ORIGINAL ARTICLE

Clinical efficacy of primary combined androgen blockadefor Japanese men with clinically localized prostate cancerunsuitable for local definitive treatment: a single institutionexperience

Minoru Kobayashi • Akinori Nukui •

Kazumi Suzuki • Shinsuke Kurokawa •

Tatsuo Morita

Received: 8 December 2010 / Accepted: 31 March 2011 / Published online: 23 April 2011

� Japan Society of Clinical Oncology 2011

Abstract

Background Primary hormonal therapy has been mostly

used for patients with advanced prostate cancer, as inter-

national guidelines do not recommend its use for patients at

earlier disease stages. However, there seems to be a dis-

crepancy between the guideline recommendations and

clinical practice on the use of primary androgen depriva-

tion therapy for localized prostate cancer in Japan. There-

fore, we retrospectively analyzed a single-institution

experience in primary combined androgen blockade (CAB)

for localized prostate cancer.

Patients and methods The study included 187 patients

with T1c–T3a prostate cancer unsuitable for local defini-

tive treatment and treated with primary CAB. Clinical

outcomes, predictive factors of PSA relapse and adverse

events were investigated.

Results The progression-free, disease-specific, and over-

all survival rates of all patients at 5 years were 63.0, 99.4

and 95.9%, respectively. Of the several parameters isolated

as predictors of prostate-specific antigen (PSA) progres-

sion, nadir PSA level and the percentage of positive biopsy

cores (%PBC) remained as independent prognostic factors

on multivariate analysis. Toxicities were mild to moderate

and well tolerated.

Conclusions Primary CAB treatment brought initial dis-

ease control without relapse in the majority of our selected

cases. The %PBC may help predict time to relapse in the

pretreatment setting. The results implicate that CAB can be

an option as a primary treatment for clinically localized

prostate cancer unsuitable for local definitive treatment. To

confirm the exact efficacy of primary CAB, these findings

should be reviewed in a large cohort of patients with long-

term follow-up from various viewpoints, including disease

control, toxicities, quality-of-life and medical cost.

Keywords Primary androgen deprivation therapy �Combined androgen blockade � Localized prostate cancer

Introduction

Widespread screening with prostate-specific antigen (PSA)

has led to a significant increase in the detection of early

stage, clinically localized prostate cancer. Currently, the

treatment of localized prostate cancer remains controver-

sial, highlighted by a recent survey on the optimal treat-

ment of a hypothetical patient with localized prostate

cancer: approximately 29% favored expectant manage-

ment, 33% favored radiotherapy and 39% chose radical

prostatectomy [1]. On the other hand, many elderly men

with localized prostate cancer receive only hormonal

therapy. However, the benefit of hormonal therapy alone in

localized cancer is not clear and can be associated with

severe toxicities in some men [2]. Therefore, the repre-

sentative guidelines do not recommended hormonal ther-

apy as a primary treatment for localized prostate cancer

[3–5]. However, this concept is now changing. Mounting

data on the efficacy and safety of hormonal therapy has

brought increased use of primary hormonal therapy for

patients with localized or locally advanced disease in many

countries, despite limited evidence to date for the impact

on clinical outcomes [6–8]. Of particular note is Japan

where increasing incidence of and mortality from prostate

cancer has been shown [9]; namely, 21% of patients present

M. Kobayashi (&) � A. Nukui � K. Suzuki � S. Kurokawa �T. Morita

Department of Urology, Jichi Medical University,

3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan

e-mail: minoruk@jichi.ac.jp

123

Int J Clin Oncol (2011) 16:630–636

DOI 10.1007/s10147-011-0232-4

with distant metastases and 19% with locally advanced dis-

ease, which is a sharp contrast to the demography in the US

with only 5% of patients having nodal or distant metastases at

the time of diagnosis [10]. Along with such higher incidence

of advanced disease, primary androgen deprivation therapy

(PADT) has been a mainstay of treatment for prostate cancer

in Japan. PADT has been commonly applied to lower stage

disease as well, accounting for half of primary treatment for

clinically localized disease [9].

The survival advantage conferred by combined andro-

gen blockade (CAB) as primary hormonal therapy in

comparison with castration monotherapy has been a con-

troversial issue. The latest meta-analysis of monotherapy

compared with CAB indicated a modest increase in

expected survival at 5 years by combined use of antian-

drogens with castration [11]. However, most of the trials

included in this meta-analysis were performed in metastatic

diseases. On the other, CAB has been predominantly used

in Japan regardless of disease stage and seems superior to

castration monotherapy in terms of progression-free and

overall survival rates in localized diseases as well [12–14].

To increase the knowledge in this area, we reviewed our

experience with CAB as a primary treatment for localized

prostate cancer at a single institution through an evaluation

of its efficacy and comorbidities. We also attempted to

isolate clinical parameters predictive of progression to

castration-resistant disease.

Patients and methods

A total of 647 patients had a diagnosis of stage T1c–T3a

prostate cancer between 2000 and 2008 at Jichi Medical

University. Of these patients, 187 patients (28.9%) who

were treated primarily with CAB were included in the

analysis. These patients selected hormonal therapy as pri-

mary treatment for various reasons, including high age,

patient’s preferences, and comorbidity such as cardiovas-

cular disease and other malignancies, although definitive

therapy such as radical prostatectomy or irradiation is the

standard treatment for patients with clinically localized

prostate cancer. The follow-up time was 5.4 ± 2.3 years

[mean ± standard deviation (SD)]. The clinical stage was

determined by the 1997 TNM classification based on the

radiological findings obtained by computed tomography,

magnetic resonance imaging and bone scan. Prostate

biopsies were performed systematically by trans-peritoneal

approach under trans-rectal ultrasound guidance. The per-

centage of positive biopsy cores (%PBC) was defined as

the number of positive biopsy cores divided by the sum of

all cores taken. Serum PSA was measured at least once

every 2 or 3 months. PSA progression was judged as ele-

vation of PSA level on three consecutive occasions. In

cases with possible clinical symptoms, radiological exam-

inations were performed to evaluate clinical disease

progression.

CAB treatment was achieved using LHRH agonists,

such as leuprolide acetate (3.75 mg/4 weeks) or goserelin

acetate (3.6 mg/4 weeks) either with the steroidal anti-

androgen (SAA) chlormadinone acetate (CMA) (100 mg/

day) or the nonsteroidal anti-androgens (NSAAs) bicalu-

tamide (BCL) (80 mg/day) or flutamide (FLT) (375 mg/

day). At PSA progression after primary CAB, anti-andro-

gen alone was discontinued in order to assess anti-androgen

withdrawal syndrome (AWS). As second- and third-line

hormonal therapy, alternative anti-androgens and estram-

ustine were administered. The selection of anti-androgens

was at the discretion of the treating doctors. No patients

received any definitive therapies (e.g, surgery or irradia-

tion) during the study period.

The response to primary hormonal therapy was evalu-

ated at 3 months after and at the time of the PSA nadir after

initiation of the therapy. Complete response (CR) was

defined as normalization of PSA levels (\4.0 ng/ml) and

partial response (PR) as a greater than 50% decrease in

PSA compared with pre-treatment levels but greater than

the normal range. Progression of disease (PD) was defined

as a greater than 25% increase in PSA compared with the

baseline pre-treatment level. Stable disease (SD) was

defined as PSA values between PR and PD. PSA half-life

refers to the time needed for PSA to reduce to half its value

from the start of hormonal therapy [15, 16]. The duration of

the response was defined as the time from the start of

hormonal therapy until PSA progression, expressed as the

mean ± SD. If PSA progression did not occur during the

follow-up period, the duration of the response was con-

sidered longer than the time from the start of therapy until

the final evaluation.

The clinical parameters regarded as possible prognostic

factors were clinico-pathological factors including age at

diagnosis (low vs. high), disease stage (T1–2 vs. T3),

Gleason score (B7 vs. C8), pretreatment PSA level (low

vs. high), the risk classification for recurrence (low vs.

intermediate vs. high) [6], %PBC (\50 vs. C50%), the

type of treatment with anti-androgen (SAA vs. NSAA), the

initial treatment responses defined by PSA response at

3 months after initiation of therapy (CR vs. PR, SD), PSA

nadir (\0.2 vs. C0.2 ng/ml) and PSA half-life (short vs.

long). Toxicities were assessed according to the Common

Toxicity Criteria for Adverse Events version 4.0 (CTCAE

4.0). The data were analyzed using Student’s t test, the

Mann–Whitney U test, the chi-squared test, or Fisher’s

exact test. Kaplan–Meier survival curves were constructed

to show progression-free, disease-specific, and overall

survival times. The log-rank test was used to analyze

prognostic parameters related to the survival times.

Int J Clin Oncol (2011) 16:630–636 631

123

Prognostic factors were assessed using Cox’s proportional

hazard model. p\0.05 was considered significant. Statisti-

cal analyses were performed using IBM-SPSS statistics

v.18.0 software (SPSS-Inc., Chicago, IL, USA).

Results

Table 1 lists the characteristics of the patients. The median

age of patients was 75 years and median pretreatment PSA

level was 22.3 ng/ml. A median of 9 biopsy cores (range

6–16) were taken. The median number of positive cores

and %PBC were 4 and 50.0% respectively. Most of the

patients (147, 80.3%) were treated with primary CAB with

NSAA (136 with BCL and 11 with FLT) and the others

(40, 19.7%) were given SAA, CMA. All but four patients

attained CR at PSA nadir, leaving 3 with PR and one with

SD. The median PSA half-life was 47.8 days. The pro-

gression-free, disease-specific, and overall survival rates of

all patients at 5 years were 63.0, 99.4, and 95.9%,

respectively (Fig. 1a, c, d). The mean duration of response

to primary hormonal therapy exceeded 3.8 ± 2.1 years.

Metastatic diseases developed in five patients (2.6%). Six

patients died during the observation period, including two

cause-specific deaths and four deaths of other malignan-

cies. The left-hand column of Table 2 shows the results of

univariate analysis by the log-rank test for PSA progres-

sion-free survival. A lower T stage (Fig. 1b), a lower PSA

level, a lower %PBC, a low risk classification for recur-

rence, a complete PSA response at 3 months after initiation

of therapy and a lower PSA nadir (\0.2 ng/ml) were the

significant factors for a longer PSA progression-free sur-

vival. Multivariate analysis by Cox’s regression model

incorporating initial PSA response and PSA nadir as time-

dependent covariates isolated %PBC and PSA nadir as

Table 1 Patient characteristics

Number of patients 187

Age: median (range) 75 (55–97)

Biopsy

Gleason score 6 or less: n (%) 73 (39.0)

Gleason score 7: n (%) 52 (27.8)

Gleason score 8–10: n (%) 62 (33.2)

Positive cores (%): median (range) 50 (7.1–100)

T category 1–2: n (%) 121 (64.7)

T category 3: n (%) 66 (35.3)

PSA trend

Baseline PSA (ng/ml): median (range) 23 (3.13–716.6)

PSA half-life (days): median (range) 48 (6.3–327.7)

Time (years)

Pro

port

ion

prog

ress

ion

free

Pro

port

ion

surv

ivin

g

Time (years)

Pro

port

ion

surv

ivin

gP

ropo

rtio

n pr

ogre

ssio

n fr

ee

Time (years)

Time (years)

T1-2

T3

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.00 2 4 6 8 10 12

0 2 4 6 8 10 12 0 2 4 6 8 10 12

0 2 4 6 8 10 12

a b

c d

Fig. 1 Kaplan–Meier plots of patients having clinically localized

prostate cancer treated with primary CAB. PSA progression-free (a),

disease-specific (c), and overall survival curves (d) in all cases and

PSA progression-free curve according to T stage (b) are illustrated.

The progression-free survival rate of T1–2 patients was significantly

higher than that of T3 patients, *p \ 0.004

632 Int J Clin Oncol (2011) 16:630–636

123

independent prognostic factors for PSA progression, the

former of which had a greater significance (Table 3, left-

hand column). On the other, the disease-specific and

overall survival rates were too high to leave room for

comparative analysis of prognosis (data not shown). Since

PADT is not a contraindication for T3 disease, statistical

analyses were also done in a separate group of patients with

T1–2 disease. The statistical trend by the log-rank test for

PSA progression-free survival was very similar to that

found in the whole patient cohort (Table 2, right-hand

column). The %PBC remained but PSA nadir was replaced

by initial PSA response as independent prognostic factors

for PSA progression on multivariate analysis (Table 3,

right-hand column).

Adverse events are summarized in Table 4. All adverse

events were limited to grade 3 or less and well tolerated

and manageable by cessation of anti-androgens (15, 8.0%)

or alternating anti-androgens (16, 8.5%). There was no

withdrawal from therapy and no treatment-related deaths

were observed during the study period.

Discussion

Despite the widespread use of PADT in clinically localized

prostate cancer, there is little information regarding the

clinical outcomes associated with this practice. Especially,

there is no literature available regarding the significance of

combined use of antiandrogens with castration for local-

ized disease except for a couple of reports from Japan,

where PADT has been widely used in the treatment of

prostate cancer at any disease stage. According to these

reports, survival advantage by CAB over castration

monotherapy was indicated [12–14]. Thus, the focus of the

present study was placed on CAB rather than castration

monotherapy as primary hormonal therapy in order to

evaluate its efficacy in terms of long-term disease control

of clinically localized prostate cancer.

Progression-free rates in the present study (66.7% at

5 years and 63.0% at 8 years) were similar to those

reported previously [12–14]; that is, nearly two-thirds of

patients were free of relapse, suggesting a possible cure of

localized prostate cancer by primary CAB. This idea may

be supported by the histological examination of resected

specimens after neoadjuvant hormonal therapy. Namely, it

has been shown that a possible histological cure revealed

by apoptic change in malignant cells accounted for 40% of

the total cases and that the recurrence-free rate of patients

who attained complete apoptosis was 100% [17]. In addi-

tion, Labrie et al. [18] performed long-term CAB in stage-

B and -C patients and discontinued the treatment in those

who did not have PSA progression. Among 33 patients

who stopped treatment after continuous CAB for more than

6.5 years, PSA increase occurred in only two patients.

Ninety percentage of this group of patients achieved

5 years with no PSA rise after CAB cessation, implying the

long-term control or possible cure of cancer [18].

The present study identified several clinical features

predictive of PSA progression after primary CAB, includ-

ing disease stage, pretreatment PSA level, risk classifica-

tion for recurrence, %PBC, initial PSA response and PSA

Table 2 Prognostic factors for PSA progression indicated by uni-

variate analysis

Prognostic factors All cases T1–2 cases

No. of

cases

p value No. of

cases

p value

Agea

Low (\median value) 103 0.536 60 0.839

High (Cmedian value) 84 61

T stage

1–2 121 0.004 Not

performed3 66

Gleason score

B7 125 0.09 96 0.313

C8 62 25

% Positive biopsy cores

\50% 86 \0.001 59 0.002

C50% 101 62

Baseline PSAa

Low (\median value) 95 \0.001 57 0.007

High (Cmedian value) 92 64

Risk group

Low 23 0.003 23 0.044

Intermediate 38 38

High 126 60

Anti-androgen type

SAA 40 0.592 27 0.421

NSAA 147 94

PSA response at 3 months

CR 153 \0.001 98 \0.001

No CR 34 23

PSA nadir

\0.2 ng/ml 151 \0.001 98 0.032

C0.2 ng/ml 36 23

PSA half-lifea

Short (\median value) 92 0.782 59 0.863

Long (Cmedian value) 95 62

p value was calculated by the log-rank test

SAA steroidal anti-androgen, NSAA nonsteroidal anti-androgena The patients were dichotomized by the median value of each factor.

The median values of age, baseline PSA and PSA half-life were

75 years, 23 ng/ml and 48 days for all cases, and 75 years, 14 ng/ml

and 45 days for T1–2 cases, respectively

Int J Clin Oncol (2011) 16:630–636 633

123

nadir. Among these parameters, %PBC, initial PSA

response and PSA nadir were isolated as independent

predictors of disease progression on multivariate analysis.

Previous studies have shown that the amount of cancer in

biopsied tissue defined by the percentage of positive cores

may help define the biochemical outcome after radical

prostatectomy [19], external beam radiation [20] and

brachytherapy [21]. The prognostic value of %PBC in

patients treated by primary hormonal therapy was recently

indicated for the first time by Normand et al. [22], in which

most of patients had locally advanced or metastatic dis-

eases and were treated with various hormonal treatment

Table 3 Prognostic factors for

PSA progression indicated by

multivariate analysis using

time-dependent covariates

a The patients were

dichotomized by the median

baseline PSA level of 23 ng/ml

CI confidence interval

Prognostic factors All cases T1–2 cases

Hazard ratio (95% CI) p value Hazard ratio (95% CI) p value

T stage

T1–2 1 0.901 Not performed

T3 1.041 (0.554–1.956)

Risk group of recurrence

Low 1 1

Intermediate 2.353 (0.264–20.966) 0.443 4.382 (0.369–52.025) 0.242

High 2.896 (0.352–23.799) 0.322 2.996 (0.353–25.437) 0.315

Gleason score

B7 1 0.773 1 0.075

C8 1.093 (0.599–1.994) 3.276 (0.083–1.129)

% Positive biopsy cores

\50% 1 0.004 1 0.022

C50% 3.436 (1.470–8.030) 2.996 (1.191–9.446)

Baseline PSAa

Low (\median value) 1 0.275 1 0.853

High (Cmedian value) 1.653 (0.670–4.077) 1.143 (0.279–4.680)

Initial PSA response

CR 1 0.079 1 0.007

No CR 1.216 (0.977–1.513) 1.587 (0.451–0.880)

PSA nadir

\0.2 ng/ml 1 0.011 1 0.216

C0.2 ng/ml 1.367 (1.074–1.739) 1.288 (0.863–1.923)

Table 4 Summary of observed

adverse eventsAdverse events Grades 1 and 2

Nos. of patients

Grade 3

Nos. of patients

Incidence of

any grade (%)

Anemia 37 2 20.8

Liver dysfunction 13 8 11.2

Hyperglycemia 3 0 1.6

Cardiovascular events 4 4 4.2

Fracture 4 0 2.1

Hot flash 28 0 14.9

Skin indurations 5 0 2.7

Weight gain 37 0 19.8

Gynecomastia 5 0 2.7

Gastrointestinal disorders 4 0 2.1

Interstitial pneumonia 1 0 0.5

Dyspnea 2 0 1.1

634 Int J Clin Oncol (2011) 16:630–636

123

modalities. Given that %PBC represents tumor volume

[23] and stage [24], the association between %PBC and

clinical outcome could be expected in clinically localized

diseases treated by PADT, as shown in the present study.

Of note, %PBC consistently remained as an independent

predictive factor of PSA progression even when focused on

T1–2 disease. On the other, the prognostic significance of

PSA nadir after hormonal therapy, which was also confirmed

in the present study, has been highlighted in localized disease

as well as metastatic disease [25–27]. However, this important

prognostic information is obviously lacking at the onset of

hormonal therapy. This is true of initial PSA response as an

independent predictor of PSA progression in T1–2 disease.

Therefore, the pretherapeutic parameter %PBC should more

efficiently predict PSA failure after PADT, thereby contrib-

uting to planning treatment strategies.

The disease-specific survival rate was very high (99.3%

at 5 years) even though 35% of patients had T3 disease.

The median age of the patients was 75 years and more

patients died from other malignancies, which may partly

explain so few deaths from prostate cancer in the present

study. However, given the long natural history of prostate

cancer, additional follow-up is necessary to confirm the

long-term survival benefit of PADT.

On the other hand, there is growing evidence that ADT

is associated with an increased risk of various comorbidi-

ties including ischemic heart disease, metabolic syndrome,

glucose intoleranc, and a decrease in bone mineral density

[28–31]. As a result, patients who received PADT have a

worse overall survival compared with conservative man-

agement [32, 33]. In contrast, several reports have also

shown no significant increase in cardiovascular mortality

with hormonal therapy in men with prostate cancer

[34–36]. Akaza et al. [37] demonstrated no difference in

overall survival in patients with localized prostate cancer

treated with PADT and men of the same age in the general

population, suggesting that there is no increase in mortality

in men treated with PADT. In the present study, toxicities

were mild to moderate and well acceptable without treat-

ment-related death during the middle-term (median of

5 years) follow-up. However, no randomized trials com-

paring survival advantage obtained by PADT with con-

servative management have been done, and thus a

consensus about watchful waiting/active surveillance in

localized prostate cancer has not matured. The present

study included 12% of patients categorized as a low risk

group, who might have been managed by active surveil-

lance, but who chose PADT because of anxiety about the

risk of progression to incurability while living with

untreated cancer. Indeed, it has been shown that the

majority of men with early prostate cancer who chose

active surveillance had favorable levels of decisional

conflict, depression, generic anxiety and prostate cancer-

specific anxiety in the short term after diagnosis [38].

Although the impact of ADT on cardiovascular events is

less certain, ADT-associated side effects should be pre-

vented and treated in order that ADT-induced toxicity does

not outweigh its benefit.

In conclusion, primary CAB brings initial disease con-

trol to nearly two-thirds of patients having clinically

localized prostate cancer who are unsuitable for local

definitive treatment. This subset of patients can be effi-

ciently predicted by the use of %PBC at the onset of

treatment. Despite their nonrandomized and retrospective

character, the present findings complemented the previous

studies [12–14], having the same flaw of an insufficient

follow-up period, and simply indicated the feasibility of

primary CAB in controlling clinically localized prostate

cancer. Since the current information is inadequate to

assess the risk–benefit balance of long-term ADT, future

trials are awaited to better assess the exact effects of pri-

mary CAB on prostate cancer mortality reduction, as well

as on toxicities, quality-of-life and medical cost. Such trials

will delineate a certain group of patients for whom this

approach would be best justified to help inform future

treatment guidelines.

Conflict of interest No author has any conflict of interest.

References

1. Schwartz RS (2009) Clinical decisions. Management of prostate

cancer-polling results. N Engl J Med 360:4

2. Heinzer H, Steuber T (2009) Prostate cancer in the elderly. Urol

Oncol 27:668–672

3. National Cancer Institute: NCI-PDQ Prostate Cancer Treatment.

Available at http://www.cancer.gov/cancertopics/pdq/treatment/

prostate

4. National Comprehensive Cancer Network: NCCN Clinical

Practice Guidelines in Oncology. Prostate cancer. Available at

http://www.nccn.org/professionals/physician_gls/f_guidelines

5. Heidenreich A, Aus G, Bolla M et al (2008) European Associa-

tion of Urology. EAU guidelines on prostate cancer. Eur Urol

53:68–80

6. Cooperberg MR, Grossfeld GD, Lubeck DP et al (2003) National

practice patterns and time trends in androgen ablation for local-

ized prostate cancer. J Natl Cancer Inst 95:981–989

7. Shahinian VB, Kuo YF, Freeman JL et al (2005) Increasing use

of gonadotropin-releasing hormone agonists for the treatment of

localized prostate carcinoma. Cancer 103:1615–1624

8. Weight CJ, Klein EA, Jones JS (2008) Androgen deprivation falls

as orchiectomy rates rise after changes in reimbursement in the

U.S. Medicare population. Cancer 112:2195–2201

9. Cancer Registration Committee of the Japanese Urological

Association (2005) Clinicopathological statistics on registered

prostate cancer patients in Japan: 2000 report from the Japanese

Urological Association. Int J Urol 12:46–61

10. Jemal A, Siegel R, Ward E et al (2009) Cancer statistics, 2009.

CA Cancer J Clin 59:225–249

11. Samson DJ, Seidenfeld J, Schmitt B et al (2002) Systematic

review and meta-analysis of monotherapy compared with

Int J Clin Oncol (2011) 16:630–636 635

123

combined androgen blockade for patients with advanced prostate

carcinoma. Cancer 95:361–376

12. Akaza H, Homma Y, Okada K et al (2003) A prospective and

randomized study of primary hormonal therapy for patients with

localized or locally advanced prostate cancer unsuitable for rad-

ical prostatectomy: results of the 5-year follow-up. BJU Int

91:33–36

13. Ueno S, Namiki M, Fukagai T et al (2006) Efficacy of primary

hormonal therapy for patients with localized and locally

advanced prostate cancer: a retrospective multicenter study. Int J

Urol 13:1494–1500

14. Hinotsu S, Akaza H, Usami M et al (2007) Current status of

endocrine therapy for prostate cancer in Japan analysis of primary

androgen deprivation therapy on the basis of data collected by

J-CaP. Jpn J Clin Oncol 37:775–781

15. Banu E, Banu A, Medioni J et al (2007) Serum PSA half-life as a

predictor of survival for hormone-refractory prostate cancer

patients: modelization using a standardized set of response cri-

teria. Prostate 67:1543–1549

16. Nayyar R, Sharma N, Gupta NP (2010) Prognostic factors

affecting progression and survival in metastatic prostate cancer.

Urol Int 84:159–163

17. Kitagawa Y, Koshida K, Mizokami A et al (2003) Pathological

effects of neoadjuvant hormonal therapy help predict progression

of prostate cancer after radical prostatectomy. Int J Urol 10:

377–382

18. Labrie F, Candas B, Gomez JL et al (2002) Can combined

androgen blockade provide long-term control or possible cure of

localized prostate cancer? Urology 60:115–119

19. Briganti A, Chun FK, Hutterer GC et al (2007) Systematic

assessment of the ability of the number and percentage of positive

biopsy cores to predict pathologic stage and biochemical recur-

rence after radical prostatectomy. Eur Urol 52:733–743

20. Spalding AC, Daignault S, Sandler HM et al (2007) Percent

positive biopsy cores as a prognostic factor for prostate cancer

treated with external beam radiation. Urology 69:936–940

21. Nurani R, Wallner K, Merrick G et al (2007) Optimized prostate

brachytherapy minimizes the prognostic impact of percent of

biopsy cores involved with adenocarcinoma. J Urol 178:1968–

1973

22. Normand G, Celhay O, Briffaux R et al (2009) Percentage of

positive biopsy cores at the onset of hormone therapy for prostate

cancer: prognostic significance. Urol Int 83:160–165

23. Sebo TJ, Cheville JC, Riehle DL et al (2001) Predicting prostate

carcinoma volume and stage at radical prostatectomy by assess-

ing needle biopsy specimens for percent surface area and cores

positive for carcinoma, perineural invasion, Gleason score, DNA

ploidy and proliferation, and preoperative serum prostate specific

antigen: a report of 454 cases. Cancer 91:2196–2204

24. Egawa S, Suyama K, Matsumoto K et al (1998) Improved

predictability of extracapsular extension and seminal vesicle

involvement based on clinical and biopsy findings in prostate

cancer in Japanese men. Urology 52:433–440

25. Morote J, Trilla E, Esquena S et al (2004) Nadir prostate-specific

antigen best predicts the progression to androgen-independent

prostate cancer. Int J Cancer 108:877–881

26. Hussain M, Tangen CM, Higano C et al (2006) Absolute prostate-

specific antigen value after androgen deprivation is a strong

independent predictor of survival in new metastatic prostate

cancer: data from Southwest Oncology Group Trial 9346

(INT-0162. J Clin Oncol 24:3984–3990

27. Soga N, Arima K, Sugimura Y (2008) Undetectable level of

prostate specific antigen (PSA) nadir predicts PSA biochemical

failure in local prostate cancer with delayed-combined androgen

blockade. Jpn J Clin Oncol 38:617–622

28. D’Amico AV, Denham JW, Crook J et al (2007) Influence of androgen

suppression therapy for prostate cancer on the frequency and timing

of fatal myocardial infarctions. J Clin Oncol 25:2420–2425

29. Braga-Basaria M, Dobs AS, Muller DC et al (2006) Metabolic

syndrome in men with prostate cancer undergoing long-term

androgen-deprivation therapy. J Clin Oncol 24:3979–3983

30. Keating NL, O’Malley AJ, Freedland SJ et al (2010) Diabetes and

cardiovascular disease during androgen deprivation therapy:

observational study of veterans with prostate cancer. J Natl

Cancer Inst 102:39–46

31. Shahinian VB, Kuo YF, Freeman JL et al (2005) Risk of fracture

after androgen deprivation for prostate cancer. N Engl J Med

352:154–164

32. Lu-Yao GL, Albertsen PC, Moore DF et al (2008) Survival fol-

lowing primary androgen deprivation therapy among men with

localized prostate cancer. JAMA 300:173–181

33. Wong YN, Freedland SJ, Egleston B et al (2009) The role of

primary androgen deprivation therapy in localized prostate can-

cer. Eur Urol 56:609–616

34. Studer UE, Whelan P, Albrecht W et al (2006) Immediate or

deferred androgen deprivation for patients with prostate cancer

not suitable for local treatment with curative intent: European

Organisation for Research and Treatment of Cancer (EORTC)

Trial 30891. J Clin Oncol 24:1868–1876

35. Roach M 3rd, Bae K, Speight J et al (2008) Short-term neoad-

juvant androgen deprivation therapy and external-beam radio-

therapy for locally advanced prostate cancer: long-term results of

RTOG 8610. J Clin Oncol 26:585–591

36. Efstathiou JA, Bae K, Shipley WU et al (2009) Cardiovascular

mortality after androgen deprivation therapy for locally advanced

prostate cancer: RTOG 85–31. J Clin Oncol 27:92–99

37. Akaza H, Homma Y, Usami M et al (2006) Efficacy of primary

hormone therapy for localized or locally advanced prostate can-

cer: results of a 10-year follow-up. BJU Int 98:573–579

38. van den Bergh RC, Essink-Bot ML, Roobol MJ et al (2009)

Anxiety and distress during active surveillance for early prostate

cancer. Cancer 115:3868–3878

636 Int J Clin Oncol (2011) 16:630–636

123