Long-term Outcomes of HDR Monotherapy for Prostate Cancer

Original Article
Long-term outcomes from a multicentre study of HDR monotherapy with a
single fraction of 19 Gy for localized prostate cancer
Wiwatchai Sittiwong
a,1
, Anna Lydon
b
, James Wylie
c
, Imtiaz Ahmed
d
,
Amarnath Challapalli
e
, Peter Hoskin
a,*
a
Mount Vernon Cancer Centre, Northwood, UK
b
Royal Devon and Exeter Hospital, Exeter, UK
c
The Christie NHS Foundation Trust, Manchester, UK
d
Southend University Hospital, Southend-on-Sea ,UK
e
Bristol Haematology and Oncology Centre, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
ARTICLE INFO
Keywords:
Prostate cancer
HDR mono-brachytherapy
Biochemical control
Survival outcomes
Toxicity
Quality of Life
PSA kinetics
ABSTRACT
Objectives: To evaluate long-term clinical outcomes, toxicity, and prognostic factors in patients with localized
prostate cancer treated with single-fraction high-dose-rate (HDR) brachytherapy.
Methods: This multicentre retrospective study included patients from ve UK centres who received a single 19 Gy
HDR brachytherapy fraction under a standardized protocol. Kaplan-Meier estimates were calculated at median 5
and 8 years for biochemical progression-free survival (bPFS), local recurrence-free survival (LRFS), nodal
recurrence-free survival (NRFS), distant metastasis-free survival (DMFS), and overall survival (OS). Prognostic
factors were assessed using Cox regression. Toxicities were graded using CTCAEv3.0. Quality of life (QoL) was
evaluated using IPSS, IIEF, and FACT-P questionnaires.
Results: A total of 320 patients were included, with a median follow-up of 94 months. Five- and 8-year rates were:
bPFS 77.1%/66.5%, LRFS 96.1%/90.9%, NRFS 98.3%/97.3%, DMFS 95.9%/93.8%, and OS 91.4%/87.0%. Low-
risk patients had signicantly better bPFS than intermediate and high-risk (HR12.55, 95%CI:1.74–90.05,p =
0.012), though no signicant differences were seen in other outcomes. Subcentimetre pelvic lymph nodes on MR
scan were associated with poorer bPFS, LRFS, DMFS, and OS. GS ≥8 predicted worse OS. Acute and late ≥grade
2 GU toxicities occurred in 3.1% and 19.3% of patients, respectively; GI toxicities in 0.8% and 1.5%. QoL scores
worsened post-treatment: IPSS +7 points (p <0.001), IIEF −9 points (p =0.043), and FACT-P −3 points (p =
0.02) and returned to baseline.
Conclusion: Single-fraction 19 Gy HDR brachytherapy was tolerable and provided disease control, though
contemporary practice favors active surveillance for most low-risk patients. For higher-risk disease, a single
fraction is not equivalent to standard multifraction regimens, indicating its role should remain limited.
Introduction
Prostate cancer remains one of the most commonly diagnosed ma-
lignancies among men worldwide, with a wide spectrum of therapeutic
options tailored to disease risk, patient comorbidities, and personal
preference [1–3]. Among curative modalities, radiation therapy is a
cornerstone treatment, and in recent years, high-dose-rate (HDR)
brachytherapy has gained prominence due to its dosimetric prole and
favourable toxicity outcome [4,5].
HDR brachytherapy can be delivered as monotherapy or as a boost to
external beam radiation therapy (EBRT) depending on the risk group of
the patients [6]. Several prospective studies have reinforced the safety
and efcacy of these fractionated regimens [7–9]. 15- and 18-year
biochemical progression-free survival (bPFS) rates of 85.1% and
78.7%, respectively, using a 38 Gy regimen in four fractions have been
reported [8] and over 90% 5-year bPFS across all risk groups has been
seen using a three-fraction regimen (11.5 Gy per fraction), with low
rates of toxicity [9]. A systematic review and meta-analysis further
* Corresponding author.
E-mail address: [email protected] (P. Hoskin).
1
Present address: Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Research was conducted while afliated with Mount Vernon
Cancer Centre, UK.
Contents lists available at ScienceDirect
Radiotherapy and Oncology
journal homepage: www.thegreenjournal.com
https://doi.org/10.1016/j.radonc.2026.111385
Received 15 October 2025; Received in revised form 7 January 2026; Accepted 14 January 2026
Radiotherapy and Oncology 216 (2026) 111385
Available online 18 January 2026
0167-8140/© 2026 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

highlighted the effectiveness of HDR brachytherapy as monotherapy for
localized prostate cancer, reporting 5-year biochemical relapse-free
survival rates of 97.5%, 93.5%, and 91% for low-, intermediate-, and
high-risk patients, respectively [10].
However, outcomes for single-fraction HDR regimens have shown
some limitations in terms of relatively poor biochemical control
[11–18]. A recent meta-analysis reported that while single-fraction HDR
brachytherapy is generally well tolerated with low toxicity rates, the
5–6-year bPFS was 72%. Similarly, another meta-analysis reported a 5-
year bPFS of 71%, suggesting a potential compromise in long-term
oncologic control compared to multi-fraction regimens [19,20]. In a
phase III randomized trial comparing single-fraction to two-fraction
HDR brachytherapy, the 8-year local failure rate was signicantly
higher in the single-fraction arm (35.9%) compared to the two-fraction
arm (11.2%), indicating inferior oncologic control and leading to the
recommendation against single-fraction monotherapy [13]. However,
long-term retrospective data have shown that while biochemical control
was reduced with single-fraction treatment, the differences were not
statistically signicant. At 10 years, Kaplan–Meier estimates of bPFS
were 64% for a single fraction, 72% for two fractions, and 76% for three
fractions [21].
Although single-fraction HDR brachytherapy is safe and well toler-
ated, long-term biochemical control is generally lower than with mul-
tifraction HDR or permanent seed brachytherapy, particularly in
intermediate- and high-risk disease. A standardized 19 Gy fraction was
selected based on dosimetric feasibility and radiobiological modelling
consistent with the low
α /β ratio of prostate cancer, providing a bio-
logically effective single dose and allowing consistent evaluation of
long-term outcomes. These ndings suggest that single-fraction mono-
therapy has a limited role and should be used selectively rather than
replacing standard fractionated approaches. This study contributes to
that effort by presenting long-term outcomes, toxicity, quality of life,
PSA kinetics, and prognostic factors following a single 19 Gy HDR
monotherapy fraction.
Methods
Study design and patient population
This retrospective analysis was conducted across ve UK cancer
centers between 2014 and 2018 who collaborated using a single agreed
protocol for inclusion criteria, implant dosimetry and follow up. Local
institutional approvals were obtained at each site. Eligible patients had
histologically conrmed localized prostate cancer and were treated with
a single 19 Gy fraction of HDR brachytherapy as denitive mono-
therapy. Patients with prior treatment using external beam radiation or
brachytherapy, as well as those diagnosed with metastatic disease, were
excluded. Baseline clinical data, including Gleason score, initial PSA
levels and the use of hormonal therapy, were collected. Diagnostic MRI
was used to assess clinical T stage and to evaluate the presence of sub-
centimetre pelvic lymph nodes.
Treatment delivery
All patients underwent transrectal ultrasound-guided transperineal
catheter implantation followed by HDR brachytherapy using an Iridium-
192 source. A single fraction of 19 Gy was prescribed to the prostate.
Treatment planning aimed to achieve precise dosimetric objectives,
including coverage of at least 95% of the clinical target volume (CTV)
dened at the prostate capsule and planning target volume (PTV) with
the prescribed dose (V100%>95%), while limiting high-dose regions
within the prostate (V150%<55%, V200%<20%, D90%>90%). Organs
at risk were carefully spared, with rectal constraints set at V15Gy<0.1cc
and D2cc<12Gy, and urethral constraints set at V22.5Gy<0.01cc,
D30%<16.5Gy, D10%<17.5Gy, and V22.5Gy<0.1cc. ADT was admin-
istered based on risk stratication: generally short-term ADT (4–6
months) for intermediate-risk patients and long-term ADT (24–36
months) for those with high-risk disease.
Outcome measurement
The primary outcome was bPFS, dened according to the Phoenix
criteria (nadir +2 ng/mL). Secondary outcomes included local
recurrence-free survival (LRFS), dened as evidence of intraprostatic
recurrence on imaging or biopsy; nodal recurrence-free survival (NRFS),
dened as radiological evidence of pelvic lymph node recurrence;
distant metastasis-free survival (DMFS), dened by conrmed distant
spread; and overall survival (OS), dened as death from any cause.
Follow-up and assessments
Follow-up assessments included serial PSA testing, with imaging as
clinically indicated. Toxicities were evaluated according to the Common
Terminology Criteria for Adverse Events (CTCAE). Patient-reported
quality of life (QoL) was assessed using the International Prostate
Symptom Score (IPSS), the International Index of Erectile Function
(IIEF), and the Functional Assessment of Cancer Therapy–Prostate
(FACT-P) questionnaire. The “Worst” IPSS, IIEF, and FACT-P scores refer
to the most severe values recorded at any time during follow-up relative
to baseline. The “Last” scores correspond to the most recent QoL
assessment at the nal follow-up visit.
Statistical analysis
Survival probabilities were estimated using the Kaplan–Meier
method. Prognostic factors, including age, T stage, Gleason score (GS),
PSA level, presence of subcentimetre pelvic lymph nodes, risk group,
and use of androgen deprivation therapy (ADT), were evaluated using
univariate and multivariate Cox proportional hazards regression
models. Survival comparisons were assessed using the log-rank test. All
p-values were two-sided, and a p-value <0.05 was considered statisti-
cally signicant. Missing data were handled using complete-case ana-
lyses without imputation.
Results
A total of 320 patients were included in the analysis. The most
common Gleason score was 7 (3 +4), observed in 137 patients (42.8%),
followed by 7 (4 +3) in 71 patients (22.1%). PSA levels were <10 ng/
mL in 177 patients (55.3%). MRI-based T staging showed a predomi-
nance of T2 disease (50.6%). Subcentimetre pelvic lymph nodes were
identied on MRI in 130 patients (40.6%), while 161 patients (50.3%)
had no nodal involvement. The largest proportion of patients (31.8%)
were classied as favourable intermediate risk. Prior TURP had been
performed in 11 patients (3.4%), and androgen deprivation therapy
(ADT) was administered to 106 patients (33.1%), including 66 (62.3%)
who received short-term ADT and 40 (37.7%) who received long-term
ADT. The median duration of short-term and long-term ADT were
6.10 months (IQR:5.56–6.79) and 32.72 months (IQR:23.47–36.52),
respectively. The proportion of missing data for Gleason score, T stage,
subcentimetre pelvic lymph nodes, prior TURP, ADT, and prostate vol-
ume ranged from 6.8% to 33.8%. Baseline characteristics are summa-
rized in Table 1.
With a median follow-up time of 94 months, the 5- and 8-year bPFS
rates were 77.1% and 66.5%, respectively, with 95 events recorded.
LRFS rates were 96.1% at 5 years and 90.9% at 8 years, based on 23
events. Nodal recurrence was observed in 7 events, corresponding to
NRFS rates of 98.3% and 97.3% at 5 and 8 years, respectively. DMFS
rates were 95.9% and 93.8% at 5 and 8 years, respectively, with 17
events. OS at 5 and 8 years was 91.4% and 80.7%, respectively, with a
total of 62 deaths reported during the study period. Kaplan–Meier curves
curves and corresponding survival rates illustrating oncologic outcomes
W. Sittiwong et al.
Radiotherapy and Oncology 216 (2026) 111385
2

by risk group stratication are presented in Fig. 1 and Supplementary
Table 1, respectively.
Among 96 biochemical recurrences, a pattern of failure could be
identied in 28 cases. Local involvement was most common (n =22),
including 17 cases conned strictly to the prostate. Mixed recurrence
patterns were uncommon, consisting of local +nodal (n =5), local +
distant (n =2), and combined local +nodal +distant (n =3). No iso-
lated nodal failures or distant-only recurrences were observed. The
remaining 63 recurrences could not be anatomically classied due to
limited imaging correlation. Among imaged patients, PET (PSMA or
choline) was used in 9 cases, and the rest were evaluated with conven-
tional imaging (CT, bone scintigraphy, and/or MRI). A Venn diagram
demonstrating the pattern of biochemical failure is presented in Sup-
plementary Fig. 1.
When stratied by risk group, a statistically signicant differences in
biochemical progression-free survival were observed between low-risk
versus favourable intermediate, unfavourable intermediate, and high-
risk patients, with a hazard ratio (HR) of 12.55 (95 %CI:1.74–90.05;
p =0.012), as shown in Fig. 2. However, no signicant differences were
found between these groups in terms of LRFS, NRFS, DMFS, or OS.
Kaplan–Meier curves and corresponding survival rates depicting onco-
logic outcomes stratied by low-risk versus intermediate- to high-risk
groups are presented in Supplementary Fig. 2 and Supplementary
Table 2, respectively. When analyses were restricted to guideline-
appropriate monotherapy candidates (low- and favourable
intermediate-risk patients), bPFS remained signicantly lower in the
favourable intermediate-risk group compared with low-risk disease
(HR11.11,95 %CI:1.51–81.30;p =0.018), indicating that the observed
efcacy limitations were not solely attributable to inclusion of high-risk
cases.
Subcentimetre pelvic lymph nodes were strongly associated with
poorer bPFS, LRFS, DMFS, and OS in univariate analysis. In multivariate
analysis, they remained an independent predictor of adverse outcomes
across all endpoints. Gleason score ≥8 also independently predicted
worse OS. Other variables, including age, T stage, PSA, and ADT use,
were not signicant in multivariate models. Full univariate and multi-
variate results are shown in Supplementary Table 3. Subcentimetre
pelvic lymph nodes were retrospectively identied on MRI and were not
used prospectively for risk stratication or treatment decisions, and
among these patients, PET imaging was not systematically performed
and ADT use reected standard NCCN risk categories rather than lymph
node size. Event counts underlying these estimates showed substantial
outcome separation. Among patients with subcentimetre pelvic lymph
nodes (n =130), there were 60 biochemical failures, 18 local re-
currences, 15 distant metastases, and 40 deaths, compared with 31, 3, 2,
and 21 events, respectively, in patients without subcentimetre nodes (n
=161).
The treatment demonstrated a favourable acute toxicity prole.
Acute ≥grade 2 GI and GU toxicities were observed in only 0.8% and
3.1% of patients, respectively. Most acute GU toxicities were grade 1,
with symptoms including frequency and urgency. Acute GI toxicities
were minimal, with only isolated cases of mild diarrhea or rectal
discomfort. In terms of late toxicity, ≥grade 2 GI toxicity occurred in
1.5% of patients, while late ≥grade 2 GU toxicity was observed in
19.3%, primarily consisting of grade 2 urinary frequency and retention.
No grade 4 or 5 toxicities were reported. No signicant association was
observed between prostate volume and acute or late grade ≥2 GU
toxicity (acute: correlation coefcient (r) =–0.03,p =0.60; late:r =
–0.11,p =0.065). The proportions of patients by CTCAE grade for GI and
GU toxicities across each symptom domain are presented in Fig. 3.
Final QoL assessments occurred at a median of 87.3 months post-
treatment (IQR 41.7–98.2). QoL declined transiently, with urinary
symptoms peaking early (median IPSS +7) before returning to baseline
levels, and the proportion with moderate–severe symptoms normalizing
(45.3% vs. 43.1%). In contrast, erectile function showed a more
persistent decline, with median IIEF dropping by 9 points and remaining
signicantly lower at last follow-up (7 vs. 14). In the mixed-effects
model, ADT exposure was associated with a borderline reduction in
overall IIEF scores (p =0.050) but did not signicantly alter the lon-
gitudinal pattern of IIEF changes over time (interaction p =0.644). The
FACT P also showed a temporary decline, with the median dropping
slightly (−3 points) at the worst point. The proportion of patients with
severely reduced FACT-P scores (0–50) rose from 2.63% at baseline to
16.3% at worst, improving to 13.33% by the nal assessment. Box-and-
whisker plots comparing IPSS, IIEF, and FACT P scores at baseline, at
their worst, and at the last follow-up are presented in Fig. 4. The pro-
portions of patients stratied by severity of QoL score for IPSS, IIEF and
FACT P are shown in Supplementary Fig. 3-5.
PSA kinetics differed between patients with and without biochemical
failure. The overall cohort had a mean pre-treatment PSA of 11.39 ng/
mL, a PSA nadir of 0.75 ng/mL, and a median time to nadir of 18
months. Patients with biochemical failure had slightly higher baseline
PSA (12.09 ng/mL), a higher nadir (1.42 ng/mL), and slower decline
(median time to failure: 34 months), whereas failure-free patients had a
lower baseline PSA (11.1 ng/mL) and a deeper nadir (0.5 ng/mL). To
assess whether ADT confounded longitudinal PSA trends, we applied a
linear mixed-effects model accounting for repeated PSA measurements.
While ADT resulted in signicantly lower absolute PSA levels (p <
0.001), it did not signicantly alter the temporal slope of PSA decline
(interaction p =0.158). PSA kinetics for the overall cohort, biochemical
failure cohort, and biochemical failure-free cohort are presented in
Fig. 5.
Discussion
This multicentre analysis reports the outcomes of single-fraction
HDR brachytherapy using 19 Gy in patients with localized prostate
cancer. At 5 and 8 years, bPFS was 77.1% and 66.5%, respectively, while
LRFS, NRFS, and DMFS remained high at 90.9%, 97.3%, and 93.8%,
respectively. The bPFS observed in this study appears to be lower than
Table 1
Baseline patient characteristics.
N =320 (%)
Gleason scores 6 53 (16.6)
7 (3 +4) 137 (42.8)
7 (4 +3) 71(22.1)
8 15 (4.7)
9 8 (2.5)
n/a*36 (11.3)
PSA <10 177 (55.3)
10–20 122 (38.1)
>20 21 (6.6)
T staging (MRI) T1 29 (9.1)
T2 162 (50.6)
T3 48 (15)
T4 1 (0.3)
n/a 80 (25)
Subcentimetre
pelvic node
(MRI)
Absence 161 (50.3)
Presence 130 (40.6)
n/a 29 (9.1)
Risk group Low 34 (10.6)
Favourable intermediate 102 (31.8)
Unfavourable intermediate 92 (28.8)
High 92 (28.8)
Previous TURP Yes 11 (3.4)
No 201(62.8)
n/a 108 (33.8)
ADT Yes 106 (33.1)
No 135 (42.2)
n/a 79 (24.7)
Prostate volume <50 ml 142 (44.4)
50–100 ml 133 (41.6)
>100 ml 23 (7.2)
n/a 22 (6.8)
*
n/a denotes missing values.
W. Sittiwong et al.
Radiotherapy and Oncology 216 (2026) 111385
3

that reported in the literature for multi-fraction HDR regimens, which
generally demonstrate 5-year bPFS rates exceeding 90% [10,13].
Although local, nodal, and distant control rates were proportionately
higher than biochemical control, a substantial proportion of biochemical
recurrences could not be anatomically classied, likely reecting
underdetection due to limited use of PET imaging rather than absence of
Fig. 1. Kaplan–Meier curves representing oncologic outcomes stratied by risk group (low, favourable intermediate, unfavourable intermediate, and high). (A)
Biochemical progression-free survival, (B) Local recurrence-free survival, (C) Distant metastasis-free survival, and (D) Overall survival.
Fig. 2. Kaplan–Meier curves depicting bPFS stratied by [A] low-risk versus intermediate- to high-risk groups and [B] low-risk versus favourable intermediate-
risk groups.
W. Sittiwong et al.
Radiotherapy and Oncology 216 (2026) 111385
4

disease progression. However, when compared with ndings from meta-
analyses focusing on single-fraction HDR monotherapy, the bPFS rates
in this study are consistent, falling within the reported 5- to 6-year bPFS
range of 61.1% to 88% [19,20], at the cost of a high erectile dysfunction
rate.
Risk group stratication revealed that patients with low-risk disease
experienced signicantly better bPFS compared to those with interme-
diate- or high-risk features. However, no statistically signicant differ-
ences were observed between groups for LRFS NRFS, DMFS or OS.
Previous studies have shown favourable bPFS in low-risk patients, but
these differences were not statistically signicant, in contrast to our
results [9,10]. Compared to other modalities used in the low-risk sub-
group, such as LDR seed implantation, the outcomes in this study are
comparable, with a 7-year biochemical failure-free survival (bFFS) of
92.8% versus 96.9% at 8 years [22]. These results are also similar to the
5-year bFFS of 95.8% reported in the PACE-B trial, which evaluated
SBRT at 36.25 Gy in 5 fractions for low- to intermediate-risk patients
[23]. A comparison of this study with those studies is presented in
Fig. 3. The proportions of patients by CTCAE grade for GI and GU toxicities across each symptom domain.
W. Sittiwong et al.
Radiotherapy and Oncology 216 (2026) 111385
5