This document discusses a study comparing urethral and bladder dosimetry and rates of late genitourinary (GU) toxicity between focal salvage (FS) and total salvage (TS) Iodine-125 brachytherapy (I-125-BT) for recurrent prostate cancer. FS I-125-BT significantly reduces dose to the urethra and bladder compared to TS. Late severe (grade 3 or higher) GU toxicity occurred in 38% of TS patients versus one case in the FS group. For TS patients, bladder D2cc of less than 70 Gy and urethral V100 of less than 0.40 cc were identified as dose constraints associated with reducing late GU toxicity

1. Iodine-125 brachytherapy
Urethral and bladder dosimetry of total and focal salvage Iodine-125
prostate brachytherapy: Late toxicity and dose constraints
Max Peters a,⇑
, Jochem van der Voort van Zyp a
, Carel Hoekstra b
, Hendrik Westendorp b
,
Sandrine van de Pol b
, Marinus Moerland a
, Metha Maenhout a
, Rob Kattevilder b
, Marco van Vulpen a
a
Department of Radiation Oncology, University Medical Center Utrecht; and b
Radiotherapeutic Institute RISO, Deventer, The Netherlands
a r t i c l e i n f o
Article history:
Received 9 April 2015
Received in revised form 22 July 2015
Accepted 17 August 2015
Available online 5 September 2015
Keywords:
Focal salvage
Total salvage
Prostate cancer
I125 brachytherapy
Dosimetry
GU toxicity
a b s t r a c t
Introduction: Salvage Iodine-125 brachytherapy (I-125-BT) constitutes a curative treatment approach for
patients with organ-confined recurrent prostate cancer after primary radiotherapy. Currently, focal sal-
vage (FS) instead of whole-gland or total salvage (TS) is being investigated, to reduce severe toxicity asso-
ciated with cumulative radiation dose. Differences in urethral and bladder dosimetry and constraints to
reduce late (>90 days) genitourinary (GU) toxicity are presented here.
Materials and methods: Dosimetry on intraoperative ultrasound (US) of 20 FS and 28 TS patients was com-
pared. The prostate, bladder, urethra and bulbomembranous (BM) urethra were delineated. Toxicity was
assessed using the CTCAE version 4.0. Dose constraints to reduce toxicity in TS patients were evaluated
with receiver operating characteristic (ROC) analysis.
Results: FS I-125 BT significantly reduces bladder and urethral dose compared to TS. Grade 3 GU toxicity
occurred once in the FS group. For TS patients late severe (Pgrade 3) GU toxicity was frequent (38% in the
total 61 patients and 56% in the 27 analyzed patients). TS patients with Pgrade 3 GU toxicity showed
higher bladder D2 cc than TS patients without toxicity (median 43 Gy) (p = 0.02). The urethral V100
was significantly higher in TS patients with several toxicity profiles: Pgrade 3 urethral strictures, Pgrade
2 urinary retention and multiple Pgrade 2 GU toxicity events. Dose to the BM urethra did not show a
relation with stricture formation. ROC-analysis indicated a bladder D2 cc <70 Gy to prevent Pgrade 3
GU toxicity (AUC 0.76, 95%CI: 0.56–0.96, p = 0.02). A urethral V100 <0.40 cc (AUC from 0.73–0.91,
p = 0.003–0.05) could prevent other late GU toxicity.
Conclusion: FS I-125 BT reduces urethral and bladder dose significantly compared to TS. With TS, there is
an increased risk of cumulative dose and severe GU toxicity. Based on these findings, bladder D2 cc
should be below 70 Gy and urethral V100 below 0.40 cc.
Ó 2015 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 117 (2015) 262–269
Localized recurrent prostate cancer after primary radiotherapy
can be treated with salvage, a second curative treatment course.
Whole-gland, or total salvage Iodine-125 brachytherapy (TS
I-125-BT) targets the entire prostatic volume. High rates of severe
genitourinary (GU) toxicity are often observed with this technique,
possibly related to an increased radiation dose to the urethra and
bladder. Often, operative re-intervention is necessary for these
grade 3–4 complications, which are on average observed in 17%
of patients [1,2]. To reduce these severe GU toxicity rates, focal
salvage has been suggested, which targets only the locally recurrent
tumour. A few focal salvage (FS) I-125-BT series have recently been
reported with only one grade 3 urethral complication [3–5].
To reduce GU toxicity rates, dose restrictions for the urethra and
bladder are necessary, but are not available for salvage. Restric-
tions for the urethra in primary BT are available from the American
Brachytherapy Society (ABS) and the European Society for Radio-
therapy and Oncology (ESTRO) [6–8]. Dose restrictions for the
bladder are not available in guidelines. Acute urinary retention
has previously been associated with bladder neck dose [9]. And
recently, a large study evaluating bladder neck dose and late GU
toxicity has been published [10]. In the salvage setting, the repair
capability of organs at risk might be compromised by previous
radiation. Theoretically, dose constraints therefore need to be set
lower. In this study, the difference between dose to the urethra
and bladder is analyzed for patients undergoing TS and FS I-125-
BT. In addition, differences in GU toxicity are analyzed in relation
to the received dose, to provide more adequate restrictions for
the salvage setting.
http://dx.doi.org/10.1016/j.radonc.2015.08.018
0167-8140/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
⇑ Corresponding author at: University Medical Center Utrecht, Department of
Radiotherapy, HP. Q00.118, Heidelberglaan 100, 3584CX Utrecht, The Netherlands.
E-mail address: M.Peters-10@umcutrecht.nl (M. Peters).
Radiotherapy and Oncology 117 (2015) 262–269
Contents lists available at ScienceDirect
Radiotherapy and Oncology
journal homepage: www.thegreenjournal.com

2. Materials and methods
Patients
The institutional review board approved this analysis. From
March 2009 to October 2012, 20 FS I-125-BT procedures were per-
formed in the University Medical Centre Utrecht (UMCU). The
recurrent lesion was defined by correlating results from multi-
parametric (mp-)MRI and systematic transrectal biopsies. MRI-
sequences consisted of T1 and T2-weighted, dynamic contrast
enhanced (DCE) and diffusion weighted imaging (DWI). The
T2-weighted MRI delineations were fused with the intraoperative
ultrasound and the gross tumour volume (GTV) delineations man-
ually adapted with treatment margins expanded up to half of the
prostate. No specific margins were adopted for this expansion.
The recurrent GTV was prescribed P145 Gy, while the rest of the
prostate was not treated. Selection, procedural details and out-
comes have been described previously [4]. Furthermore, 62
patients were treated with TS I-125-BT in the UMCU and the Radio-
therapeutic Institute RISO, Deventer, the Netherlands, from
December 2001 to April 2010. In both centres, the prostate without
margin was treated with P145 Gy. Images and dosimetry were
analyzed with the available brachytherapy planning software:
Sonographic Planning of Oncology Treatment (SPOT) or OnCentra
Prostate (OCP) (Nucletron BV, Veenendaal, the Netherlands) in
the UMCU. RISO patients were analyzed using VariseedTM
version
8 (Varian Medical Systems, Palo Alto, CA). Amersham Health
(model 6711) or IBt model 1251L stranded seeds were used in
the RISO patients and Isotron model 130.002 loose seeds (125
I
selectSeedTM
seeds) in UMCU patients.
Delineations and dosimetry
In SPOT and OCP, ultrasound (US)-delineations were performed
every 2.5 mm, in Variseed every 5 mm. The sagittal, transverse and
coronal imaging planes were used. The prostate, GTV (FS patients),
bladder, prostatic urethra, peri-apical urethra and bulbomembra-
nous (BM) urethra delineations were re-evaluated by two indepen-
dent radiation-oncologists (CH, JVZ) before assessment of toxicity.
For uniformity in urethral volume, delineations were performed
5 mm above the base and 5 mm below the prostatic apex, with a
diameter of 5 mm. A Foley-catheter allowed adequate delineation.
The peri-apical part of the urethra was delineated 5 mm above
and below the prostatic apex [11]. CT-based dosimetry was ana-
lyzed around the postoperative period (CT1) and after 30 days
(CT30, excluding the urethra since it was not clearly visible due to
earlier removal of the catheter), and compared to intraoperative
dosimetry. CT1 scans were made either intra-operatively (C-arm
with cone-beam CT for RISO-patients) or 1 day post-implantation
(UMCU patients). Six UMCU patients had CT-scans within 5 h
post-implantation. Delineations were done every 2–3 mm on CT.
The BM urethra was delineated on US and CT1 extending 15 mm
from the apex. Tumour location in FS patients could have influenced
bladder dosimetry. Bladder dosimetry between patients with basal
peripheral recurrences and with mid prostate or apical peripheral
recurrences was therefore compared. Dose constraints for primary
prostate BT from the ABS and ESTRO were used [6–8], supple-
mented with parameters from the literature and institutional
guidelines [9–14]. Parameters evaluated in the literature were
applied to the bladder [9,10]. For the urethra, the minimum dose
to most irradiated 0.01 cc (D0.01 cc) was regarded as maximal dose
[15]. The 100% dose corresponds to the prescription level of 145 Gy.
Toxicity
After dosimetry assessment, the primary researcher (MP) ini-
tially scored toxicity using the common terminology criteria for
adverse events (CTCAE) version 4.0, after which two independent
radiation oncologists (CH and JVZ) separately evaluated these
scores. Late toxicity was defined as occurring >90 days after salvage.
The CTCAE-4 defines severe GU toxicity (Pgrade 3) as the need for
elective operative/endoscopic intervention. Grade 4 GU toxicity
encompasses a life-threatening adverse event, requiring immediate
intervention or ICU hospitalization. Grade 2 toxicity is generally
defined as (moderate) symptoms requiring local only or non-
invasive interventions, except for retention, where grade 2 includes
suprapubic catheter placement. Grade 1 toxicity was not assessed.
Statistical analysis
Continuous variables with a skewed distribution, most impor-
tantly dosimetry parameters, are presented as medians and ranges.
Normally distributed data are presented as mean ± SD. Differences
between skewed data were assessed with a Mann–Whitney U test
and in normally distributed data with an independent samples t-
test. Differences in the US and CT-based dosimetry within patients
were tested with a Wilcoxon signed-rank test. Categorical variables
were compared using a Pearson’s v2
-test and a Fisher’s exact test if
the frequency in a cell was <5. GU toxicity in TS patients was eval-
uated for all late Pgrade 3 GU toxicity. Specific subgroups were fur-
ther analyzed: late Pgrade 3 urethral strictures at every location,
late Pgrade 2 urethral strictures at every location and late Pgrade
2 retention. Also, 2 or more separate late Pgrade 2 GU toxicities
were analyzed, since patients almost uniformly had at least one late
Pgrade 2 event. No dose-toxicity relations were assessed for FS
patients, since only 4 Pgrade 2 GU toxicities were observed. Lastly,
primary radiation treatment (I-125 BT or EBRT) and number of
seeds and needles used during TS were analyzed in relation to late
Pgrade 2 GU toxicity. Dosimetry cut-off values were assessed using
receiver operating characteristic-analysis (ROC). Sensitivity of 100%
was pursued, to exclude false-negatives. Differences in biochemical
disease free survival (BDFS) between TS and FS patients were
assessed with the Kaplan–Meier method and the log-rank test. Sta-
tistical significance was defined as p 6 0.05. All statistical analyses
were performed using IBM SPSS version 20 (Statistical Package for
the Social Sciences Inc, Chicago, IL).
Results
Patient characteristics and follow-up
Table 1 summarizes baseline differences between TS and FS
patients and between TS patients with and without late Pgrade
3 GU toxicity. Primary radiation doses were often lower for TS
patients (64.4 Gy), because they were often treated in an earlier
period. The pre-salvage PSA was median 6.7 ng/ml (range 2.5–
18.0) in TS patients versus 4.7 (0.3–14) in FS patients (p = 0.01).
Due to smaller implanted volumes, a significant reduction was
observed for the number of needles and seeds used in FS patients:
median 18 needles in TS patients (range 13–22), compared to 9 (6–
12) in FS patients (p < 10À4
). For seeds, this was median 59 (37–90)
versus 32 (17–46) (p < 10À4
).
Patients with late Pgrade 3 GU toxicity were older than
patients without toxicity: mean (±SD) 71 (5.1) years versus 67
(4.4) years (p = 0.04). Other baseline characteristics did not differ
between these groups. Estimated Kaplan–Meier 36 month BDFS
was 62% for FS (n = 20) patients and 50% for TS (n = 62) patients
(log rank: p = 0.14).
Dosimetry availability
Intraoperative ultrasound images with the dose distribution
were available for 20 FS and 28 TS patients. For up to 13 FS and
M. Peters et al. / Radiotherapy and Oncology 117 (2015) 262–269 263

3. 10 TS patients, CT-based dosimetry (CT1 and CT30) could be
obtained.
Late GU toxicity
In the TS database, GU toxicity of 61 patients was available, of
which 23 (38%) experienced late Pgrade 3 GU toxicity. Late GU
toxicity was available for 27 out of 28 patients with
US-dosimetry (one patient died before three months follow-up
due to congestive heart failure, unrelated to treatment). Of these
patients 15 (56%) patients experienced one or more late Pgrade
3 GU toxicity, consisting of urethral strictures (n = 10), urinary
retention (n = 4), urinary incontinence (n = 1) and recto-urethral
(n = 2) or recto-vesical fistula (n = 1) formation. Three patients
experienced 2 separate grade 3 toxicity events. Patients developed
late Pgrade 3 toxicity at a median 12 months (range
4–72 months). Additionally, late Pgrade 2 urethral strictures at
every location occurred in 12 (44%) patients, late Pgrade 2 urinary
retention in 6 (22%) patients, and 8 patients (29%) experienced
more than 1 late Pgrade 2 GU toxicities.
US-based TS and FS dosimetry
Table 2 describes the dosimetry differences between TS and FS
implants on US, CT1 and CT30. On US, prostatic V100 was reduced
from median 98% to 44% (p < 10À6
). The GTV D90 in FS patients
was median 200 Gy (range 150–328). Prostatic urethral dose was
significantly lower in the FS group. Median D10 and D30 reduc-
tions were 71 Gy (p < 10À6
) and 83 Gy (p < 10À6
). D10 (<150%
= 217.5 Gy) and D30 (<130% = 188.5 Gy) urethral constraints were
completely met in the FS group, while they were exceeded in 4
(15%) and 11 (41%) patients in the TS group. The urethral V100
decreased from median 0.56 cc, to 0.005 cc (p < 10À6
). An example
of the difference in urethral dose between FS and TS is depicted in
Fig. 1.
A significant peri-apical urethral dose reduction was observed
in FS patients. Median dose reductions were 97 Gy (p < 10À6
) and
94 Gy (p < 10À6
) for the D10 and D30, respectively. Other peri-
apical dosimetry parameters were also significanly reduced (see
table). Bladder dose was significantly reduced in FS patients. The
only parameter recently associated with late Pgrade 2 GU toxicity
is the bladder neck D2 cc (and a restriction of <50%, i.e. 72.5 Gy is
provided) [10]. This restriction is met in 18 (90%) FS patients
(two patients minimally exceeded this restriction with 76 and
80 Gy), compared to 7 (26%) TS patients (highest D2 cc 144 Gy).
The bulbomembranous (BM) part of the urethra has been asso-
ciated with stricture formation [12,13]. Dose reductions for the
BM-part were significant in favor of FS: approximately 100 Gy for
the D0.01 cc, D10 and D30 (p < 10À4
).
Median differences for bladder V100, V150, D0.1 cc and D2 cc
between patients with basal peripheral recurrences and with mid
prostate or apical peripheral recurrences were 0.06 cc, 0 cc, 29 Gy
Table 1
Baseline characteristics of the study populations.
Variable FS (n = 20) TS (n = 28) p
Mean (±SD) age at salvage, years 69 (5.0) 69 (5.1)
Primary therapy
I-125 brachytherapy, 145 Gy 7 (35%) 6 (21%)
EBRT, 64.4 Gy, 28 fractions 0 (0%) 14 (50%) <10À4
EBRT, 70 Gy, 35 fractions 6 (30%) 2 (7%) 0.02
IMRT, 76 Gy, 35 fractions 7 (35%) 1 (4%) <0.01
Other or unknown 0 (0%) 5 (18%) 0.07
Median (range) interval primary-salvage, months 79 (42–144) 68 (3–126)
Hormonal therapy before salvage 8 (40%) 13 (46%)
Median (range) PSA before salvage, ng/ml 4.7 (0.3–14.0) 6.7 (2.5–18.0) 0.01
Median (range) follow-up, months 36 (10–45) 72 (5–126) NA
Needles, median (range) 9 (6–12) 18 (13–22) <10À4
Seeds, median (range) 32 (17–46) 59 (37–90) <10À4
Variable TS: Pgrade 3 + (n = 15) TS: Pgrade 3 À (n = 12) p
Mean (±SD) age at salvage 71 (5.1) 67 (4.4) 0.04
Primary therapy
I-125 brachytherapy, 145 Gy 3 (20%) 3 (25%)
EBRT, 64.4 Gy, 28 fractions 9 (60%) 4 (33%)
IMRT, 76 Gy, 35 fractions 0 (0%) 1 (8%)
Other/unknown 2 (13%) 4 (33%)
Median (range) interval between primary – salvage, months 60 (3–126) 86 (47–120)
Pre-salvage ADT 8 (53%) 4 (33%)
Pre-salvage PSA, ng/ml, median (range) 6.7 (2.5–18) 6.5 (3.1–16.4)
Median (range) follow-up after salvage, months 74 (12–126) 72 (24–120)
Needles, median (range) 17 (14–20) 19 (13–22)
Seeds, median (range) 55 (37–76) 63 (45–90)
Relevant comorbidity
Cardiovasculara
3 (20%) 2 (17%)
Diabetes 2 (13%) 0 (0%)
Smoking, current or former 8 (53%) 5 (42%)
Prostatic volume 24.6 (15.3–71) 21.4 (10.7–36.5)
Prostatic D90 164 (154–189) 170 (158–200)
Prostatic V150 10.3 (5.5–41.1) 11.1 (6.5–15.7)
IPSS before salvage 5 (2–15) 9 (3–18)
Primary differentiation grade G1 = 10; G2 = 4 G1 = 4; G2 = 6
Primary T-stage T1 = 3; T2 = 7; T3 = 5 T1 = 1; T2 = 5; T3 = 4
Abbreviations: FS = focal salvage; TS = total salvage; I-125 = Iodine-125; EBRT = external beam radiotherapy; IMRT = intensity modulated radiotherapy; PSA = prostate specific
antigen; NA = not applicable; + and À denote the groups with and without late Pgrade 3 GU toxicity, respectively. D90 = minimum dose to 90% of the prostatic volume.
V150 = prostatic volume receiving 150% of the prescribed dose (i.e. 217.5 Gy).
Significant p-values are depicted.
a
Cardiovascular event in history: myocardial infarction, stroke, peripheral artery disease.
264 Salvage Iodine-125 prostate brachytherapy: late genitourinary toxicity and dose constraints

4. Table 2
Dosimetry data for the focal and total salvage treatment plans.
Organ Variable TS group (n = 28) FS group (n = 20) Primary constraintsa
p-Value
Prostate D90 (Gy) 167 (154–200) NA P145 Gy (TS)
V100 (%) 98 (92–100) 44 (25–57) P95% of CTV <10À6
V150 (%) 48 (22–84) 30 (16–39) 667% of CTV (TS) <10À6
GTV Volume (cc) 4.8 (0.7–17)
D90 (Gy) 200 (150–328) P145 Gy
V100 (%) 100 (91.3–100) P95% of GTV TS CT1 (n = 8) FS CT1 (n = 13) TS CT30 (n = 10) FS CT30 (n = 13)
Urethra, prostatic part Volume (cc) 0.69 (0.5–0.93) 0.76 (0.5–0.95) 0.08 0.86 (0.78–1.03)+
0.82 (0.61–0.95)
D0.01 cc (Gy) 218 (162–345) 139 (106–224) <10À6
203 (177–273) 154 (84–286)
D10 (Gy) 193 (157–322) 122 (98–179) D10 < 150% (<218.5 Gy) <10À6
178 (153–212) 110 (66–221)
D30 (Gy) 184 (154–281) 101 (84–150) D30 < 130% (<188.5 Gy) <10À6
168 (144–197) 97 (55–177)
V100 (cc) 0.56 (0.29–0.9) 0.005 (0–0.26) <10À6
0.6 (0.31–0.85) 0.02 (0–0.42)
V150 (cc) 0.01 (0–0.52) 0 (0–0.01) <0.001 0 (0–0.06) 0 (0–0.09)
Urethra, peri-apical part D0.01 cc (Gy) 172 (91–370) 76 (38–164) <10À6
176 (122–224) 74 (42–197)
D10 (Gy) 166 (82–269) 69 (36–147) <10À6
169 (117–196) 57 (40–173)
D30 (Gy) 149 (68–202) 55 (30–111) <10À6
160 (95–167) 46 (32–124)
V100 (cc) 0.07 (0–0.2) 0 (0–0.02) <10À6
0.12 (0–0.21) 0 (0–0.04)
V150 (cc) 0 (0–0.03) 0 <0.05 0 (0–0.01) 0 (0–0.01)
Urethra, (bulbo)membranous part
(TS: n = 8, FS: n = 12)
D0.01 cc (Gy) 160 (81–191) 61 (31–96) <10À4
164 (76–179) 57 (24–88)
D10 (Gy) 158 (75–176) 53 (28–83) <10À4
154 (73–168) 48 (22–79)
D30 (Gy) 141 (59–161) 40 (22–54) <10À4
134 (51–151) 33 (18–64)
V100 (cc) 0.07 (0–0.18) 0 <0.001 0.05 (0–0.12) 0
V150 (cc) 0 0 NA 0 0
Bladder D0.1 cc (Gy) 215 (59–341) 143 (76–238) <200 Gy <0.001 231 (140–319) 154 (66–216) 238 (123–320) 148 (73–203)
D2 cc (Gy) 101 (33–147) 42 (8–80) <72.5 Gy <10À5
111 (79–118) 68 (39–95)*
117 (81–175) 60 (31–83)*
V100 (cc) 0.54 (0–2.09) 0.07 (0–0.5) <1 cc <0.001 0.51 (0.05–0.8) 0.11 (0–0.48) 0.88 (0.02–3.73) 0.115 (0–0.32)
V150 (cc) 0.095 (0–0.61) 0 (0–0.13) 0.001 0.12 (0–0.24) 0 (0–0.10) 0.14 (0–1.13) 0.005 (0–0.08)
Abbreviations: TS = total salvage; FS = focal salvage; CT1 = CT made intra-operatively or within the first 5 h or day post-implantation. CT30 = CT 30 days post-implantation. CTV = clinical target volume (=prostate); GTV = gross
tumour volume; NA = not applicable. Medians and their corresponding ranges are depicted. Significant p-values for the comparison between US-based dosimetry for FS and TS patients are depicted bold.
a
Constraints for primary BT from the ABS and ESTRO.
*
Only for the FS bladder D2 cc, the difference between US-based and CT-dosimetry was significant (p = 0.003 for CT1 and p = 0.008 for CT30).
+
the urethral volume differed significantly between US and CT1 for TS patients (p = 0.02).
M.Petersetal./RadiotherapyandOncology117(2015)262–269265

5. and 9 Gy in favor of mid prostate and apical recurrences; p-values:
0.57, 0.94, 0.25 and 0.28, respectively).
TS dosimetry and GU toxicity
Table 3 summarizes all dose differences between patients with
different toxicity profiles. The most important differences are sum-
marized here. Late Pgrade 3 GU toxicity patients had significantly
higher bladder D2 cc: median 114 (range 77–144) Gy versus 71
(33–147) Gy (p = 0.02) (Fig. 2). Urethral V100 was significantly
higher in the patients with late Pgrade 3 and Pgrade 2 strictures
at every location: 0.59 cc (0.43–0.90) versus 0.51 cc (0.29–0.75)
(p = 0.05) and 0.59 cc (0.43–0.90) versus 0.45 cc (0.29–0.70)
(p = 0.01), respectively. Patients with late Pgrade 2 urinary reten-
tion also had a higher urethral V100: 0.71 cc (0.58–0.90) versus
0.51 cc (0.29–0.70) (p < 0.01). Lastly, patients with multiple
Pgrade 2 late GU toxicities had a significantly higher urethral
V100: 0.61 cc (0.43–0.90) versus 0.51 cc (0.29–0.70) (p = 0.02).
Fig. 2 depicts the urethral V100 reduction in relation to different
GU toxicity profiles.
Fig. 1. Urethral (= yellow) D10 difference for TS (A) compared FS (B). The urethral D10 in A was 270 Gy versus 100 Gy in B.
Table 3
Dose reductions for different toxicity profiles.
Toxicity type Toxicity present
Median (range)
Toxicity absent
Median (range)
Median reduction (Gy/cc) p-Value
Pgrade 3 GU
Bladder D2 cc (Gy) 114 (77–144) 71 (33–147) 43 0.02
Pgrade 3 urethral strictures
Prostatic urethra
Volume (cc) 0.71 (0.50–0.93) 0.68 (0.51–0.78) 0.03 0.04
V100 (cc) 0.59 (0.43–0.90) 0.51 (0.29–0.75) 0.08 0.05
Pgrade 2 urethral strictures
Prostatic urethra
Volume (cc) 0.74 (0.50–0.93) 0.64 (0.51–0.78) 0.10 <0.01
V100 (cc) 0.59 (0.43–0.90) 0.45 (0.29–0.70) 0.14 0.01
Bladder
D0.1 cc (Gy) 267 (167–331) 174 (59–341) 93 0.01
D2 cc (Gy) 116 (77–144) 91 (33–147) 25 0.02
V100 (cc) 1.07 (0.27–1.89) 0.20 (0.00–2.09) 0.87 0.02
V150 (cc) 0.19 (0.01–0.57) 0.06 (0.00–0.61) 0.13 0.02
Pgrade 2 urinary retention
Prostatic urethra
Volume (cc) 0.77 (0.69–0.93) 0.68 (0.50–0.87) 0.09 0.01
V100 (cc) 0.71 (0.58–0.90) 0.51 (0.29–0.70) 0.20 <0.01
Peri-apical urethra
V100 (cc) 0.14 (0.07–0.20) 0.06 (0.00–0.20) 0.08 0.04
D30 (Gy) 164 (149–176) 144 (68–202) 20 0.03
Pgrade 2 GU (>1 event)
Prostatic urethra
D0.01 cc (Gy) 247 (186–345) 215 (162–310) 32 0.05
V100 (cc) 0.61 (0.43–0.90) 0.51 (0.29–0.70) 0.10 0.02
Bladder
V100 (cc) 1.19 (0.27–1.89) 0.51 (0.0–2.09) 0.68 0.04
Abbreviations: GU = genito-urinary, Vx = volume of the structure receiving x% of the prescribed dose, Dx = minimal dose received by x% or minimal dose to maximal irradiated
xcc of the structure its volume, Gy = Gray.
266 Salvage Iodine-125 prostate brachytherapy: late genitourinary toxicity and dose constraints

6. Needles, seeds, primary therapy and GU toxicity
Of the entire cohort (n = 61), there was no difference in late
Pgrade 2 or Pgrade 3 GU toxicity between patients undergoing
primary I-125 BT (n = 14) or EBRT (n = 48) (p = 0.74 and p = 0.82,
respectively). TS patients with late Pgrade 2 GU toxicity (n = 51)
had a median 19 (10–29) needles used, versus 15 (8–24) in the
group without toxicity (p = 0.05). The difference for the number
of implanted seeds was 62 (36–90) versus 54 (31–88) (p = 0.053).
US and CT-based dosimetry
The differences between CT1 and CT30 and US-based dosimetry
for the different urethra delineations (CT1) and the bladder
(CT1 + CT30) were not significant for TS patients. Only in the FS
patients, the bladder D2 cc increased significantly on CT1 and
CT30 compared to US-based dosimetry (median 26 and 18 Gy
increase [p = 0.003 and p = 0.008, respectively]).
ROC-analysis
ROC-analysis was performed on TS patients for the bladder
D2 cc in relation to late Pgrade 3 GU toxicity and the urethral
V100 for the other toxicity profiles. The bladder D2 cc was signifi-
cantly increased in patients with Pgrade 3 toxicity. The urethral
V100 was analyzed because of the consistent relation with differ-
ent toxicity profiles. The results are depicted in Table 4. The blad-
der D2 cc shows an AUC of 0.76, 95%CI 0.56–0.96 (p = 0.02). The
urethral V100 for the different toxicity profiles has AUC values of
0.73, 95%CI 0.54–0.93 (p = 0.05); 0.79, 95%CI 0.61–0.96 (p = 0.01);
0.91, 95%CI 0.79–1.00 (p < 0.01) and 0.79, 95%CI 0.60–0.98
(p = 0.02), respectively. Cut-off values/dose constraints with 100%
sensitivity and maximal specificity are bladder D2 cc <69 Gy and
urethral V100 <0.42 cc.
Discussion
This study is the first analysis of bladder and urethral dosimetry
differences between TS and FS I-125-BT and the first to present
dose constraints for salvage. Significant dose reductions for the
urethra and bladder can be achieved with FS, possibly resulting
in the observed low toxicity rates. The only other FS I-125 BT sal-
vage study mentioning dosimetry is the study by Hsu et al. [3],
which also shows low urethral doses, with comparably low toxicity
rates [3,4]. Median urethral V100 in their study was approximately
0.09 cc (2.8% of 3.2 cc). Although this is higher than the median
0.005 cc in this study, their delineated volume was larger. Also, it
is still considerably lower than the constraint of 0.4 cc proposed
here.
The restrictions found here (prostatic urethra V100 <0.4 cc and
bladder D2 cc <70 Gy) could be regarded as an extra guide to per-
forming salvage, either totally or focally. However, technically cor-
rect planning of the salvage implant (e.g. regarding prostatic
restrictions) is essential in automatically abiding by these
restrictions.
Radiation damage to the surrounding organs at risk (urethra,
rectum, bladder) impairs their normal repair capacity. This makes
these organs prone to severe adverse reactions after re-irradiation/
salvage. Several overviews of salvage BT show severe (grade 3–4)
Fig. 2. On the left: Urethral V100 differences for late GU toxicity. + denotes toxicity present, À absent. A: Pgrade 3 urethral strictures at every location; B: Pgrade 2 urethral
strictures at every location; C: Pgrade 2 urinary retention; D: multiple Pgrade 2 GU toxicity events. On the right: Difference in bladder D2 cc between patients with(+) and
without(À) late Pgrade 3 GU toxicity.
Table 4
ROC analysis of the bladder D2 cc and urethral V100 for late GU toxicity.
Variable AUC 95% CI p-Value Restriction Clinical recommendation
Bladder D2 cc, PGr 3 0.76 0.56–0.96 0.02 69 Gy <70 Gy
Urethral V100, PGr 3 strictures 0.73 0.54–0.93 0.05 0.42 cc <0.40 cc
Urethral V100, PGr 2 strictures 0.79 0.61–0.96 0.01 0.42 cc <0.40 cc
Urethral V100, PGr 2 retention 0.91 0.79–1.00 <0.01 0.58 cc <0.50 cc
Urethral V100, PGr 2 multiple events 0.79 0.60–0.98 0.02 0.42 cc <0.40 cc
Abbreviations: ROC = receiver operating curve/characteristic, D2 cc = minimal dose to maximum 2 cc of the structure volume, V100 = volume receiving 100% of the prescribed
dose (145 Gy), AUC = area under the curve, CI = confidence interval, Gr = grade.
M. Peters et al. / Radiotherapy and Oncology 117 (2015) 262–269 267

7. GU toxicity in up to 47% of cases, averaging around 17%
[1,2,4,16,17]. Dose escalation in primary IMRT for prostate cancer
could further increase the dose to the urethra and bladder base
[18,19]. Dose constraints for the salvage setting are therefore of
vital importance and are probably more strict than the constraints
for the primary setting.
Urethral constraints are currently not comprehensively defined
[6,7]. The restrictions for primary BT set by the ABS and ESTRO
(D10 and D30) were often exceeded in TS patients. These restric-
tions are doses to relative volumes and therefore dependent on
the delineated volume. Absolute parameters (e.g. V100 and
D0.01 cc) were therefore analyzed as well. Here, the urethral
V100 was consistently larger in patients with different toxicity pat-
terns. The V100 is associated with IPSS resolution in primary BT
[14]. The ABS mentions the V150 as an important dosimetry
parameter as well [6,8]. However, because of the small volumes
receiving 150% dose in these salvage patients, no relation with tox-
icity could be assessed.
The V100 urethral constraint of 0.40 cc seems to be the best
estimate to prevent a variety of late GU toxicity, including urinary
strictures, retention and multiple Pgrade 2 toxicity events. This
restriction was met in 4 (14%) TS patients and all 20 FS patients.
These findings should be interpreted with care. First, the ROC-
analyses were performed on small groups. The wide 95%-
confidence intervals of the AUC are an indication of the relatively
low precision. ROC-analysis was performed on TS patients due to
baseline differences between the two salvage cohorts (especially
primary radiation dose and method). Dose restriction based on
both TS and FS patients are more precise, but would be based on
groups unequally distributed in prognostic determinants for late
GU toxicity. A multivariable prognostic model based on more
patient data and more events could separately assess the indepen-
dent influence of several factors on toxicity.
Second, the urethra in this study was delineated with a speci-
fied diameter of 5 mm. Other delineated volumes might lead to a
different V100 constraint. The restrictions found in this study are
probably only applicable to this specific delineation procedure.
In addition, the Foley catheter distorts urethral morphology.
Urethral volume is underestimated and the morphology is signifi-
cantly different when visualized using aerated gel. The post-
implant urethral angulation can increase the actual received dose
[20]. Thus, the correlation between urethral US and CT30-
dosimetry is unknown. Studies investigating this relationship often
estimate the urethral position [21,22]. However, delineations on
the CT30 based on the geometrical center have been found to be
unreliable [23]. Therefore, the amount of misclassification of ure-
thral dose on CT30 when using interactive catheter based planning
remains unknown in this study. On the other hand, misclassifica-
tion of dosimetry is possibly non-differential (i.e. ‘on average’ the
same for all patients), which could add to the validity of intraoper-
ative restrictions.
Lastly, it seems dosimetry for the urethra and bladder did not
change significantly on CT1 (and bladder CT30) for TS patients. This
could be an indication of the relative noncompliance of these struc-
tures in the salvage setting (due to fibrosis), thereby potentially
making the intraoperative US-based dosimetry a valid method to
base dosimetry restrictions on. In FS patients, the US-based D2 cc
for the bladder seems to be maximally 26 Gy underestimated. Still
only 3 FS patients exceeded the proposed 70 Gy restriction, com-
pared to 2 based on intraoperative US-dosimetry.
There was no relation between peri-apical urethral dose and
stricture formation. The dose to the peri-apical and BM part of
the urethra was significantly reduced in the FS group (up to
>100 Gy). This could suggest that FS has potential to reduce the risk
of stricture formation. The peri-apical and BM urethra have been
associated with stricture formation in other studies [11–13]. Vary-
ing delineations for the BM urethra were used in these cohorts, for
example a length of 10, 15 or 20 mm below the prostatic apex
[12,13]. Because the 15 mm-BM urethra could be delineated in just
8 patients (accounting for 3 strictures Pgrade 2) in the TS groups
due to insufficient US scan length, a difference could not be
assessed between dosimetry parameters in stricture and non-
stricture patients. When strictures at every location were taken
together, the V100 of the prostatic urethra seems to provide a use-
ful restriction.
A somewhat unexpected outcome is that almost all bladder
dosimetry parameters showed a significant difference in the stric-
ture group, possibly indicating the importance of the bladder neck
as a predictor of late GU toxicity [9,10,24].
Regarding urinary retention, no significant relation was seen
with prostatic volume, as has previously been observed [9,14,25].
Instead, urethral parameters (both prostatic urethra and the peri-
apical part) were increased in retention patients. The relation with
retention and urethral dosimetry was not seen in the primary set-
ting [9], potentially pointing to an increased sensitivity of the ure-
thra in the salvage setting. However, only 6 retention patients
could be analyzed.
There are some additional limitations for the bladder. The
prostate-bladder interface is harder to ascertain on ultrasound
than on CT-images. Therefore, the dosimetry of the bladder base
found here can be a less precise reflection. The restriction for the
bladder (D2 cc <70 Gy) to prevent late Pgrade 3 GU toxicity is
almost equal to the dose recommended in the study by Hathout
et al. [10], in which they suggest restricting the dose to the bladder
neck to <50% (<72.5 Gy). In contrast, their restriction applied to late
Pgrade 2 GU toxicity (for primary patients), while the restriction
in this study might prevent Pgrade 3 GU toxicity, potentially
reflecting increased sensitivity of the bladder base after primary
radiation.
The association of the bladder dose with multiple toxicity pro-
files might further be an indication of its importance. It is, however,
not exactly clear whether the increased GU toxicity is associated
with dose to this region, or needle trauma [10,26,27]. A relation
with GU toxicity and the number of needles used is seen in both
the acute and late phase [10].
Technical aspects of BT might also have contributed to the
results. The type of seeds used can lead to changes in post-
implant dosimetry. In this study, both stranded and loose seeds
have been used, which might lead to differences in post-implant
dosimetry [28–30]. The effect this has on urethral and bladder
dosimetry is unknown.
Conclusion
A significant dose reduction to the urethra and bladder can be
achieved with FS I-125 BT compared to TS in patients with recur-
rent prostate cancer after primary radiotherapy. FS patients expe-
rience very low rates of severe GU toxicity compared to total
salvage patients.
Based on these findings, to prevent late severe GU toxicity dur-
ing TS and FS, the bladder D2 cc should ideally be <70 Gy and the
urethral V100 <0.40 cc.
Funding
None.
Conflict of interest
The authors declare no conflicts of interest.
268 Salvage Iodine-125 prostate brachytherapy: late genitourinary toxicity and dose constraints

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