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<h5 class="section-title" id="d796381e284">Background</h5>
<p id="P4">The NRG/RTOG 9413 study showed that whole pelvic radiotherapy (WPRT) plus
neoadjuvant
hormonal therapy (NHT) improved progression-free survival in patients with intermediate-risk
or high-risk localised prostate cancer compared with prostate only radiotherapy (PORT)
plus NHT, WPRT plus adjuvant hormonal therapy (AHT), and PORT plus AHT. We provide
a long-term update after no years of follow-up of the primary endpoint (progression-free
survival) and report on the late toxicities of treatment.
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<h5 class="section-title" id="d796381e289">Methods</h5>
<p id="P5">The trial was designed as a 2 × 2 factorial study with hormonal sequencing
as one
stratification factor and radiation field as the other factor and tested whether NHT
improved progression-free survival versus AHT, and NHT plus WPRT versus NHT plus PORT.
Eligible patients had histologically confirmed, clinically localised adenocarcinoma
of the prostate, an estimated risk of lymph node involvement of more than 15% and
a Karnofsky performance status of more than 70, with no age limitations. Patients
were randomly assigned (1:1:1:1) by permuted block randomisation to receive either
NHT 2 months before and during WPRT followed by a prostate boost to 70 Gy (NHT plus
WPRT group), NHT 2 months before and during PORT to 70 Gy (NHT plus PORT group), WPRT
followed by 4 months of AHT (WPRT plus AHT group), or PORT followed by 4 months of
AHT (PORT plus AHT group). Hormonal therapy was combined androgen suppression, consisting
of goserelin acetate 3·6 mg once a month subcutaneously or leuprolide acetate 7·5
mg once a month intramuscularly, and flutamide 250 mg twice a day orally for 4 months.
Randomisation was stratified by T stage, Gleason Score, and prostate-specific antigen
concentration. NHT was given 2 months before radiotherapy and was continued until
radiotherapy completion; AHT was given at the completion of radiotherapy for 4 months.
The primary endpoint progression-free survival was analysed by intention to treat.
This study is registered with
<a data-untrusted="" href="http://ClinicalTrials.gov" id="d796381e293" target="xrefwindow">ClinicalTrials.gov</a>,
number NCT00769548. The trial has been terminated to additional follow-up collection
and this is the
final analysis for this trial.
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<h5 class="section-title" id="d796381e300">Findings</h5>
<p id="P6">Between April 1, 1995, and June 1, 1999, 1322 patients were enrolled from
53 centres
and randomly assigned to the four treatment groups. With a median follow-up of 8·8
years (IQR 5·07–13·84) for all patients and 14·8 years (7·18–17·4) for living patients
(n=346), progression-free survival across all timepoints continued to differ significantly
across the four treatment groups (p=0·002). The 10-year estimates of progression-free
survival were 28·4% (95% CI 23·3–33·6) in the NHT plus WPRT group, 23·5% (18·7–28·3)
in the NHT plus PORT group, 19·4% (14·9–24·0) in the WPRT plus AHT group, and 30·2%
(25·0–35·4) in the PORT plus AHT group. Bladder toxicity was the most common grade
3 or worse late toxicity, affecting 18 (6%) of 316 patients in the NHT plus WPRT group,
17 (5%) of 313 in the NHT plus PORT group, 22 (7%) of 317 in the WPRT plus AHT group,
and 14 (4%) of 315 in the PORT plus AHT group. Late grade 3 or worse gastrointestinal
adverse events occurred in 22 (7%) of 316 patients in the NHT plus WPRT group, five
(2%) of 313 in the NHT plus PORT group, ten (3%) of 317 in the WPRT plus AHT group,
and seven (2%) of 315 in the PORT plus AHT group.
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<h5 class="section-title" id="d796381e305">Interpretation</h5>
<p id="P7">In this cohort of patients with intermediate-risk and high-risk localised
prostate
cancer, NHT plus WPRT improved progression-free survival compared with NHT plus PORT
and WPRT plus AHT at long-term follow-up albeit increased risk of grade 3 or worse
intestinal toxicity. Interactions between radiotherapy and hormonal therapy suggests
that WPRT should be avoided without NHT.
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<h5 class="section-title" id="d796381e310">Funding</h5>
<p id="P8">National Cancer Institute.</p>
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