Randomized Phase 3 Study On The Assessment Of Late Toxicity By Comparing IMRT High Dose External Beam Radiotherapy Only With External Beam Radiotherapy Combined With HDR Or PDR Brachytherapy In Patients With Intermediate/high Risk Prostate Cancer

There is by now accumulating evidence that high radiation dose (* 75 Gy) is
necessary for tumour control when treating intermediate and high risk prostate
cancer. To treat safely at high doses with external beam therapy (EBRT),
3-Dimensional Conformal Radiotherapy (3D-CRT) or Intensity Modulated
Radiotherapy (IMRT) techniques must be used. In this way using the IMRT with a
validated position verification protocol as standard of care, the toxicity can
be limited while the dose to the prostate is escalated. However, despite the
use of IMRT the incidence rates for GI and GU toxicity are still high and the
adverse effect of EBRT dose distribution pattern on the long term has to be
evaluated. Another way of delivering high dose to the prostate, but limiting
the dose to the neighbouring organs is with brachytherapy. For treating
intermediate risk prostate cancer with brachytherapy, brachytherapy and EBRT
are combined. EBRT is used to deliver an elective dose to the prostate and
seminal vesicles. Brachytherapy is used as a boost (EBRT+BRACHY). The main
advantage of brachytherapy is the limited dose in neighbouring organs and
potentially causing less toxicity. In this study, differences in outcome of
treatment between EBRT only and EBRT+BRACHY will be investigated in a
prospective randomized setting. It is hypothesized that the incidence of grade
* 2 RTOG long-term genitourinary (GU) and gastrointestinal (GI) toxicity of
EBRT+BRACHY is half of EBRT only (3 year incidence is 15% vs. 30%). Because
less long-term toxicity is expected with EBRT+BRACHY differences in
quality-of-life need to be assessed with validated questionnaires. Because the
dose to the prostate is similar for both groups, no difference in tumour
control, expressed as Biochemical Disease Free Survival (bDFS) and relapse free
survival (RFS), is anticipated.

The primary study objective is to show a 50% reduction of the incidence of
long-term gastrointestinal and genito-urinary toxicity in the treatment of
prostate cancer in the intermediate and high risk group, by treatment with EBRT
followed by brachytherapy (EBRT+BRACHY), compared to treatment with EBRT alone
(EBRT). Secondary objectives are to investigate the effect of this combined
treatment on acute toxicity, tumour control, Quality of Life (QOL), overall
survival, costs and cost-effectiveness compared to standard treatment with IMRT
alone.

Randomized, prospective, multicentric, phase III study

Patients will be randomized into two groups. One group will be treated with
high dose external beam radiotherapy using the IMRT technique (standard
treatment). The other group will be treated with external beam radiotherapy
(EBRT) combined with HDR or PDR brachytherapy as boost.

Patients who will participate in the study and randomize for arm 2
(EBRT+brachytherapy) will visit the hospital less frequently during the
treatment phase (21 times), compared to standard treatment (35 times).
However, for brachytherapy catheters/needles need to be placed inside the
prostate gland under general or spinal anaesthesia. The HDR brachytherapy will
be given in one fraction without the need of hospital admission, and for PDR
brachytherapy the fractions are administered in a hospital stay of 2 days. It
is expected that in arm 2 the incidence of acute and late GI and GU toxicity
will be lower than in arm 1 (standard treatment). Unlike non-study patients,
all patients participating in the study will complete Quality of Life
questionnaires (QLQ-C30, QLQ-PR25, IPSS, and IIEF) at baseline and then every 6
months until 3 years after treatment completion and yearly thereafter until 5
years after treatment completion.