Cancer/Radiothérapie 25 (2021) 400–409

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Review article

Brachytherapy boost (BT-boost) or stereotactic body radiation

therapy boost (SBRT-boost) for high-risk prostate cancer (HR-PCa)
Boost de curiethérapie ou de radiothérapie stéréotaxique pour les cancers de
prostate à haut risque ?
G. Peyraga a,b,∗ , T. Lizee c , J. Khalifa a , E. Blais b , G. Mauriange-Turpin d , S. Supiot e , S. Krhili f ,
P. Tremolieres c , P. Graff-Cailleaud a
a
Radiation department, Toulouse university institute of cancer, Oncopôle, Toulouse, France
b
Radiation therapy department, Groupe de radiotherapie et d’oncologie des Pyrénées, chemin de l’Ormeau, 65000 Tarbes, France
c
Radiation therapy department, Integrated centre of oncology (Paul Papin), Angers, France
d
Radiation therapy department, University hospital centre, Limoges, France
e
Radiation therapy department, Integrated centre of oncology (Rene Gauducheau), Saint-Herblain, France
f
Radiation therapy department, Curie Institute, Paris, France

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

Article history: Systematic review for the treatment of high-risk prostate cancer (HR-PCa, D’Amico classification
Received 30 March 2020 risk system) with external body radiation therapy (EBRT) + brachytherapy-boost (BT-boost) or with
Received in revised form EBRT + stereotactic body RT-boost (SBRT-boost). In March 2020, 391 English citations on PubMed matched
21 November 2020
with search terms “high risk prostate cancer boost”. Respectively 9 and 48 prospective and retro-
Accepted 25 November 2020
spective studies were on BT-boost and 7 retrospective studies were on SBRT-boost. Two SBRT-boost
trials were prospective. Only one study (ASCENDE-RT) directly compared the gold standard treatment
Keywords:
[dose-escalation (DE)-EBRT + androgen deprivation treatment (ADT)] versus EBRT + ADT + BT-boost. Bio-
Prostate cancer
High-risk prostate cancer
chemical control rates at 9 years were 83% in the experimental arm versus 63% in the standard arm.
Brachytherapy Cumulative incidence of late grade 3 urinary toxicity in the experimental arm and in the standard arm
Stereotactic body radiation therapy was respectively 18% and 5%. Two recent studies with HR-PCa (National Cancer Database) demonstrated
Brachytherapy boost better overall survival with BT-boost (low dose rate LDR or high dose rate HDR) compared with DE–EBRT.
Stereotactic body radiation therapy boost These recent findings demonstrate the superiority of EBRT + BT-boost + ADT versus DE–EBRT + ADT for
HR-PCa. It seems that EBRT + BT-boost + ADT could now be considered as a gold standard treatment for
HR-PCa. HDR or LDR are options. SBRT-boost represents an attractive alternative, but the absence of ran-
domised trials does not allow us to conclude for HR-PCa. Prospective randomised international phase III
trials or meta-analyses could improve the level of evidence of SBRT-boost for HR-PCa.
© 2020 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All
rights reserved.

r é s u m é

Mots clés : Revue systématique de la prise en charge du cancer de la prostate à haut risque (système de classi-
Cancer de la prostate fication des risques de D’Amico) par radiothérapie externe et boost de curiethérapie ou radiothérapie
Cancer de la prostate à haut risque externe et boost de radiothérapie stéréotaxique. En mars 2020, 391 citations en anglais sur PubMed
Curiethérapie correspondaient aux termes de recherche « high risk prostate cancer boost ». Respectivement neuf et
Radiothérapie corporelle stéréotaxique
48 études prospectives et rétrospectives concernaient le boost de curiethérapie et sept études rétro-
Stimulation de la curiethérapie
spectives concernaient le boost de radiothérapie stéréotaxique. Deux essais de boost de radiothérapie
Stimulation de la radiothérapie corporelle
stéréotaxique stéréotaxique étaient prospectifs. Une seule étude (ASCENDE-RT) a directement comparé le traitement de

∗ Corresponding author at: Radiation therapy department, groupe de radiotherapie et d’oncologie des Pyrénées, chemin de l’Ormeau, 65000 Tarbes, France.
E-mail address: guillaume.peyraga@hotmail.com (G. Peyraga).

https://doi.org/10.1016/j.canrad.2020.11.004
1278-3218/© 2020 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
G. Peyraga et al. Cancer/Radiothérapie 25 (2021) 400–409

référence (radiothérapie externe avec escalade de dose et déprivation androgénique) à la radiothérapie

externe avec déprivation androgénique et boost de curiethérapie. Les taux de contrôle biochimique à 9
ans étaient de 83% dans le bras expérimental contre 63% dans le bras standard. Les incidences cumulées
de la toxicité urinaire tardive de grade 3 dans le bras expérimental et dans le bras standard étaient respec-
tivement de 18% et 5%. Deux études récentes sur le cancer de la prostate à haut risque (National Cancer
Database) ont démontré une meilleure probabilité de survie globale avec le boost de curiethérapie (de bas
ou haut débit de dose) sur la radiothérapie externe avec escalade de dose. Ces résultats récents démon-
trent la supériorité de la radiothérapie externe avec boost de curiethérapie et déprivation androgénique
sur la radiothérapie externe avec escalade de dose pour les cancers de la prostate à haut risque. Il semble
donc que la radiothérapie externe avec boost de curiethérapie et déprivation androgénique puisse être
considérée comme un traitement de référence pour les cancers de la prostate à haut risque. Le boost de
radiothérapie stéréotaxique représente une alternative intéressante, mais l’absence d’essais randomisés
ne nous permet pas de conclure pour les cancers de la prostate à haut risque. Des essais internationaux
randomisés de phase III prospectifs ou des méta-analyses pourraient améliorer le niveau de preuve du
boost de radiothérapie stéréotaxique pour les cancers de la prostate à haut risque.
© 2020 Société française de radiothérapie oncologique (SFRO). Publié par Elsevier Masson SAS. Tous
droits réservés.

1. Introduction 2. Materials and methods

Worldwide Prostate Cancer (PCa) is the second most frequently
diagnosed cancer (1.1 million new cases in 2012) and the fifth lead-
ing cause of cancer death among men (307,000 deaths in 2012) [1].
PCa is the most common cancer in developed countries (15% of can-
cers) [2]. More than 200,000 new cases are diagnosed each year in
the United States (American Cancer Society), mainly through the
development of biochemical and clinical screening. The increase in
screening resulted in a decrease of the rate of HR-PCa at initial diag-
nosis (from > 40% in 1989 to 15% in 2002) [3]. The PCa classification
risk system is evolving. The latest risk classification system from
the National Comprehensive Cancer Network (NCCN classification)
[4] divides patients in five risk groups: very low risk (VLR), low risk
(LR), intermediate risk (IR, favourable and unfavourable), high risk
(HR) and very high risk (VHR). This classification succeeds the pre-
vious classification [D’Amico: low risk (LR), intermediate risk (IR)
and high risk (HR)] [5]. These classifications mainly depend on Glea-
son score, clinical data and biochemistry (PSA rate). The prognosis
of PCa depends on this NCCN classification, with low specific mor-
tality for LR-PCa and higher specific mortality for HR-PCa (> 15%)
[6].
Prostatic tumours have a relatively low alpha/beta ratio, usu-
ally estimated to be less than 2 [7]. Therefore, PCa is relatively
sensitive to fractionation [8,9] and exclusive brachytherapy (BT)
is one of the therapeutic options for VLR and LR-PCa, and moder-
ate hypofractionated external body radiation therapy (EBRT) is an
alternative to conventionally fractionated radiation therapy (RT) in
the management of IR-PCa [10–12]. However, standard treatment
for HR-PCa is EBRT, associated with long-term androgen depriva-
tion treatment (ADT), which aims at optimising radiosensitivity and
decreasing the development of micro-metastatic disease [13,14].
Dose-escalation (DE) up to 80 Gy has demonstrated superiority
compared to 70 Gy EBRT [15]. However, hypofractionation remains
underused for the treatment of HR-PCa. According to NCCN Guide-
lines, EBRT + brachytherapy-boost (BT-boost) + ADT is an option for
HR-PCa, with a lower level of evidence (Category 2A, Category 1
for ADT) than DE-EBRT + ADT (Category 1 level of evidence). To
date, stereotactic body radiation therapy (SBRT) has no place in the
treatment of HR-PCa. However, SBRT seems to be an alternative
for patients who are not eligible for BT-boost (inoperable patients,
urinary functional symptoms, prostatic volume). Therefore, we
reviewed the literature concerning the retrospective and prospec-
tive studies of combined modality RT (CMRT = EBRT + boost) for
HR-PCa (D’Amico risk classification), with BT-boost or SBRT-boost.
In order to carry out an exhaustive review of the literature, we
conducted a research on an independent database: PubMed. The
PubMed database was chosen because it remains the most widely
used resource for medical literature. Search terms selected for this
study were: “high-risk prostate cancer stereotactic radiation ther-
apy boost” and “high-risk prostate cancer brachytherapy boost”.
Each abstract was read and each publication whose abstract met the
search criteria was analysed. Only items published in English were
reviewed. “ClinicalTrials.gov” database was consulted in order not
to omit ongoing prospective comparative trials (BT-boost/SBRT-
boost).
3. Results
On March 21, 2020, 391 citations on PubMed matched with
study search terms “high-risk prostate cancer boost”. The combi-
nation of search terms “high-risk prostate cancer brachytherapy
boost” identified 236 items and the combination of search terms
“high-risk prostate cancer stereotactic and radiation therapy boost”
identified 33 items. Respectively 9 and 48 prospective and retro-
spective studies evaluated BT-boost and 7 retrospective studies
evaluated SBRT-boost. Two SBRT-boost trials were prospective. The
methodological flow-chart is summarised in Fig. 1.
4. Prospective trials of BT-boost
Nine prospective trials have assessed EBRT + BT-boost. One of
them is a phase I/II trial [16], two are phase II trials [17,18] and
six are randomised prospective phase III trials [19–24]. Of the six
phase III trials, two trials directly compared the gold standard (Cat-
egory1 level of evidence, NCCN) treatment DE-EBRT + ADT versus
EBRT + BT-boost [21,24], one trial compared EBRT without ADT
versus EBRT + ADT and/or DE (DE–EBRT or EBRT + BT-boost) [22],
and one trial compared DE–EBRT versus EBRT + BT-boost [19]. Two
phase III trials compared several doses of BT-boost [20,23]. BT-
boost was delivered with low-dose rate (LDR) in four of these
nine prospective trials, with pulse-dose rate (PDR) in two trials
and with high-dose rate (HDR) in three trials. In seven of these
nine studies, EBRT was pelvic lymph nodes irradiation associated
with prostate and seminal vesicles irradiation, with a conventional
fractionation of 1.8 or 2 Gy (normofractionated) in eight trials. In
one trial, EBRT was hypofractioned [21]. Only one study directly
compared DE–EBRT + ADT (12 months) versus normofractionated

401
G. Peyraga et al.
Fig. 1. Methodological flow-chart.
EBRT + ADT + BT-boost (LDR-boost) [24]. Data from these trials are
summarised in Table 1.
ASCENDE-RT phase III trial [24] compared DE-EBRT + ADT
versus normofractionated EBRT + ADT + BT-boost for IR-PCa or HR-
PCa (D’Amico classification [5]) and was recently published. In
the DE–EBRT + ADT arm, DE–EBRT was a normofractionated RT
(78 Gy). First, EBRT concerned pelvic lymph nodes, prostate and
seminal vesicles (46 Gy). In a second step, dose escalation con-
cerned prostate and seminal vesicles. In the experimental arm
(EBRT + ADT + BT-boost), EBRT was the same as standard arm EBRT.
BT-boost was LDR-boost with a minimal peripheral dose of 115 Gy.
With a median follow-up of 6.5 years, biochemical control rates at
5 and 9 years were respectively 89% and 83% in the experimental
arm versus 84% and 63% in the standard arm. However, cumula-
tive incidence of late grade 3 urinary toxicity in the experimental
arm and in the standard arm was respectively 18% and 5% [25],
correlated with a decline in quality of life (physical and urinary
function scales) [26]. The main limit of this trial is the inclusion
criteria of patients, which includes both HR-PCa (69%) and IR-PCa
(31%). Moreover, the duration of ADT (12 months) could appear
under optimal in the light of the gold standard treatment accord-
ing to the NCCN recommendations (≥ 1.5 to 3 years, long-term ADT
for HR-PCa).
In the trial published by Hoskin [21], EBRT was hypofractionated
(2.75 Gy per fraction). Standard arm was DE–EBRT (55 Gy in 20 frac-
tions of 2.75 Gy) + ADT (75% of the patients). Experimental arm was
EBRT (37.75 Gy in 13 fractions of 2.75 Gy) + BT-boost (HDR; 17 Gy
in 2 fractions of 8.5 Gy) + ADT (3 to 6 months, 77% of patients). Most
of patients were HR-PCa (54%), but a significant number of patients
were IR-PCa (about 42%) and 4% of patients were LR-PCa. With a
median follow-up of 4 years in the experimental arm, 5-year and
7-year biochemical control rates were respectively 75% and 66%
and overall survival rates at 5 years and 7 years were respectively
88% and 81%. There was no difference in toxicity between the two
arms.
In the trial published by Sathya [19], there were several biases
in the interpretation of the results. Indeed, standard arm EBRT (no
pelvic lymph nodes irradiation) was performed without DE and
appears to be insufficient (only 66 Gy). There was no information
concerning the administration and duration of ADT, and patients
were HR-PCa or IR-PCa. With a follow-up of 8.2 years, biochemical
control rate and overall survival rate at 5 years in the experimental
group were respectively 71% and 95%. Grade 3 and 4 late urinary
402
Cancer/Radiothérapie 25 (2021) 400–409
toxicity was increased in the experimental group (15.8%). In Den-
ham’s trial [22], the main limitation was the composite objective
of the study, which compared two ADT arms (long-term versus
short-term) and several RT doses (EBRT with or without DE). All
patients received ADT (6 or 18 months). Most of the 237 patients
(91%) in the experimental arm (EBRT + PDR-boost; 19.5 Gy in 3 frac-
tions of 6.5 Gy) were HR-PCa. In this trial, there were three standard
arms and there were three EBRT protocols (66, 70 or 74 Gy). With
a follow-up of 6.5 years, clinical control rates in the experimen-
tal arm and in the 74 Gy standard arm were respectively 93% and
87%. Urinary obstruction rate was significantly higher in the experi-
mental arm (12.7% in the experimental arm versus 3.8% in the 74 Gy
standard arm).
In the two other randomised phase III trials [20,23], which did
not directly compared DE-EBRT versus EBRT + BT-boost, 10-year
biochemical control rates for EBRT + BT-boost arm were 80.8% [20]
and 81.1% [23]. Only 3% of grade 3 late urinary toxicity was found
in a trial [23]. In the three other phase II or III trials (16–18), 5-year
biochemical control rates were ranging from 81.4% to 85.6% and
overall survival rates at 5 years were ranging from 85.7 to 92.9%.
In a trial [16], respectively 26.9%, 2.3% and 0.7% of grade 2, 3 and 4
late urinary toxicity were found. In the two other trials, there was
no grade 2 late urinary toxicity.
5. Retrospective studies of BT-boost
Forty-eight retrospective studies were relevant on EBRT + BT-
boost [27–38,38–62,62–75]. There is a lot of heterogeneity in
therapeutic modalities, both in EBRT or BT-boost, and in admin-
istration and duration of ADT. The survival and toxicity data from
these studies are summarised in Table 4 (Supplementary materi-
als).
In most of these studies, BT-boost is delivered by HDR-BT (39
studies with HDR-BT-boost, 8 studies with LDR-BT and one study
with pulse-dose-rate-BT [43]). Except in four studies [33,35,44,69],
EBRT is normofractionated (1.8 or 2 Gy per fraction).
Nineteen of these 48 retrospective studies were according to
NCCN guidelines. Indeed, the treatment protocol of these studies
included normofractionated EBRT (irradiation of the prostate, sem-
inal vesicles and pelvic lymph nodes), associated with BT-boost
(LDR or HDR) and ADT (short-term or long-term ADT). However,
only thirteen of these studies had more than 50 HR-PCa (n > 50).
Nineteen BT-boost retrospective studies were not according to
 G. Peyraga et al.
Table 1
Prospective trials of EBRT + BT-boost in high-risk prostate cancer (HR-PCa).
Author, Prospective,n HR-PCa EBRT Pelvic ADT (%) Total OS (%) bRFS (%) Grade of acute GU Grade of acute GI Grade of late GU Grade of late GI
year BT boost (%) dose (Gy) EBRT boost toxicities% toxicities % toxicities % toxicities %
dose (Gy)

At 5 years At x years At 5 years At x years Gde 2 Gde 3 Gde 4 Gde 2 Gde 3 Gde 4 Gde 2 Gde 3 Gde 4 Gde 2 Gde 3 Gde 4
Lettmaier, Phase II, 130 43.8 50.4 Yes 59.2 25 to 35 85.7 At 9 85.6 At 9 na na na na na na 7.5 0 0 13.8 0.7 0
2012 [18] PDR years: years: 79
80.3
Denham, Phase III, 237 92 46 Yes 100 19.5 na na na At 6.5 na na na na na na na na na na na na
2015 [22] PDR years: 93
Dibiase, Phase II, 42 100 45 Yes na 100 to 89.6 At 7 83.3 At 7 24 26 0 10 4.2 0 4 0 0 2 0 0
2011 [17] LDR 108 years: years:
86.5 80.1
Hoskin, Phase III, 110 54 35.75 Yes 77 17 88 At 7 75 At 7 na na na na na na na na na na na na
2012 [21] LDR years: 81 years: 66
403

Sathya, phase III, 51 59 40 No na 35 94 na 71 na na 3.9 (3/4) na 7.8 (3/4) na 15.7 (3/4) na 7.8 (3/4)
2005 [19] LDR
Merrick, Phase III, 247 na 20 or 44 No 32.4 115 or 90 na At 10 na At 10 na na na na na na na na na na na na
2012 [20] LDR years: years:
75.4 80.8
Morris, Phase III, 398 69 46 Yes 100 115 na na 89 At 9 na na na na na na na 18 0 na 9 1
2017 [24] LDR years: 83
Martinez, Phase III, 472 na 46 Yes na 16.5 to 23 na na na At 10 na na na na na na na 3 0 na 0.5 0
2011 [23] HDR years:
56.9 to
81.1
Vargas, Phase I/II, 197 na 46 Yes No 16.5 to 23 92.9 na 81.4 na na na na na na na 26.9 2.3 0.7 11.5 11.5 1.5
2006 [16] HDR
HR-PCa = high-risk prostate cancer; EBRT = external body radiation therapy; Gy = Gray; ADT = androgen deprivation treatment; OS = overall survival; bRFS = biological recurence free survival; LDR = low dose rate; PDR = pulse dose
rate; HDR = high dose rate; GU = genito-urinary; GI = gastro-intestinal; Gde = grade; na = non available; BT = brachytherapy.

Cancer/Radiothérapie 25 (2021) 400–409

G. Peyraga et al.
these criteria. In some studies, pelvic lymph nodes irradiation was
omitted or was hypofractionated (> 2.2 Gy/fraction). In other stud-
ies, ADT was omitted.
Of the 13 studies according to the criteria and with strength of
more than 50 HR-PCa, the boost was delivered with LDR in 4 studies
[36,38,60,62] and with HDR in 9 studies [32,40,47,51,59,72,75,76].
LDR doses were ranging from 73 to 110 Gy. Only two studies with
LDR-boost were relevant on overall survival. At 8 and 10 years, over-
all survival rates were respectively 79% [62] and 69.4% [38]. At 5, 8,
10 and 14, the biochemical control rates were respectively ranging
from 81% to 89% [60,62], from 73% to 87% [60,62], 90% [38] and 72%
[36]. Unfortunately, no toxicity data are available in these 4 studies.
Of the 13 studies according to the criteria and with strength of
more than 50 of HR-PCa, the boost was delivered with HDR in 9
studies. However, in one study, the boost was delivered in “two-
steps” [32]: a first EBRT-boost in the prostate and seminal vesicles
(14 Gy in 7 fractions of 2 Gy), and a BT-boost (HDR-BT) of 9 Gy
(single fraction). In this study, 347 HR-PCa received EBRT (46 Gy
in 23 fractions of 2 Gy) in prostate, seminal vesicles and pelvic
lymph nodes, associated with the “two-steps” boost. With a median
follow-up of 50 months, biochemical control rate and overall sur-
vival rate at 5 years were respectively 91 and 88%. In the other 8
studies, EBRT (prostate, seminal vesicles and pelvic lymph nodes)
was normofractionated (from 45 to 50.4 Gy, fractions of 1.8 or 2 Gy).
HDR-boost was delivered in one to three fractions, for a total dose
of 14 to 23 Gy. One of these studies did not investigate survival
data but focused on toxicity data [40], with a limited follow-up,
which does not allow to conclude on late toxicities. Among the
seven other studies, the 5-year overall survival rate and the 5-year
biochemical control rate were available in 5 studies and were rang-
ing respectively from 88% to 96% [47,59,72,75,76] and from 75%
to 89% [47,59,71,72,75,76]. The 10-year overall survival rate and
the 10-year biochemical control rate were available in 2 studies
and were ranging respectively from 81% to 82% and from 72% to
84% [59,72]. In these retrospective studies of HDR-boost, urinary or
digestive toxicity rates are low. Acute grade > 2 toxicity rate is less
than 5% and late grade > 2 toxicity rate is less than 7%.
Finally, in these 48 retrospective BT-boost studies, acute
grade > 2 urinary toxicity does not exceed 7%. The rate of late
grade > 2 urinary toxicity exceeds 10% in only 3 studies [27,29,48].
The rate of late grade > 2 digestive toxicity does not exceed 7%.
6. Retrospective studies of SBRT-boost
Only seven retrospective studies are published on EBRT + SBRT-
boost [70,77–83]. Few HR-PCa were selected in these studies, and
only two studies included more than 50 patients according to the
selected criteria of our review [70,82,83] (e.g. 137 HR-PCa in the
Johansson study [70]). In 71% of these studies, EBRT included irra-
diation of pelvic lymph nodes. EBRT was normofractionated (1.8
or 2 Gy per fraction). SBRT-boost was heterogeneous. SBRT-boost
total doses were ranging from 18 Gy to 21 Gy (2 to 4 fractions from
5 to 10.5 Gy). Three to six fiducials (gold fiducials or other fiducials)
were placed in the prostate prior to treatment planning. Most of
these irradiations were delivered using a CyberKnife® (with track-
ing). In one study, SBRT-boost was hypofractionated with protons
(20 Gy in 4 fractions of 5 Gy) [70]. In one of these studies [78], only
toxicity data are available. These data are summarised in Table 2
(with data from SBRT-boost prospective trials).
In 3 of these studies, 3-year biochemical control rates were
respectively 71.1%, 89.8% and 92% [77,79,82]. In 4 studies, 5-year
biochemical control rates were respectively 60%, 82%, 83% and
89.5% [77,79,80]. In one of these studies [81], 4-year biochemical
control rate and overall survival rate were respectively 91.9% and
92.2%. In these studies, only 2% of acute grade 3 urinary toxicities
404
Cancer/Radiothérapie 25 (2021) 400–409
were reported in one study [82,83]. No acute grade 3 digestive tox-
icity. The rate of late grade 3 urinary toxicity was ranging from 0.5%
to 6%. Only 1% of late grade 3 digestive toxicities were reported in
one study [82,83]. Finally, a multicentric registry [84] including 437
patients did not find acute or late grade > 2 urinary toxicity. Survival
data of this registry were not analysable because there were only
33 HR-PCA and SBRT-boost protocols were heterogeneous.
7. Prospective trials on SBRT-boost
Only one SBRT-boost trial was prospective (phase II):
PROMETHEUS trial (Table 2) [85]. One hundred and thirty-five
patients (76% of IR-PCa and 24% of HR-PCa) were treated with
gantry-based SBRT, 19 or 20 Gy in two fractions delivered one
week apart, followed by conventionally fractionated EBRT (46 Gy
in 23 fractions, only 8% of pelvic radiation). The study mandated
MRI fusion for RT planning, rectal displacement, and intrafraction
image guidance. In this trial, with a 24-month follow-up, the 2-
year freedom from biochemical recurrence was 98.6%. Acute grade
2 gastrointestinal toxicity occurred in six patients (4.4%) with no
acute grade 3. Acute grade 2 urinary toxicity occurred in 36 patients
(26.6%) with no acute grade 3. The cumulative incidence of late
grade ≥ 2 and grade 3 gastrointestinal toxicity was 4.5 and 2%
respectively, and the cumulative incidence of late grade ≥ 2 and
grade 3 urinary toxicity was 24.9 and 2.2% respectively.
Another study on SBRT-boost was prospective (dose-escalation
phase I). The BOOSTER trial [86] evaluates the toxicity profile of
three SBRT-boost fractionations (2 fractions): 20, 22 and 24 Gy,
in 36 patients (64% of HR-PCa, 36% of IR-PCa). With a 24-month
follow-up, the 3-year freedom from biochemical recurrence was
93.3%. No acute grade 2 and 3 gastrointestinal toxicity occurred.
Acute grade 2 urinary toxicity occurred in 8% of patients and acute
grade 3 in 6% of patients. There were no late grade ≥ 2 gastrointesti-
nal toxicity and the cumulative incidence of late grade 2 urinary
toxicity was 14%.
A prospective SBRT-boost dose escalation phase I (one fraction,
from 10 to 15 Gy) has recently been published, but included only IR-
PCa (30 patients). Authors report one grade 4 rectal toxicity (fistula,
after repeated biopsies for a grade 3 rectal ulcer).
8. Ongoing trials
In the “ClinicalTrials.gov” database, we found one randomised
phase III trial (NCT01839994) comparing DE-EBRT with ADT versus
EBRT followed by boost (BT-boost or SBRT-boost) with ADT. The last
update status was in 2013 (April), results are not available to date,
and the recruiting status is “unknown”.
Among five trials corresponding to the study criteria, one is a
phase III trial, three are phase II trials, and one is a phase I trial (dose-
escalation). “HYPOPROST” is a Polish phase III trial, and inclusions
of the 288 HR-PCa have been completed since December 2019. In
this trial, SBRT-boost is directly compared with DE-EBRT, with 24
months of ADT [87]. Results of this trial are expected to increase the
level of evidence of SBRT-boost (15 Gy, 2 × 7.5 Gy), as an alternative
to conventional normofractionated DE-EBRT, such as BT-boost. Two
phase II trials [88,89] test SBRT-boost in 3 fractions (19.5 to 21 Gy),
and one phase II trial (recruiting) tests a carbon ions SBRT-boost
[90]. Finally, there is a phase I dose-escalation trial comparing two
SBRT-boost doses: 19 or 21 Gy (3 fractions) [91,92].
9. Discussion
There are many studies of BT-boost (9 prospective trials and
48 retrospective studies). We found only 7 retrospective studies of
 G. Peyraga et al.
Table 2
Retrospective studies and prospective trials of EBRT + SBRT-boost in high-risk prostate cancer (HR-PCa).
Author, year n HR (%) EBRT dose (Gy) Pelvic EBRT HT (%), duration Total boost dose (Gy) Overall survival % Biological RFS % Grade of acute GU Grade of acute GI Grade of late GU Grade of late GI
toxicities % toxicities % toxicities % toxicities %

At 5 years At x years At 5 years At x years Gde 2 Gde 3 Gde 4 Gde 2 Gde 3 Gde 4 Gde 2 Gde 3 Gde 4 Gde 2 Gde 3 Gde 4
Eade, 2019 36 23 (64) 46 Yes 22 (61), na 20 to 24 na na na na 8 6 0 0 0 0 14 0 0 0 0 0
(prospective) [86]
Pryor, 2019 135 32 (24) 36 or 46 Option na, 18 to 24 19 to 20 na na na na 26.6 0 0 4.4 0 0 24.9 2 0 4.5 2 0
(prospective) [85]
Johansson, 2019 504 137 (26) 50 Yes na, na 20 (protons) 95 At 10 years: 77 82 At 10 years: 63 na na na na na na na na na na na na
[70]
Anwar, 2016 [77] 48 34 (71) 50 Yes 45 (94), 3 to 28 19 or 21 na na 83 na 37 0 0 10 0 0 25 0.5 0 0 0 0
months
405

Jabbari, 2012 [78] 18 13 (72.2) 45 or 50 Yes na, 3 to 36 months 19 na na na na 39 0 0 17 0 0 8 5 0 3 0 0

Katz, 2014 45 45 (100) 45 Yes na 18 or 19.5 or 21 na na 60 na na na na na na na 2.3 2.3 0 13.3 0 0
[79]
Kim, 2016 39 19 (48.7) 45 No na 21 na na 89.5 na 23.1 0 0 20.5 0 0 10.3 0 0 12.8 0 0
[80]
Lin, 2014 41 41 (100) 45 Yes 38 (92.5), na 21 na At 4 years: 92 na At 4 years: 92 27 0 0 12 0 0 11 0 0 0 0 0
[81]
Mercado, 2014 108 59 (55) 45 or 50.4 No na, 3 to 36 months 19.5 na na na At 3 years: 89 18 2 na 6 0 na 34 6 na 11 1 na
Paydar, 2017
[82,83]
HR-PCa = high-risk prostate cancer; EBRT = external body radiation therapy; Gy = Gray; ADT = androgen deprivation treatment; OS = overall survival; bRFS = biological recurence free survival; GU = genito-urinary; GI = gastro-
intestinal; Gde = grade; na = non available; SBRT = stereotactic body radiation therapy.

Cancer/Radiothérapie 25 (2021) 400–409

G. Peyraga et al.
Table 3
Boost comparative table to help physicians’ decision in high risk prostate cancer (HR-PCa).
Which prostate boost for HR-PCa? DE-EBRT
Evidence based medicine +++
Availability +++
Radiation oncologist education +++
Medico-economic +/-
Radiation protection +++
Survival data ++
Anterior tumour +++
T3 tumour +++
Late toxicities (> gde 2) ++
Comorbidities +++
Authors subjectively chose to classify treatments (2020) and attribute: +++: very good; ++: good; +: moderate; +/-: bad; -: very bad; ?: data expected. DE-EBRT = dose-escalation
external body radiation therapy; BT = brachytherapy; HDR = high dose rate; LDR = low dose rate; SBRT = stereotactic body radiation therapy.
SBRT-boost, and two prospective trials. Data from prospective trials
are summarised in Table 5 (supplementary materials).
We observed heterogeneity in the design of these studies, which
impacts the level of evidence of these treatments. Populations are
rarely exclusively focused on HR-PCa. Moreover, the definition of
biochemical relapse depends on studies, although Phoenix criteria
are often used [5]. The use of ADT is uneven, without uniformity
in duration (3 months to 3 years), and RT volumes differ from one
study to another (inclusion or not of pelvic lymph nodes and/or
seminal vesicles). Fractionation, spreading and total dose of EBRT
depend on studies, without uniformity in the use of DE-EBRT.
Finally, boost delivery depends on studies, either by BT (LDR, PDR
or HDR) or by SBRT (with or without tracking), with heterogeneity
in fractionation, spreading and dose.
The only prospective randomised trial comparing DE-EBRT ver-
sus BT-boost with ADT was conducted by Morris et al. [24,26].
Survival data were recently published, randomising 398 patients
(including more than 66% of HR-PCa). A significant improvement
of biochemical control rate (P = 0.003 for intermediate risks and
P = 0.048 for high risk) was found with BT-boost (LDR-BT), with
no overall survival improvement (P = 0.293). The prospective study
conducted by Martinez et al. [23] allows to identify the best HDR-
BT boost protocol to apply if access to LDR-BT is restricted. In
this study, the best biochemical control rate was obtained at 10
years with a biological equivalent dose greater than 268 Gy to the
prostate, i.e., a 46 Gy EBRT (pelvic lymph nodes, prostate and sem-
inal vesicles) + BT-boost (HDR-BT, 2 fractions of more than 8.5 Gy).
Moreover, a recently published trial [76] did not show any dif-
ference in tolerance between a monofractionated or fractionated
BT-Boost (HDR one fraction versus ≥ 2 fractions). A study pub-
lished by Glaser et al. [93] identified 113,719 patients (National
Cancer Database, from 2004 to 2013) with IR-PCa and HR-PCa
(n = 44833) treated with either DE–EBRT or EBRT + BT-boost. Over-
all survival rates at 5 and 10 years were significantly improved by
BT-boost, both for IR-PCa and HR-PCa (respectively 88.7% and 82%
for DE–EBRT + BT-boost and DE–EBRT alone at 5 years, and respec-
tively 63% versus 50.4% for DE–EBRT + BT-boost and DE–EBRT alone
at 10 years). In the National Cancer Database, 42,765 high-risk and
clinically localised prostate cancers were treated with either radical
prostatectomy (RP), EBRT + ADT, or EBRT + BT-boost ± ADT. The data
reported suggest that EBRT + BT-boost ± ADT and RP are associated
with similar survival, and suggest that the survival of EBRT + ADT
was inferior to RP and EBRT + BT-boost ± ADT [94]. A large retro-
spective cohort study [95] in 12 tertiary centres (11 in the United
States, 1 in Norway, 1809 patients between 2000 and 2013), com-
pared EBRT + BT-boost + ADT and DE–EBRT + ADT among patients
with Gleason score 9–10 prostate cancer. This study shows a bet-
ter prostate cancer-specific mortality and longer time to distant
metastasis with BT-boost (adjusted 5-year prostate cancer-specific
mortality rates were 13% for DE–EBRT + ADT, and 3% for EBRT + BT-
boost + ADT).
406
Cancer/Radiothérapie 25 (2021) 400–409
LDR-boost HDR-boost SBRT boost
++ ++ +/-
+/- + ++
+/- + ++
+++ ++ +++
- + ++
+++ +++ ?
+/- + ++
+/- + ++
+ +++ ?
+ +/- ++
The recent update of the National Comprehensive Cancer Net-
work guidelines still places the DE–EBRT + ADT (1.5 to 3 years) as
the gold standard treatment for HR-PCa and very HR-PCa (Category
1 level of evidence). The choice between EBRT + BT-boost + ADT (1
to 3 years) and DE–EBRT + ADT (1.5 to 3 years) depends on sev-
eral factors recently identified [93]. BT-boost depends on patient
characteristics (age, comorbidities, residential setting and area,
academic versus non academic department, race, insurance status)
and tumour characteristics. A part of decision seems to be the radio-
therapy department availability of each treatment. Indeed, BT has
decreased since the 2000s, due to the reduction in the training and
education of new radiation oncologists, and the advent of new RT
modalities (intensity modulated RT and SBRT). Availability of LDR-
BT is limited in some regions of the world, particularly in Europe.
Therefore, many radiotherapy departments chose to develop either
SBRT or HDR-BT (or PDR-BT), its accessibility being facilitated com-
pared to the LDR-BT and because of radioprotection. Moreover, a
recent publication (National Cancer Database) identified 122,896
patients who were diagnosed with IR-PCa or HR-PCa between 2004
and 2014 and treated with DE-EBRT (75.6–86.4 Gy), LDR boost, or
HDR boost [96]. They compared OS among the three groups. For
HR-PCa, the OS adjusted hazard ratio (AHR) between LDR boost and
HDR boost was 1 (P = 0.98). HDR-boost was associated with a signif-
icantly better OS than DE-EBRT (AHR 1.36; P < 0.001). HDR BT-boost
yields similar OS benefits compared with LDR BT-boost. Therefore,
HDR boost is an alternative to LDR boost. For BT-boost, ADT must
be associated for ≥ 1 year (up to 3 years), regarding ASCENDE-RT
results and the update of the results of TROG 03.04 trial (RADAR
trial) [97].
There is a medico-economic rationale to develop hypofraction-
ated RT to reduce the costs associated with normofractionated RT
by reducing the number of daily trips from the patient’s home to
the treatment centre. In this sense, prospective randomised tri-
als (PROFIT, CHHiP, HYPRO) demonstrated similar survival results
between hypofractionated EBRT and normofractionated EBRT for
IR-PCa [10–12]. Moreover, for low and intermediate risk prostate
cancer, HDR and LDR BT is statistically less costly than EBRT, and
LDR BT is less costly than HDR brachytherapy [98]. A recent study
investigated [99] the cost-effectiveness of EBRT + BT-boost + ADT
and DE-EBRT + ADT in the treatment of intermediate and high-risk
prostate cancer. The estimated expected lifetime cost of BT-boost
was $68,696 for EBRT + BT-boost + ADT, compared to $114,944
for EBRT alone. EBRT + BT-boost + ADT decrease the incidence of
metastatic castration-resistant prostate cancer, cutting the use
of expensive targeted therapy for metastatic castration-resistant
prostate cancer. BT-boost is more effective (for HR-PCa [93]) and
efficient than DE-EBRT for HR-PCa, and SBRT-boost seems promis-
ing.
Indeed, a recent publication [100] demonstrated that there
is a drastic polarisation in opinions regarding incorpora-
tion of BT boost into EBRT + ADT for patients with HR PCa
G. Peyraga et al.
Fig. 2. Comparative radar chart of late toxicities and biochemical recurrence at 5 years. Data are averaged data for late toxicities from prospective trials, and average data for
biochemical recurrence at 5 years from prospective and retrospective trials. 5% steps, 0 to 25%. GI = gastrointestinal; GU = genitourinary; DE-EBRT = dose-escalation external
body radiation therapy; BT = brachytherapy; HDR = high dose rate; LDR = low dose rate; SBRT = stereotactic body radiation therapy.
among North American Genito-Urinary radiation oncology experts,
and may suggest that an alternative is needed. SBRT-boost seems to
provide less grade ≥ 3 late urinary toxicities than BT-boost. How-
ever, prospective randomised trials (BT-boost versus SBRT-boost)
are needed before concluding on the effectiveness and efficiency
of SBRT-boost compared with BT-boost. Nevertheless, in order to
include SBRT-boost as an option for HR-PCa, results of direct com-
parison of SBRT-boost versus DE–EBRT (with ADT) are needed. In
this sense, prospective results of the Polish “HYPOPROST” trial are
expected.
Finally, BT-boost and SBRT-boost might not be considered
as opposed but rather complementary treatments. SBRT-boost
should be considered in case of ineligibility to BT-boost. In order
to guide the physicians’ decision, several parameters must be
taken into account. Among them, we must consider the avail-
ability of RT modalities, the education and training of radiation
oncologists, the medico-economic evolution and the radiation pro-
tection, the characteristics of the tumour (location, stage) and the
patient’s comorbidities. These parameters must be balanced on
a case-by-case patient analysis with survival data from prospec-
tive randomised trials, and toxicities data. Authors suggest a boost
comparative table (Table 3) to help physicians’ decision and a com-
parative “radar chart” for late toxicities and biochemical recurrence
at 5 years (Fig. 2), with data from prospective and retrospective
trials, such as three randomised prospective trials for DE–EBRT
[15,101,102], concluding that the patient’s choice remains essen-
tial.
10. Conclusion
EBRT + BT + ADT (1 to 3 years) is currently an option for
the treatment of HR-PCa (NCCN classification risk system and
guidelines). Nevertheless, the gold standard treatment remains a
DE–EBRT + ADT (1.5 to 3 years). However, recent findings from
the ASCENDE-RT trial and data from the National Cancer Database
demonstrate the superiority of EBRT + BT-boost + ADT versus DE-
EBRT + ADT. It seems that this treatment (EBRT + BT-boost + ADT)
could now be considered as a gold standard treatment. Now, the
main challenge is to allow all patients to benefit from this treat-
ment and to solve access problems to this treatment. SBRT-boost
represents an attractive alternative, but the lack of randomised
trials does not allow us to conclude on it for HR-PCa. A strict selec-
tion of eligible patients and prospective randomised phase III trials
407
Cancer/Radiothérapie 25 (2021) 400–409
or meta-analyses could improve the level of evidence of SBRT-boost
for HR-PCa.
Disclosure of interest
The authors declare that they have no competing interest.
Appendix A. Supplementary data
Supplementary data associated with this arti-
cle can be found, in the online version, at
https://doi.org/10.1016/j.canrad.2020.11.004.
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