ORIGINAL ARTICLE

Preimplant Factors Affecting Prostate D90 after Transperineal
Interstitial Prostate Brachytherapy with Loose 125I Seeds
Akitomo Sugawara,1 Jun Nakashima, 2 Etsuo Kunieda, 3 Hirohiko Nagata,4 Ryuichi Mizuno,4 Atsuya Takeda, 5Satoshi Seki,1 Yutaka Shiraishi,1 Ryuichi Kouta,1 Mototsugu Oya4 and Naoyuki Shigematsu1
1 Department of Radiology, School of Medicine, Keio University, Tokyo, Japan
2 Department of Urology, Tokyo Medical University, Tokyo, Japan

3 Department of Radiation Oncology, Tokai University School of Medicine, Kanagawa, Japan
4 Department of Urology, School of Medicine, Keio University, Tokyo, Japan
5 Department of Radiology, Ofuna Chuo Hospital, Kanagawa, Japan(Received for publication on September 17, 2011)(Revised for publication on October 5, 2011)(Accepted for publication on October 17, 2011)

The dose received by 90% of the prostate volume (D90) is the key parameter of dosimetric analysis inprostate brachytherapy. The aim of this analysis was to identify preimplant factors affecting prostate
D90 after transperineal interstitial prostate brachytherapy with loose 125I seeds. We reviewed the records of 210 patients who underwent transperineal interstitial prostate brachytherapy with loose 125I
seeds for clinical T1/T2 prostate cancer at our institution. Patients who received supplemental externalbeam radiation therapy were excluded. One hundred and nine patients (51.9%) received neoadjuvant
hormonal therapy (NHT). One month after seed implantation, postimplant computed tomography anddosimetric analysis were performed. Univariate and multivariate analyses were carried out to identify
preimplant factors affecting postimplant prostate D90. The postimplant prostate D90 values ranged
from 123.3 to 234.1 Gy (mean ± standard error, 177.1 ± 1.4 Gy). Postimplant prostate D90 differedsignificantly between patients who had and had not undergone NHT (P = 0.001). In addition, simple
regression analyses showed positive correlations with the estimated preimplant prostate D90, preimplant prostate volume by transrectal ultrasound (TRUS), total radioactivity, number of needles, andnumber of seeds. On stepwise multiple regression analysis, postimplant prostate D90 showed significant
negative correlations with NHT and preimplant prostate volume by TRUS, and a significant positive
correlation with total radioactivity. In conclusion, NHT, preimplant prostate volume by TRUS, andtotal radioactivity are significant preimplant factors affecting postimplant prostate D90 in prostatecancer patients treated with transperineal interstitial prostate brachytherapy with loose 125I seeds.
(Keio J Med 61 (3) : 89–94, September 2012)

Keywords: brachytherapy, dosimetry, 125I, prostate cancer, seed

Introduction

ing medical conditions, concerns about the effects oftreatment on quality of life, and other factors. The treatment alternatives for localized prostate cancer include
watchful waiting, androgen deprivation therapy, radical prostatectomy, external-beam radiation therapy, andbrachytherapy.

There are a number of treatment options for clinically
localized prostate cancer; treatment selection depends onlife expectancy, the clinical stage, the serum prostatespecific antigen (PSA) level, the Gleason score, compet-

Reprint requests to: Akitomo Sugawara, MD, Department of Radiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku,
Tokyo 160-8582, Japan, E-mail: h4411@wave.plala.or.jp
Copyright © 2012 by The Keio Journal of Medicine
89

90

In recent years, transperineal interstitial prostatebrachytherapy with radioactive seeds has become apopular treatment option for localized prostate cancer.
Substantial advantages of prostate brachytherapy include
better potency preservation, less risk of urinary incontinence, and greater patient convenience.1 Previous investigators have suggested that outcomes with prostatebrachytherapy in selected patients are equivalent to thosewith other treatment modalities for localized prostatecancer, including radical prostatectomy and externalbeam radiation therapy.2
With the widespread use of prostate brachytherapy,
there is growing interest in quality assurance that includes dosimetric analysis.3–6 It is recommended that preimplant and postimplant dosimetric analyses for prostatebrachytherapy be performed routinely.7,8 In brief, before
implantation, the prostate is contoured on transrectal ultrasound (TRUS) images, and radioactive seed placementis planned with a computer-assisted treatment planningsystem. Then, a dose–volume histogram is generated,and dosimetric parameters, such as the dose received by
90% of the prostate volume (D90), are calculated. After
implantation, dosimetric analysis is also performed withcomputed tomography (CT) images.
Prostate D90 is one of the key parameters of dosimetric analysis in prostate brachytherapy.7–11 In 1998, Stockand colleagues were the first to describe prostate D90 as
an indicator of implant quality that showed a good correlation with the probability of achieving biochemical
control.11 They showed that a prostate D90 of 140 Gy
is a highly significant factor in predicting PSA relapsefree survival.11 A subsequent publication by Potters andcoworkers confirmed the correlation between prostate
D90 and the probability of achieving biochemical control.9 Moreover, Stock and colleagues suggested in a later
study of the results of posttreatment biopsies that a prostate D90 > 160 Gy was associated with increased tumor
control and that a prostate D90 > 180 Gy was associatedwith an increased risk of long-term urinary toxicity frombrachytherapy.10 The American Brachytherapy Society
recommends that prostate D90 should be reported after
prostate brachytherapy.7,8
We sometimes encounter results in which the postimplant prostate D90 value is higher or lower than expected.
Previous investigators have suggested that it is difficult
to achieve the exact preplanned dose coverage because
of seed misplacement, seed migration, and postimplant
prostatic swelling.12–16 These factors cannot be predicted
preoperatively. It is important to evaluate preimplant factors associated with postimplant prostate D90 because
suboptimal or excessive values of prostate D90 are associated with increased biochemical failure or increased morbidity, respectively. The present study was undertaken to
identify preimplant factors affecting postimplant prostate
D90 in prostate cancer patients treated with transperineal
interstitial prostate brachytherapy with loose 125I seeds.

Sugawara A, et al: Preimplant Factors Affecting D90

Materials and Methods
We reviewed the records of 210 patients who underwent
transperineal interstitial prostate brachytherapy withloose 125I seeds for clinical T1/T2 prostate cancer at Keio
University Hospital. Patients who received supplemental
external-beam radiation therapy were excluded from thisanalysis. Neoadjuvant hormonal therapy (NHT), which
consisted of a luteinizing hormone-releasing hormone
agonist and antiandrogens, was generally administered topatients with a prostate volume >40 cm3 and to those withpubic arch interference at the preimplant volume study
by TRUS.17 Hormonal therapy was not continued past thedate of seed implantation.
One month before seed implantation, a preplan was obtained with TRUS images taken at 5-mm intervals fromthe base to the apex of the prostate with the patient in thedorsal lithotomy position. The prostate contour was outlined at each level by a single radiation oncologist (AS).
The planning target volume included the prostate gland
and a margin of 3 mm anteriorly and laterally and 5 mmin the cranial and caudal directions. No margin was added posteriorly at the rectal interface. Treatment planning
used a peripheral or a modified peripheral approach. For
the 210 patients, the prescribed brachytherapy dose was
145 Gy for the first 133 patients and 160 Gy for the subsequent 77 patients. Preplan dosimetry aimed for a prostate
D90 of <125% of the prescribed dose, a prostate V100 (%of the volume receiving the prescribed dose or greater) of>99%, and a prostate V150 (% of the volume receiving
150% of the prescribed dose or greater) of <60%. VariSeed 7.1 (Varian Medical Systems, Palo Alto, CA, USA)software was used both in the planning and in the calculation of the final dosimetry. TG 43 formalism was usedin the preplanning and postimplant dosimetry analyses.18
All 210 patients were treated with loose 125I radioactive
seeds using a Mick applicator (Mick Radio-Nuclear Instruments, New York, NY, USA). Postimplant axial CT
images of the prostate at 2.5- to 3.0-mm intervals were
undertaken 1 month after seed implantation. The prostatic margins were outlined by a single radiation oncologist (AS). Postimplant dosimetry calculations were performed.
The following information was recorded: patient characteristics, implant characteristics, preimplant prostate
D90, and postimplant prostate D90. The following parameters were included as preimplant predictive variables: patient age, serum PSA, whether the patient had
undergone NHT, Gleason score (<7 vs. 7), preimplant
prostate D90, preimplant prostate volume by TRUS, total
radioactivity, radioactivity per unit volume, number ofneedles, and number of seeds.

Keio J Med 2012; 61 (3): 89–94

91

Table 1 Patient characteristics (n =210)
Variable

Value

Range

Age, years

68.9 ± 0.4(53 – 80)

Initial PSA, ng/mL

7.47 ± 0.24

(4.01 – 19.88)

Gleason score <7, n (%)

130 (61.9)

Gleason score =7, n (%)

80 (38.1)

NHT (+), n (%)

109 (51.9)

NHT (−), n (%)

101 (48.1)

Preimplant prostate volume by TRUS, cm3

23.0 ± 0.4(9.3 – 40.8)

Data are presented as mean ± standard error (range) or number (percent) of patients.
PSA, prostate-specific antigen; NHT, neoadjuvant hormonal therapy; NHT (+), patients who received NHT; NHT (−), patients who did notreceive NHT; TRUS, transrectal ultrasound.

Table 2 Implant characteristics (n =210)
Variable

Value

Range

Preimplant estimate of prostate D90, Gy

184.8 ± 0.9(148.0 – 208.9)

Total radioactivity, MBq

920.5 ± 11.6

(482.9 – 1300.0)

Radioactivity per unit volume, MBq/cm3

41.1 ± 0.4(27.6 – 63.1)

Number of needles

24.4 ± 0.3(12 – 37)

Number of seeds

72.2 ± 0.8(40 – 95)

Data are presented as mean ± standard error (range).
D90, dose received by 90% of the volume of the prostate.

Statistical analysis
Data are presented as the mean ± standard error (SE).
A paired t test was performed to determine if there wasa difference between preimplant and postimplant prostate D90 values. Student’s t test was used to compare
postimplant prostate D90 values between patients who
had and had not undergone NHT and between patientswith a Gleason score <7 and with a Gleason score of 7.
Simple regression analyses were performed to investigate
the relationship between postimplant prostate D90 andcontinuous preimplant variables. Stepwise multiple regression analysis was performed to identify independent
predictors of postimplant prostate D90 from preimplantvariables. A P value of <0.05 was considered statisticallysignificant.
Results
Tables 1 and 2 summarize the patient and implant characteristics, respectively, for all 210 patients. The postim-

plant prostate D90 values ranged from 123.3 to 234.1 Gy.
There was a significant difference between the preimplantand postimplant D90 (184.8 ± 0.9 vs. 177.1 ± 1.4 Gy, P <0.001). Figure 1 shows postimplant prostate D90 values
vs. preimplant prostate D90 values for all 210 patients.
The mean ± SE postimplant prostate D90 was 169.4 ±1.7 Gy in patients who had received NHT and 185.3 ±2.0 Gy in those who had not received NHT (P = 0.001).
Postimplant prostate D90 was 175.5 ± 1.8 and 179.6 ± 2.2
Gy in patients with Gleason score <7 and Gleason score=7, respectively (P = 0.148). Postimplant prostate D90
showed positive correlations with preimplant prostate
D90 (r =0.355, P < 0.001), preimplant prostate volume by
TRUS (r =0.338, P < 0.001), total radioactivity (r =0.490,
P < 0.001), number of needles (r =0.372, P < 0.001), andnumber of seeds (r =0.482, P < 0.001), but did not show
significant correlations with age (r =0.068, P = 0.327),
serum PSA (r = –0.018, P = 0.794), and radioactivity perunit volume (r = –0.034, P = 0.626) in simple regression
analyses (Table 3).
Postimplant prostate D90 showed significant negative

Sugawara A, et al: Preimplant Factors Affecting D90

92

Fig. 1 Postimplant prostate D90 vs. preimplant prostate D90.
Data are shown for all 210 patients. D90, dose received by 90% of the volume of the prostate.

correlations with NHT (P < 0.001) and preimplant prostate volume by TRUS (P < 0.001), and a significant positive correlation with total radioactivity (P < 0.001) in the
stepwise multiple regression analysis (Table 3).
Discussion
The purpose of the present study was to identify preimplant factors affecting postimplant D90 in prostate cancer patients treated with transperineal interstitial prostatebrachytherapy with loose 125I seeds. The results showedthat NHT, preimplant prostate volume by TRUS, and total
radioactivity are significant independent factors affecting
postimplant prostate D90.
In univariate and multivariate analyses, NHT was associated negatively with postimplant prostate D90, meaning that a patient receiving NHT had a lower D90 thana patient who did not receive NHT. These results are inagreement with a previous report.19 Ash and coworkers
reported that postimplant prostate D90 was significantly
different between patients who had and had not undergone NHT (130.8 vs. 145.1 Gy, P ≤ 0.001).19 A possible
explanation for the negative effect of NHT on postimplant
prostate D90 is that NHT is associated with an increasein prostate volume after implantation, which results in alower D90.19 Ash and coworkers reported that the ratio of
the postimplant CT scan volume to the preimplant TRUS
volume of the prostate (CT/TRUS volume ratio), whichindicates the volume change of the prostate from before
to after implantation, was significantly different between
patients who had and had not undergone NHT (1.17 vs.
0.98, P < 0.001).19 Our previous study also showed that
the CT/TRUS volume ratio was significantly different
between patients who had and had not undergone NHT(1.30 vs. 1.05, P < 0.001), meaning that patients who had
undergone NHT had a greater increase in prostate volume after implantation.20
The next factor affecting postimplant prostate D90 was
the preimplant prostate volume by TRUS. Simple regression analysis revealed that preimplant prostate volume by
TRUS was positively correlated with postimplant prostate D90, although the correlation was weak (r =0.228, P< 0.001). This result is in agreement with those of previous reports.21,22 McNeely and coworkers reported that alarger gland was associated with a higher D90 in univariate analyses.21 Moreover, Stock and colleagues reported
that preimplant prostate volume by TRUS was a factor
that significantly affected postimplant prostate D90, although the correlation was weak in univariate analyses (r=0.223, P < 0.001).22 Their possible explanation was thatthe activity per volume table calls for a greater activity
in large glands than may be needed to achieve the desired dose.22 From the results of these previous studies, it
seems that larger glands tend to have higher D90s. However, in multiple linear regression analysis in the present

Keio J Med 2012; 61 (3): 89–94

93

Table 3 Univariate and multivariate analyses for postimplant prostate D90
Covariate

Simple regression
P value

Stepwise multiple regression
P valueB

SE<0.001−12.146

2.449

Age, years

0.327

Initial PSA, ng/mL

0.794

Gleason score =7 vs. Gleason score <70.148*NHT (+) vs. NHT (−)

0.001*

Preimplant prostate D90, Gy<0.001Preimplant prostate volume by TRUS, cm3<0.001<0.001−1.521

0.386

Total radioactivity, MBq<0.001<0.001

0.095

0.014

Radioactivity per unit volume, MBq/cm3

0.626

Number of needles<0.001

Number of seeds<0.001*Student's t test was used.
D90, dose received by 90% of the volume of the prostate; B, unstandardized coefficients; PSA, prostate-specific antigen; NHT, neoadjuvant
hormonal therapy; NHT (+), patients who received NHT; NHT (−), patients who did not receive NHT; TRUS, transrectal ultrasound.

study, preimplant prostate volume by TRUS had a significant negative effect on postimplant prostate D90. These
results seem contradictory. A possible explanation forthe discrepancy might be that for a larger gland, a given
amount of radioactivity tends to have a lower D90.
The last significant factor affecting postimplant prostate D90 was total radioactivity. In univariate and multivariate analyses, total radioactivity was associatedpositively with postimplant prostate D90. Thus, a higher
amount of radioactivity leads to a higher D90. It is obvious that the dose received by the prostate should increase
with the increase in total radioactivity when the volumeof the prostate is given. The other possible reason is thatthe negative effect of seed misplacement or seed migration on the dose coverage of the prostate would decrease
with the increase in total radioactivity.
The results of the present study show that the preimplant prostate D90 value calculated by the computerassisted treatment planning system was not adequate forpredicting postimplant prostate D90. Although postimplant prostate D90 showed a positive correlation withpreimplant prostate D90 in the simple regression analysis, the correlation was not strong (r =0.355, P < 0.001)(Fig. 1). Moreover, in the stepwise multiple regression
analysis, preimplant prostate D90 was not a significant
independent factor affecting postimplant prostate D90.
These results indicate that we should not depend solely on
preimplant prostate D90 values calculated by a computerassisted treatment planning system. It is recommended
that preimplant factors shown to affect postimplant prostate D90 should be considered.

The present results indicate that postimplant prostate
D90 is often lower in patients with a larger prostate glandand in patients who have undergone NHT. To achieve optimal dose coverage of the prostate, this group of patients
may need more seeds than that calculated by the computer-assisted treatment planning system. Moreover, whensuboptimal dosimetric results are predicted and prostatebrachytherapy is not considered to be an appropriate
treatment, especially for patients with larger prostates
and those who have undergone NHT, other treatment options such as radical prostatectomy or external-beam radiation therapy can be offered.
In conclusion, the results of the present study show that
NHT, preimplant prostate volume by TRUS, and total
radioactivity are significant preimplant factors affecting
postimplant prostate D90. Thus, the combination of thesethree factors can be used to predict postimplant prostate
D90 in prostate cancer patients treated with transperineal
interstitial prostate brachytherapy with loose 125I seeds.
References
1. Wallner K, Roy J, Harrison L: Tumor control and morbidity following transperineal iodine 125 implantation for stage T1/T2
prostatic carcinoma. J Clin Oncol 1996; 14: 449–453. [Medline]
2. Kupelian PA, Potters L, Khuntia D, Ciezki JP, Reddy CA, Reuther AM, Carlson TP, Klein EA: Radical prostatectomy, externalbeam radiotherapy <72 Gy, external beam radiotherapy >or =72
Gy, permanent seed implantation, or combined seeds/externalbeam radiotherapy for stage T1-T2 prostate cancer. Int J Radiat
Oncol Biol Phys 2004; 58: 25–33. [Medline] [CrossRef]
3. Hoinkis C, Hakenberg OW, Lehmann D, Winkler C, Wirth MP,
Herrmann T: Evaluation of dose-volume histograms after pros-

94
tate seed implantation. Four-year experience. Strahlenther Onkol
2004; 180: 550–556. [Medline] [CrossRef]
4. Martin T, Baltas D, Kurek R, Roddiger S, Kontova M, Anagnostopoulos G, Dannenberg T, Buhleier T, Skazikis G, Tunn U, Zamboglou N: 3-D conformal HDR brachytherapy as monotherapy for
localized prostate cancer. A pilot study. Strahlenther Onkol 2004;
180: 225–232. [Medline] [CrossRef]
5. Mock U, Bogner J, Georg D, Auberger T, Potter R: Comparative
treatment planning on localized prostate carcinoma conformal
photon- versus proton-based radiotherapy. Strahlenther Onkol
2005; 181: 448–455. [Medline] [CrossRef]
6. Pinkawa M, Maurer U, Mulhern A, Gagel B, Block T, Borchers H,
Grieger J, Henkel T, Eble M: Inverse automated treatment planning with and without individual optimization in interstitial permanent prostate brachytherapy with high- and low-activity 125I.
Strahlenther Onkol 2003; 179: 417–422. [Medline]
7. Nag S, Beyer D, Friedland J, Grimm P, Nath R: American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol
Phys 1999; 44: 789–799. [Medline] [CrossRef]
8. Nag S, Bice W, DeWyngaert K, Prestidge B, Stock R, Yu Y: The
American Brachytherapy Society recommendations for permanent prostate brachytherapy postimplant dosimetric analysis. Int J
Radiat Oncol Biol Phys 2000; 46: 221–230. [Medline] [CrossRef]
9. Potters L, Cao Y, Calugaru E, Torre T, Fearn P, Wang XH: A
comprehensive review of CT-based dosimetry parameters andbiochemical control in patients treated with permanent prostatebrachytherapy. Int J Radiat Oncol Biol Phys 2001; 50: 605–614.
[Medline] [CrossRef]
10. Stock RG, Stone NN, Dahlal M, Lo YC: What is the optimal dosefor 125I prostate implants? A dose-response analysis of biochemical control, posttreatment prostate biopsies, and long-term urinary
symptoms. Brachytherapy 2002; 1: 83–89. [Medline] [CrossRef]
11. Stock RG, Stone NN, Tabert A, Iannuzzi C, DeWyngaert JK: A
dose-response study for I-125 prostate implants. Int J Radiat Oncol Biol Phys 1998; 41: 101–108. [Medline] [CrossRef]
12. Dawson JE, Wu T, Roy T, Gu JY, Kim H: Dose effects of seeds
placement deviations from pre-planned positions in ultrasoundguided prostate implants. Radiother Oncol 1994; 32: 268–270.
[Medline] [CrossRef]

Sugawara A, et al: Preimplant Factors Affecting D90
13. Gao M, Wang JZ, Nag S, Gupta N: Effects of seed migration
on post-implant dosimetry of prostate brachytherapy. Med Phys
2007; 34: 471–480. [Medline] [CrossRef]
14. Roberson PL, Narayana V, McShan DL, Winfield RJ, McLaughlin
PW: Source placement error for permanent implant of the prostate. Med Phys 1997; 24: 251–257. [Medline] [CrossRef]
15. Waterman FM, Yue N, Corn BW, Dicker AP: Edema associatedwith I-125 or Pd-103 prostate brachytherapy and its impact on
post-implant dosimetry: an analysis based on serial CT acquisition. Int J Radiat Oncol Biol Phys 1998; 41: 1069–1077. [Medline][CrossRef]
16. Willins J, Wallner K: CT-based dosimetry for transperineal I-125
prostate brachytherapy. Int J Radiat Oncol Biol Phys 1997; 39:
347–353. [Medline] [CrossRef]
17. Saito S, Nagata H, Kosugi M, Toya K, Yorozu A: Brachytherapy
with permanent seed implantation. Int J Clin Oncol 2007; 12:395–407. [Medline] [CrossRef]
18. Nath R, Anderson LL, Luxton G, Weaver KA, Williamson JF,
Meigooni AS: Dosimetry of interstitial brachytherapy sources:
recommendations of the AAPM Radiation Therapy Committee
Task Group No. 43. American Association of Physicists in Medicine. Med Phys 1995; 22: 209–234. [Medline] [CrossRef]
19. Ash D, Al-Qaisieh B, Bottomley D, Carey B, Joseph J: The impact of hormone therapy on post-implant dosimetry and outcome
following Iodine-125 implant monotherapy for localised prostatecancer. Radiother Oncol 2005; 75: 303–306. [Medline] [CrossRef]
20. Sugawara A, Nakashima J, Kunieda E, Nagata H, Asakura H, Oya
M, Shigematsu N: Preimplant factors affecting postimplant CTdetermined prostate volume and the CT/TRUS volume ratio after transperineal interstitial prostate brachytherapy with 125I free
seeds. Radiat Oncol 2010; 5: 86. [Medline] [CrossRef]
21. McNeely LK, Stone NN, Presser J, Chircus JH, Stock RG: Influence of prostate volume on dosimetry results in real-time 125I seed
implantation. Int J Radiat Oncol Biol Phys 2004; 58: 292–299.
[Medline] [CrossRef]
22. Stock RG, Stone NN, Lo YC, Malhado N, Kao J, DeWyngaert JK:
Postimplant dosimetry for (125)I prostate implants: definitions
and factors affecting outcome. Int J Radiat Oncol Biol Phys 2000;
48: 899–906. [Medline] [CrossRef]