Probach.

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, 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 IMRT 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 IMRT are combined.
IMRT is used to deliver an elective dose to the prostate and
seminal vesicles. Brachytherapy is used as a boost
(IMRT+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 IMRT only and IMRT+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 IMRT+BRACHY is half of IMRT
only (3 year incidence is 15% vs. 30%). Because less long-term
toxicity is expected with IMRT+BRACHY differences in qualityof-
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.
Study objectives 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 IMRT followed by brachytherapy
(IMRT+BRACHY), compared to treatment with IMRT alone
(IMRT). 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.
Study design Randomized, prospective, phase III study
Patient population Patients with prostate cancer, belonging to the intermediate- and
partially high-risk profile are candidates for the study, provided
brachytherapy can be performed.
Intervention 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 (IMRT) combined with
HDR or PDR brachytherapy as boost.
Duration of treatment For both arms the total equivalent dose in 2-Gy fractions (EQD2)
is 79 Gy. For the IMRT arm the dose is delivered in 35 fractions
of 2.20 Gy, resulting in an EQD2 dose of 79.2 Gy.
Total treatment duration will be 7 weeks. The IMRT+BRACHY
group is treated up to 44 Gy in 2.20 Gy daily fractions (EQD2 =
45.3Gy) with IMRT and a High Dose Rate (HDR) or Pulsed
Dose Rate (PDR) brachytherapy treatment is applied for the
boost. The HDR dose is equivalent (EQD2) to 33.4 Gy
calculated with an alpha/beta ratio for prostate of 5 Gy, given in
a single fraction of 13 Gy. The PDR dose is 24 times 1.27 Gy
(EQD2 33.8 Gy). Total treatment duration will be 6 weeks.
Subsequently, patients will be followed for evaluation of acute
and late toxicity, bDFS, RFS, OS, Quality of Life and costs.
Target number of
patients
240
Expected duration of
accrual
3 years
Main study endpoints Primary endpoint: the incidence of late gastro-intestinal and
genito-urinary toxicity (grade ¡Ý 2 RTOG) during 3 years of
follow-up after treatment completion.
Confidential Page 9 version 1.0
Final February 04, 2013
Secondary endpoints: Incidence of acute toxicity, bDFS, RFS,
OS, QOL, costs and cost-effectiveness (all costs of treatment
and during 5 years of FU after treatment completion).
Benefit and nature and
extent of the burden and
risks associated with
participation
Patients who will participate in the study and randomize for arm
2 (IMRT+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.
Planned interim analysis
and DSMB (if applicable)
No interim analysis is planned for this study. No DSMB will be
installed due to the minimal risk involved in participation in the
study.

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 IMRT followed by brachytherapy
(IMRT+BRACHY), compared to treatment with IMRT alone
(IMRT). 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.

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.

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 (IMRT) combined with
HDR or PDR brachytherapy as boost.

Duration of treatment For both arms the total equivalent dose in 2-Gy fractions (EQD2)
is 79 Gy. For the IMRT arm the dose is delivered in 35 fractions
of 2.20 Gy, resulting in an EQD2 dose of 79.2 Gy.
Total treatment duration will be 7 weeks. The IMRT+BRACHY
group is treated up to 44 Gy in 2.20 Gy daily fractions (EQD2 =
45.3Gy) with IMRT and a High Dose Rate (HDR) or Pulsed
Dose Rate (PDR) brachytherapy treatment is applied for the
boost. The HDR dose is equivalent (EQD2) to 33.4 Gy
calculated with an alpha/beta ratio for prostate of 5 Gy, given in
a single fraction of 13 Gy. The PDR dose is 24 times 1.27 Gy
(EQD2 33.8 Gy). Total treatment duration will be 6 weeks.