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Original Article: Clinical Investigationiju_3125 185..192

Early quality of life outcomes in patients with prostatecancer managed by high-dose-rate brachytherapy

as monotherapyAkira Komiya,1 Yasuyoshi Fujiuchi,1 Takatoshi Ito,1 Akihiro Morii,1 Kenji Yasuda,1 Akihiko Watanabe,1

Tetsuo Nozaki,1 Hiroaki Iida,1 Kuninori Nomura2 and Hideki Fuse1

Departments of 1Urology and 2Diagnostic and Therapeutic Radiology, Graduate School of Medicine and Pharmaceutical Sciences for

Research, University of Toyama, Toyama, Japan

Abbreviations & Acronyms

ADT = androgen deprivation

therapy

AE = adverse events

CT = computed tomography

CTCAE = CommonTerminology Criteria for

Adverse Events

CTV= clinical target volume

EBRT = external beam

radiation therapy

ED = erectile dysfunction

FACT-P = Functional

Assessment of Cancer

Therapy-Prostate

GI = gastrointestinal

GTV= gross tumor volume

GU = genitourinary

HDR-BT= high-dose-rate

brachytherapy

IIEF = International Index of

Erectile Function

Questionnaire

IPSS = International Prostate

Symptom Score

LDR-BT = low-dose-rate

brachytherapy

M = month

MRI= magnetic resonance

imaging

NS = not significant

PCa = prostate cancer

PSA = prostate-specific antigen

QOL = quality of life

TRUS = transrectal ultrasound

W = week

Y=

year

Correspondence:Akira Komiya

M.D., Ph.D., Department of Urology,

Graduate School of Medicine and

Pharmaceutical Sciences for

Research, University of Toyama,

2630 Sugitani, Toyama-shi, Toyama

930-0194, Japan. Email:

[email protected]

Received 6 February 2012; accepted

26 July 2012.

Online publication 21 August 2012

Objectives: To evaluate the early quality of life outcomes in prostate cancer patients

managed by high-dose-rate brachytherapy as monotherapy.

Methods: A total of 51 patients with cT1cT3aN0M0 prostate cancer treated between

July 2007 and January 2010 were included in this study. The average age was 69 years,

and the average initial serum prostate-specific antigen was 10.98 ng/mL. A total of 25, 18and eight patients were considered to be low, intermediate and high risk, respectively.

All patients received one implant of Ir-192 and seven fractions of 6.5 Gy within 3.5 days

for a total prescribed dose of 45.5 Gy. For high-risk prostate cancer, neoadjuvant andro-

gen deprivation therapy was carried out for at least 6 months, and continued after

high-dose-rate brachytherapy. Quality of life outcomes were measured by using the

International Prostate Symptom Score, the Functional Assessment of Cancer Therapy-

Prostate and the International Index of Erectile Function Questionnaire. The oncological

outcome was assessed by serum prostate-specific antigen and diagnostic imaging.

Adverse events were also recorded.

Results: The Functional Assessment of Cancer Therapy-Prostate scores decreased for

a few months after high-dose-rate brachytherapy, and recovered to pretreatment con-

dition thereafter. The International Prostate Symptom Score significantly increased

2 weeks after treatment for each of its items and their sum, and it returned to baseline

after 12 weeks. Sexual function decreased at 2 and 4 weeks, and recovered after

12 weeks. Severe complications were rare. Within a median follow up of 17.2 months,

two patients showed a prostate-specific antigen recurrence.

Conclusions: High-dose-rate brachytherapy for prostate cancer is a feasible treat-

ment modality with acceptable toxicity and only a limited impact on the quality of life.

Key words: high-dose-rate brachytherapy,Ir-192,prostate cancer,radiation therapy.

IntroductionPCa is a leading cause of death in Western countries. The incidence and mortality of PCa are

also increasing in Japan, despite efforts to screen patients to provide an early diagnosis, and

despite intensive efforts to treat this disease.1,2 Similar to other countries, PCa screening has

induced stage migration to early-stage disease in Japan. In parallel with this change, the

number of modalities for PCa treatment has been increasing, especially for localized PCa. 3

However, there is no definitive difference in the efficacy among curative therapies, although

each PCa treatment was reported to be associated with a distinct pattern of changes in QOL

domains related to urinary, sexual, bowel and hormonal function. 47 Only one randomized

Scandinavian trial showed an improvement in metastasis-free, prostate cancer-specific and

overall survival among patients who underwent prostatectomy against watchful waiting.8

The other treatments have not been proven to have any survival advantages against controls.

Therefore, it is difficult to determine the best treatment option. In this context, it is important

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International Journal of Urology (2013) 20, 185192 doi: 10.1111/j.1442-2042.2012.03125.x

2012 The Japanese Urological Association 185

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(rectal) margin. The posterior margin varied from 2 to 5 mm

depending on the distance to the rectal wall. The planned

target volume was equal to the CTV, except in the cranial

direction, for which it was greater. The top 2 cm of the

applicators were placed within the urinary bladder, so that

the planned target volume included a 1-cm margin in thecranial direction from the CTV. This margin was established

as prevention not only of the cold area at the base of the

prostate, but also of distal displacement of the applicators.

One hour before each irradiation fraction, a urinary balloon

catheter was clamped in place to keep the urine within the

urinary bladder so that the opposite side of the bladder wall

and the rectosigmoid colon were kept away from the irra-

diation field.

The treatment planning was carried out with the aid of

the PLATO software program (Nucletron, Veenendaal, The

Netherlands) using geometric optimization and one pre-

scription dose point (5 mm distant from one source). Thesource dwell positions were located on the prostate surface

and inside the prostate (except in the cranial direction, for

which it was located 1 cm outside the prostate).

Patients remained in bed under epidural anesthesia for

3.5 days from Tuesday to Friday and underwent irradiation

twice daily, with an interval of at least 6 h. We used gradu-

ated compression stockings and intermittent external pneu-

matic calf compression for prevention of deep vein

thrombosis. The treatment consisted of seven fractions of

6.5 Gy each (total 45.5 Gy). The isoeffective dose used in

the present study corresponded to approximately 96.69 or

86.45 Gy administered at 2 Gy/fraction according to thelinear-quadratic model, assuming an alpha/beta ratio of 2 or

3 for PCa, respectively.1214 Prophylactic antibiotics were

given twice daily from the day of implant through to day 5.11

We used continuous epidural anesthesia during the whole

period of this treatment, and this is usually enough for pain

control.

Follow up and toxicity analysis

Urologists and radiation oncologists carried out the follow

up evaluations at regular intervals (every 3 months). CT,MRI, TURS and bone scans were carried out as required.

The oncological outcome was assessed by serum PSA

levels, DRE, CT, MRI, TRUS and bone scans. After provid-

ing their informed consent, the patients were given a set of

questionnaires including the IPSS, FACT-P and the IIEF to

be completed before HDR-BT, and also at 2, 4 and

12 weeks, and 6, 9, 12 and 24 months after HDR-BT, and to

be returned at that time. The patient QOL outcomes were

measured by these questionnaires. Adverse events were

described using the CTCAE v.3.0. Late toxicity was defined

as symptoms that persisted or presented beyond 6 months

after treatment completion.

In the present study, we defined two types of recurrence:

biochemical recurrence and clinical recurrence. Clinical

recurrence was determined by clinical evidence of recur-

rence (e.g. detection of metastasis on a CT scan or bone

scan). Biochemical recurrence was determined according to

the Houston criteria; that is, when the first PSA rise of atleast 2 ng/mL greater than the nadir was observed.15 The

progression-free survival curves were calculated by the

KaplanMeier method.

Statistical analysis

An unpaired two-tailed t-test was used for comparisons

between the baseline and each point of time of follow up in

the QOL analyses. Values ofP< 0.05 were considered to be

significant.

Results

QOL outcomes

FACT-P

The FACT-P total score was not changed significantly during

follow up (Fig. 1a). The FACT-P score in the physical well-

being domain was decreased at 2 and 4 weeks, but was

recovered by 12 weeks (Fig. 1b). The FACT-P score in the

social/family well-being domain was decreased at 12 weeks

and 9 months, but recovered by 1 year (Fig. 1c). The

FACT-P scores in the emotional or functional well-beingdomains were not changed significantly (Fig. 1d,e). The

FACT-P score in the additional concerns domain (prostate-

related symptoms) significantly decreased at 2 and 4 weeks,

but recovered thereafter (Fig. 1f).

IIEF

The erectile function did not change significantly in the

patients with neoadjuvant ADT, as assessed by the IIEF

(Fig. 2a). In contrast, this function was significantly

impaired at 2 and 4 weeks in the patients without neoadju-

vant ADT (Fig. 2b). However, after 12 weeks, it was not

different from the pretreatment status. IIEF scores were not

statistically different between the two groups.

IPSS

Lower urinary tract symptoms were assessed by the IPSS.

The IPSS total score was increased significantly at 2 and

4 weeks, but had recovered to pretreatment values by

12 weeks (Fig. 2c). In storage and voiding symptom sub-

scores, the same changes were observed (Fig. 2d,e). The

IPSS QOL score also showed the same change (Fig. 2f).

QOL in HDR-BT monotherapy for PCa


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PSA decline and survival

PSA decline to less than 4 ng/mL was achieved in 90.2% of

the patients at 3 months after HDR-BT. During a median

follow up of 17.2 months, two cases showed PSA failure

with no evidence of metastasis. One was the initial fifth

patient in our experience with low-risk PCa (initial PSA

4.5 ng/mL; biopsy Gleason score 3 + 3 =6; T1cN0M0),

who showed PSA failure at 30 months after HDR-BT. Pros-

tate needle biopsy was carried out at PSA failure; however,

no malignant cells were found. Therefore, this patient is stillunder observation without any additional treatments and his

PSA is stable. The other was the initial sixth patient in our

experience with low-risk PCa (initial PSA 4.6 ng/mL;

biopsy Gleason score 3 + 3 = 6; T1cN0M0), who showed

PSA failure at 27 months after HDR-BT. Prostate needle

biopsy was carried out at PSA failure and prostatic adeno-

carcinoma with a Gleason score of 3 + 4 was found. There-

fore, androgen deprivation therapy with leuprolide acetate

and bicalutamide was started, and serum PSA level had

declined to less than 0.01 ng/mL at the last follow up. The

others did not show PSA or clinical progression during

follow up (Fig. 3).

Toxicities

Only a few patients experienced severe AE in this cohort

(Table 2). Acute toxicities were mainly grades 12 GU

events including urinary retention, urinary frequency/

urgency, pain or hemorrhage. Grade 1 or 2 AE were found in

39 (76.5%) patients. One patient experienced a grade 3 hem-

orrhage, which was managed by transurethral coagulation.

Acute GU toxicities were generally related to applicator

placement. GI or non-GU/GI toxicities were mainly grade 1.

Late toxicities wereless commonand mostly in thegrade 1or 2 category, which were found in 24 (47.1%) patients. Two

patients complained of grade 3 ED. In another five patients

with ED, phosphodiesterase 5 inhibitors were effective.

Discussion

Currently, patients with localized or locally advanced PCa

have a number of treatment options; however, there is a lack

of information regarding the differences in survival after the

different treatments. Therefore, the QOL outcome of each

treatment is one of the key factors that should influence the

patients decision. In this context, we evaluated the early

Fig. 1 Changes in the FACT-P scores.

(a) The FACT-P total score. (b) The physi-

cal well-being. (c) The social/family well-

being. (d) The emotional well-being. (e)

The functional well-being. (f) Additional

concerns. *P < 0.05 versus before

HDR; **P < 0.01 versus before HDR;

***P < 0.001 versus before HDR.

24 24 18 23 20 18 13 3n 38 43 41 41 37 31 22 5n

25 29 26 26 21 21 16 5n

36 38 34 41 32 30 21 6n39 42 40 42 34 32 20 6n

39 41 42 41 35 34 24 6n

(a) (b)

(c)

(e) (f)

(d)

Points(meanS.D.)

Points(meanS.D.)

Po

ints(meanS.D.)

Points(meanS.D.)

Points(meanS.D.)

Points(meanS.D.)

160

140

120

100

80

25

20

15

10

30

25

20

15

10

35

30

25

20

15

10

5

45

40

35

30

25

20

30

25

20

15

Before 2W 4W 12W 6M 9M 1Y 2Y






NS

NS

NS

A KOMIYA ET AL.

188 2012 The Japanese Urological Association

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QOL and oncological outcomes related to HDR-BT in

patients with clinically localized or locally advanced PCa.

Although the follow-up period was too short to adequatelyanalyze disease control, we found good QOL outcome after

HDR-BT. The health-related QOL as assessed by the

FACT-P was impaired for a few months, but recovered in a

relatively short period of time. Scores in the physical well-

being and the additional concern domains decreased at 2 and

4 weeks. This could be a result of treatment procedure and

impaired urinary function. Scores in the social/family well-

being domain decreased at 12 weeks and 9 months; the

score at 6 months was not significantly different from the

scores at 12 weeks and 9 months. Therefore, it can be said

that the social/family well-being was impaired from

3 months to 9 months after HDR-BT. It is difficult to define

Fig. 2 Sexual and urinary functions. (a)

The changes in the IIEF score in patients

with neoadjuvant androgen deprivation

therapy. (b) The changes in the IIEF score

in patients without neoadjuvant andro-

gen deprivation therapy. (c) The changes

in the IPSS total score. (d) The changes in

the IPSS storage symptoms subscore. (e)

The changes in the IPSS voiding symp-

toms subscore. (f) The changes in the

IPSS QOL score. *P < 0.05 versus before

HDR; **P < 0.01 versus before HDR;

***P < 0.001 versus before HDR.

9 12 13 12 13 10 6

Before 2W 4W 12W 6M 9M 1Y Before 2W 4W 12W 6M 9M 1Y


Before 2W 4W 12W 6M 9M 1Y 2Y Before 2W 4W 12W 6M 9M 1Y 2Y


n 16 15 14 13 13 18 10n

19 48 43 43 39 33 23 6n 19 45 43 42 38 32 23 6n

19 48 43 43 39 33 23 6n 19 48 43 43 38 33 23 6n

(a) (b)

(c)

(e) (f)

(d)

Points(meanS.D.)

Points(mean

S.D.)

Points(meanS.D.)

Points(mean

S.D.)

Points(meanS.D

.)

Points(meanS.D.)

45

40

35

30

25

20

15

10

5

0

5

14

12

10

8

6

4

2

0

16

14

12

10

8

6

4

2

0

45

40

35

30

25

20

15

10

5

0

35

30

25

20

15

10

5

0

7

6

5

4

3

2

1

0

NS

PSAprogressionfreesurvival

Time (months)

(n=51)

0 5 10 15 20 25 30 35

1

.8

.6

.4

.2

0

Fig. 3 PSA progression-free survival in all patients.



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the reason for this change. The other domains and FACT-P

total score did not show significant change over time. Sexual

function as assessed by the IIEF did not change significantly,

except for at the initial 4 weeks in the patients without ADT.

Decrease in IIEF at 2 and 4 weeks seemed to be a result of

treatment trauma rather than radiation-induced erectile dys-function. Much of radiation therapy-induced erectile dys-

function will not usually be apparent until 25 years of

follow up. In the patients with neoadjuvant ADT, the change

in sexual function was similar to those without neoadjuvant

ADT; however, the difference was not statistically signifi-

cant. IIEF scores before HDR-BT were slightly lower than

in those without ADT, and most of the cases discontinued

ADT after HDR-BT. This means sexual function did not

recover after cessation of ADT at least until 1 year, possibly

as a result of delay in recovery of testicular function.

Urinary functions, as assessed by the IPSS, were also

impaired for a few months, but improved thereafter. Thesefindings are the first report of the HDR-BT monotherapy-

related QOL outcomes, and can provide important informa-

tion to help prostate cancer patients choose which therapy

they wish to receive.

The QOL decline observed within the first 2 weeks is

likely related to the treatment procedure and the effects of

the radiation; patients have to remain in bed under epidural

anesthesia for 4 days and 3 nights with applicator needles

placed from the perineal skin to the prostate and urinary

bladder. This might be a disadvantage of HDR-BT mono-

therapy. However, this treatment is completed within 4 days,

which can thus explain the early recovery in the QOL scores.

Although the treatment protocols were different, there

have been a few reports about the survival outcome after

HDR-BT monotherapy. Martinez et al. reported the PSA

progression-free survival to be 98% at 3 years and 91% at

5 years after HDR-BT monotherapy (38 Gy/4 fractions/

2 days).12,16 Yoshioka et al. reported 83% progression-freesurvival at 5 years after 54 Gy/9 fractions/5 days.17 The

follow up in the present study was too short to adequately

judge disease control. However, PSA failure was observed

in two cases from the low-risk group, which were the initial

fifth and sixth patients from the beginning of this treatment

in Toyama University Hospital, Toyama-shi, Japan. Longer-

term results will eventually dilute that effect with additional

successful patient accrual.

Early and late toxicities were mild, and severe complica-

tions were rare in the present study. In the literature, grade 3

or higher adverse events were reported in 03.8% of patients

and 0% of the patients for acute GU and GI toxicities,respectively. Grade 3 or higher late GU and GI toxicities

were observed in 1.211% and 01.2% of patients after

HDR-BT.13,1820 The present results are comparable with the

previous reports. In particular, urethral stricture as a late

toxicity was rare and found as grade 2 in only one patient.

This might be a result of the outcome of our efforts to reduce

the radiation dose to the urethra, which is the most important

organ at risk in HDR-BT. Rare urethral stricture also might

be a result of short follow up, or simply not being examined

unless patients complain of urinary symptoms.

HDR-BT + EBRT has recently been the most common

treatment procedure, especially for locally advanced PCa.

Table 2 Toxicities

Adverse events Acute toxicities Late toxicities

Grade (CTCAE v.3.0) Grade (CTCAE v.3.0)

1 2 3 4 1 2 3 4

GU Urinary retention 5 10 0 0 2 2 0 0

Urinary frequency/urgency 4 2 0 0 5 0 0 0

Pain urethra 9 2 0 0 2 1 0 0

Hemorrhage bladder or urethra 0 9 1 0 0 2 0 0

Stricture urethra 0 0 0 0 0 1 0 0

Subtotal (%) 38 (74.5) 1 (2.0) 17 (33.3) 0 (0.0)

GI Anorexia 1 0 0 0 0 1 0 0

Constipation 2 0 0 0 0 0 0 0

Pain anus 1 0 0 0 1 0 0 0

Hemorrhage anus 1 0 0 0 1 0 0 0

Subtotal (%) 5 (9.8) 0 (0.0) 3 (5.9%) 0 (0.0)

Non-GU/GI Erectile dysfunction 0 2 0 0 1 5 2 0Pain head/headache 1 0 0 0 0 0 0 0

Pain extremity-limb 0 1 0 0 0 0 0 0

Subtotal (%) 4 (7.8) 0 (0.0) 6 (11.8%) 2 (3.9)

Total (%) 39 (76.5) 1 (2.0) 24 (47.1) 2 (3.9)

A KOMIYA ET AL.


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Mohammed et al. reported a comparison of toxicities

between HDR-BT and HDR-BT+ EBRT.21 The incidences

of any acutegrade 3 GI or GU toxicities were 8% for both

BT and EBRT + HDR.Any late GU toxicitiesgrade 3 were

present in 5% and 12% for HDR-BT, and HDR-BT +EBRT,

respectively. Patients receiving EBRT + HDR had a higherincidence of urethral stricture and retention, whereas dysuria

was most common in patients receiving HDR-BT. Any

grade 3 late GI toxicities were 0.3% and 1% for the

HDR-BT and HDR-BT + EBRT groups. The differences

were most pronounced for rectal bleeding, with 3-year rates

of 0.9% and 6% for HDR-BT and HDR-BT+ EBRT, respec-

tively. Therefore, acute toxicity was the same, but the chronic

toxicity was greater for combined HDR-BT + EBRT than it

was for HDR-BT monotherapy. Regarding the QOL out-

comes in HDR-BT + EBRT, the FACT-P and IPSS scores

were reported to recover at approximately 23 months.2224 In

comparison with these studies, the present study demon-strated that HDR-BT monotherapy showed comparable or

even better GU/GI toxicities and QOL recovery.

The results in terms of erectile dysfunction varied. Morton

et al. showed a decrease in IIEF score at 612 months and a

recovery at 24 months after HDR-BT plus EBRT.24 In con-

trast, Noharaet al. reported that 80% of their patients main-

tained erectile function at 1 year after HDR-BT + EBRT.9

Our cohort did not show a significant decrease in IIEF scores,

except for the ones at 2 and 4 weeks after HDR-BT, which

seemed better than the result in HDR-BT +EBRT.

Another seed implant technique, LDR-BT, is also carried

out to treat localized PCa. After LDR-BT, Feigenberg et al.reported that the FACT-P scores remained below the base-

line in 2034% of patients at 1 year.25 Leeet al. reported that

the decline in the total FACT-P score at 1 and 3 months

improved at 1 year after LDR-BT.26 Urinary function usually

requires approximately 1 year to recover to the baseline

level by IPSS.25,27 Therefore, LDR-BT impairs HR-QOL

longer than HDR-BT monotherapy as compared with the

present data. ED is also observed after LDR-BT. Merrick

et al. reported ED in 60% of patients at 1 year, and 50% at

3 years after LDR-BT.28 Wyleret al. reported potency in

50% of patients at 524 months, and 30% at 2553 months

after LDR-BT.29 Martinez suggested HDR-BT mightcompare favorably to LDR-BT in terms of ED, but it was not

statistically significant;16 however, our cohort did not show a

significant decrease in IIEF. Although LDR-BT is a simple

procedure, the influence on the health-related QOL, urinary

function and sexual function seem to be prolonged com-

pared with HDR-BT.

There were limitations in the present study. Patients

follow up was relatively short.The sample size was relatively

small. The results could have been different if the study was

carried out in a larger cohort with longer follow-up periods.

In addition, we could not describe QOL during the insertion

of the applicator needles. If patients were asked to fill out the

questionnaires during insertion of applicators for HDR-BT,

the scores might have been much worse. IIEF could have

been much worse, because sexual intercourse was impos-

sible during insertion of applicators. IPSS should have been

much worse, because a Foley catheter was placed in the

urethra and urinary bladder, which means patients could noturinate. General QOL should have been worse, because

patients must keep lying on their back during insertion of

applicators for HDR-BT. However, we did not collect QOL

data during this procedure, because these sorts of studies are

usually carried out to compare QOL before and after treat-

ments. Therefore, the examination of QOL during treatment

is not usually carried out. For example, a representative QOL

outcome study by Sandaet al. showed QOL in patients who

underwent radical prostatectomy, external-beam radio-

therapy or brachytherapy at the time-points of pretreatment,

2 months, 6 months, 12 months and 24 months, but not

during the treatments.7

It is also impossible to investigateQOL during radical prostatectomy under general anesthesia.

IPSS is a questionnaire that inquires about urinary symptoms

during the past 1 month. IIEF is a questionnaire that inquires

about erectile function during the past 4 weeks. FACT-P also

inquires about prostate cancer therapy-related QOL during

the past 7 days. Therefore, these questionnaires are not

designed for real time assessment of QOL. In any case, the

present study showed that recovery was fast when assessed

by FACT-P, IIEF and IPSS.

In conclusion, the present study suggests that HDR-BT

for localized or locally advanced PCa is a feasible treatment

modality with limited influence on patient QOL, and accept-able acute and late toxicities. Further studies are required

to confirm these results and to determine the oncological

outcomes.

Acknowledgments

We are grateful to Ms Yoko Kawauchi, and Dr Yoshihiro

Asao and Dr Keisuke Ichimatsu for their valuable advice

and suggestions.

Conflict of interest

None declared.

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