EURURO Vol. 72 No. 5

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Grade 3 and 4 toxicities were similar between the two arms.
However, 70% of patients treated with bicalutamide devel-
oped gynaecomastia compared to 11% of patients treated
with RT alone. When considering the results of the RTOG
9601 trial it should be noted that the use of antiandrogens
alone is not a common treatment regimen in contemporary
patients and is no longer Food and Drug Administration
approved in the USA . This limits the generalizability of
these findings to contemporary patients, where GnRH
agonists or antagonists should be considered. However,
which is the optimal regimen for these molecules is still
unknown. The RADICALS HD trial will provide more
information regarding the oncologic efficacy of 6-mo versus
12-mo GnRH analogue administration at the time of RT.
3.10. Side effects of postoperative RT
Overall, four randomized controlled studies
and 20 retrospective investigations reporting adverse events
in men undergoing postoperative RT were identified
. When considering the three
available prospective randomized trials comparing immedi-
ate RT versus observation sRT, patients included in the
immediate RT arm had higher rates of Grade 2 or higher
genitourinary (GU) and gastrointestinal (GI) toxicity compared
with those in the observation arm . In the SWOG
trial, 47% versus 5% patients had tenderness and urgency with
bowel movements at 6 wk (ie, acute side effects) . Urinary
frequency at 6 wk was also more common in men undergoing
immediate RT (35% vs 20%). Considering late side effects, at 10-
yr the Grade 2 or higher GU toxicity reported by the EORTC trial
was 8.2% higher (21.3% vs 13.5%) for aRT versus initial
observation . No differences were observed in 10-yr GI
toxicity (2.5% vs 1.9% for aRT vs observation, respectively,
p > 0.05). Overall, patients undergoing immediate RT had a
cumulative incidence of Grade 3 side effects 2.8% higher than
those managed with observation at 10 yr (5.3% vs 2.5%). This
was confirmed by a meta-analysis of these trials, concluding
that aRT increased the risk of acute GI toxicity, urinary stricture
(risk difference: 0.05), and incontinence (risk difference: 0.04)
. Conversely, aRT did not impact on erectile function
. However, limited data on this issue were available: only
one trial reported comprehensive data on sexual function
. Moreover, the SWOG trial reported no differences
between patients undergoing aRT and observation with
regards to quality of life at intermediate term .
Retrospective studies have described higher adverse GU
and GI events associated with immediate RT. However,
conflicting results are reported regarding the impact of aRT
on urinary incontinence and erectile dysfunction. Suardi
et al evaluated a large cohort of patients treated with
RP and suggested that individuals undergoing aRT were less
likely to recover urinary continence. This was confirmed by
Hegarty et al in >6000 patients treated with aRT versus
sRT versus RP alone. Conversely, a recent population-based
study failed to show a higher rate of urinary incontinence
among men treated with aRT . When considering sexual
function, Sia et al reported an increase in the rate of
erectile dysfunction after RT. Although these results
correlate with recent studies showing an association
between aRT and erectile dysfunction , popula-
tion-based investigations failed to confirm this association
. These discrepancies might be related to the
definition of continence and erectile function, as well as
to the follow-up period, baseline characteristics, selection
bias, and type of RT
Considering the side effects associated with sRT, Cremers
et al reported that approximately 40% of the patients
treated with this approach experience Grade 2 or higher GU
toxicity and 1.6% of them experienced GI side effects.
Nonetheless, Grade 4 toxicities were not recorded. Hegarty
et al suggested that men undergoing sRT are at
increased risk of urinary incontinence and GI complications
compared to those treated with RP alone. However, it has
been hypothesized that the risk of long-term side effects
associated with sRT depend on the time elapsed between RP
and sRT. Indeed, individuals receiving salvage approaches
more than 6–12 mo from surgery experienced better sexual
satisfaction and urinary function recovery compared with
those treated earlier . Therefore, it may be desirable
to postpone postoperative RT when oncologically safe to
improve long-term functional outcomes.
The role of treatment regimens and RT techniques on the
subsequent risk of adverse events during follow-up has also
been assessed. Although dose escalation might improve
outcomes, its downside is the increased risk of side effects. In
particular, doses above 72 Gy have been associated with an
increased rate of acute Grade 3 toxicity in some but not all
studies . One prospective trial currently randomizes
patients undergoing sRT to 64 Gy or 70 Gy (NCT01272050)
and reported a relatively low rate of Grade 2 or higher
GU and GI acute toxicity at 3 mo, where the only impact of
dose-intensified sRT was on urinary symptoms. Hypofrac-
tionated RT (ie, daily dose of 2.2–3.0 Gy/fraction in 20–28
fractions) has been proposed to reduce treatment duration
and improve patient compliance without impairing out-
comes . However, Cozzarini et al reported that the
5-yr risk of late urinary toxicity was significantly higher
among patients undergoing dose escalation (median dose
70.4 Gy) and hypofractionation compared with standard
fractionation. Therefore, the potential benefits of hypofrac-
tionation and radiation dose should be carefully balanced
with the detrimental effects. Other studies assessed the
impact of RT technique on the risk of acute and late toxicity.
A noncomparative study by Ost et al reported no Grade
3 acute GI toxicity in 104 patients treated with IMRT with a
median dose of 74 Gy. Moreover, late grade GU 3 toxicity
was reported in only four (4%) patients. This is comparable or
lower to what reported by other studies using three-
dimensional conformal RT and lower doses . Similarly,
Alongi et al evaluated 172 patients undergoing whole-
pelvis three-dimensional conformal versus IMRT and
reported a lower risk of acute GI toxicity in the latter group.
This was confirmed when considering patients treated with
sRT: Goenka et al showed a reduction in the risk of late
Grade 2 or higher GI toxicity in men receiving IMRT
compared with those treated with three-dimensional
conformal. The extent of the radiation field might also play
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