ORIGINAL ARTICLE

Five-year potency preservation after iodine-125 prostatebrachytherapy

Shuichi Nishimura • Atsunori Yorozu • Toshio Ohashi • Masanori Sakayori •

Yasuto Yagi • Toru Nishiyama • Shiro Saito • Yutaka Shiraishi • Kayo Yoshida •

Kazuhito Toya • Naoyuki Shigematsu

Received: 13 July 2013 / Accepted: 11 October 2013

� Japan Society of Clinical Oncology 2013

Abstract

Background We aimed to evaluate long-term erectile

function following prostate brachytherapy, based on patient

characteristics and treatment factors.

Methods Between 2003 and 2006, 665 men with local-

ized prostate cancer were treated with 125I permanent seed

implantation. None was given adjuvant hormone therapy.

Erectile function was assessed before treatment, and at

6 months, 1, 2, 3, 4 and 5 years after implantation using the

Mount Sinai Erectile Function Score (MSEFS) of 0–3

(0 = no erections, 1 = erections insufficient for inter-

course, 2 = suboptimal erections but sufficient for inter-

course, 3 = normal erectile function). Potency was defined

as score 2 or 3, and 382 men were potent before treatment.

Univariate and multivariate analyses were performed on

the data from these 382 patients to identify variables

associated with potency preservation.

Results In patients who were potent before treatment, the

actuarial potency preservation rate fell to 46.2 % at

6 months after brachytherapy, and then slowly recovered

reaching 52.0 % at 5 years after brachytherapy. In multi-

variate logistic regression analysis, patient age (p = 0.04)

and pre-treatment MSEFS (p \ 0.001) were predictors of

5-year potency preservation. Neoadjuvant hormone therapy

affected potency preservation only at 6 months after

brachytherapy.

Conclusions Patient age at implantation and pre-treatment

erectile function are predictive factors for the development

of erectile dysfunction following prostate brachytherapy.

Keywords Prostate cancer � Brachytherapy �Potency � Preservation

Introduction

Definitive therapies for patients with localized prostate

cancer include radical prostatectomy, conformal or exter-

nal beam radiation therapy (EBRT), and permanent pros-

tate brachytherapy. For patients with low-risk prostate

cancer, brachytherapy is as effective for disease control as

radical prostatectomy or EBRT [1, 2]. Penile erectile

function is an important consideration for many patients

when deciding on the therapy modality for their prostate

cancer. Compared to patients receiving prostatectomy or

EBRT, those given brachytherapy tend to have higher rates

of potency preservation [3–5]. Nevertheless, many patients

receiving brachytherapy experience varying degrees of

decreased erectile function after treatment. Identifying

factors affecting erectile function after brachytherapy is

important for patients trying to decide between the cur-

rently available therapies.

The rate of potency preservation after prostate brachy-

therapy depends on various clinical factors. According to a

recent study, racial differences may affect erectile function

after brachytherapy [6]. Though a few reports have focused

on brachytherapy-related erectile dysfunction (ED) [7–9],

S. Nishimura � A. Yorozu � M. Sakayori � K. Yoshida � K. Toya

Department of Radiology, National Hospital Organization

Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku,

Tokyo 152-8902, Japan

T. Ohashi (&) � Y. Shiraishi � N. Shigematsu

Department of Radiology, Keio University School of Medicine,

35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

e-mail: ohashi@rad.med.keio.ac.jp

Y. Yagi � T. Nishiyama � S. Saito

Department of Urology, National Hospital Organization Tokyo

Medical Center, 2-5-1 Higashigaoka, Meguro-ku,

Tokyo 152-8902, Japan

123

Int J Clin Oncol

DOI 10.1007/s10147-013-0632-8

there have been no large-scale studies on this subject in

Asian countries.

In Japan, use of the iodine-125 (125I) seed source was

permitted in July 2003, and the first administration of I-125

prostate brachytherapy took place at our institution in

September of the same year. In this study, we evaluated the

5-year potency preservation rate in 665 consecutive

patients and analyzed factors predicting ED development.

Patients and methods

During the period from September 2003 through November

2006, we treated 665 consecutive patients with localized

prostate cancer at the National Hospital Organization

Tokyo Medical Center using 125I permanent seed implan-

tation. The following risk factors were assessed: prostate-

specific antigen (PSA) level, Gleason score and T-category

(according to the 1997 American Joint Commission on

Cancer). The subjects were divided into a low risk (T1–

T2a, PSA \10 ng/mL and Gleason score B6), an inter-

mediate risk (T2b–T2c, PSA = 10–20 or Gleason

score = 7) and a high risk (T3a, PSA [20 ng/mL or

Gleason score C8) group. For the low risk group, seed

implantation alone (monotherapy) was performed, whereas

for the intermediate and high risk groups a combination of125I seed implantation at a reduced radiation dose and

EBRT was preferred (combined therapy). The intermediate

risk group patients with PSA \10 ng/mL, Gleason

score = 7 and positive core needle biopsy rates \33 %

received monotherapy.

Neoadjuvant hormone therapy (HT) was administered to

538 patients (80.9 %) and consisted of a luteinizing hor-

mone-releasing hormone (LH-RH) agonist in 183 patients

(27.5 %), an antiandrogen in 209 (31.4 %) and both in 146

(22.0 %). The median duration of HT was 8 months (range

2–72). The proportion of subjects receiving HT was higher

in this than in past studies. There are three main reasons for

this difference. First, many of our patients had been waiting

to receive brachytherapy for a long time, in some cases for

more than a year; therefore, neoadjuvant HT was started

even in low risk patients. The second reason involves the

legal issue of discharge criteria in Japan: total seed activity

at the time of discharge must be lower than 1,300 MBq,

such that patients with pre-treatment prostate volumes

[40 mL have to undergo HT to achieve the cytoreduction

necessary to prevent prolonged hospitalization. Third, and

this is particularly true in Japan, HT is often started in both

early and advanced stages of prostate cancer. In the sur-

veillance study reported by the Japanese Urological

Association, 72.6 % of clinically-confirmed T1c–T3 cases

received HT [10]. On the other hand, none of our present

patients received adjuvant HT after implantation.

Of the 665 patients, the first 227 consecutive men were

treated by a preplanning technique, followed by 438 men

treated by an intraoperative technique. The prescribed dose

was 145 Gy in the monotherapy group and 100 Gy in the

combined therapy group. Our planning techniques have

previously been described in detail [11, 12], and there were

no significant differences in post-implant dosimetric results

between the two methods [13].

For post-implant dosimetric analysis, a computerized

tomography (CT) scan was obtained 1 month after

implantation. The calculated parameters used were the

percentage volume of the prostate receiving 150 % of the

prescribed dose (prostate V150) and the values of the

minimal dose received by 90 % of the prostate volume

(prostate D90). In the combined therapy group, supple-

mental EBRT was started 1 month after brachytherapy.

The prescribed EBRT doses were 45 Gy in 25 fractions of

1.8 Gy per fraction using 6 MV photons delivered by the

3D-conformal technique in the supine position, including

the prostate and seminal vesicles plus a 0.8-cm rectal-side

margin and a 1.5-cm margin on the other sides. The bio-

logically effective doses (BEDs) were calculated from the

prostate D90 and the EBRT dose using an a/b ratio of 2

(Gy2), applying the formulas described previously by

Stock et al. [14]. The total BED for the combination

therapy was the sum of the BED from the implant and that

from the EBRT.

Patients were reviewed clinically prior to treatment, at

6 months, and then yearly thereafter until 5 years post-

implantation. Six hundred and fifty-nine patients under-

went pre-implant and post-implant erectile function

assessments. Of them, 550 patients were assessed until

5 years after implantation. Erectile function was assessed

by medical interview or mailed questionnaire using the

Mount Sinai Erectile Function Score (MSEFS): 0, unable

to have erections; 1, erections insufficient for intercourse;

2, suboptimal erections but sufficient for intercourse; 3,

normal erectile function [15]. Potent was defined as an

MSEFS C2 with or without the use of a PDE-5 inhibitor,

and 382 men were potent before treatment. Patients who

had received neoadjuvant HT in other hospitals were

evaluated retrospectively by medical interview.

In this study, analyses were designed for patients who

were potent before treatment. The clinical and treatment-

related factors included patient age, pre-treatment MSEFS,

diabetes, pre-implant prostate volume, supplemental

EBRT, the utilization of neoadjuvant HT, prostate V150,

prostate D90 and total BED. Univariate analysis was per-

formed using an independent samples t test. Multivariate

analysis was performed using logistic regression analysis.

Analyses were carried out using SPSS 20.0 (SPSS Inc.,

Chicago, IL, USA). Differences were regarded as statisti-

cally significant at a p-value \0.05.

Int J Clin Oncol

123

Results

The clinical characteristics of patients are shown in

Table 1. In patients who were potent before treatment, the

rates of 6-month, 1-, 2-, 3-, 4- and 5-year potency preser-

vation were 46.2, 49.0, 51.0, 47.9, 49.3 and 52.0 %,

respectively (Fig. 1). The potency rate had fallen at

6 months, after which a gradual recovery trend was

observed. Of the patients who became impotent during the

course of follow-up, 109 were prescribed PDE-5 inhibitors,

in response to which 79 patients regained potency. None of

our patients received penile prostheses.

In logistic regression analysis, pre-treatment MSEFS

and utilization of neoadjuvant HT were associated with

potency preservation at 6 months (Table 2). Age, pre-

treatment MSEFS and diabetes mellitus were significant

factors at 1 year. Only age and pre-treatment MSEFS

remained significantly associated with potency preser-

vation at 5 years (Table 3), the same results as at

2–4 years.

Neoadjuvant HT was considered to have played a role in

the potency rate decrease at 6 months. Compared to hor-

mone-naı̈ve patients, patients with antiandrogen therapy

alone showed no significant differences in potency pres-

ervation at 6 months (64.1 vs. 61.3 %, p = 0.718),

whereas those receiving LH-RH agonist, with or without

antiandrogen therapy, had a significantly lower rate of

potency preservation (30.9 %, p \ 0.001) (Fig. 2). There

were no significant differences among the hormone-naı̈ve

(59.3 %), antiandrogen therapy alone (55.0 %) and LH-RH

Table 1 Patient characteristics (n = 665)

Potent

(n = 382)

Impotent

(n = 277)

Age (years)

Mean (range) 65 (49–84) 70 (53–85)

Initial PSA (ng/mL)

Mean (range) 7.7 (1.1–43.3) 7.6 (3.5–38.9)

Pre-implant prostate volume (ml)

Mean (range) 20.5 (6.2–49.6) 20.6 (7.0–46.3)

MSEFS

0 0 147

1 0 130

2 190 0

3 192 0

Clinical stage

T1c–2a 311 (81.3 %) 227 (81.9 %)

T2b–2c 70 (18.4 %) 47 (17.0 %)

T3a 1 (0.3 %) 3 (1.1 %)

Gleason score

\7 222 (58.1 %) 117 (42.2 %)

=7 151 (39.5 %) 142 (51.3 %)

[7 9 (2.4 %) 18 (6.5 %)

Neoadjuvant hormone therapy 315 (82.5 %) 220 (79.4 %)

Diabetes mellitus 36 (9.4 %) 30 (10.8 %)

Supplemental EBRT 181 (47.4 %) 160 (57.8 %)

PSA prostate-specific antigen, MSEFS Mount Sinai Erectile Function

Score, EBRT external beam radiation therapy

Fig. 1 Rate of potency preservation after brachytherapy for patients

who were not impotent prior to treatment

Table 2 Univariate and multivariate analyses of factors affecting

6-month potency preservation rate

Factors Univariate

analysis

Multivariate analysis

p value Odds

ratio

95 % CIp value

Clinical

Age 0.001 0.195

Diabetes mellitus 0.571 0.672

Pre-treatment MSEFS

(2 vs 3)

0.001 0.001 4.017 2.548–6.335

Treatment-related

Pre-implant prostate

volume

0.669 0.328

Neoadjuvant hormone

therapy

0.001 0.001 3.635 2.187–6.041

EBRT 0.456 0.845

Dosimetric

Prostate V150 0.300 0.151

Prostate D90 0.980 0.834

Total BED 0.995 0.753

Age, pre-implant prostate volume, prostate V150, prostate D90 and total

BED were analyzed as continuous variables. Remaining covariates were

analyzed as categorical variables

95 % CI 95 % confidence interval, MSEFS Mount Sinai Erectile Function

Score, EBRT external beam radiation therapy, prostate V150 the percent

volume of the post-implant prostate receiving 150 % of the prescribed

dose, prostate D90 the minimum dose received by 90 % of the prostate

volume, BED biologically effective dose

Int J Clin Oncol

123

agonist with or without antiandrogen therapy (47.6 %)

cohorts at 5 years.

By age groups, patients B60 years old showed a good

potency preservation rate at 5 years (71.4 %), as compared

to those 61–70 and C71 years old (p \ 0.001). On the

other hand, there was no marked difference between the

61–70 and C71 year age groups (50.8 vs. 39.2 %,

p = 0.085) (Fig. 3).

Pre-treatment MSEFS correlated strongly with post-

treatment potency over the entire follow-up period. Patients

with an initial MSEFS = 3 and MSEFS = 2 had actuarial

5-year potency preservation rates of 74.7 and 27.7 %,

respectively (p \ 0.001) (Fig. 4).

Discussion

There are several scales for evaluating ED. In this study,

we used the MSEFS. This 4-point scoring system is con-

sidered to be reliable and is simple to apply. The

Table 3 Univariate and multivariate analyses of factors affecting

5-year potency preservation rate

Factors Univariate

analysis

Multivariate analysis

p value p value Odds

ratio

95 % CI

Clinical

Age 0.001 0.040 1.045 1.002–1.089

Diabetes mellitus 0.827 0.995

Pre-treatment

MSEFS (2 vs 3)

0.001 0.001 6.620 3.986–10.996

Treatment-related

Pre-implant

prostate volume

0.124 0.084

Neoadjuvant

hormone therapy

0.097 0.835

EBRT 0.007 0.077

Dosimetric

Prostate V150 0.100 0.536

Prostate D90 0.257 0.192

Total BED 0.061 0.267

Age, pre-implant prostate volume, prostate V150, prostate D90 and

total BED were analyzed as continuous variables. Remaining covar-

iates were analyzed as categorical variables

95 % CI 95 % confidence interval, MSEFS Mount Sinai Erectile

Function Score, EBRT external beam radiation therapy, prostate V150

the percent volume of the post-implant prostate receiving 150 % of

the prescribed dose, prostate D90 the minimum dose received by

90 % of the prostate volume, BED biologically effective dose

Fig. 2 Rate of potency preservation stratified by neoadjuvant

hormone therapies. Open circles indicate hormone-naı̈ve patients.

Plus symbols correspond to patients receiving an antiandrogen

prescription. Triangles correspond to patients receiving LH-RH

agonist with or without an antiandrogen. Vertical bars represent

95 % confidence interval

Fig. 3 Rate of potency preservation stratified by patient age at the

time of implantation. Open circles indicate patients B60 years old.

Plus symbols represent patients 61–70 years old. Triangles represent

patients C71 years old. Vertical bars represent 95 % confidence

interval

Fig. 4 Rate of potency preservation stratified by pre-implant Mount

Sinai Erectile Function Scores (MSEFS). Open circles indicate

patients with MSEFS = 3. Plus symbols represent patients with

MSEFS = 2. Vertical bars represent 95 % confidence interval

Int J Clin Oncol

123

International Index of Erectile Function (IIEF) is also

widely used for evaluating ED, and Zagar et al. [16]

showed MSEFS results to correlate strongly with those of

the IIEF.

Various studies have assessed sexual function after

prostate brachytherapy. Five-year potency preservation

rates in patients who were potent before treatment were

reportedly 50–60 % [17, 18], similar to our result (52.0 %).

Snyder et al. [19] reported a higher 5-year potency pres-

ervation rate of 68.0 %. One reason for this difference

might be the use of PDE-5 inhibitors (740 of 1063 patients

at Mount Sinai vs. 109 of 659 at our institution).

Age had a strong impact on erectile function, with a

32.2 % lower 5-year potency preservation rate for patients

older than 70, compared with patients who were\61 years

old. Taira et al. [17] reported 7-year potency preservation

rates of 73.5, 48.1 and 33.3 % for men \60, 60–70 and

[70 years old, respectively. Our results showed the same

tendency for age groups. Furthermore, Kollmeier et al. [20]

reported post-brachytherapy erectile function in men

B60 years old to be favorable and that the majority did not

require medications.

Patients with an initial MSEFS = 3 had a 47.0 % higher

5-year potency preservation rate than those with

MSEFS = 2. This tendency was previously demonstrated

by Stock, Stone and colleagues [8, 15]. Snyder et al.

reported that patients with an initial MSEFS = 3 had a

22.5 % higher rate of potency preservation than those with

MSEFS = 2. This dependence on pre-treatment potency

status was also demonstrated by Merrick et al. [9]. They

reported 3-year potency preservation rates for patients with

pre-implant IIEF scores of 24–30, 18–23 and 13–17 to be

57.6, 48.0 and 22.1 %, respectively.

Previous studies have shown that neoadjuvant HT with

EBRT or brachytherapy was associated with long-lasting

sexual symptoms [3]. We recommend that patients, espe-

cially young men, waiting for brachytherapy receive neo-

adjuvant antiandrogen therapy in terms of potency

preservation, because no actuarial difference was seen in

our study between the hormone-naı̈ve cohort and that

receiving only antiandrogen therapy. We also found that

erectile function of patients with neoadjuvant LH-RH

agonist therapy decreased at 6 months, but improved at

1–5 years after brachytherapy. To our knowledge, this

outcome has not previously been reported.

A correlation between additional EBRT and potency

preservation has been suggested [18, 19]. On the other

hand, there are also data suggesting that no actuarial cor-

relation exists between additional EBRT and potency

preservation [9, 17]. In our univariate analysis, patients

receiving monotherapy had a higher actuarial 5-year

potency preservation rate than those given the combination

of EBRT and brachytherapy (59.2 vs. 44.4 %, p = 0.007).

In our multivariate analysis, however, we found no sig-

nificant difference in potency rate with the addition of

EBRT (p = 0.077). This might be explained by con-

founding factors such as hormone therapy, as numerous

patients given the combination therapy also received neo-

adjuvant HT.

In our study, 109 patients were prescribed PDE-5

inhibitors. This prescription rate was lower than that in the

study at Mount Sinai Hospital [19], possibly reflecting a

difference in attitudes towards sexual issues among nations

or races. Zelefsky et al. [21] reported that sildenafil was

associated with a 74 % response rate, a significant increase

compared to no treatment, in patients with ED after

radiotherapy for localized prostate cancer, and that patients

with less severe ED after radiotherapy were more likely to

respond than those with complete absence of erectile

function. Early use of PDE-5 inhibitors after prostatectomy

or brachytherapy reportedly improves IIEF scores, and

contributes to rapid recovery of erectile function [22, 23].

These data also suggested that patients might be more

likely to benefit from earlier (i.e., before their potency

scores decrease) and more aggressive use of PDE-5

inhibitors.

The limitations of this study include medical interview

bias. The initial assessments might have been unreliable

when the patients were asked to recall erectile function

prior to treatment, especially if they had received hormone

therapy at other hospitals. Accordingly, appropriate pre-

treatment evaluations are needed employing a detailed

questionnaire about the sexual functions of individual

patients.

Conclusion

Over a 5-year follow-up period, 52.0 % of patients with

prostate brachytherapy maintained their potency. On mul-

tivariate analysis, patient age at implantation and pre-

treatment erectile function score were associated with

5-year potency preservation. Although neoadjuvant LH-RH

agonist therapy affected the 6-month actuarial potency

preservation rate, no definite impact on this rate was seen at

5 years after implantation. In addition, over the entire study

period, no significant differences were seen between

patients receiving no hormone therapy and those given

antiandrogen treatment alone.

Acknowledgments The authors are grateful to Ms. Kazuko Ogawa

at Keio University School of Medicine for her support and assistance.

Conflict of interest The authors declare that they have no conflict

of interest.

Int J Clin Oncol

123

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