This finding
suggests that even in early prostate cancer,
bone metastasis is possible. Kyo Chul
Koo et al (2015) retrospectively analyzed
248 patients with bone metastatic
prostate cancer with 27 patients (11%)
in T2, 130 patients (52.4%) in T3 and
91 patients (36.6%) with T4 stage [8].
In a study of 2,607 patients with stage IV
prostate cancer, Giorgio Gandagliaa et al
found that 91.1% had bone metastases,
8.7% had nodal metastases, 5.7% had
lung metastases, 7% had liver metastases,
1.8% had brain metastases, 1.3% had

gastrointestinal tract metastases, 1.3% had
abdominal and peritoneal metastases,
0.6% had kidney and adrenal metastases.
154

On the other hand, of the 3,093 patients
with bone metastases, 422 patients (13.6%)
had organ metastases [6]. In 44 patients
with bone metastases, we found that
3 patients (6.8%) had both nodal
metastases and 8 patients (18.1%) with
organ metastases. The survival is gradually
deteriorated in the following order: distant
nodal metastasis, bone metastasis, and
organ metastasis.
Folasire et al (2015) studied 82 bone
metastases in 67 patients with prostate
cancer, 33% had metastatic bone. The
most common bone metastases were:
spinal 94%, of which 92.2% had metastatic
lumbar spine; pelvis (67%); rib (40%).
Bone with rare metastases is ulna (1%)
and tibial bone (1%). The two most common
metastases in our study were spinal
bones (88.6%) and pelvic bone (77.3%),
70.5% of patients in our study had a
high metastatic mass. Christopher J.
Sweeney et al (2015) studied 790 bone
metastatic prostate cancer patients,
147 patients (18.6%) had low metastasis

volume and 643 patients (81.4%) had
high metastasis volume [3]. A number of
clinical trials showed that docetacel
supplementation in antiandrogen prolonged
non-progressive and life-saving regimens
in patients with a high metastatic volume.
Table 3: Distribution of patients according
to treatment regimen.
Scheme

Number

Rate (%)

Opreation + casodex
+ pamisol

22

50

Agonist LHRH +
casodex + pamisol

22

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Journal of military pharmaco-medicine no1-2019

Antiandrogen therapy is the standard
treatment for bone metastatic prostate
cancer. Scrotal ablation (LHRH agonist or
LHRH antagonist) and surgical removal of
two testicles are equally effective [1]; many
studies have also shown that maximum
antiandrogen (combination of scrotal ablation
or surgery with nonsteroidal antiandrogen)
improved the duration of onset and
survival, decreases the risk of death. In
patients with bone metastatic prostate
cancer, the combination of antiandrogen
and anti-bone mineral (zoledronic) prolongs
the time to scrotal ablation [7]. In our study,
50% of patients opted for scrotal ablation
and 50% opted for scrotal ablation by
medicine. Patients were treated with
maximum antiandrogen (casodex) and
anti-spasmic pamisol.
Table 4: Response to treatment.
Number

Rate
(%)

< 1.7

42

95.4

≥ 1.7

02

4.6

Response

42

95.4

No response

2

4.6

Item
Testosterone
(nmol/L)
PSA response

PSA nadir
(ng/mL); n = 37

Minimum

0.00

Maximum

> 154

≤4

25

67.6

>4

12

32.4

Levels of testosterone < 1.7 nmol/L are
considered as scrotal ablation. However,
due to advances in test technique, some
studies showed that the average testosterone
in the blood after scrotal ablation surgery
was 0.003 nmol/L. Some authors proposed

a new testosterone level of 0.7 nmol/L.
The authors also showed that survival
without scrotal ablation was longer in
patients with lower testosterone levels
than in the other three groups < 0.7 nmol/L;
< 1.7 nmol/L and ≥ 1.7 nmol/L [2]. We used

testicular testosterone levels of < 1.7
nmol/L according to NCCN guidelines.
Among 44 patients studied, 2 patients
(4.6%) had testosterone ≥ 1.7 nmol/L
after one month of treatment. Notably,
1 patient treated with scrotal ablation by
medicine (zoladex + casodex) and then
scrotal ablation surgery had a testosterone
level < 1.7 nmol/L. Some studies showed
that from 2 to 12.5% of patients with
scrotal ablation by LHRH antagonist had
a testosterone level of ≥ 1.7 nmol/L [2].
In our study, there were 2 cases in
which testosterone did not reach the
scrotal ablation level. In one case of
treatment of scrotal ablation by medicine
after scrotal ablation surgery, testosterone
level reached the scrotal ablation level, but
in both cases, the PSA did not reach the
biological response. Both patients had
early death (less than 12 months).
In the 44 patients we studied, one had
non-decreasing PSA; the PSA level at
the time of diagnosis was the lowest
(> 154 ng/mL). 04 patients had unstable
test results, we could not identify PSA
nadir. 20 patients at the end of the study,
the PSA was continuing to decline. Of the
37 patients whose PSA nadir was identified,
25 patients (67.6%) had PSA nadir

≤ 4 ng/mL, 12 patients (32.4%) had PSA
nadir > 4 ng/mL. In 917 patients with bone
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Journal of military pharmaco-medicine no1-2019
metastatic prostate cancer treated with
antiandrogen in the control group of
STAMPEDE test, only 457 patients had
their PSA nadir identified. There were
78% of paients had PSA nadir < 4 ng/mL,
22% had PSA nadir ≥ 4 ng/mL [10].

Chart 1: Non-progressive survival.
There were 42 patients responding
to treatment. At the end of the study,
30 patients progressed. The shortest
follow-up was 8 months, the longest was
71 months, and the mean follow-up was
24.5 months. The overall survival of
44 patients was shown in figure 2. The
median overall survival was 38.6 months.
In the control group of STAMPETE test,
with an average follow-up of 20 months,
non-progressive survival and median
overall survival observed in the 917 were
11 months and 42 months, respectively
[10]. Kazuhiro Nagao et al used antiandrogen
and zoledronic for bone metastatic
prostate cancer, median progression time

was 25.2 months.
156

Chaiyut Kongseang et al reviewed
248 patients with bone metastatic prostate
cancer treated with androgens, high ALP
levels, systemic condition ≥ 1 patients,
and high PSA nadir levels were bad
predictors of survival [8].

Chart 2: OS.
CONCLUSION
Most patients with bone metastatic
prostate cancer achieved scrotal ablation
level and achieved a PSA response when
treated with maximum antiandrogen therapy
and pamisol, however, the median nonprogressive survival was short. This results
posed the need to add chemicals,
endocrine or immunotherapy to prolong
the response time.
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Journal of military pharmaco-medicine no1-2019

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