Multicentric Phase II Trial of Salvage Radiotherapy Combined With Hormonotherapy in Oligometastatic Pelvic Node Relapses of Prostate Cancer (OLIGOPELVIS / GETUG P07)
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Institut Cancerologie de l'Ouest

Brief Protocol 
Short title :  
 
OLIGOPELVIS 1_GETUG P07 
Ref ICO :  
 
ICO-N-2014-02 
N° ID-RCB : 
 
2014-A00138-39 
 
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PROTOCOL OLIGOPELVIS 1_GETUG P07 
 
A) CLINICAL TRIAL IDENTIFICATION  
STUDY TITLE 
Multicentric phase II study of high-dose radiotherapy and hormone therapy in 
oligometastatic relapses of the pelvic lymph nodes of prostate cancer 
SHORT TITLE 
OLIGOPELVIS 1_GETUGP 07 
INVESTIGATOR COORDINATOR  
Pr Stéphane SUPIOT 
ID-RCB  
2014-A00138-39 
REF ANSM  
140494B-12 AUTORISATION 13/06/14 
ETHICS COMMITTEE NAME 
CPP OUEST-IV 
REF ETHICS COMMITTEE  
19/14 SESSION OF 13/05/14 
N° CLINICAL TRIAL.GOV  
NCT02274779 
 
 
B) STUDY BACKGROUND 
There is a growing body of evidence reporting the existence of a subset of prostate cancer patients who, at relapse, 
present with a limited number of metastases (fewer than five lesions). This oligometastatic state has also been 
identified in other tumor types, such as melanoma, soft tissue sarcoma, liver, lung, and breast cancers, and has led 
to a shift in management toward more aggressive local treatments, including surgical resection. 
Positron Emission Tomography–Computed Tomography (PET-CT), using tracers such as choline or acetate, has 
proven to be a reliable tool for detecting oligometastatic disease following biochemical recurrence in prostate 
cancer. For patients in this setting, an intensified therapeutic approach—combining androgen deprivation therapy 
(ADT) with high-dose radiation therapy directed at PET-CT-detected lesions—may be proposed. 
This strategy has the potential to prolong the interval between successive courses of ADT or, in selected patients 
with a limited metastatic burden, may even offer the possibility of cure. 
In this study, the investigators aim to evaluate the 2-year biochemical or clinical relapse-free survival of prostate 
cancer patients with 1 to 5 oligometastases treated concomitantly with high-dose conformal radiation therapy and 
LH-RH agonists. 
 
C) STUDY INFORMATION 
INDICATION 
Oligometastatic lymph nodes pelvic prostate cancer patients 
METHODOLOGY 
Non randomized, prospective, national multicentre, phase II 
Primary Objective and Endpoint 
Primary objective 
Endpoint 
Evaluation time 
The primary objective is to evaluate the 
biochemical or clinical relapse-free 
survival at 2 years. 
The primary endpoint is the 2-year relapse-
free survival probability. 
Biochemical or clinical relapse is defined as: 
• A PSA level higher than the pre-
treatment PSA value, confirmed by 
2 years 

Short title : 
OLIGOPELVIS 1_GETUG P07 
 
Ref ICO :  
ICO-N-2014-02 
 
 
 
 
 
 
 
N° EudraCT : 2014-A00138-39 
 
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two consecutive increases measured 
in the same laboratory; 
and/or 
• 
An increase in the number of 
metastatic sites on follow-up imaging 
assessments. 
SECONDARY OBJECTIVES AND ENDPOINTS 
Secondary objectives 
Endpoints 
Evaluation time 
a) Biochemical relapse-free survival 
A PSA > 0.2 ng/mL after the post-treatment 
nadir (or PSA > nadir + 0.2 ng/mL if nadir > 
0.2 ng/mL).  
For patients without a history of 
prostatectomy, biochemical recurrence is 
defined by:  
• 
A PSA > pre-treatment nadir 
AND 
• 
A PSA > 0.2 ng/mL after the post-
treatment nadir 
2 years 
b) Time to resumption of hormone 
therapy 
 
Resumption of hormone therapy 
5 years 
c) Time to initiation of any subsequent 
treatment 
Resumption of any treatment 
5 years 
d) Assessment of toxicity (acute toxicity 
assessed 1 month after the end of 
radiotherapy, and late toxicity assessed 
at 2 years), with particular attention to 
gastrointestinal events 
NCI-CTC-AE v4.0 scale 
5 years 
e) Site of relapse: within the irradiated 
field or at distant (non-irradiated) sites 
At least one morphological imaging 
(depending on recurrence location and 
center practice): 
• 
Abdominopelvic CT scan 
• 
and/or Pelvic MRI 
• 
and/or Bone scintigraphy 
• 
and/or FCH-PET (post-treatment PET 
will be optional). 
5 years 
f) Overall survival 
Overall survival 
5 years 
g) Quality of life 
QLQ-C30 + QLQ-PR25 
5 years 
h) Optional ancillary biological study: 
validation of a novel mutational 
signature in patients with 
oligometastatic prostate cancer treated 
with radiotherapy 
 
 
INCLUSION CRITERIA 
1) Histologically proven adenocarcinoma of the prostate 
2) Patients aged 18 years or more  
3) PS 0-1  

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N° EudraCT : 2014-A00138-39 
 
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4) Previous radical treatment to the prostate (radiotherapy or surgery) 
5) PSA increase of at least 3 assays in the same laboratory over the last 12 months.  
6) 1-5 pelvic lymph node metastases detected with 18FCH-PET. A relapse in the dressing 
prostatectomy is associated possible.  
7) Upper limit of lymph node metastases: aortic bifurcation  
8) Respect of dosimetry constraints to organs at risk  
9) Treatment with hormone therapy may be started before inclusion, to a maximum of 
three months prior to Day 1 of radiotherapy. This hormone will necessarily be 
preceded by a free interval treatment of at least 6 months since the last injection, by 
adding the duration of action of this predictable injection (1, 3 or 6 months)  
10) Patient affiliated to a social security scheme  
11) Patient Information and written informed consent form signed 
NON-INCLUSION CRITERIA 
1) Bone or visceral metastatic relapse associated 
2) Para-aortic nodal relapse (the upper limit is tolerated aortic bifurcation)  
3) More than 5 lymph node metastases 
4) Proof of metastases at initial diagnosis 
5) Evidence of distant metastases in the pelvic lymph nodes or outside the prostate bed 
prior pelvic lymph nodes irradiation. Irradiation of the bed of the prostate is not an 
exclusion criterion, but the junction between prior irradiation bed prostatectomy and 
radiation field pelvic lymph nodes should be examined carefully  
6) Castration resistance defined by clinical or biochemical progression despite a 
combined androgen blockade 
7) Known contraindications to pelvic irradiation (eg, chronic inflammatory bowel 
disease, ...) 
8) Known 
contraindications 
to 
hormone 
therapy, 
according 
to 
standard 
recommendations in force 
9) Serious hypertension not controlled by appropriate treatment 
10) Other concomitant cancer or history of cancer (within 5 years prior to study entry), 
except basal cell or squamous cell carcinomas of the skin. 
11) Patient with a psychological, familial, sociological or geographical potentially 
hampering compliance with the study protocol and follow-up schedule 
12) Patient already included in another interventional study involving the approval of a 
cpp during his screening for the study Oligopelvis 
13) Private person of liberty or major trust 
 
 
E) INVESTIGATIONAL TREATMENT DESCRIPTION 
Experimental procedure 
• Radiation therapy 
A simultaneous integrated boost will be applied to PTVs. It will be administered 5 days per week during 5 to 7 
weeks. 
The radiation therapy will start three months (+/- 15 days) after the first injection of IADT. 
General recommendations 
The use of intensity-modulated radiation therapy (IMRT) is mandatory.  
Irradiation will be delivered to patients with an empty rectum. It is recommended that the patient empties his 
bladder and rectum one hour before the planning CT scan and before each radiotherapy treatment, and then drink 
at least 1/3 L of water after voiding. The one-hour delay will be adapted to the patient’s continence.  
If the prostate bed has been previously irradiated, it is recommended that the irradiation be delivered with the 
bladder empty in order to avoid re-irradiation of the bladder due to overlapping fields. 
Daily verification of patient’s organ positioning using IGRT is mandatory.  
The use of a record and verify processing software is mandatory.  

Short title : 
OLIGOPELVIS 1_GETUG P07 
 
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Preparation of treatment 
A planning CT of the pelvic cavity that includes all of the pelvic lymph nodes will be performed in the supine position, 
with intravenous contrast agent to aid visualization of the pelvic vessels. Oral contrast agent will also be 
administered to assist in the determination of the small bowel volume. The minimum CT resolution will be at least 
3 mm thick slices every 3 mm, but thinner slices may be necessary for very small volume lymphadenopathy. Merging 
the CT with pelvic MRI may help to visualize the vascular axes and pelvic lymph nodes.  
Fusion with FCH-PET (or PSMA-PET): The FCH-PET (or PSMA-PET) images will be segmented using a threshold 
adapted to the size of the lymphadenopathy. These images will be used to locate the pathological lymph nodes, 
but the tumor volume (GTV) will be contoured on the planning CT. 
 
Target Volumes 
a) 
Metastatic lymph nodes 
GTV1 to GTV5 will be delineated on the planning CT-scan with the aid of FCH or PSMA PET. 
A margin of 3-5 mm around the GTVs will define the clinical target volumes (CTVs). 
An additional margin of 3-5 mm around the CTVs will define the planned target volumes (PTVs). The intersection 
between PTVs and small intestine will be removed from the PTVs. 
 
b) 
Whole pelvic lymph node irradiation 
Pelvic lymph nodes will be contoured according to the recommendations in the GETUG consensus statement (20). 
The pelvic lymph node CTV (PLN CTV) will include the common iliac, external iliac, internal iliac, pre-sacral (S1-S3) 
and obturator regions. 24The PLN CTV will be based on the pelvic vessels (arteries and veins) with an expansion of 
7 mm, reduced where necessary at the bone, muscle, bowel and bladder boundaries. The upper limit is defined by 
the bifurcation of the abdominal aorta. If the prostate/prostate bed has been previously irradiated, the lower limit 
will be modified in accordance with the previous dosimetry in order to avoid overlap with regions which have 
received more than 20 Gy.  
A margin of 5 mm around the PLN CTV will define the PTV. The intersection between PTVs and the small bowel will 
be removed from the PLN PTV 
 
c) 
Prostate bed 
Irradiation of the prostate bed will be considered if the prostate bed has not been irradiated.  
The prostate bed CTV (PB CTV) will be defined according to the recommendations of the RTOG consensus (21).  
Boundaries 
Below the upper edge of the pubic symphysis, the prostate bed boundaries are: 
- 
anteriorly: the posterior border of the pubic bone; 
- 
posteriorly: the rectal wall; 
- 
caudally: 8–12 mm below the vesicoureteral anastomosis;  
- 
laterally: the levator ani and internal obturator muscle.  
 
Above the upper edge of the pubic symphysis, its boundaries are:  
- 
anteriorly: including 1–2 cm of the posterior wall of the bladder;  
- 
posteriorly: the mesorectal fascia;  
- 
cranially: the end of the vas deferens or 3–4 cm  above the pubic symphysis;  
- 
laterally: the sacro-recto-genito-pubic fascia.  
 
A margin of 7mm will be added to the PB CTV to form the PB PTV.  
 
d) 
PB relapse PTV 
In case of prostate bed relapse, a PB relapse GTV will be defined based on PET-CT and MRI. A margin of 3-5 mm 
around the PB relapse GTV will define the clinical target volume (PB relapse CTV). 
An additional margin of 3-5 mm around the PB relapse CTV will define the planned target volume (PB relapse PTV).  
e) 
Organs at risk (OARs) 
OARs will be contoured as recommended by the RTOG (22). No margin will be added (PRV) around organs at risk. 

Short title : 
OLIGOPELVIS 1_GETUG P07 
 
Ref ICO :  
ICO-N-2014-02 
 
 
 
 
 
 
 
N° EudraCT : 2014-A00138-39 
 
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- 
Bladder: the outer contour of the bladder on all sections where it appears. The bladder volume is the 
volume between the outer contour and an inner contour that is defined 7mm from the outer contour. 
- 
Rectum: the external contour of the rectum from the recto-sigmoid junction to the anal canal. The rectal 
wall is the volume between the outer contour and an inner contour that is defined 5mm from the outer 
contour. 
- 
Intestine: the external contours of the sigmoid, colon and the small intestine are defined as an “intestinal 
bag” including the abdominal cavity as a whole. It will be important not to create areas of overlap between 
the intestine and the CTVs. 
- 
Femoral head. 
 
Dose prescription 
A simultaneous integrated boost will be applied to the PTV1-5 and PLN PTV. The PB PTV will be treated using 
conventionally fractionated radiotherapy (2 Gy/fraction) 
- 
PTV1-PTV5: 66 Gy in 30 fractions of 2.2 Gy 
- 
PLN PTV: 54 Gy in 30 fractions of 1.8 Gy 
- 
PB PTV: 63 Gy in 30 fractions of 2.1 Gy if the prostate bed has not been irradiated previously. 
- 
PB relapse PTV: 66 Gy in 30 fractions of 2.2 Gy  
 
Dose constraints 
95 % of the PTV volumes will receive 95 % of the prescribed dose. 
The QUANTEC recommendations advise that the maximum dose for the various organs at risk should be: 
- 
Bladder: the bladder volume receiving a dose > 65 Gy will be no greater than 50 %. 
- 
Rectum: V50 < 50%, V60 < 35%, V65 <2 5%.  
- 
Bowel: the volume receiving 45 Gy will be less than 195 ml; V60<50 ml 
- 
Femoral head: <5 % of each femoral head should receive a dose > 50 Gy. 
 
Where the PTV coverage conflicts with the OAR constraints, OAR protection will be favoured, so the PTV may be 
reduced to the CTV. 
 
Respect of dosimetric constraints to organs at risk. This is of major importance for patients with a past history of 
prostate/prostate bed irradiation delivering a maximum of 20 Gy to the metastatic pelvic lymph nodes  
 
Image guidance 
Image-guided radiotherapy (IGRT) will be performed daily. The daily registration will be based at least on bone 
structures. It will be possible to readjust to the nodal structures in case of displacements > 1 cm. 
 
Quality control 
A GETUG RT quality assurance committee has been established consisting of a radiation oncologist and a radiation 
physicist. This committee is available for consultation should questions arise concerning the treatment protocol. 
The committee will initially accredit each centre on the basis of an electronic copy of a single case plan that 
demonstrates: 
- 
CTV and PTV contoured according to protocol;  
- 
organs at risk (bladder and rectal walls and femoral heads) contoured according to protocol;  
- 
DVH for intestine, bladder and rectal wall, PTV and CTV that meet dose constraints;  
- 
a statement that patients will be treated with an approved daily image guidance technique. 
 
All treatment plans will be sent via a web-based platform for central review and approval prior to beginning 
radiotherapy.  
 

Short title : 
OLIGOPELVIS 1_GETUG P07 
 
Ref ICO :  
ICO-N-2014-02 
 
 
 
 
 
 
 
N° EudraCT : 2014-A00138-39 
 
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Quality control of IMRT: all IMRT plans will undergo quality assurance evaluation with ion chamber measurements 
or an equivalent method of dose verification to verify the absolute dose for each IMRT field, and film dosimetry to 
measure the relative dose for each IMRT field, as is standard clinical practice. An independent monitor unit 
calculation may be substituted for ion chamber dosimetry when available. 
 
Management of previously irradiated patients 
When the prostate/prostate bed has been irradiated previously, a cumulative dosimetric study will be performed 
to assess for radiotherapy volumes overlap, and the 20 Gy isodose will be drawn.  
If any PTV1-5 has received more than 20 Gy during a previous course of irradiation, the patient should be excluded 
from the study.  
If less than 20 Gy was delivered to PTV1-5, the lower limit of PLN PTV will be restricted to PTV1-5. No modification 
of the dose constraints will be applied.  
 
Dose adjustment 
No dose adjustments will be made. 
• Hormonotherapy 
Hormone therapy is recommended Eligard 45 mg acting for 6 months.  
It will be ideally administered the day of start of radiation therapy or within 3 months before the first day of 
radiotherapy.  
 
Nevertheless, free prescription is left to investigators.  
When using other hormonal strategies (anti-androgen agonists, LHRH antagonists or LHRH), an administration for 
six months will be critical. 
 
 
F) STATISTICAL CONSIDERATIONS 
SAMPLE SIZE DETERMINATION  
It is difficult to accurately identify a control population. The recent adoption of FCH 
PET has enabled the detection of metastases in patients in biochemical relapse which 
the usual imaging modalities (bone scan, CT chest, abdomen and pelvis, pelvic MRI) 
were unable to detect. These patients therefore represent an intermediate group 
between patients with a rising PSA alone, and frank metastatic disease. To calculate 
the patient population, we can only rely on studies relating to a rising PSA patient 
population on one hand, and on first-line metastatic patients on the other hand. 
Prospective randomized data gathered from patients with a rising PSA showed that 
the median duration of biochemical control was 20 months with intermittent ADT 
[1]. Prospective randomized data concerning intermittent ADT in metastatic patients 
showed that 75 % of patients had resumed ADT after a mean duration of 15 months 
off [3]. Based on retrospective data, Ost et al. estimated that 51 % of patients are 
progression-free one to three years after salvage surgery or radiotherapy for pelvic 
oligometastatic disease [10]. Moreover, Rischke et al. showed a 50 % clinical 
recurrence at 2 year for patients undergoing both salvage lymphnode dissection and 
pelvic radiotherapy [18]. We therefore estimate that a biochemical relapse-free 
survival at 2 years of 70 % would be a significant result. 
Based on a one-step Fleming design [19], we wish to be 95 % (α < 5 %) certain that 
any difference observed between the standard and experiment treatment groups is 
not due to the play of chance. We also want to be able to detect such a difference 
with 95 % power (b = 5 %). With these α and b, rejecting the null hypothesis H0: Π ≤ 
50 %, and accepting the alternative hypothesis H1: Π ≥ 70 %, will require 63 evaluable 
patients. 

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Around 10 % of patients may be lost to follow-up before the evaluation of 
biochemical relapse at 2 years, so to ensure that we retain at least 63 patients until 
this evaluation it will be necessary to recruit 70 patients to this study. If 39 or more 
of these 63 evaluable patients are still free of biochemical relapse at 24 months, we 
may reject the null hypothesis H0: Π ≤ 50 % with a risk of error of 3.85 % and a power 
of 93.5 % to detect the alternative hypothesis H1: Π ≥ 70 %. 
DESCRIPTION OF ANALYSIS SETS  The statistical analysis will be conducted with SAS 9.4 (Institute Inc., Cary, NC, USA), 
Stata 13.1 Special Edition (StataCorp LP, College Station, Texas, USA). For all analyses, 
a p-value of less than 0.05 was considered as statistically significant. All reported p-
values are two sided. 
 
Description of analysis sets 
Data from all evaluable patients will be analyzed.  
 
Descriptive statistics 
A descriptive analysis of the patients included will be carried out. This analysis will 
include point estimates, numbers and percentages for qualitative variables, and 
mean, standard deviation, median, quantiles and range for quantitative variables.  
 
Analysis of safety endpoints 
If a patient presented the same toxic event several times, only the higher grade event 
was analyzed. 
 
Analysis of survival endpoints 
The different survival endpoints were analyzed are defined as follows: 
 
Progression-free survival (PFS): time from randomization until biochemical-clinical 
failure or death from any cause. The definition of a biochemical-clinical failure is 
detailed in section 8.5.1.  
Overall survival (OS): time from randomization until death from any cause. 
 
Patients for whom the event will not occur during the follow-up period will be 
censored at their last follow-up date.  
For PFS and OS, the determination of survival curves will be performed by means of 
Kaplan-Meier method. 
 
Analysis of quality of life scoring 
Quality of life scores were compared between baseline and 6 months, and between 
baseline and 12 months using a Wilcoxon signed test for matched pairs. A Benjamini-
Hochberg procedure was applied to control for false discovery rate. Quality of life 
differences were considered as clinically relevant when greater than 10. 
 
Statistical criteria for stopping the study 
An analysis of acute toxicity persisting at one month after radiotherapy will be 
performed after the inclusion of the 20th patient to ensure that the toxicity of the 
irradiation protocol is not higher than expected. 
If, among the first 20 patients, 10 or more patients present with grade 2 toxicity, we 
can state that the rate of grade 2 complications is greater than the reference norm 
of 30 % (p = 0.048). In this case the Data Safety Monitoring Board (DSMB) will meet 
to analyze the toxicity and decide whether to continue the study. 
If, among the first 20 patients, 2 or more patients present with grade 3 toxicity, we 
can state that the rate of grade 3 complications is above the reference norm of 2 % 

Short title : 
OLIGOPELVIS 1_GETUG P07 
 
Ref ICO :  
ICO-N-2014-02 
 
 
 
 
 
 
 
N° EudraCT : 2014-A00138-39 
 
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(p = 0.059). In this case the DSMB will meet to analyze the toxicity and decide 
whether to continue the study. 
 
 
G) STUDY CALENDAR 
DURATION OF INCLUSION PERIOD 
24 months 
TREATMENT DURATION 
ADT + IG-IMRT: 6 months of ADT / 6 to 7 weeks (30 
fractions) of IG-IMRT 
POST TREATMENT FOLLOW UP 
10 years 
PRIMARY ENDPOINT ANALYSIS EXPECTED DURATION 
2 years 
STUDY COMPLETION DURATION (INCLUDING FU PERIOD) 
12,5 years 
 
SCHEDULE OF STUDY ASSESSMENTS 
 
 
 
 
 
 

Short title : 
OLIGOPELVIS 1_GETUG P07 
 
Ref ICO :  
ICO-N-2014-02 
 
 
 
 
 
 
 
N° EudraCT : 2014-A00138-39 
 
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STUDY DIAGRAM