Introduction
Prostate cancer is the second most commonly diagnosed
cancer and the fifth leading cause of cancer death
among men worldwide.[] Prostate brachytherapy has
proven to be an effective treatment for T1-T2 prostate
tumors. In low-dose-rate (LDR) prostate brachytherapy,
small radioactive iodine sources, specifically
Iodine-125 (I-125), are permanently implanted into
the prostate. The primary advantage of brachytherapy
over external beam radiotherapy (EBRT) is the rapid
dose reduction around the radioactive sources, thereby
preserving the surrounding normal tissues. I-125 seed
implantation requires only a one-day hospital stay.
Prior retrospective investigations have not shown
notable outcome disparities among radical prostatectomy,
external beam radiotherapy (EBRT), and brachytherapy
in the context of low-risk prostate cancer.[-]
Research has consistently indicated outstanding tumor
control and survival rates in localized prostate cancer
through I-125 LDR brachytherapy,[,] with results
comparable to those attained with radical prostatectomy
or external beam radiotherapy.[]
Prostate brachytherapy pre-planning is undertaken
to ascertain the prostate volume before treatment,
determine the required number of needles/seeds, and
assess anatomical barriers in the patient"s anatomy,
such as the pubic arch. Furthermore, the ultrasound
(US) images obtained during pre-planning are utilized
to formulate an optimal treatment plan without time
constraints. The objective is to replicate the treatment
plan developed during pre-planning using online US
images obtained intraoperatively.
Real-time planning during the procedure instantly
adjusts the dose distribution with each seed placement,
compensating for any deviations from the planned
coordinates when loading needles based on pre-planning.
This allows for the correction of cold and hot
spots that may arise during the procedure. Through
the assessment of real-time planning, additional seed
placements or omissions can be adjusted to achieve
the desired dose distribution. In post-implant dosimetry,
there is no intervention in the dose distribution;
it serves solely as a verification of the application.[]
The D90, V100, and V90 planning parameters recommended
by the American Brachytherapy Society
for evaluating plan quality and ensuring that the target
volume receives an adequate dose have been assessed
in numerous studies.[-] Previous studies have
shown that rectal and urethral complication rates are
dose-dependent.[,] It is recommended to report these doses and evaluate them in post-implant dosimetry
in clinical practice. During pre-planning and
intraoperative treatment planning, US is employed,
while post-implant planning is conducted using computed
tomography (CT) after the implant. Due to the
use of different modalities, variations in timing, and
differences in body positions, dosimetric discrepancies
between the US plan and post-implant CT analyses are
inherent. This study aims to investigate the dosimetric
differences between the plans created during preplanning
and the extent to which they can be achieved
during intraoperative planning (IOP). Additionally, it
explores the dosimetric variations between the dose
distribution obtained during the procedure and the
post-implant dosimetry (PID) conducted approximately
four weeks after the application.
Methods
The study involved 143 patients who underwent lowdose-
rate (LDR) prostate brachytherapy between 2000
and 2019. These patients exclusively received brachytherapy
monotherapy for low- or intermediate-risk
prostate cancer, with the following T stages: T1c in 12
patients, T2a in 68 patients, T2b in 57 patients, and T3
in 6 patients. The median number of needles used was
28 (range: 18-35), and the median number of seeds
used was 85 (range: 65-110), with an average seed activity
of 0.49 U per seed (range: 0.43-0.50).
Pre-planning and Intraoperative Planning
For all patients, pre-planning was executed using
the Permanent Seed Implant Brachytherapy Treatment
Planning Software VariSeed? version 7.1 (Varian
Medical Systems, Inc., Palo Alto, Calif.). Transrectal
ultrasound (TRUS) images with 5-mm intervals were
obtained using B&K Ultrasonography and Probe for
treatment planning. Patients were positioned in a high
lithotomy position under general anesthesia during
both pre-planning and intraoperative planning. A stepping
unit provided real-time feedback to the operator
and planning system based on TRUS images. A Foley
catheter and gel enhanced urethral visibility during imaging.
Contours were drawn on the pre-planning images,
and optimal treatment plans were formulated. Seed
activities, determined based on the treatment plan"s needle
and seed counts, were approximately 0.49 U per seed
on the application day. Most seeds were in strand form,
with loose seeds used in regions requiring individual
additions. During intraoperative application, seeds were
placed according to the pre-plan. Needle placement was manually performed based on planned coordinates,
with needle position verification using a C-arm fluoroscopy
device. In cases where seed implantation to the
planned coordinates was hindered by edema and tissue
hardness resulting from needle application, seed implantation
was adjusted to unplanned points to achieve
the same dosimetric parameters as in pre-planning.
The target volume for treatment planning was defined
as the prostate, with the rectum and urethra designated
as organs at risk. Minimum peripheral doses
(mPD) were set at 145 Gy for brachytherapy. In both
pre-planning and intraoperative planning, prostate
volumes receiving 90%, 100%, and 150% of the prescribed
dose (pV90, pV100, pV150), the dose received
by 90% of the prostate volume (pD90), and the doses
received by 10%, 30%, and 50% of the urethra volume
(uD10, uD30, uD50) were determined. Additionally,
volumes receiving the entire prescribed dose and 150%
of the dose (uV100, uV150), and the rectal volumes
receiving the entire prescribed dose and 150% of the
dose (rV100, rV150) were assessed. These parameters
were evaluated according to the primary treatment
criteria based on AAPM TG 137 recommendations.
[19] For the prostate: pD90 ?100% of the prescription
dose, pV100 >95%, and pV150 ?50%. For the rectum: rV100 <2 mL, rV150 <0.1 mL. And for the urethra:
D10 <150% of the prescription dose, uD30 <130% of
the prescription dose, and uV150 <15%.
Post-implant Dosimetry
Post-implant dosimetry was conducted using CT/MR
imaging taken in the supine position approximately
four weeks after the application. Verification of the
intraoperative plan was carried out by identifying the
implanted seeds using the VariSeed software and generating
a dose distribution. The prostate, rectum, and
urethra were contoured on the sections to obtain dosevolume
histogram (DVH) parameters. Performing imaging
in the supine position for post-implant dosimetry,
without the intraoperative probe and considering
edema, led to dosimetric differences. Nevertheless, we
believe that a simple comparison, incorporating these
effects from CT-based to US-based planning, remains
beneficial in the clinical setting. Figure 1 displays a
patient"s pre-planning (PP), intraoperative planning
(IOP), and post-implant dosimetry (PID) plans, along
with a 3D image of the application.
Fig. 1. Patient's (a) Pre-planning (PP), (b) intraoperative planning (IOP), (c) post-implant dosimetry (PID) plans, (d) 3D
image of the application.
Statistical Analysis
Within the study, a comparison was conducted to assess
the differences in dose distributions among preplanning (PP), intraoperative planning (IOP), preplanning
and post-implant dosimetry (PID), as well as
intraoperative planning and post-implant dosimetry.
To analyze these distinctions, statistical analyses were
performed using paired sample T-tests and Two Related
Samples Test-Wilcoxon tests.
Results
Dosimetric data and the volumetric comparisons for
the prostate are summarized in Table 1. The mean
prostate volume was measured as 33.9 mL in preplanning,
33.5 mL in intra-op, and 30.89 mL in postplanning.
The study revealed a significant difference
between pre-planning (PP) and intraoperative planning
(IOP) prostate volumes (p=0.049). However,
the differences were more pronounced between IOP
and post-implant dosimetry (PID) (p<0.001) and between
PP and PID (p<0.001). In the PID performed
four weeks after implantation, prostate volumes were
found to be significantly smaller.
Table 1 Presents the mean±SD results for all prostate volume examined parameters, along with the p-values for the comparisons
The pD90 values (Gy) for PP, IOP, and PID were
164.42±14.6 Gy, 164.99±19.3 Gy, and 157.2±19.5 Gy,
respectively. When comparing pD90 between PP and
IOP, PP and PID, and IOP and PID applications, the pvalues
were found to be p=0.393, p<0.001, and p<0.001,
respectively. Regarding the prostate volume receiving
90% of the prescribed dose (pD90), it was observed that
in PP, IOP, and PID treatment plans, it was 116.75%,
117.12%, and 111.22%, respectively. All parameters met
the recommended values (>100%) for prostate D90.
For pV90 (%), the mean ± standard deviation for
PP, IOP, and PID were found to be 99±2.22, 97.91±5.75,
and 96.32±3.32, respectively. When comparing pV90 between IOP and PP, PP and PID, and IOP and PID
applications, the p-values were found to be p = 0.084,
p<0.001, and p<0.001, respectively. The target for this
value was to achieve ?95%. The mean pV100 (%) was
found to be 96.92% in PP and 96.24% in IOP, meeting
the desired level of 95%. However, in PID, it was lower
at 93.1%. Significant differences were observed when
comparing pV100 (mL) between PP and IOP, PP and
PID, and IOP and PID applications.
Although it is preferred for the prostate volume
receiving 150% of the prescribed dose (pV150) to remain
at 50%, in both PP and IOP treatment plans, it
was found to be higher than expected at 56% and 60%,
respectively. Also, in the PID planning, it surpassed the
anticipated value, reaching 64%. Table 1 displays the
mean±SD results and comparison p-values for all prostate
parameters in PP, IOP, and PID.
As shown in Table 1, the reference value of pD90
?100% Rx is achieved in all three plans. pV100 >95% is
attained in PP and IOP, with a 2% lower value in PID.
The volume is found to be 6.22% higher in PP, 10.88%
higher in IOP, and 14.84% higher in PID than the recommended
pV150 ≤50%.
Table 2 presents the dosimetric parameters and their
comparisons for the urethra. The difference between
urethra volumes in PP and IOP was not found to be
significant (p=0.226). However, significant differences
were observed between IOP and PID (p<0.001) and between
PP and PID (p<0.001) for urethra volumes. The
recommended value for uD10 <150% Rx is achieved in
PP and IOP, but in PID, it is found to be 156%, which is
6% higher than the suggested value. Similarly, for uD30
<130% Rx, it is achieved in PP and IOP, but in PID, it is
found to be 136%, which is 6% higher than the recommended value. In terms of uV150 <15%, it is achieved
in PP and IOP, whereas in PID, it is 23.9%, which is
8.9% higher. The intended parameter values for the
urethra were met in the PP and IOP plans. In PID, D10
and D30 doses, as well as V150 volume, were found to
be slightly higher than intended.
Table 2 Presents the mean±SD results uretra volume examined parameters, along with the p-values for the comparisons
Table 3 displays the dosimetric parameters and
comparisons for the rectum. No significant difference
was found between the volumes in pre-planning (PP)
and intraoperative planning (IOP) (p=0.244). However,
significant differences were observed between IOP
and post-implant dosimetry (PID) (p<0.001) as well as
between PP and PID (p<0.001) for rectum volumes.
Table 3 Presents the mean±SD results for rectum volume examined parameters, along with the p-values for the comparisons
The recommended value for rV100 <2 mL was
achieved in pre-planning (PP), intraoperative planning
(IOP), and post-implant dosimetry (PID), with values
of 0.23 mL, 0.24 mL, and 0.59 mL, respectively, which
are significantly lower than the suggested values. For rV150 <0.1 mL, representing the rectal volume receiving
150% of the Rx dose, it is close to zero in all three
plans. All intended parameters were successfully obtained
in the rectum for all three plans.
Although there was a significant difference between
IOP and PID DVH parameters, the dose constraints
for the urethra were found to be well below the intended
values. The intended values for the urethra were set
at uD10 <150% Rx (217.5 Gy-150% of the prescribed
dose of 145 Gy, equivalent to 217.5 Gy). In PID, the
mean±SD was found to be 218.89±42.01, and uD30 was
aimed to be < 130% Rx (188.5 Gy), with a mean±SD in
PID of 194.26±33.52. For uV150, the goal was set at
<15%, but the mean±SD was found to be 23%. As for
rectal dose constraints, rV100 was intended to be <2
cc, and in PID, the mean±SD was 0.59±0.65. Similarly,
for rV150 <0.1 cc, the intended value was achieved
with a mean±SD of 0.088±0.025.
Discussion
In this study, the primary objective was to investigate
the consistency of dose distributions obtained from
pre-planning (PP), intraoperative planning (IOP), and
post-implant dosimetry (PID) in low-dose-rate prostate
brachytherapy.
However, it was observed that the dose distribution designed
in pre-planning could not be replicated in the intraoperative
plan due to changes in patient position and shifts
in seed placement during the application. Furthermore,
the dose distribution obtained during intraoperative application
differed from the intraoperative plan. Statistically
significant differences in dose distribution and dose-volume
histograms of the seeds on the post-plan dosimetry
day were observed due to factors such as seed displacement
and prostate volume enlargement due to edema.
In a study conducted by Ishiyama et al.,[] differences
were identified between intraoperative ultrasound
(US)-based dosimetry and postoperative computed tomography
(CT)-based dosimetry. They noted that certain
dosimetric disparities were expected between the
analyses of US-based plans and post-implant CT plans,
particularly due to the presence of the probe during US
planning. It was emphasized that despite variations in
rectal shape deformation and rectal contouring, the
high-dose area near the prostate remained consistent.
The study indicated that these rectum-related contouring
differences did not significantly impact the data.
In this study, even though the definition of rectal wall
volume differed between US and CT images, it was found
that rV100 (rectal volume receiving the entire prescription
dose) was lower than 1 mL, similar to rV50 doses in
the post-op CT plan compared to the intra-op plan. In
Ishiyama et al.[]'s study, they observed that prostate
parameters tended to be higher in US-based intraoperative
dosimetry than in CT-based postoperative dosimetry.
This difference was attributed to seed locations
being more centrally defined in the prostate, resulting
in higher US parameters compared to CT parameters.
In my study, I preferred peripheral seed placement, and
I observed that prostate parameters, except for pV150
volumes, tended to decrease in the post-operative plan
compared to the intra-operative plan. However, urethra
doses tended to increase in post-plan dosimetry, despite
the preference for peripheral placement.
In their study, Gregory et al.[] examined the impact
of contouring and image alignment uncertainty on
dosimetric outcomes when employing different prostate
implantation (PID) methods. They reported that the dosimetry
method utilizing CT images in PID disregards the effect of edema, and D90 values may fluctuate due to
swelling and edema of the prostate caused by needle insertion
during application. They further highlighted that
the most significant impact might be on the D90 dose due
to contour differences induced by edema and variations
in the inferior-superior direction during contouring. In
our study, we observed that the pD90 value was similar in
the pre- and intra-operative plans but tended to decrease
in post-implant dosimetry. Although the pD90 dose in
PID was lower than in the pre-plan and intra-operative
plans, it was considered to still exceed the prescribed dose
(157.2±19.5 Gy) to account for uncertainties.
In our study, the post-implant dosimetry results
were evaluated based on AAPM TG 137.[] Treatment
criteria for prostate pD90 ?100% of the prescription
dose, pV100 >95%, and pV150 ≤50%, it was found that
D90 was better than the recommended values, while
V100 and V150 values were very close to the recommended
values. For the rectum: rV100 <2 mL, rV150
<0.1 mL. According to the criteria, V100 and V150 volumes
were within the recommended criteria. For the
urethra: D10 <150% of the prescription dose, uD30 <
130% of the prescription dose, and uV150 <15%, D10
and D30 doses and V150 volume were found to be
slightly higher than the recommended values.
While there were changes in dose-volume histogram
(DVH) parameters between pre-planning (PP), intraoperative
planning (IOP), and PID plans, our previous study
found that the 5-, 10-, and 12-year disease-free survival
rates were 99.9%, 93%, and 93% in the low-risk group and
100%, 92%, and 74% in the medium-risk group.[,]
Despite efforts to replicate the dose distribution obtained
in pre-planning in the IOP plan for all patients,
significant differences were observed in the PID results.
Target volume conformality and high-dose target
volume results met the desired values in all three plans.
Conclusion
Studies have consistently reported that transperineal
I-125 brachytherapy for localized prostate cancer yields
favorable clinical control, overall survival, and acceptable
late-term toxicity. In our study, we successfully
maintained the target volume and rectal anterior wall
(RAO) doses within tolerance limits, with dose control
confirmed through post-implant dosimetry. Although
significant differences were observed between the applications,
it can be confidently asserted that low-dose-rate
(LDR) prostate brachytherapy represents a viable treatment
option for both early and late-stage toxicity when
evaluated in terms of treatment efficacy and side effects.
Ethics Committee Approval: The study was approved by
the Acıbadem Mehmet Ali Aydınlar University Medical Research
Ethics Committee (no: 2024-4/136, date: 14/03/2024).
Authorship contributions: Concept - Ö.Ş., E.T.; Design
- Ö.Ş., E.T., I.A.; Supervision - I.A., G.K.; Materials - I.A.,
A.A., G.K., S.K.; Data collection and/or processing - H.K.,
G.K.; Data analysis and/or interpretation - Ö.Ş., E.T., I.A.;
Literature search - Ö.Ş., E.O.G., E.T.; Writing - Ö.Ş., E.T.,
I.A.; Critical review - H.K., S.K.
Conflict of Interest: All authors declared no conflict of interest.
Use of AI for Writing Assistance: No AI technologies utilized.
Financial Support: None declared.
Peer-review: Externally peer-reviewed.
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram
I, Jemal A, et al. Global Cancer Statistics
2020: GLOBOCAN estimates of incidence and mortality
worldwide for 36 cancers in 185 countries. CA
Cancer J Clin 2021;71:209-49.
D"Amico AV, Whittington R, Malkowicz SB, Schultz
D, Blank K, Broderick GA, et al. Biochemical outcome
after radical prostatectomy, external beam radiation
therapy, or interstitial radiation therapy for clinically
localized prostate cancer. JAMA 1998;280:969-74.
Kupelian PA, Potters L, Khuntia D, Ciezki JP, Reddy
CA, Reuther AM, et al. Radical prostatectomy,external
beam radiotherapy <72 Gy, external beam radiotherapy
>=72 Gy, permanent seed implantation, or
combined seeds/external beam radiotherapy for stage
T1-T2 prostate cancer. Int J Radiat Oncol Biol Phys
2004;58:25-33.
Peschel RE, Colberg JW. Surgery, brachytherapy, and
external-beam radiotherapy for early prostate cancer.
Lancet Oncol 2003;4:233-41.
Colberg JW, Decker RH, Khan AM, McKeon A, Wilson
LD, Peschel RE. Surgery versus implant for early
prostate cancer: Results from a single institution,
1992-2005. Cancer J 2007;13:229-32.
Potters L, Morgenstern C, Calugaru E, Fearn P, Jassal
A, Presser J, et al. 12-year outcomes following permanent
prostate brachytherapy in patients with clinically
localized prostate cancer. J Urol 2005;173:1562-6.
Zelefsky MJ, Kuban DA, Levy LB, Potters L, Beyer DC,
Blasko JC, et al. Multi-institutional analysis of longterm
outcome for stages T1-T2 prostate cancer treated
with permanent seed implantation. Int J Radiat Oncol
Biol Phys 2007;67:327-33.
Sahgal A, Roach M. Permanent prostate seed
brachytherapy: A current perspective on the evolution
of the technique and its application. Nat Clin Pract
Urol 2007;4:658-70.
Willins J, Wallner K. CT based dosimetry for transperineal
I-125 prostate brachytherapy. Int J Radiat Oncol
Biol Phys 1997;39:347-53.
Merrick GS, Butler WM, Dorsey AT, Walbert HL.
Prostatic conformal brachytherapy: I-125/Pd-103
post-operative dosimetric analysis. Rad Onc Invest
1997;5:305-13.
Merrick GS, Butler WM, Dorsey AT, Walbert HL.
The influence of timing on the dosimetric analysis of
transperineal ultrasound guided prostatic conformal
brachytherapy. Rad Onc Invest 1998;6:182-90.
Moerland MA, Wijrdeman HK, Beersma R, Bakker
CJG, Batterman JJ. Evaluation of permanent I-125
prostate implants using radiography and magnetic imaging.
Int J Radiat Oncol Biol Phys 1997;37:927-33.
Merrick GS, Butler WM, Dorsey AT, Lief JH, Walbert
HL, Blatt HJ. Rectal dosimetric analysis following
prostate conformal brachytherapy. Int J Radiat Oncol
Biol Phys 2000;43:1021-7.
Butler WM, Dorsey AT, Nelson KR, Merrick GS.
Quality assurance calibration of I-125 rapid strand
in a sterile environment. Int J Radiat Oncol Biol Phys
1998;41:217-22.
Stock RG, Stone NN, DeWyngaert JK, Lavagnini P,
Unger PD. Prostate specific antigen findings and biopsy
results following interactive ultrasound guided
transperineal brachytherapy for early stage carcinoma.
Cancer 1996;77:2386-92.
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;41:101-8.
Merrick GS, Butler WM, Dorsey AT, Walbert HL.
The influence of timing on the dosimetric analysis of
transperineal ultrasound guided prostatic conformal
brachytherapy. Rad Onc Invest 1998;6:182-90.
Merrick GS, Butler WM, Dorsey AT, Lief JH, Walbert
HL, Blatt HJ. Rectal dosimetric analysis following
prostate conformal brachytherapy. Int J Radiat Oncol
Biol Phys 2000;43:1021-7.
Nath R, Bice WS, Butler WM, Chen Z, Meigooni AS,
Narayana V, et al. AAPM recommendations on dose
prescription and reporting methods for permanent interstitial
brachytherapy for prostate cancer: Report of
Task Group 137. Med Phys 2009;36:5310-22.
Ishiyama H, Nakamura R, Satoh T, Tanji S, Uemae
M, Baba S, et al. Differences between intraoperative
ultrasound-based dosimetry and postoperative computed
tomography-based dosimetry for permanent
interstitial prostate brachytherapy. Brachytherapy
2010;9:219-23.
Gregory KJ, Pattison JE, Bibbo G. Measurement uncertainty
analysis of low-dose-rate prostate seed
brachytherapy: post-implant dosimetry. Australas
Phys Eng Sci Med 2015;38:71-81.
Aslay I, Kemikler G, Küçücük S, Akıncı M, Özveri H,
Özbay I, et al. Twelve years treatment results of LDR
brachytherapy for prostate cancer in Turkey. Radiother
Oncol 2015;115:882.
Özen H, Türkeri L, Bedük Y, Çal Ç. Uro-oncology
Book- Volume II, In: I Aslay, H Özveri, S Küçücük,
eds. Brachytherapy in Prostate Cancer, 2nd ed. Pelin
Ofset Tipo Matbaacılık 2017, p. 869-894.
