Radiotherapy and Oncology xxx (2017) xxx–xxx

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Radiotherapy and Oncology

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Original article

High dose rate brachytherapy as monotherapy for localised prostate

cancer q
Iosif Strouthos a,⇑,1, Nikolaos Tselis b,1, Georgios Chatzikonstantinou b, Saeed Butt c, Dimos Baltas d,e,
Dimitra Bon f, Natasa Milickovic c, Nikolaos Zamboglou b
a
Department of Radiation Oncology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg; b Department of Radiotherapy and Oncology, J. W. Goethe
University of Frankfurt, Frankfurt am Main; c Division of Medical Physics, Department of Radiation Oncology, Sana Klinikum Offenbach, Offenbach; d Division of Medical Physics,
Department of Radiation Oncology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg; e German Cancer Consortium (DKTK), Partner Site Freiburg;
and f Institute for Biostatistics and Mathematical Modeling, J. W. Goethe University of Frankfurt, Frankfurt am Main, Germany

a r t i c l e i n f o a b s t r a c t

Article history: Background and purpose: To evaluate the oncological outcome of a three-implant high dose rate (HDR)
Received 3 July 2017 brachytherapy (BRT) protocol as monotherapy for clinically localised prostate cancer.
Received in revised form 28 September Material and methods: Between February 2008 and December 2012, 450 consecutive patients with clin-
2017
ically localised prostate cancer were treated with HDR monotherapy. The cohort comprised of 198 low-,
Accepted 28 September 2017
Available online xxxx
135 intermediate- and 117 high risk patients being treated with three single-fraction implants of 11.5 Gy
delivered to an intraoperative real-time, transrectal ultrasound defined planning treatment volume up to
a total physical dose of 34.5 Gy with an interfractional interval of 21 days. Fifty-eight patients (12.8%)
Keywords:
Prostate cancer
received ADT, 32 of whom were high- and 26 intermediate-risk. Biochemical failure was defined accord-
High-dose-rate ing to the Phoenix Consensus Criteria and genitourinary/gastrointestinal toxicity evaluated using the
Interstitial brachytherapy Common Toxicity Criteria for Adverse Events version 3.0.
Iridium-192 Results: The median follow-up time was 56.3 months. The 60-month overall survival, biochemical con-
Monotherapy trol and metastasis-free-survival rates were 96.2%, 95.0% and 99.0%, respectively. Toxicity was scored
per event with late Grade 2 and 3 genitourinary adverse events of 14.2% and 0.8%, respectively. Late
Grade 2 gastrointestinal toxicity amounted 0.4% with no instances of Grade 3 or greater late adverse
events to be reported.
Conclusions: Our results confirm HDR BRT to be a safe and effective monotherapeutic treatment modality
for clinically localised prostate cancer.
Ó 2017 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2017) xxx–xxx

High-dose-rate (HDR) brachytherapy (BRT) has been success-
fully implemented as high-precision radiotherapy modality [1]
for the safe monotherapy of localised prostate cancer [2] with bio-
chemical control (BC) rates comparable to radical prostatectomy
[3], low-dose-rate (LDR) BRT [4] and dose-escalated external beam
radiotherapy (EBRT) [5]. In the absence of phase 3 comparative
efficacy data, however, the optimal management of locally-
confined prostate adenocarcinoma remains controversial with
treatment assignment being influenced mainly by physician’s bias
and patient’s preference. Against this background, quality of life
issues are gaining increasing importance with HDR monotherapy
q
This work has been presented at the Annual Meeting of the Japanese Society of
Radiation Oncology (JASTRO), November 25-27, 2016, Kyoto, Japan.
⇑ Corresponding author at: Department of Radiation Oncology, University
Medical Center Freiburg, 79106 Freiburg, Germany.
E-mail address: iosif.strouthos@uniklinik-freiburg.de (I. Strouthos).
1
Both authors contributed equally.
sustaining momentum due to its low morbidity [6] and excellent
long term clinical results [7–9]. In line with these experiences,
our most recent publication reported on HDR monotherapy for
localised prostate cancer including 226 patients treated with a
three-implant scheme [10]. This current report updates and
expands our previous results for this three-implant approach
encompassing in total 450 consecutive patients.
Patients and methods
Patient characteristics
Since 2002, we have treated more than 1000 patients with HDR
monotherapy for clinically localised prostate cancer. During this
period, three different protocols were implemented reflecting an
evolution aiming to improve clinical workflow and patient com-
fort. From January 2002 to February 2004, 141 patients were trea-
ted with one implant of four fractions ά 9.5 Gy. From March 2004

https://doi.org/10.1016/j.radonc.2017.09.038
0167-8140/Ó 2017 Elsevier B.V. All rights reserved.

Please cite this article in press as: Strouthos I et al. High dose rate brachytherapy as monotherapy for localised prostate cancer. Radiother Oncol (2017),
https://doi.org/10.1016/j.radonc.2017.09.038
2 HDR-Brachytherapy as monotherapy by prostate cancer

to January 2008, 351 patients received two implants, separated by Table 1

14 days, each of two fractions ά 9.5 Gy. From February 2008, our Patient and tumour characteristics.

HDR scheme consists of three single-fraction implants, each Characteristics (n = 450)

delivering 11.5 Gy, with an interfractional interval of 21 days. Median follow-up (months) 56.3 (4.4–91.7)
The current report encompasses our clinical experience with this Age at treatment (years)
three-implant approach during the time frame from February Mean 69.1
2008 to December 2012 when we treated a cohort of 456 consec- Median 70.3

utive patients. Six patients, however, have been excluded from Pre-treatment PSA (ng/ml)
analysis due to loss of follow-up thus resulting in 450 patients Mean 7.5
Median 6.6
included for data evaluation. n (%)
All patients had histologically proven adenocarcinoma of the
Stage
prostate and were staged according to the American Joint Commit- T1b-c 151 (33.6%)
tee on Cancer, 6th edition, staging guidelines [11]. Pre-treatment T2a 153 (34.0%)
staging included digital rectal examination, transrectal ultrasound T2b 80 (17.8%)
(TRUS) and, if clinically indicated, computed tomography T2c 64 (14.2%)
T3a 2 (0.4%)
(CT)/magnetic resonance imaging (MRI) and bone scintigraphy.
The Memorial Sloan Kettering group definition [12] was used to Gleason Score
6 303 (67.3%)
classify patients into risk groups. Briefly, this risk stratification
7 102 (22.7%)
system divides patients into low risk (T1c-T2a and GS  6 and >7 45 (10.0%)
PSA  10), intermediate risk (T2b and/or GS = 7 and/or PSA >
Pre-treatment PSA (ng/ml)
10–20) and high risk (T2c or PSA > 20 or GS 8–10 or 2 10 403 (89.6%)
intermediate-risk-criteria). Eligibility criteria were clinically 11–20 42 (9.3%)
organ-confined disease in the absence of lower urinary tract symp- >20 5 (1.1%)
toms requiring treatment. Patients who had previous transurethral Age at treatment (years)
resection of the prostate (TURP) were not excluded from treatment <60 54 (12.0%)
but assigned at six months after resection. High-risk patients who 60–69 160 (35.6%)
70 236 (52.4%)
were clinically diagnosed as unsuitable for prostatectomy or dose- Androgen deprivation therapy 58 (12.8%)
escalated EBRT, or who rejected prostatectomy or definitive EBRT
Risk group
were also assigned for HDR monotherapy at the discretion of the Low 198 (44.0%)
treating physician. Exclusion criteria were metastatic disease, pre- Intermediate 135 (30.0%)
vious pelvic EBRT for another malignancy or previous open surgery High 117 (26.0%)
of the prostate.
A total of 58 patients (12.8%) received androgen deprivation
therapy (ADT), 32 (55.2%) of whom were high-risk, 16 (27.6%) treatment planning including catheter reconstruction and PTV/
intermediate-risk, and ten (17.2%) low-risk. Hormonal therapy OARs contouring according to the new image set. Evaluation of
was prescribed either neoadjuvantly and continued concurrently implant conformity was based on dose-volume parameters for
with radiation or adjuvantly for an overall duration of median nine PTV coverage in compliance with OAR dose constraints (Fig. 1).
months (range, 3–14 months). The duration of ADT for the sub- Dose specification was given as the mean dose on the PTV surface.
groups of low-risk, intermediate-risk, and high-risk patients was Using three single-fraction implants separated by 21 days, the pre-
median 4 months (range, 3–6 months), 6 months (range, 6– scribed reference dose was 11.5 Gy delivered to a total physical
10 months) and 9 months (range, 9–14 months), respectively. dose of 34.5 Gy. Dosimetry assessment parameters and OAR con-
Androgen deprivation therapy was supervised by the referring straints are shown in Table 2. All implants were performed under
urologists. Patient and tumour characteristics are shown in Table 1. spinal, or if indicated, general anaesthesia. All treatments were
performed using a 192Iridium HDR afterloading system (microS-
electron–HDR, Elekta-Brachytherapy, Elekta AB, Sweden). Written
Brachytherapy protocol
informed consent was obtained from all patients. In our series,
Our solely TRUS-based clinical workflow has been described in two patients were staged with cT3a disease. The PTV in these cases
detail elsewhere [10,13]. In short, transperineal catheter implanta- was defined as the prostate capsule plus 5.0 mm in all directions
tion was performed under TRUS-guidance in high-lithotomy posi- (except for the posterior rectal margin), allowing for coverage of
tion using a perineal template. For inverse preplanning, transversal extracapsular invasion as confirmed on pre-treatment pelvic MRI.
ultrasound (US) images of the prostate, bladder, urethra and ante-
rior rectal wall were acquired in real-time using a continuous
Follow-up and statistical analysis
probe movement technique and three-dimensional (3D) volumes
were reconstructed based on 1.0 mm image distance. The planning All patients presented in our department at six weeks after
target volume (PTV) was defined as the entire prostate gland with- completion of treatment and then every three months for the first
out margins. Based on the acquired 3D anatomy, appropriate vir- year, every six months for the second year and annually thereafter.
tual catheter positions were generated using the intraoperative During these visits, gastrointestinal/genitourinary toxicities were
treatment planning system Oncentra Prostate (Oncentra Brachy, evaluated-documented and the performed PSA control values
Elekta AB, Stockholm, Sweden) and dose volume histograms recorded. Radio-oncological follow up visits were independent
(DVHs) for the PTV and the organs at risk (OARs, i.e. bladder, ure- from PSA controls performed by referring urologists based on
thra and rectum) were calculated for evaluation of the anatomy- national recommendations regarding PSA controls after treatment
based dose optimisation. As the preplanning dosimetry parameters for prostate cancer (i.e. at 3 month-intervals for the first two years,
fulfilled our clinical protocol, TRUS-guided implantation of steel every 6 months for the 3rd and 4th year and annually onwards).
catheters (200 mm length, 1.9 mm diameter) was performed at Upon request additional information were deduced from attending
previously defined positions. After completion of implantation, a urologists. For the current analysis, the patient sample was
final 3D TRUS data set was acquired for intraoperative real-time deduced from our prospectively maintained database and

Please cite this article in press as: Strouthos I et al. High dose rate brachytherapy as monotherapy for localised prostate cancer. Radiother Oncol (2017),
https://doi.org/10.1016/j.radonc.2017.09.038
 I. Strouthos et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx 3

(a)

(b)

Fig. 1. Intraoperative real-time TRUS-based treatment planning. (a) Three-dimensional reconstruction of the prostate, organs at risk (i.e., rectum, urethra, bladder), in situ
catheters, and the source dwell positions as calculated using the real-time treatment planning system Oncentra Prostate (Oncentra Brachy, Elekta AB, Stockholm, Sweden) for
the final treatment plan; (b) Isodose distribution after anatomy-based dose optimisation using hybrid inverse planning optimisation (HIPO) in axial view. The isodose colour
code convention is: dark red = 300% {isodose = 34.5 Gy}; brown = 250% {isodose = 28.75 Gy}; orange = 200% {isodose = 23.0 Gy}; yellow = 150% {isodose = 17.25 Gy};
green = 125% {isodose = 14.38 Gy}; turquoise = 100% {isodose = 11.5 Gy}; dark blue = 50% {isodose = 5.75 Gy}.

Table 2
Total physical prescription doses and normal tissue dose constraints (as percent of prescribed reference dose).
3 3 3
Treatment scheme PTV D10/D 0.1 cm-Rectum D10/D 0.1 cm-Bladder D10/D 0.1 cm-Urethra D90 V100 V150 BED
11.5 Gy x 3 34.5 Gy 75%/80% 75%/80% 115%/120% 100% 90% 35% 299/167 Gy

Abbreviations: BED = biologically effective dose considering a a/b-ratio for prostate cancer of 1.5/3.0 Gy with a potential doubling time of Tpot = 42 days (10);
D10-Rectum = dose delivered to 10% of the rectum; D10-Bladder = dose delivered to 10% of the bladder; D10-Urethra = dose delivered to 10% of the urethra; D30.1 cm = minimum
dose to the most exposed 0.1 cm3 of the organ; D90 = dose delivered to 90% of the PTV; V100, V150 = percent of PTV receiving 100% and 150% of the prescription dose.

consequently retrospectively analysed. Gastrointestinal (GI) and
genitourinary (GU) toxicities were documented with reference to
the National Cancer Institute Common Toxicity Criteria for Adverse
Events, version 3.0. Follow-up ended during October 2014 and June
2015 with all patients receiving between March and June 2015
additionally a final questionnaire assessing their current PSA level
and the presence as well as grade of adverse events at that period
of time. As late toxicity were referred side effects that began or
persisted six months after treatment completion. Adverse events
were scored per event and the highest value noted during
follow-up was selected to calculate toxicity percentages. Biochem-
ical relapse was defined using the Phoenix criteria (sustained post-
treatment PSA value > nadir +2 ng/ml) [14]. The definition of
potency was noted as the ability of achieving an erection sufficient
for intercourse. Using the Kaplan–Meier method, the likelihood of
events was deduced and thereafter compared using the log-rank

Please cite this article in press as: Strouthos I et al. High dose rate brachytherapy as monotherapy for localised prostate cancer. Radiother Oncol (2017),
https://doi.org/10.1016/j.radonc.2017.09.038
4 HDR-Brachytherapy as monotherapy by prostate cancer
test. A two-sided p-value of 0.05 was set as statistically signifi-
cant. The Cox proportional hazards model was used for multivari-
ate analysis. Statistical analyses were performed with SPSS Version
20 (SPSS, Inc, Chicago, IL, USA) and WinSTAT (WinSTAT, R. Fitch
Software, Bad Krozingen, Germany).
Results
Oncological outcomes
In our cohort of 450 patients, 22 (4.9%) patients experienced a
biochemical relapse and 5 (1.1%) developed distant metastases.
The estimated BC was 95.0% (95% CI 92.6–97.4) at 60-months.
The estimated overall survival (OS) and metastasis-free survival
(MFS) were 96.2% (95% CI 94.2–98.3) and 99.0% (95% CI 98.8–
100.0) at 60-months, respectively. Fig. 2(a) depicts BC, MFS and
OS of the patient’s sample.
Actuarial BC at 60 months in regard to risk group stratification
was 96.1% (95% CI 92.4–99.3), 96.1% (95% CI 92.1–99.9), and
92.1% (95% CI 86.3–97.8) for low-, intermediate- and high-risk
patients, respectively, proven to be statistically insignificant
(p = 0.5076, Fig. 2(b)). Actuarial BC at 60 months based on pre-
treatment PSA was 96.2% (95% CI 93.8–98.4) vs. 87.9% (95% CI
78.5–97.2) for iPSA  10 vs. > 10 ng/ml, respectively, showing sta-
tistical significance (p = 0.0157). With regard to clinical tumour
stage (cT), BC was 94.4% (95% CI 91.3–97.6), 96.6% (95% CI 91.9–
100.0) and 96.1% (95% CI 90.7–100.0) for patients with cT  T2a,
T2b and T2c, respectively, without statistically significant differ-
ence (p = 0.7706). At 60 months, the actuarial BC according to Glea-
son score (GS) was 96.4% (95% CI 92.7–98.9), 94.0% (95% CI 88.7–
99.4) and 87.3% (95% CI 75.4–99.3) for patients with GS  6, 7a
and 7b, respectively, also not showing statistical significance
(p = 0.1743).
Characteristics used for multiple regression analyses to corre-
late with BC were cT (T2a, T2b, T2c), GS (6, 7a, 7b), iPSA
(10, >10 ng/ml) and ADT. The multivariate Cox regression analy-
ses could not identify independent prognostic factors for biochem-
ical failure. The median follow-up was 56.3 months with 444, 443,
440 and 433 patients reaching the 24, 36, 48 and 60 month sur-
vival time points, respectively. Final follow-up questionnaires were
returned by 433 (96.2%) patients during July and August 2015,
while 17 (3.8%) patients were not alive at the time of reporting.
Follow-up details are given in Table 1.
Toxicity
Table 3 shows the results for late GU and GI adverse events
analysis for the entire cohort. Four (0.8%) patients reported late
GU complications Grade 3 and a single patient developed late
Grade 4 urinary incontinence/retention requiring permanent
urostomy. Two patients (0.4%) developed late Grade 2 GI toxicity.
No Grade 3 or higher late GI toxicities were reported.
Erectile dysfunction Grade 3, defined as consistent inability to
sustain an erection sufficient for sexual intercourse despite impo-
tence agents, was reported by 29 (6.4%) patients prior to treatment.
Of the 421 patients who reported Grade 0–2 erectile dysfunction
prior to treatment, 67 (14.9%) confirmed a decline to Grade 3 after
BRT. In the final questionnaire 354 patients (78.7%) reported an
erection sufficient for sexual intercourse achieved with or without
the use of erectile aids.
Dosimetry and PSA kinetics
Dosimetry quality assessment parameters were determined by
the DVH of the PTV. The median planned D90 value (dose delivered
to 90% of the PTV) was 105.8% (range 100.2–112.0) of the pre-
Please cite this article in press as: Strouthos I et al. High dose rate brachytherapy as monotherapy for localised prostate cancer. Radiother Oncol (2017),
https://doi.org/10.1016/j.radonc.2017.09.038
scribed reference dose. The median values for V100, V150 and V200
(percentage of the PTV receiving 100%, 150% and 200% of the pre-
scribed reference dose) were V100 = 94.1% (range 90.1–97.4),
V150 = 32.3% (range 22.7–36.1) and V200 = 9.9% (range 5.9–13.2).
The respective mean values of the reported dosimetric indices
were: D90 = 105.7% (range 100.2–112.0), V100 = 93.9% (range
90.1–97.4), V150 = 31.6% (range 22.7–36.1) and V200 = 9.9% (range
5.9–13.2).
A transient increase in the PSA level of >0.1 ng/ml occurred in
39% of patients with PSA nadir ranging from 0.06 ng/ml to
2.1 ng/ml. The median bounce magnitude was 0.6 ng/ml (range
0.2–7.9) and the median time to bounce was 13 months (range
6–68).
Discussion
Clinical data suggest that dose escalation for definitive radio-
therapy (RT) of localised prostate cancer improves biochemical
failure-free survival [15–17] thus implying that an additional pos-
itive impact on the therapeutic ratio may be achieved by escalating
the treatment dose while enhancing conformity. In this regard,
recent research supports a low alpha/beta (a/b)-ratio for prostate
adenocarcinoma, similar to or lower than that of late responding
normal tissue of bladder or rectum, indicating that a hypofraction-
ated dose regimen is favoured for tumour control without increas-
ing late sequelae [3,18–20]. High-dose-rate BRT meets this
objective optimally by exploiting the radiobiological advantage of
hypofractionation while ensuring superior 3D dosimetry. By now,
a growing body of literature corroborates HDR as safe and effective
monotherapy with consistent intermediate- and long-term BC
rates over a range of risk groups [2,7–10,21–30].
Hauswald et al. [7] reported on 448 patients with low- and
intermediate-risk disease treated to a median of 43.5 Gy with 6
fractions in 2 implants spaced 1 week apart. Of those, 42 (9%) were
treated with temporary ADT. At a median follow-up of 6.5 years
the actuarial 6-and 10-year overall BC rate was 98.6% and 97.8%,
respectively. No significant difference was noted between the
low- and intermediate-risk groups with 98.9% versus 95.2% bio-
chemical progression free survival at 10 years, respectively. The
authors documented no late grade 3–4 GI and 4.9% late grade 3–
4 GU toxicity. One patient (0.2%) experienced grade 4 late GU
sequelae developing a urethral-rectal fistula after multiple transur-
ethral resections. Yoshioka et al. [9] reported their experience on
190 patients with intermediate- and high-risk disease who were
treated with total physical doses ranging from 45.5 Gy in 7 frac-
tions to 54.0 Gy in 9 fractions using a single implant over 4–5 days.
Forty-four percent of intermediate- and 94% of high-risk patients
received additionally temporary ADT. With 19-year maximum
follow-up (median 7.7 years), the authors reported an 8-year BC
rate of 91% for the intermediate-risk and 77% for the high-risk
group. There was no grade 4 toxicity at all with late grade 3 GI
and GU adverse events of 1% and 2%, respectively. These data cor-
roborate the experience of other groups indicating that HDR BRT is
applicable for intermediate- and selected high-risk cases
[2,7,9,28,31,32]. Hoskin et al. [2] treated 197 patients within a
dose-finding trial consisting predominantly of intermediate-
(52%) and high-risk (44%) cases. The prescribed total physical doses
were 34 Gy in 4 fractions, 36 Gy in 4 fractions, 31.5 Gy in 3 frac-
tions, or 26 Gy in 2 fractions. The authors reported a 4-year BC rate
of 87% for the high-risk group which included clinical stages T3 in
21%, GS  8 in 10%, and PSA > 20 ng/ml in 25% of patients with 92%
of cases receiving temporary ADT. The incidence of acute grade 3
GU morbidity was 3–7% with no cases of acute GI toxicity. Late
grade 3 GU toxicity was 3–16% with late grade 3 GI toxicity docu-
mented in 1% of patients. Our current data report a 5-year BC, MFS
 I. Strouthos et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx 5

(a) 1
0.9

Proportion surviving / Control

0.8
0.7
Biochemical Control
0.6
0.5
Overall Survival
0.4
0.3
Metastasis Free Survival
0.2
0.1
0
0 12 24 36 48 60 72 84 96
Months

(b) 1
0.9
0.8
Biochemical Control

0.7
0.6
Low Risk (n=198)
0.5
Intermediate Risk (n=135)
0.4
High Risk (n=117)
0.3
0.2
0.1
0
0 12 24 36 48 60 72 84 96
Months

Fig. 2. Kaplan–Meier actuarial analysis of all 450 patients for (a) biochemical control, overall survival and metastasis-free survival; (b) biochemical control by risk group
stratification.

Table 3
Late toxicity results (n = 450).

No. of occurrences (%)

Grade
Toxicity 1 2 3 4
Genitourinary
Frequency/Urgency 148 (32.9%) 21 (4.7%) 1 (0.2%) –
Dysuria 46 (10.2%) 5 (1.1%) 1 (0.2%) 0
Incontinence 47 (10.4%) 27 (6.0%) 1 (0.2%) 1 (0.2%)
Retention 72 (16.0%) 11 (2.4%) 0 0
Erectile Dysfunction 115 (25.6%) 87 (19.3%) 84 (18.7%) –
Gastrointestinal (Rectum)
Pain 7 (1.6%) 1 (0.2%) 0 0
Mucositis/Necrosis 3 (0.7%) 1 (0.2%) 0 0
Diarrhoea 5 (1.1%) 0 0 0

Please cite this article in press as: Strouthos I et al. High dose rate brachytherapy as monotherapy for localised prostate cancer. Radiother Oncol (2017),
https://doi.org/10.1016/j.radonc.2017.09.038
 6
https://doi.org/10.1016/j.radonc.2017.09.038
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Table 4
Oncological results of HDR monotherapy for localised prostate cancer.

Study n HDR protocol Median f/u (y) Biochemical control* BED (Gy) EQD2 (Gy)
Gy/fraction Fractions (Implants) Total
Yoshioka et al. [9] 190 6.0 Gy 8 (1 Implant) 48.0 Gy 7.6 93% IR , 81% HR at 5 years 240–270 103–116
6.0 Gy 9 (1 Implant) 54.0 Gy
6.5 Gy 7 (1 Implant) 45.5 Gy

HDR-Brachytherapy as monotherapy by prostate cancer

Hauswald et al. [7] 448 7.0–7.25 Gy 6 (2 Implants) 42–43.5 Gy 6.5 98.9% LR, 95.2% IR at 10 years 238–253 102–108
Jawad et al. [8] 494 9.5 Gy 4 (1 Implant) 38.0 Gy 4.1 98% LR, 95% IR at 5 years 270–279 115–119
12.0 Gy 2 (1–2 Implants) 24.0 Gy 92% LR, 81% IR at 5 years
13.5 Gy 2 (1–2 Implants) 27.0 Gy 100% LR,79% IR at 5 years
Prada et al. [22] 60 19.0 Gy 1 (1 Implant) 19.0 Gy 6.0 66% LR, 63% IR at 6 years 260 111
Kukiełka et al. [23] 77 15.0 Gy 3 (3 Implants) 45.0 Gy 4.7 96.7% all risk groups at 5 years 495 212
Komiya et al. [28] 51 6.5 Gy 7 (1 Implant) 45.5 1.4 94% all risk groups at 17 months 243 104
Hoskin et al. [2] 197 8.5–9.0 Gy 4 (1 Implant) 34–36.0 Gy 3.1 95% IR , 87% HR at 4 years 227–252 97–108
10.5 Gy 3 (1 Implant) 31.5 Gy
13.0 Gy 2 (1 Implant) 26.0 Gy
Rogers et al. [26] 284 6.5 Gy 6 (2 Implants) 39.0 Gy 2.7 94% IR at 5 years 208 89
Zamboglou et al. [10] 718 9.5 Gy 4 (1 Implant) 38.0 Gy 4.4 95% LR, 93% IR 93% HR at 5 years 279–299 119–128
9.5 Gy 4 (2 Implants) 38.0 Gy
11.5 Gy 3 (3 Implants) 34.5 Gy
Barkati et al. [25] 79 10–11.5 Gy 3 (1 Implant) 30–34.5 3.3 85.1% LR/IR at 5 years 230–299 99–128
Demanes et al. [21] 298 7.0 Gy 6 (2 Implants) 42.0 Gy 5.2 97% LR/IR at 5 years 238–279 102–119
9.5 Gy 4 (1 Implant) 38.0 Gy
Mark et al. [24] 301 7.5 Gy 6 (2 Implants) 45.0 Gy 8.0 88% all risk groups at 8 years 270 117
Grills et al. [30] 65 9.5 Gy 4 (1 Implant) 38.0 Gy 2.9 98% LR/IR at 3 years 279 119
Current series 450 11.5 Gy 3 (3 Implants) 34.5 Gy 4.7 96.1% LR, 96.1% IR 92.1% HR at 5 years 299 128

Abbreviations: LR = low-risk group; IR = intermediate risk group; HR = high-risk group; f/u = follow-up; y = years; BED = biologically effective dose considering an a/b-ratio for prostate cancer of 1.5, EQD2 = equieffective dose
administered in 2.0 Gy-fractions considering an a/b-ratio for prostate cancer of 1.5 Gy.
*
Biochemical failure defined by the Phoenix definition [14].
 I. Strouthos et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx
and OS of 96.1%, 100.0%, and 96.3% for low-risk, 96.1%, 100.0%,
94.9% for intermediate-risk and 92.1%, 96.3%, 97.9% for high-risk
patients. Late grade 3 GU toxicity was experienced by 0.8% of the
population with one patient experiencing late grade 4 complica-
tions. No late Grade 3 GI adverse events were documented. Late
Grade 2 rectal morbidity was overall 0.4% with two patients requir-
ing symptomatic relief due to rectal mucositis.
With focus on erectile dysfunction following BRT, potency
preservation rates of 60–90% have been documented in the recent
literature [6,7,10,22,26–30,33]. Ghadjar et al. [29] reported on 36
patients with low- and intermediate-risk prostate cancer treated
with one implant and four fractions of 9.5 Gy. Fourteen percent
of patients received concomitant ADT. At a median follow-up of
6.9 years, the crude erectile function preservation rate in patients
without ADT was 75%. In the series by Hauswald et al. [7], 315 of
the 448 treated patients (70%) were able to have an erection suffi-
cient for intercourse before treatment. Sexual function data suit-
able for evaluation were available for 225 of 315 patients at a
median of 6 years after treatment. Ability to have intercourse, with
or without the use of erectile aids, was reported by 60% of patients
whose median age at the final assessment was 69 years.
In our series, erectile dysfunction Grade 3 was reported by 6.4%
of patients prior to treatment. Of the 421 patients who reported
Grade 0–2 erectile dysfunction prior to treatment, 14.9% confirmed
a decline to Grade 3 after BRT with overall 78.7% of patients self-
reporting an erection sufficient for sexual intercourse in the final
evaluation questionnaire, with a median age of 75 years at docu-
mentation time.
Although BRT had a negative impact on sexual function, we
consider the rate of erectile preservation still encouraging and con-
sistent with other data reported for HDR monotherapy.
In our sample group, tumour stage, GS and iPSA did not attain
statistical significance using Kaplan–Meier actuarial estimates of
freedom for biochemical failure. Likewise in the series of Yoshioka
et al. [34], Hoskin et al. [2], and Rogers et al. [26] the fore men-
tioned factors have not been proven to have a prognostic relevance
in regard to biochemical failure. In our cohort, the relatively small
number of patients (12.8%) exposed to ADT, allowed for no valu-
able statistical outcome to be extrapolated, regarding the useful
impact of temporary hormonal therapy. In fact, the issue remains
unclear, with ongoing discussion in lack of definitive evidence of
additional ADT within a HDR monotherapy scheme [35,36].
Overall, the clinical outcome data of HDR monotherapy reflect
current radiobiological considerations for optimal tumour control
through hypofractionation. The biologically effective dose (BED)
values in Table 4 range from 208 to 299 Gy with a median value
of 256 Gy, based on an a/b-ratio of 1.5 Gy. By employing our
HDR dose-fractionation scheme, a tumour BED of 299 Gy or
EQD2 of 128 Gy could be generated, tendering such dose coverage
impossible to be achieved with current EBRT techniques. However,
there are some limitations in our study, including the inherent
drawbacks of retrospective analyses. Our data were generated
from a prospectively maintained database which was analysed ret-
rospectively. Adding to that, the relation correlating patient’s tox-
icity outcome and dosimetry profile was not investigated in our
analysis. Finally, despite advancements in TRUS imaging, intrapro-
static calcifications may impair image quality thus posing as a lim-
iting factor for the whole procedure. Therefore we recommend that
the ‘‘technical eligibility” of each patient be evaluated prior to
treatment through a TRUS examination.
Conclusions
The results of the present study support the notion stating that
HDR monotherapy is an excellent modality for the management of
Please cite this article in press as: Strouthos I et al. High dose rate brachytherapy as monotherapy for localised prostate cancer. Radiother Oncol (2017),
https://doi.org/10.1016/j.radonc.2017.09.038
7
low- and intermediate-risk prostate cancer with a low side effect
rate. Long-term follow-up data are also available for its safe and
effective implementation in the treatment of selected cases of loca-
lised high-risk disease.
Conflict of interest notification
The authors would like to ensure that no financial support has
been received in conjunction with the generation of the current
submission and none of the authors has any personal or institu-
tional financial interest in materials or devices described in this
paper.
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