Randomized Phase II Study Evaluating Late Toxicity Following Intensity-Modulated Radiotherapy and Two Image-Guided Strategies With Corresponding Treatment Margins. (RCMIGI)
Phase: NA
Conditions: Prostate Cancer
Sponsor: Institut du Cancer de Montpellier - Val d'Aurelle

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
Page 1 / 42 
 
 
 
 
Randomized phase II study evaluating late toxicity following 
Intensity-Modulated Radiotherapy and two Image-Guided 
strategies with corresponding treatment margins. 
RCMIGI 
 
 
ID-RCB n°: 2015-A00817-42 
Sponsor Code: ICM-URC 2015/33 
 
Study sponsor Institut régional du Cancer de Montpellier 
208, rue des Apothicaires 
34298 Montpellier Cedex 5 – France 
http://www.icm.unicancer.fr/ 
Phone: +33 4 67 61 31 02 
Fax: +33 4 67 41 30 23 
Medical Coordinator 
Dr Olivier RIOU 
Institut régional du Cancer de Montpellier 
Department of Radiation Oncology – Pr David AZRIA 
Phone : +33 4 67 61 31 32 
Fax: +33 4 67 61 31 35 
olivier.riou@icm.unicancer.fr 
Medical Physicist Pascal FENOGLIETTO 
Institut régional du Cancer de Montpellier 
Department of Radiation Oncology 
Phone: +33 4 67 61 85 05 
Fax: +33 4 67 61 31 35 
pascal.fenoglietto@icm.unicancer.fr 
Biostatistician Sophie GOURGOU / Marta JARLIER 
Institut régional du Cancer de Montpellier 
Biometrics Unit 
Phone: +33 4 67 61 45 57 
Fax: +33 4 67 61 37 18 
marta.jarlier@icm.unicancer.fr 
Clinical Research Associate Laetitia MEIGNANT 
Institut régional du Cancer de Montpellier 
Department of Clinical Research 
Phone: +33 4 67 61 47 38 
Fax: +33 4 67 61 30 76 
Laetitia.meignant@icm.unicancer.fr 
Ethics committee approval (CPP Sud Méditerranée III): 4/03/2016 
ANSM approuval: 19/05/2016 
The information provided in this document is confidential and the property of Montpellier Cancer Institute. It is intended solely for parties associated with the clinical 
investigation or for regulatory purposes. Reproduction and/or distribution of the information contained therein is not authorized without the consent of Montpellier 
Cancer Institute, except the information necessary to obtain informed consent of individuals participating in this clinical trial. 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
Page 2 / 42 
 
 
 
 
 
Table of content 
 
 
1. 
Background and Rationale  .................................................................................................................................. 15 
1.1. 
Radiotherapy for protate cancer  .................................................................................................................... 15 
1.2. 
Image-guided radiotherapy (IGRT)  ................................................................................................................. 16 
1.3. 
Calypso® system  ............................................................................................................................................. 16 
1.4. 
Hypothesis  ...................................................................................................................................................... 17 
2. 
Study design  ......................................................................................................................................................... 17 
2.1. 
Trial design  ..................................................................................................................................................... 17 
2.2. 
Estimated study duration  ............................................................................................................................... 18 
3. 
Trial objectives  ..................................................................................................................................................... 18 
3.1. 
Primary objective  ........................................................................................................................................... 18 
3.2. 
Secondary objectives  ...................................................................................................................................... 18 
4. 
Patient selection  ................................................................................................................................................... 18 
4.1. 
Inclusion criteria  ............................................................................................................................................. 19 
4.2. 
Non-inclusion criteria  ..................................................................................................................................... 19 
4.3. 
Patient enrolment and registration  ................................................................................................................ 20 
5. 
Treatments  ............................................................................................................................................................ 20 
5.1. 
Patient workflow for implant and simulation  ................................................................................................ 20 
5.2. 
Contouring  ...................................................................................................................................................... 20 
5.3. 
Dose prescription  ........................................................................................................................................... 21 
5.4. 
Beam delivery  ................................................................................................................................................. 22 
5.5. 
Patient setup and verification  ........................................................................................................................ 22 
5.6. 
Concomitant androgen deprivation  ............................................................................................................... 22 
6. 
Expected Adverse events  .................................................................................................................................... 22 
7. 
Study plan and timing procedures  ..................................................................................................................... 24 
7.1. 
Flow chart of the study ................................................................................................................................... 24 
7.2. 
Clinical evaluation and follow-up procedures  ................................................................................................ 26 
7.2.1. 
Baseline  ................................................................................................................................................. 26 
7.2.2. 
Before radiotherapy (after randomization)  ....................................................................................... 26 
7.2.3. 
During radiotherapy  ............................................................................................................................. 27 
7.2.4. 
End of radiotherapy  ............................................................................................................................. 27 
7.2.5. 
Follow-up period (1, 3, 6, 12, 18, 24, 36, 48, 60 months from the end of radiotherapy)  ........ 27 
8. 
Assessment endpoints  ......................................................................................................................................... 27 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
Page 3 / 42 
 
 
 
 
8.1. 
Primary endpoint  .......................................................................................................................................... 27 
8.2. 
Secondary endpoints  ................................................................................................................................... 27 
9. 
Rila test .................................................................................................................................................................. 28 
10. 
Statistical considerations  ................................................................................................................................. 28 
10.1. 
Sample size calculation ............................................................................................................................ 28 
10.2. 
Statistical analysis  .................................................................................................................................... 30 
10.3. 
Study population  ...................................................................................................................................... 31 
10.4. 
Modifications of the statistical analysis plan and initial strategy  ....................................................... 31 
11. 
Procedures for data collection  ........................................................................................................................ 31 
12. 
Vigilance  ............................................................................................................................................................ 32 
12.1. 
Adverse events  ......................................................................................................................................... 32 
12.1.1. 
Definition  ........................................................................................................................................... 32 
12.1.2. 
Collection and reporting of adverse events  .................................................................................. 32 
12.1.3. 
Severity criteria  ................................................................................................................................ 33 
12.2. 
Device effect  ............................................................................................................................................. 33 
12.3. 
Device efficiency (MDR Article 2(59))  ................................................................................................... 33 
12.4. 
Serious Adverse Event  ............................................................................................................................. 34 
12.4.1. 
Definition  ........................................................................................................................................... 34 
12.4.2. 
Reportable Events  ............................................................................................................................ 34 
12.5. 
Causality  .................................................................................................................................................... 35 
12.5.1. 
Unanticipated SADE (MDCG 2020-10/1 10,2.18-RDM (EU) 2017/45) ....................................... 35 
12.5.2. 
Suspected Unexpected Serious Adverse Reaction  ....................................................................... 36 
12.5.3. 
SAE/New Event, Device Deficiency, Notification procedure  ....................................................... 36 
13. 
Quality assurance  ............................................................................................................................................. 37 
13.1. 
Management of the study  ....................................................................................................................... 37 
13.2. 
Confidentiality  ........................................................................................................................................... 37 
13.3. 
Archiving  .................................................................................................................................................... 37 
14. 
Ethical and Regulatory considerations  .......................................................................................................... 37 
14.1. 
Ethics Committee  ..................................................................................................................................... 38 
14.2. 
Subject information and consent  ........................................................................................................... 38 
15. 
Study insurance  ................................................................................................................................................ 38 
16. 
Publication Policy  .............................................................................................................................................. 38 
17. 
References  ........................................................................................................................................................ 39

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
 
Page 4 / 42 
 
 
 
 
 
 
 
 
TITLE 
Randomized phase II study evaluating late toxicity following Intensity-
Modulated Radiotherapy and two Image-Guided strategies with 
corresponding treatment margins 
PROTOCOL CODES 
Acronym: RCMIGI 
Sponsor Code: ICM-URC 2015/33 
ID-RCB number: 2015-A00817-42 
STUDY SPONSOR 
Institut régional du Cancer de Montpellier (ICM) Direction de Recherche 
Clinique et Innovation (DRCI) 208 rue des Apothicaires 
34298 Montpellier Cedex 05 – France 
 
Contact names : 
Dr Jean-Pierre BLEUSE 
Phone: +33 4 67 61 31 02 
E-mail: jean-pierre.bleuse@icm.unicancer.fr 
Mme Laetitia MEIGNANT Clinical research associate of DRCI  
Phone : + 33 4 67 61 47 38 
Email : laetitia.meignant@icm.unicancer.fr 
STUDY 
COORDINATOR   
Dr Olivier RIOU 
Institut régional du Cancer de Montpellier Department of Radiation Oncology – Pr 
David AZRIA 208 rue des Apothicaires 
Phone: +33 4 67 61 31 32 
E-mail: olivier.riou@icm.unicancer.fr 
MEDICAL 
PHYSICIST 
M. Pascal FENOGLIETTO 
Department of Radiation Oncology 208 rue des Apothicaires 
Phone: +33 4 67 61 85 05 
E-mail: pascal.fenoglietto@icm.unicancer.fr 
METHODOLOGY 
AND DATA 
MANAGEMENT 
CENTER 
Institut régional du Cancer de Montpellier 
Biometrics Unit 
208 rue des Apothicaires 
34298 Montpellier Cedex 05 – France 
 
Mme Marta JARLIER 
Phone: + 33 4 67 61 45 57 
E-mail: marta.jarlier@icm.unicancer.fr 
CLINICAL 
RESEARCH 
VIGILANCE UNIT 
Institut régional du Cancer de Montpellier 
208 rue des Apothicaires 
34298 Montpellier Cedex 05 – France 
 
Mme Nadia BENSMAIL 
Phone: + 33 4 67 61 45 68 
E- mail: nadia.bensmail@icm.unicancer.fr 
BACKGROUND 
AND
AND 
RATIONALE 
Prostate cancer is the most frequent cancer in men. Radiotherapy is one of the 
reference treatments for localized prostate cancer. Prostate was initially thought to be 
a non-moving target, but the newest reports have raised the contrary as evidence. 
Image-guided radiotherapy (IGRT) is a current standard treatment for localized 
prostate cancer which enables to take into account interfractional prostate motion 
before treatment. 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
 
Page 5 / 42 
 
 
 
 
The Calypso® System (Varian Medical Systems, Inc., Palo Alto, CA) is a recent 
technology using electromagnetic transponders implanted within the prostate.  It is 
a real-time target tracking system that takes into account both inter- and 
intrafractional target motion. So the exact position and movement of the prostate 
can be determined during radiation therapy treatment. 
As Planned Target Volume (PTV) margins integrate set-up margins and the 
management of organ motion, margin reduction can reasonably be considered in 
case of target motion management improvement. 
To date, no prospective randomized clinical data is available using this technique 
for the treatment of low- or intermediate-risk prostate cancer patients with modern 
standard fractionation radiotherapy and image guidance. 
The aim of this study is to assess pelvic late toxicity rate after intensity- modulated 
radiotherapy (IMRT) when using the Calypso® System with a reduction of 
treatment margins. In this randomized study, patients will receive IGRT treatment 
using the Calypso system or a conventional IGRT treatment. 
STUDY 
OBJECTIVE(S)   
Primary objective 
The main objective of the study is to assess the late pelvic toxicity rate after intensity-
modulated radiotherapy (IMRT) when using the Calypso® System with a reduction of 
the treatment margins. 
 
Secondary objectives 
The secondary objectives are to assess: 
- 
any acute toxicity, 
- 
any other late toxicity, 
- 
biochemical control, 
- 
complication relapse-free survival (CRFS), 
- 
quality of life, 
- 
correlation  between  late  toxicities  and  the  radiation-induced  T- lymphocyte 
apoptosis (RILA) rate. 
STUDY DESIGN 
Open, prospective, monocentric, randomized, phase II clinical trial. 
INVESTIGATIONAL 
SITE 
One investigator center will participate in the study: Montpellier Cancer Institute 
(ICM). 
ELIGIBILITY 
CRITERIA 
i) Inclusion criteria 
- 
Localized prostate cancer, histologically proven. 
- 
No evidence of metastases (M0). 
- No evidence of lymph nodes involvement (N0) (bilateral lymph node dissection 
is not mandatory if lymph node involvement risk is low according to the Partin 
tables). 
- Low-risk or intermediate clinical stage according to the D9Amico classification 
(T1-T2 and Gleason < 8 and PSA < 20 ng/ml) (appendix 3). 
- No grade g 2 urinary or rectal clinical sign or symptom according to the CTCAE 
V4.03 scale. 
- Performance status ECOG f 1. 
- No hip prosthesis or metallic vascular graft near the prostate. 
- No endopenian stent. 
- No pace maker, implanted defibrillator or neurostimulator. 
- No allergy to local anesthetics. 
- No irreversible 
anticoagulation 
or 
antiplatelet 
treatment 
for
 
the implantation period. 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
 
Page 6 / 42 
 
 
 
 
- Pelvic and abdominal anatomy compatible with the use of the Calypso® system 
(predictive detector to fiducials distance less than 19 cm, evaluated on planning 
CT-scan) (distance from skin surface to prostate center less than 17 cm. 
Furthermore, it is necessary to make sure that the patient9s anatomy allows the 
positioning of the receiver over 30 cms, in a cranio-caudal manner, on both sides 
of the isocentre position. 
- Patient aged g 18 and less than 80 years old. 
- Dated and signed written informed consent available. 
- Patients must be affiliated to a French Social Security System. 
ii) 
Exclusion criteria 
- Indication of pelvic nodes irradiation. 
- Prior pelvic irradiation. 
- Biopsy-proven seminal vesicle invasion. 
- Prior bilateral orchiectomy. 
- Prior radical prostatectomy. 
- Other malignancy except adequately-treated basal cell carcinoma of the skin or 
other malignancy from which the patient has been disease-free for at least 5 
years. 
- Psychological, familial, sociological or geographical condition potentially hampering 
compliance with the study protocol and follow-up schedule; those conditions 
should be discussed with the patient before registration in the trial. 
- Other 
uncontrolled systemic disease (cardiovascular, renal, liver, 
pulmonary embolism, etc.). 
- Known VIH positive patients (no specific test needed). 
- Known homozygote ATM Mutation (Ataxia telengiectasia). 
TREATMENT 
MODALITIES 
Two image guided strategies during intensity-modulated radiotherapy in the treatment 
of localized prostate cancer will be considered: 
 
Arm 1 : (control) : Image-guided radiation therapy (IGRT) with standard margins 
 
Arm 2 : Calypso tracking system with margin reduction 
The control arm (arm 1) will represent an internal control to validate the hypothesis 
of the Fleming design used for calculation of the sample size. 
 
 
Registration and randomization will be performed at the Biometrics Unit of the 
Montpellier Cancer Institute (France). 
 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
 
Page 7 / 42 
 
 
 
 
STUDY ENDPOINTS Primary endpoint: 
The primary endpoint is defined by the incidence of grade g 2 late pelvic toxicities 
between 3 months and 2 years after radiation period (based on the Common 
Terminology Criteria for Adverse Events Version 4.03). 
 
Secondary endpoints: 
The secondary endpoints include: 
 
Any acute toxicity (until 3 months post radiotherapy) 
Any late toxicity (between 3 months and 2 years post radiotherapy), 
Biochemical relapse-free survival (BRFS) at 5 years is assessed by PSA tests: PSA 
nadir + 2, 
Complication relapse-free survival (CRFS) (at 2 years), 
Complication relapse-free survival (CRFS) (at 5 years), 
Quality  of  life  evaluation  using  EORTC  QLQ-C30  and  QLQ-PR25 questionnaires, 
Specific questionnaires for urinary obstruction (International Prostate Symptom 
Score: IPSS) and for erectile function (International Index of Erectile Function: IIEF5), 
Correlation between late toxicities (between 3 months and 2 years post 
radiotherapy) and the radiation-induced T-lymphocyte apoptosis (RILA) rate (low 
(f15) versus high (>15)). 
SAMPLE SIZE 
The primary endpoint of this study is the incidence of late pelvic grade ≥ 2 
toxicities. 
Sample size calculation for the experimental arm (Calypso system) will be based on 
a single-stage Fleming design for phase II trials. Fleming design is formulated in terms 
of success rate. 
 
In the context of this study, we define a success as a patient without grade 
≥2 late pelvic toxicity occurring after 3 months and until 2 years  after  
treatment  (based  on  the  Common  Terminology  Criteria  for Adverse Events Version 
4.03). 
 
Considering that the common expected success rate in this indication is 85% (p0), the 
smallest success rate expected in the experimental arm is set at 95% (p1). Using a 
one-stage Fleming design with one-sided α=0.05 and β=0.10, it will be necessary to 
include 75 evaluable patients. 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
 
Page 8 / 42 
 
 
 
 
The experimental treatment (Calypso system) may be considered sufficiently safe if 
at least 69 patients (among 75 evaluable patients) show a treatment success, 
otherwise the Calypso system will be considered as insufficiently safe. 
 
 
Stage 
Nb.of patients 
Insufficiently 
active safe if 
Sufficiently 
active safe if 
1 
75 first 
evaluable 
patients 
f 68 successes 
g 69 successes 
 
A concurrent control arm of a size equal to half that experimental, that is 38 patients, 
will be included in the study using a 2:1 randomization ratio (Calypso : Control).  
 
Taking into account a 10% rate of non-evaluable patients, a total of 83 patients will be 
required in CALYPSO arm whereas 42 patients in Control arm.    
 
Accordingly, a total of 125 patients will be recruited in the trial, 83 and 42 
patients in Calypso and Control (IGRT) arms respectively. 
 
Randomisation will be stratified according to the: 
Radiation-induced  lymphocyte  apoptosis  (RILA)  test  (low  (f15) versus high 
(>15)), 
Indication for hormonotherapy (yes versus no), 
Anticoagulation treatment (yes versus no), 
Diabetes patient status (yes versus no) 
STUDY PERIOD 
 
- 
Study start date: April 2016 
- 
Planned enrolment duration: 120 months 
- 
Study completion date: December 2028(12 years) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
 
Page 9 / 42 
 
 
 
 
LIST OF ABREVIATIONS 
 
 
 
 
 
ADL 
Activities of Daily Living 
Ae 
Adverse Event 
Aes 
Adverse Events 
AP 
Abdomino-Pelvic 
ATM 
Ataxia Telangiectasia Mutated 
BRFS 
Biochemical Relapse-Free Survival 
CBCT 
Cone-beam Computed Tomography 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRFS 
Complication Relapse-Free Survival 
CT 
Computed Tomography 
CTV 
Clinical Target Volume 
Gy 
Gray 
IGRT 
Image-Guided Radiation Therapy 
IIEF5 
International Index of Erectile Function 
IMRT 
Intensity-Modulated Radiotherapy 
IPSS 
International Prostate Symptom Score 
ITT 
Intent-To-Treat 
LH-RH 
Luteinizing Hormone - Releasing Hormone 
MRI 
Magnetic Resonance Imaging 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
OBI 
On-Board Imager 
PTV 
Planned Target Volume 
PP 
Per-Protocol 
RCMI 
Radiothérapie Conformationnelle avec Modulation d'Intensité 
RCMIGI 
Radiothérapie Conformationnelle avec Modulation d'Intensité Guidée par l'Image 
RILA 
Radiation-Induced Lymphocyte Apoptosis 
RT 
Radiotherapy 
RTGI 
Radiothérapie Guidée par l'Image 
SAP 
Statistical Analysis Plan 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
 
Page 10 / 42 
 
 
 
 
 
 
1. Background and Rationale 
 
 
1.1. RADIOTHERAPY FOR PROTATE CANCER 
 
Prostate cancer is the most frequent cancer in men [1]. Radiotherapy is one of the reference 
treatments for localized prostate cancer [2]. The results of radiotherapy versus surgery 
(radical prostatectomy) are modulated by the patients9 prognostic factors, and are 
considered equivalent [3]. Most patients survive for many years following external beam 
radiotherapy (RT) for non-metastatic prostate cancer and are therefore at risk of late 
treatment sequelae. The favorable outcomes after radiotherapy for prostate cancer allows 
treated patients to be considered as long-term survivors. They are thus exposed to the 
possibility of late secondary effects, negatively impacting their quality of life. The expected 
main late toxicities after prostate radiotherapy are mainly digestive, urinary and sexual 
toxicities. For prostate-only radiotherapy (without pelvic irradiation), digestive toxicities are 
only rectal: proctitis, rectal bleeding, rectal pain, rectal stenosis, rectal mucositis and diarrhea. 
Urinary toxicities are related to bladder and urethra radiotherapy, and are mainly cystitis, 
dysuria, pollakiuria, nycturia, hematuria, uretral stenosis, urine incontinence, urinary 
urgencies, urinary tract obstruction, urinary tract pain. Expected late sexual toxicities are 
erectile dysfunction and ejaculation disorders [4–6]. 
 
Many factors influence the occurrence of these toxicities, including the treated volume, total 
dose, fractionation and patient radiosensitivity [7, 8]. The reduction of the treatment margins, 
when safely possible, might thus improve the toxicity profile of radiotherapy by reducing 
the treatment volume. 
 
In 2014-2015, when the protocol was written, dose-escalated normo-fractionated external 
beam radiotherapy (EBRT) was a standard of care for low to intermediate risk prostate cancer. 
That9s why a standard fractionation of 2 Gy x 40 fractions was chosen for the first years of 
inclusion. 
However, since then, the results of major studies of moderate hypofractionation EBRT have 
been released. 
In 2016, 2 non inferiority trials and 1 superiority trial were published [9]. 
The CHHiP trial was a large 3 arms trial establishing that moderate hypofractionation of 3 gy 
x 20 fractions was non inferior to normo fractionated EBRT in terms of biochemical and clinical 
control [10]. 
The RTOG 0415 trial confirmed that moderate hypofractionation was non inferior to 
normofractionation regarding cancer control (5-year DFS) [11]. 
However, the HYPRO trial failed to demonstrate that moderate hypofractionation was superior 
to dose-escalated normo fractionated EBRT with respect to 5-year relapse-free survival [12]. 
In 2017, 2 additional trials of moderate hypofractionation for prostate cancer were published 
[9]. 
The Regina Elena National Cancer Institute trial did not demonstrate a superiority of 62 Gy 
given in 3.1 Gy fractions over 80 Gy normo fractionated trial for cancer control. However, 
overall toxicity was similar between the 2 arms [13]. 
The PROFIT trial established that moderate hypofractionation was non inferior to dose-
escalated 78 Gy normo fractionated EBRT regarding biochemical-clinical failure [14]. 
When looking to CHHiP and PROFIT trial, probably the best and largest trials on moderate 
hypofractionation for prostate cancer, late pelvic toxicity was not significantly different in 
hypofractionated Vs normofractionated arms. 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
 
Page 11 / 42 
 
 
 
 
On the basis of these results, moderate hypofractionated EBRT has been gradually adopted as 
an attractive therapeutic option for the treatment of low and intermediate risk prostate cancer 
patients. Without calling into question the interest of dose-escalated normo fractionated 
radiotherapy, moderate hypofractionation also has the advantage of reducing treatment time 
by half, which simplifies patient care.  
EAU-EANM-ESTRO-ESUR-SIOG 2020 guidelines has endorsed moderate hypofractionation has 
a standard of care [15]. 
ESTRO-GIRO recently published a survey on hypofractionation which confirmed that 
hypofractionation was widely adopted by the radiotherapy community for the treatment of low 
to intermediate risk prostate cancer. Indeed, more than 60 % of EBRT for this cancer type in 
Europe and 80 to 90 % in Northern America were treated with hypofractionation [16]. 
As our center has a good experience of moderate hypofractionation of 3.1 Gy x 20 fractions, 
we propose to switch to this fractionation for the remaining patients to include in the study 
[17]. 
 
1.2. IMAGE-GUIDED RADIOTHERAPY (IGRT) 
 
Organ motion is a recent concern during prostate radiotherapy. Prostate was initially thought 
to be a non-moving target, but newest reports have raised the contrary as an evidence [18, 
19]. Image-guided radiotherapy (IGRT) is a current standard treatment for localized prostate 
cancer which enables taking into account interfractional prostate motion before treatment 
[20-22]. Few systems have been developed to account for intrafractional target motion [23-
27]. The newest linear accelerators for example are able to use kilovoltage images of the on- 
board imager (OBI) to check for the intrafractional fiducials position at several time points 
during radiotherapy delivery. 
 
IGRT protocols in use are highly variable depending of in-house policies at the different 
hospitals and imaging capabilities of the linear accelerators available [22, 26]. No consensual 
guidelines regarding IGRT for prostate cancer IMRT are available. A minimal requiring for 
accordance to the definition is to provide at least daily imaging. Some protocols use fiducial 
implants to improve repositioning, others tridimensional on-board imaging, but the optimal 
protocol remains to be defined [28]. 
 
 
1.3. CALYPSO® SYSTEM 
 
The Calypso® System (Varian Medical Systems, Inc., Palo Alto, CA) is a real-time target 
tracking system that takes into account both inter- and intrafractional target motion [19]. 
This system consists in an electromagnetic array that can continuously detect, with sub- 
millimeter accuracy, the positions of signal-emitting transponders implanted in the target 
[29, 30]. It was shown to be more accurate than on-board imaging repositioning in 
observational prospective and retrospective studies [27, 29, 31]. Electromagnetic positioning 
seems to be the most precise system for real-time monitoring and inter/intra fractional 
prostate motion prediction as compared with setup using skin marks or stereoscopic X-ray 
localization of fiducials [27, 32, 33]. 
 
As Planned Target Volume (PTV) margins integrate set-up margins and the management of 
organ motion, the reduction of the treatment margins can reasonably be considered in case 
of target motion management improvement. 
 
The system was recently analyzed in feasibility studies in a limited number of patients [19, 
30, 34-37], and in a phase II study assessing stereotactic ablative body radiotherapy in low- 
risk prostate cancer patients [38]. One cohort study retrospectively compared a margin 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
 
Page 12 / 42 
 
 
 
 
reduction cohort using the Calypso® System with a conventional-margin cohort in terms of 
acute morbidity in prostate cancer patients treated with high-dose IMRT [39]. 
 
To date, no prospective randomized clinical data is available using the Calypso technique for 
the treatment of low- or intermediate-risk prostate cancer patients with modern standard 
fractionation radiotherapy and image guidance. 
 
Whether margin reduction could be translated into an improved toxicity rate with equal 
efficacy is an important question to be answered before widespread clinical implementation 
of the technique. 
 
 
1.4. HYPOTHESIS 
 
The tolerance profiles could be different between the conventional IGRT protocol and the 
IGRT protocol using the Calypso® System in patients with low- or intermediate-risk prostate 
cancer. The Calypso® System takes into account the target motion of the prostate and could 
reduce the margins. This would result in improving the pelvic toxicity rate with the same 
treatment efficiency. 
 
We hypothesize that the rate of grade g 2 pelvic toxicities will be f 5% with the use of the 
Calypso system. The results obtained will allow an assessment of the Calypso system in 
terms of late pelvic toxicities. 
 
 
 
2. Study design 
 
 
2.1. TRIAL DESIGN 
 
This trial is a phase II, monocentric, open-label, two- arm and randomized study using two- 
image guided strategies during intensity-modulated radiotherapy treatment: IGRT with 
standard margins (Arm 1) and the Calypso tracking system with margin reduction (Arm 2) in 
the treatment of localized prostate cancer. 
 
The Control arm will represent an internal control to validate the hypothesis of the Fleming 
desing used for calculation of the sample size. 
 
A total of 113 evaluable patients (125 patients if we consider a 10% of non-evaluable 
patients) will be randomized into arms 1 and arm 2 in a 2:1 ratio. 
 
 
Arm 1: IGRT arm with standard margins (38 evaluable patients)  
Arm 2: Calypso® arm with margin reduction (75 evaluable patients) 
 
 
 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
 
Page 13 / 42 
 
 
 
 
 
 
 
Randomization 2:1 will be stratified according to the: 
 
- 
Radiation-induced lymphocyte apoptosis (RILA) test (low (f 15) versus high (>15)) 
[40, 41], 
- 
Indication for hormonotherapy (yes versus no), 
- 
Anticoagulation treatment (yes versus no), 
- 
Diabetes patient status (yes versus no) 
 
 
2.2. ESTIMATED STUDY DURATION 
 
The subject accrual period is planned to last approximately 60 months. 
-           Submission to the Ethics committee : December 2015 
- 
     Start of inclusions : April 2016 
- 
End of inclusions : April 2026 
- 
Statistical analysis : December 2028 
 
 
3. Trial objectives 
 
 
 
3.1. PRIMARY OBJECTIVE 
 
The main objective of the study is to assess the late pelvic toxicity rate after intensity- 
modulated radiotherapy (IMRT) when using the Calypso® System with a reduction of the 
treatment margins. 
 
 
3.2. SECONDARY OBJECTIVES 
 
The secondary objectives are to assess: 
 
- 
any acute toxicity, 
- 
any other late toxicity, 
- 
biochemical control, 
- 
complication relapse-free survival (CRFS), 
- 
quality of life, 
- 
correlation between late toxicities and the radiation-induced T-lymphocyte apoptosis 
(RILA) rate. 
 
 
4. Patient selection 
 
Each patient should meet all of the inclusion criteria (Section 4.1) and none of the non- 
inclusion criteria (Section 4.2), for this study. 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
 
Page 14 / 42 
 
 
 
 
 
 
4.1. INCLUSION CRITERIA 
 
The patients must fulfill all the following criteria to be eligible to enter the study: 
 
- 
Localized prostate cancer, histologically proven. 
- 
No evidence of metastases (M0). 
- 
No evidence of lymph nodes involvement (N0) (bilateral lymph node dissection is not 
mandatory if lymph node involvement risk is low according to the Partin tables). 
- 
Low-risk or intermediate clinical stage according to the D9Amico classification (T1-T2 and 
Gleason < 8 and PSA < 20 ng/ml) (appendix 3). 
- 
No grade g 2 urinary or rectal clinical sign or symptom according to the CTCAE V4.03 
scale. 
- 
Performance status ECOG f 1. 
- 
No hip prosthesis or metallic vascular graft near the prostate. 
- 
No endopenian stent. 
- 
No pace maker, implanted defibrillator or neurostimulator. 
- 
No allergy to local anesthetics. 
- 
No irreversible anticoagulation or antiplatelet treatment for the implantation period. 
- 
Pelvic and abdominal anatomy compatible with the use of  the  Calypso®  system 
(predictive detector to fiducials distance less than 19 cm, evaluated on planning CT-scan) 
(distance from skin surface to prostate center less than 17 cm. Furthermore, it is necessary 
to make sure that the patient9s anatomy allows the positioning of the receiver over 30 cms, 
in a cranio-caudal manner, on both sides of the isocentre position. 
- 
Patient aged g 18 and less than 80 years old. 
- 
Dated and signed written informed consent available. 
- 
Patients must be affiliated to a Social Security System. 
 
 
4.2. NON-INCLUSION CRITERIA 
 
Patients presenting with any of the following non-inclusion criteria will not be included in the 
study: 
 
- 
Indication of pelvic nodes irradiation. 
- 
Prior pelvic irradiation. 
- 
Biopsy-proven seminal vesicle invasion. 
- 
Prior bilateral orchiectomy. 
- 
Prior radical prostatectomy. 
- 
Other malignancy except adequately-treated basal cell carcinoma of the skin or other 
malignancy from which the patient has been disease-free for at least 5 years. 
- 
Psychological, familial, sociological or geographical condition potentially hampering 
compliance with the study protocol and follow-up schedule; those conditions should be 
discussed with the patient before registration in the trial. 
- 
Other uncontrolled systemic disease (cardiovascular, renal, liver, pulmonary 
embolism, etc.). 
- 
Known VIH positive patients (no specific test needed). 
- 
Known homozygote ATM Mutation (Ataxia telengiectasia). 
 
 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
 
Page 15 / 42 
 
 
 
 
4.3. PATIENT ENROLMENT AND REGISTRATION 
 
Enrolment in the study is defined as both the signing of the Informed Consent and validation 
of eligibility criteria by the investigator. The inclusion and exclusion criteria should be 
checked during the screening period to ensure appropriate subjects are assigned to 
participate in the present study. 
Eligible patients will be randomized prior to starting therapy. 
 
Randomization will be stratified by following factors: 
 
- 
RILA test (low (f 15) versus high (>15)) , 
- 
Indication for hormonotherapy (yes versus no), 
- 
Anticoagulation treatment (yes versus no), 
- 
Diabetes patient status (yes versus no) 
 
 
Registration and randomisation will be performed at the Biometrics Unit of the Montpellier 
Cancer Institute (France). 
 
Investigators should use a dedicated registration form (see appendix 4) inserted into the CRF 
and fax the filled and signed form to: 
 
 
Biometrics Unit – Montpellier Cancer Institute (Montpellier) 
From Monday through Friday (9.00 AM to 5.00 PM) 
Fax: +33 4 67 61 37 18 
Phone: +33 4 67 61 45 40 / 45 48 
 
 
Afterward, the investigator will receive by fax the notification form with the patient9s 
identification number be reported on each CRF page and the treatment arm assigned (either 
IGRT with standard margins or Calypso with margin reduction). 
 
 
 
5. Treatments 
 
 
5.1. PATIENT WORKFLOW FOR IMPLANT AND SIMULATION 
 
Patients will undergo Computed Tomography (CT) scan based and Magnetic Resonance 
Imaging based (optional) virtual simulations before fiducial implants in order to enhance 
target volume accuracy. 
 
They will then undergo a Calypso beacon implant (arm 2) according to the treatment arm 
allocation (see appendix 5 for the implantation instructions). The Calypso beacon implant will 
be performed at the Beau Soleil Clinic Urology Department (Montpellier). 
 
Arm 2: patients will undergo a second CT-scan simulation 14 to 28 days after the implant for 
radiotherapy planning. The radiotherapy will be performed 3 to 6 weeks after the implantation. 
 
 
5.2. CONTOURING 
 
Organs 
Prostate has to be defined as Clinical target Volume (CTV). Seminal vesicles will be delineated 
in their proximal part, i.e. 2 cm from their prostate attachment in the cranio- caudal and 
lateral directions. Rectum is defined 2 cm upper and lower the CTV1. The bladder should be 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
 
Page 16 / 42 
 
 
 
 
drawn on each slide where it appears. Femoral heads are defined from the head of the 
acetabulum to the trochanter. 
 
Planning volumes 
CTV1 = prostate + seminal vesicles 
CTV2 = prostate 
• 
ARM 1: 
 
o PTV1 = CTV1 + 1cm (0.5 cm in the posterior direction) 
o PTV2 = CTV2 + 1cm (0.5 cm in the posterior direction) 
o PTV2 3mm = CTV2 + 0.3 cm 
• 
ARM 2: 
o PTV1 = PTV2 + [ VS+ (1 cm cranial, 1 cm lateral, 0.3 cm anterior and 0.5 cm 
posterior)] 
o PTV2 3mm = CTV2 + 0.3 cm 
 
 
Dose constraints 
ARM 1: IGRT arm with standard margins 
PTV2: 95% of the volume covered by the 95% prescription dose (59 Gy). 
D 99%  g  90%  of  the  prescribed  dose  (55,8  Gy),  D  107%  f  2%  of  volume,  
Dmax (0.1%)<110% 
 
 
PTV1: 95% of the volume covered by the 95% prescription dose (42 Gy)  
 
Rectum: Dose 0.1% f 62 Gy (59 Gy if possible), 
 V53 Gy f 50% 
Bladder: D0.1% f 63 Gy.  
V53 Gy f 50% 
 
ARM 2: Calypso® arm with margin reduction 
PTV2: 
D 99.5% (99% accepted) of the volume g 95% prescription dose 59 gy.  
V 100 % of the prescribed dose (62 Gy) g90% PTV2 
 
PTV1:  
D 99.5% (99% accepted) g 95% prescription dose 42 Gy  
V 100 % of the prescribed dose (89 Gy) g90% PTV1 
 
Rectum: Dose 0.1% f  62 Gy (59 Gy if possible),  V53 Gy f 50% 
Bladder: D0.1% f 63 Gy. V53 Gy f 50% 
 
 
5.3. DOSE PRESCRIPTION 
 
62 Gy will be delivered to the PTV2 for patients in arm 1 and PTV2 3mm for patients in arm 
2, and 44 Gy to the PTV1 for patients in both arms in 20 fractions. 
 
The period treatment will be of 4 weeks. 
 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
 
Page 17 / 42 
 
 
 
 
 
5.4. BEAM DELIVERY 
 
All treatment will be delivered with Volumetric Modulated Arc therapy using 2 arcs. 
 
 
5.5. PATIENT SETUP AND VERIFICATION 
 
Arm 1: CBCT and kV-kV positioning + per-fraction verification with kV imaging each 90° of 
rotation and gating with True Beam V2.0. 
 
Arm 2: CBCT and Calypso positioning + calypso per-treatment tracking. 
 
 
5.6. CONCOMITANT ANDROGEN DEPRIVATION 
 
Concomitant hormonotherapy using 3 to 6 months Luteinizing Hormone – Releasing Hormone 
(LH-RH) agonists will be used in intermediate-risk patients unless medical contra- indication, 
according to the standard practice. 
 
 
6. Expected Adverse events 
 
Adverse events (AEs) will be assessed according to the NCI-CTCAE v4.03 toxicity scale (see 
appendix 2). 
 
The most frequent AEs due to the beacon implant are: 
- 
Bleeding (hematuria, hematospermia, hematochezia), 
- 
Pain (procedural, anal, perineal, bowel movements, unspecified), 
- 
Dysuria, 
- 
Infection (urinary tract infection with prostate infection which occur in <2% of 
patients), 
- 
Fever. 
 
Other observed AEs include: 
- 
Urinary retention, 
- 
Urinary obstructive symptoms (urinary frequency, weak stream, etc.), 
- 
Implant migration. 
 
The following AEs also have been documented following transrectal biopsy; however, they 
occur in <1% of patients: 
- 
Nausea or sickness 
- 
Allergic reaction to antibiotic prophylaxis 
- 
Perineal swelling 
- 
Sepsis 
- 
Epididymitis 
- 
Temporary fecal incontinence 
- 
Urethral perforation 
- 
Deep venous thrombosis 
- 
Vascular embolization of the implant (pulmonary embolism) 
- 
Vasovagal episode 
- 
Cardiac arrhythmia 
 
Expected acute AEs due to the radiotherapy are: 
- 
Moderate fatigue, 
- 
An increase in the frequency of urination and defecation, 
- 
Rectal burning sensation with sometimes hemorrhoids crisis, 
- 
Increased frequency to defecate without exoneration of stools. 

RCMIGI trial – Protocol Version n° 6.0 22/10/2021 RCB n°2015-A00817-42 
 
 
Page 18 / 42 
 
 
 
 
 
Expected late AEs due to the radiotherapy are: 
- 
Difficulty to urinate, 
- 
An increase in the frequency of urination and defecation, 
- 
Rectal or bladder bleeding 
- 
Sexual difficulties. 
 
 
The  decision  to  discontinue  radiotherapy  due  to  inacceptable  toxicity  will  be  taken  in 
agreement with the coordinator and the investigator. 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
 
 
 
 
 
 
 
Page 24 / 42 
 
 
 
 
 
 
7. Study plan and timing procedures 
7.1. FLOW CHART OF THE STUDY 
 
 
Baseline 
Before 
radiotherapy 
During 
Radiotherapy 
End of 
radiotherapy 
Follow-up (from end of radiotherapy) 
M1 
M3 
M6 
M12 
M18 
M24 
M36 
M48 
M60 
Signed informed consent form1 
+ 
 
 
Review of eligibility criteria 
+ 
 
 
Demographic information 
+ 
 
 
Medical, surgical and oncologic 
history2 
+ 
 
 
Height3, Weight 
+ 
 
 
ECOG performance status 
+ 
 
 
Clinical examination 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Toxicity evaluation (CTCAE V4.03) 
+ 
+4 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Pelvic MRI or AP CT-scan4 5 
+ 
 
 
Bone scan or whole-body bone 
MRI 6 
+ 
 
 
PSA test 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
Before 
randomization 
Simulation CT-scan 
(optional MRI) 
+ 
 
 
 
 
 
After 
randomization 
Arm 1: Conventional 
IGRT7 
+ 
Conventional 
positioning 
 
 
Arm 2: Calypso 
beacon implant 8 
Simulation CT-scan9 
+ 
Calypso 
positioning and 
tracking 
 
 
RILA test 
+ 
 
 
Quality of life EORTC questionnaires 
QLQ-C30 and QLQ-PR250 
+ 
+ 
 
+ 
+ 
+ 
+ 
 
+ 
+ 
+ 
+ 
+ 
IPPS and IIEF5 questionnaires11 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
 
 
 
 
 
 
 
Page 25 / 42 
 
 
 
 
 
 
1 Signed informed consent form: prior to any study procedures 
2 Medical, surgical and oncologic history: including cancer diagnosis, prior surgery, concurrent illness, concomitant treatment. 
3 Height: only at baseline. 
4 Toxicity evaluation (CTCAE V4.03): if the patient is randomly assigned to the arm 2 then the toxicity evaluation (including urinary, rectal and sexual symptoms) will be 
performed before and after the Calypso beacon implant. 
5, 6  Pelvic magnetic resonance imaging (MRI) or abdomino-pelvic (AP) CT-scan and Bone scan or whole-body bone MRI are required for the intermediate 
clinical stage. AP CT-scan and Bone scan or whole-body bone MRI are left at the investigator9s discretion for the low-risk clinical stage. 
During and after the treatment radiologic procedures are left at the investigator9s discretion. 
7 Conventional IGRT if the patient is randomly assigned to the arm 1. 
8 Calypso beacon implant if the patient is randomly assigned to the arm 2. 
9 Simulation CT-scan if the patient is randomly assigned to the arm 2: will be performed 14 to 28 days after the implant for radiotherapy planning. 
10, 11 Quality of life evaluation using questionnaires will be performed before and at the end of treatment and at each evaluation (1 month, 3 months, every 6 months until 
two years then every year from end of radiotherapy). 
11 International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF5). 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 26 / 42 
 
 
 
 
 
 
7.2. CLINICAL EVALUATION AND FOLLOW-UP PROCEDURES 
 
 
7.2.1. 
BASELINE 
 
The following procedures and assessments will be performed before any treatment: 
The patient must provide a signed informed consent form prior to any study related 
procedures. 
 
 
- 
Review of eligibility criteria (medical, surgical and cancer histories), 
- 
Demographic information, 
- 
Medical, surgical and oncologic history including cancer diagnosis, prior surgery, 
concurrent illness, concomitant treatment: 
o Concurrent illness: diabetes*, 
o indication for hormonotherapy*, 
o Anticoagulant treatment*, 
- 
Height, weight, 
- 
ECOG performance status (appendix 1), 
- 
Clinical examination, 
- 
Toxicity evaluation, 
- 
Pelvic MRI or AP CT-Scan within 4 months prior to starting treatment, 
- 
Bone scan or whole-body bone MRI within 4 months prior to starting treatment, 
- 
PSA test, 
- 
RILA test (see paragraph 9)*, 
- 
Quality  of  life  using  QLQ-C30  (appendix  10)  and  QLQ-PR25  (appendix  11) 
questionnaires [42], 
- 
IPPS (appendix 12) and IIEF5 (appendix 13) questionnaires [43]. 
 
 
* Those procedures are required for randomization. 
 
 
The RILA test will be performed during the first consultation or at the time of simulation CT- 
scan visit and after signed informed consent form. 
 
 
Before randomization, a simulation CT-scan (optional MRI) will be performed. 
A consultation with an anesthetist will be planned in order to perform the Calypso beacon 
implant. According to the randomization result, the consultation will be only performed in the 
Calypso arm (arm 2) and cancelled in the arm 1. 
 
 
7.2.2. 
BEFORE RADIOTHERAPY (AFTER RANDOMIZATION) 
 
- Conventional IGRT protocol if the patient is randomly assigned to the arm 1. 
- Calypso beacon implant if the patient is randomly assigned to the arm 2. The toxicity 
evaluation (including urinary, rectal and sexual symptoms) will be performed before and 
after the Calypso beacon implant. The information concerning the implant and the patient 
monitoring will be noted in the medical record. Patients will be instructed to contact the 
centre in case of any complication after the beacon implantation. 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 27 / 42 
 
 
 
 
 
 
7.2.3. 
DURING RADIOTHERAPY 
 
 
Toxicity evaluation will be done. 
Toxicities will be assessed every week during radiation period according to the CTCAE V4.03. 
 
 
7.2.4. 
END OF RADIOTHERAPY 
 
- 
Clinical examination, 
- 
Toxicity evaluation (CTCAE V4.03), 
- 
Quality of life using QLQ-C30 and QLQ-PR25 questionnaires, 
- 
IPPS and IIEF5 questionnaires. 
 
 
7.2.5. 
FOLLOW-UP PERIOD (1, 3, 6, 12, 18, 24, 36, 48, 60 MONTHS FROM THE END OF 
RADIOTHERAPY) 
 
- 
Clinical examination, 
- 
Toxicity evaluation (CTCAE V4.03), 
- 
PSA test, 
- 
Quality of life using QLQ-C30 and QLQ-PR25 questionnaires, 
- 
IPPS and IIEF5 questionnaires. 
 
 
8. Assessment endpoints 
 
 
8.1. PRIMARY ENDPOINT 
 
The primary endpoint is defined by the incidence of grade g 2 late pelvic toxicities between 
3 months and 2 years after treatment (based on the Common Terminology Criteria for 
Adverse Events Version 4.03). 
 
 
8.2. SECONDARY ENDPOINTS 
 
The secondary endpoints include: 
 
- 
Any acute toxicity (until 3 months post radiotherapy) 
- 
Any late toxicity (between 3 months and 2 years post radiotherapy), 
- 
Biochemical relapse-free survival (BRFS) at 5 years is assessed by PSA tests: PSA 
nadir + 2*, 
- 
Complication relapse-free survival (CRFS) (at 2 years)* *, 
- 
Complication relapse-free survival (CRFS) (at 5 years)* *, 
- 
Quality of life evaluation using EORTC QLQ-C30 and QLQ-PR25 questionnaires before 
and at the end of treatment and at each evaluation (1 month, 3 months, every 6 
months until two years then every year from end of radiotherapy), 
- 
Specific questionnaires for urinary obstruction (IPSS) and for erectile function (IIEF5) 
before and at the end of treatment and at each evaluation (1 month, 3 months, every 
6 months until two years then every year from end of radiotherapy), 
- 
Correlation between late toxicity (between 3 months and 2 years post radiotherapy) 
and the radiation-induced T-lymphocyte apoptosis (RILA) rate (low (f15) versus high 
(>15)). 
 
 
 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 28 / 42 
 
 
 
 
*BRFS is defined as the interval between the date of randomization and the date of 
detection of a biochemical failure (definition below*), clinical relapse or death, whichever occurs 
first. 
Biochemical failure after radiation therapy is defined an increase in the PSA value more than 
the nadir of the PSA + 2 ng/ml. 
 
**CRFS is defined as the interval between the date of randomization and the date of rectal 
or urinary grade 2 or more late toxicity, biochemical relapse, clinical relapse or death, 
whichever occurs first 
 
COVID-19 Heath crisis, and after reporting data during this period, didn9t have an impact on 
the protocol medical care of patients included in this study and therefore didn9t have an 
impact on the assessment endpoint defined initially. 
 
9. Rila test 
 
 
The RILA test results will be used for the stratified randomization and for the correlation 
between the late toxicity and the RILA rates (see appendix 7). 
 
For the RILA test, one 10 ml Lithium Heparin (LiH) blood tube should be collected on 
Monday or on Tuesday at baseline and before randomization. 
Tubes will be identified with the subject9s study code, date and time of sampling, and 
identification number of the investigational site. 
 
 
The tubes will be then sent to the Institut de Recherche en Cancérologie de Montpellier - 
INSERM: 
 
Laura Bourillon- Equipe AP (Laura.Bourillon@icm.unicancer.fr) 
INSERM - U1194- IRCM (EX U896) 
Magasin sous-sol du Bât. Recherche F2 
31 rue de la croix verte 
34298 MONTPELLIER CEDEX 05 
(phone: 04 67 61 24 34) 
 
 
10. 
Statistical considerations 
 
 
10.1. SAMPLE SIZE CALCULATION 
 
The primary endpoint of this study is the incidence of late pelvic grade g 2 toxicities. 
 
Sample size calculation for the experimental arm (Calypso system) will be based on a single- 
stage Fleming design for phase II trials. Fleming design is formulated in terms of success 
rate. 
 
In the context of this study, we define a success as a patient without grade g2 late pelvic 
toxicity occurring after 3 months and until 2 years after treatment (based on the Common 
Terminology Criteria for Adverse Events Version 4.03). 
 
Considering that the common expected success rate in this indication is 85% (p0), the 
smallest success rate expected in the experimental arm is set at 95% (p1). Using a one- 
stage Fleming design with one-sided α=0.05 and β=0.10, it will be necessary to include 75 
evaluable patients. 
Taking into account a 10% rate of non-evaluable patients, a total of 83 patients will be 
required in Calypso arm. 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 29 / 42 
 
 
 
 
The number of success will be evaluated on the first 75 evaluable patients. 
 
The experimental treatment (Calypso system) may be considered sufficiently safe if at least 
69 patients (among 75 evaluable patients) show a treatment success, otherwise the Calypso 
system will be considered as insufficiently safe. 
 
Stage 
Nb. of patients 
Insufficiently 
safe if 
Sufficiently safe 
if 
1 
75 first evaluable 
patients 
f68 successes 
g69 successes 
 
A concurrent control arm of a size equal to half that experimental, that is 38 patients, will be 
included in the study using a 2:1 randomization ratio (Calypso : Control).  
 
Taking into account a 10% rate of non-evaluable patients, a total of 83 patients will be required 
in CALYPSO arm whereas 42 patients in Control arm.    
 
Accordingly, a total of 125 patients will be recruited in the trial, 83 and 42 patients in 
Calypso and Control (IGRT) arms respectively. 
 
The control group is used as a validation of the hypothesis that success rate without Calypso 
system is 85%. The 90% Confidence Interval (90%CI) of the success rate will be estimated 
on the 38 evaluable patients of the control group. If 85% is included in the 90%CI, the final 
conclusion will be the Fleming design conclusion. Conversely, if 85% is not included in the 
90%CI, the final conclusion will be taken as follows: 
 
IGRT (Control) Group 
: observed 90%CI 
Calypso system : Fleming plan 
Positive result 
Negative result 
85% < lower 
boundary 
Discuss the result 
Fleming design 
conclusion 
85% within the 
90%CI 
Fleming design 
conclusion 
Fleming design 
conclusion 
85% > upper 
boundary 
Fleming design 
conclusion 
Discuss the result 
 
 
Randomisation will be stratified according to the: 
- 
RILA test (low (f15) versus high (>15)), 
- 
Indication for hormonotherapy (yes versus no), 
- 
Anticoagulation treatment (yes versus no), 
- 
Diabetes patient status (yes versus no) 
 
Note: Sample size is not modified. The proposed change on prescribed dose and fractioning 
does not alter the original scope of the research as the result of the above cited large non-
inferiority trials provide enough evidence of no difference in late pelvic toxicity between 
normofractionned and moderate hypofractionation. Nonetheless, a subgroup analysis is 
henceforth planned and a meta-analytic approach will be used to provide a pooled estimation 
of the proportion of success (and its IC95%) in the experimental Calypso arm (cf. §10.2. 
Statistical analysis). 
 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 30 / 42 
 
 
 
 
 
 
 
10.2. 
STATISTICAL ANALYSIS 
 
A detailed statistical analysis plan (SAP) will be elaborated before the database is frozen. No 
formal statistical comparison will be made between the treatment arms. 
 
Data will be summarized using frequencies and percentages for categorical variables and 
using medians and ranges for continuous variables. 
 
The percentage of patients without gradeg2 late pelvic toxicity (Pobs) (success) occurring 
after 3 months and until 2 years after treatment, as well as the percentage of patients 
experiencing at least a gradeg2 late pelvic toxicity in that period (1-Pobs ; primary endpoint of 
the trial) will be presented for each arm with their respective 90% (and 95%) confidence 
interval based on binomial exact distribution. 
 
The decision about the effect of the experimental arm (Calypso system with reduction of 
treatment margins) in terms of late pelvic toxicity rate will be stated according the decision 
rules described in previous section (sample size calculation). 
 
Moreover, in order to control for the additional heterogeneity introduced with the switch to 
moderate hypofractionation RT we will use a meta-analytic approach in order to consider this 
factor (i.e. the fractionation-group: normofractionned or moderate hypofractionned) into the 
calculation of a global pooled proportion of success (and its IC95%) in the experimental 
Calypso arm. 
 
This analysis will be performed using the Metaprop Stata module, implemented to perform 
meta-analysis of proportions in the Stata software (References are listed here below). A random 
effect model will be used to calculate a pooled global estimated of the proportion of success. 
Metaprop also allows computation of 95%CI using the score statistics and the exact binomial 
method, and incorporates the Freeman-Tukey double arcsine transformation of proportions. I2 
statistic will be used to describe the percentage of total variation due to the inter fractionation-
group heterogeneity. All the details concerning this part of the analysis will be also specified in 
the SAP [44, 45]. 
 
Biochemical and complication relapse-free survival curves will be estimated using the Kaplan- 
Meier method. 
 
The analysis of QLQ C30 and QLQ PR25 questionnaires will be performed in accordance with 
the EORTC guidelines. 
 
Specific questionnaires for urinary obstruction (IPSS) and erectile function (IIEF5) will be 
described at each evaluation and over time. 
 
Subgroup analysis:  a subgroup analysis into the experimental arm (Calypso system) will be 
conducted between the subgroup of patients that have followed a conventional RT and those 
who have followed a hypofractionned RT. This analysis concerns mainly the primary endpoint 
as well as toxicity-related secondary endpoints.  
 
All statistical analyses will be performed with the Stata v16 software (StataCorp LP, College 
Station, TX). 
 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 31 / 42 
 
 
 
 
Note: previous to the present protocol modification, an analysis was conducted on December 
2020, focussed on the incidence of pelvic late grade g 2 toxicity. This analysis based on 35 
evaluable patients in Calypso system (24 evaluable in RTGI standard) revealed only two failures 
overall, one in each group.  
Despite of this interim analysis, the planned sample size in this phase 2 trial (non-comparative) 
still large enough for a final analysis with an adequate final trade-off between α and β errors. 
 
 
Statistical reports planned: 
 
According to estimated study duration (Paragraph § 2.2):  
 
The final statistical analysis is planned at the end of 2028 (end of inclusions planned for April 
2026) including primary and secondary endpoints with a minimal median follow-up of 5 years. 
A statistical report will be delivered at that occasion. 
 
 
 
10.3. 
STUDY POPULATION 
 
All statistical analyses will be performed on an intent-to-treat (ITT) basis and per-protocol 
(PP) population. 
 
Populations for analysis are defined as follows: 
 
Intent-to-treat (ITT) population includes all patients who were randomized to one treatment, 
whether or not any study treatment was administered. Patients will be analyzed in the 
treatment group in which they were assigned by randomization. 
 
PP population includes all eligible and evaluable patients. 
 
 
The <Safety= Population includes all patients who received at least one administration of the 
treatment (radiotherapy). 
 
 
10.4. MODIFICATIONS  OF  THE  STATISTICAL  ANALYSIS  PLAN  AND  INITIAL 
STRATEGY 
 
Any modification to the initial statistical analysis plan (SAP) will be detailed with all the 
necessary arguments reported in an updated version of SAP. These modifications can include 
supplementary or exploratory analyses that were not initially planned. 
 
 
11. 
Procedures for data collection 
 
Study data will be recorded on the case report form (CRF) by the person designated by the 
investigator. A CRF is required and should be completed for each included subject. It is the 
investigator's responsibility to ensure the integrity of the information transcribed in the CRF. 
CRFs must be signed by the investigator or by an authorized staff member. These signatures 
will attest that the information contained in the CRFs is true. The investigator agrees to keep 
records, including the identity of all participating subjects, all original signed informed 
consent forms, copies of all CRFs, and source documents. 
 
 
 
It is the expectation of the Sponsor that all data entered into the CRF has source 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 32 / 42 
 
 
 
 
documentation available at the investigational site. The Study Data Management Center 
(Biometrics unit of Montpellier Cancer Institute) will record source documentation into a 
database in an ongoing basis. Systems with procedures that assure the quality of every 
aspect of study data management will be implemented, using Clinsight® software v6.2. 
 
 
12. 
Vigilance 
 
According to Article R1123-46 of the Public Health Code, Regulation (EU) 2017/745 of the 
European Parliament and of the Council of April 5, 2017 on medical devices (MDCG) and the 
MDCG 2020-10 / 1 
 
 
12.1. 
ADVERSE EVENTS ((MDR Article 2 (57))  
 
12.1.1. 
DEFINITION 
 
Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, 
including an abnormal laboratory finding, in subjects, users or other persons, in the context of 
a clinical investigation, whether or not related to the investigational device. 
 
An Adverse Event (AE) is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered an investigational radiotherapy/product and which does 
not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (for example: an abnormal laboratory finding), symptom, 
disease, or worsening of a pre-existing medical condition temporally associated with the use 
of an investigational radiotherapy/product, whether or not considered related to the 
investigational radiotherapy/ product. 
 
Disease progression in not an AE. 
 
Only abnormal laboratory findings that are clinically significant should be considered an AE. 
Abnormal laboratory findings are clinically significant if an active medical intervention is 
indicated, such as a dose modification of the investigational radiotherapy/ product; an 
interruption of the investigational radiotherapy/ product; the withdrawal of the investigational 
radiotherapy/ product; the introduction of a (symptomatic) treatment; the performance of 
additional diagnostic procedures; the increase in monitoring frequency. 
 
An AE related to the investigational radiotherapy/ product is also called an adverse reaction 
or effect. Disease progression is not an AE. 
 
12.1.2. 
COLLECTION AND REPORTING OF ADVERSE EVENTS 
 
Every AE occurring during the clinical trial should be recorded on the corresponding page of 
the Case Report Form. Every AE should be documented, monitored and followed until the AE 
is recovered or until 5 years after the end of the radiation period. 
 
Clinically significant abnormal laboratory findings should be monitored regularly by specific 
analysis until their values return within the normal reference ranges, to the baseline value or 
until an adequate explication of the out of range value has been found. 
 
For every AE, the following items will be documented by the Investigator: 
 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 33 / 42 
 
 
 
 
• 
A clear description of the event using the adequate medical terms; 
• 
The seriousness of the event; 
• 
The severity or grade of the event (severity criteria  are  described in  the  next 
paragraph); 
• 
The onset and end dates of the event; 
• 
The actions taken and the necessity to introduce a corrective treatment or not; 
• 
Whether the AE caused or not the withdrawal of the subject from the study; 
• 
The outcome of the event. In case of a non-fatal outcome, the AE should be 
documented until recovered, until the return to baseline conditions of the event or 
until stabilization of the event9s sequelae (the nature of the sequelae should be 
documented) ; 
• 
The causality between the event and the device/investigational radiotherapy/ product; 
• 
The eventual causality between the event and the study procedures (time laps 
without treatment, complementary assessments required by the protocol, etc.), the 
study pathology, a concomitant treatment, a concomitant pathology or any other 
factor. 
 
12.1.3. 
SEVERITY CRITERIA 
 
The severity criteria should not be mistaken with the seriousness criteria which determine 
the conditions of notification. The severity or grade of adverse events is evaluated by the 
Investigator following the NCI-CTCAE classification version 4.03. 
 
The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each 
AE based on this general guideline: 
 
• 
Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• 
Grade 2 = Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL (Activities of Daily Living)*. 
• 
Grade 3  =  Severe  or  medically  significant  but  not  immediately  life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
• 
Grade 4 = Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 = Death related to AE. 
 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
 
12.2.             DEVICE EFFECT 
 
An adverse device effect is an adverse event related to the use of an investigational device. A 
serious adverse device effect is an adverse device effect that has resulted in any of the 
consequence characteristics of a serious adverse event 
 
12.3. 
DEVICE DEFICIENCY (MDR Article 2(59)) 
 
Any inadequacy in the identity, quality, durability, reliability, safety or performance of an 
investigational device, including malfunction, use errors or inadequacy in information supplied 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 34 / 42 
 
 
 
 
by the manufacturer. 
 
 
12.4 SERIOUS ADVERSE EVENTS (MDR Article 2(58)) 
 
 
 
12.4.1 DEFINITION 
 
A Serious Adverse Event (SAE) is an adverse event which: 
 
• 
results in death 
• 
serious deterioration in the health of the subject, that resulted in any of the following: 
- 
is life-threatening illness or injury 
- 
permanent impairment of a body structure or a body function, 
- 
requires in-patient hospitalization or prolongation of existing hospitalization, 
- 
medical or surgical intervention to prevent life-threatening illness or injury 
or permanent impairment to a body structure or a body function 
- 
chronic disease, 
 
foetal distress, foetal death or a congenital physical or mental impairment or birth 
defect 
 
 
 
12.4.2 Reportable events  
 
 The following events are considered reportable events in accordance with MDR Art. 80(2) 
 
 
a- any serious adverse event that has a causal relationship with the investigational device, 
the comparator or the investigation procedure or where such causal relationship is 
reasonably possible; 
 
b) any device deficiency that might have led to a serious adverse event if appropriate action 
had not been taken, intervention had not occurred, or circumstances had been less fortunate; 
 
c) any new findings in relation to any event referred to in points a) and b) 
 
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to a reaction that hypothetically might have caused 
death if more severe. 
 
A hospitalization scheduled by the protocol (biopsy, hormonotherapy...) is not considered a 
SAE. A hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE is not considered a SAE. A hospitalization planned prior to 
patient enrolment is not considered a SAE, provided that his occurrence/outcome is clearly 
not aggravated by investigational device/radiotherapy/ product.  
 
Disease progression or any medical event related to disease progression linked to disease 
under study is not considered a SAE. 
 
The terms <disability= and <incapacity= match with all physical/psychological temporary or 
permanent handicaps, clinically significant with consequences for physical or mental 
functioning and/or the patient9s quality of life of the patient. 
 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious events, such as important medical events that might not be 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 35 / 42 
 
 
 
 
immediately life-threatening or result in death or hospitalization but might put at risk the 
subject or might require intervention to prevent one of the other outcomes listed above. 
Such events are considered serious with seriousness criterion <medically relevant=. Examples 
of such events are allergic bronchospasm, torsade de pointes or convulsions. 
 
The EudraVigilance Expert Working Group (EV-EWG) has coordinated the development of an 
Important Medical Event Terms (IME) list, which could help Investigators to determine 
whether an AE is serious or not: 
 
http://eudravigilance.ema.europa.eu/human/textforIME.asp 
 
The IME list is intended for guidance purposes only, and is not a mandatory requirement for 
seriousness assessment and regulatory reporting. 
 
Another example of a serious adverse event with seriousness criterion <medically relevant= is 
a suspected transmission via a medicinal product of an infectious agent. 
 
 
12.5 CAUSALITY  
For every SAE the Investigator and the Sponsor evaluate separately the possible causal 
relationship to the investigational device/ radiotherapy/ product. These evaluations might be 
different one from the other (for example: in the Investigator9s opinion the SAE is not related 
to the investigational device/radiotherapy/ product and in the Sponsor9s opinion the SAE is 
related to the investigational device/ radiotherapy/ product). 
 
The relationship between the use of the medical device (including the medical - surgical 
procedure) and the occurrence of each adverse even shall be assessed and categorized. 
 
During causality assessment activity, clinical judgement shall be used and the relevant 
documents, shall be consulted. The presence of confounding factors, such as concomitant 
medication/treatment, the natural history of the underlying disease, other concurrent illness 
or risk factors shall also be considered. 
 
For the purpose of harmonizing reports, each SAE will be classified according to four different 
levels of causality: 
1. Not related 
2. Possible 
3. Probable 
4. Causal relationship 
 
The sponsor and the investigators will use the following definitions to assess the relationship 
of the serious adverse event to the investigational device, the comparator or the investigation 
procedure. 
 
12.5.1 UNANTICIPATED SADE  (MDCG 2020-10/1 10.2.18- RDM (EU) 2017/745 
 
 
An Unanticipated Serious Adverse Device Effect is an effect which by its nature, incidence, 
severity or outcome has not been identified in the current risk assessment. Procedures 
associated with the use of a device should be addressed in the risk assessment, which makes 
it possible to determine whether the procedure related SAEs are Unanticipated Serious Adverse 
Device Effect or not. SAEs related to procedures imposed by the clinical investigation plan but 
not with the use of the device should not be considered Serious Adverse Device Effects. 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 36 / 42 
 
 
 
 
The Sponsor evaluates the unexpectedness of the SAE by consulting the study protocol and 
instruction for use of beacon care package for prostate. 
 
 
 
12.5.2 NEW EVENT  (article R1123-46 du CSP) : 
 
Any new data leading to a reassessment of the benefits / risks balance of the research or product 
of the research, to changes in the use of the product or in the conduct on documents related to 
the research, or to discontinuation, arrest or modification of the research protocol or that of 
similar research. 
 
 
 
12.5.3 SAE/New Event, DEVICE DEFICIENCY, NOTIFICATION PROCEDURE 
 
Every SAE, expected or unexpected, any device deficiency leading to SAE occurring during 
the study period (from the signature of the informed consent form until up to 2 years after 
the end of the radiation period) should be notified to the Sponsor without any further delay, 
using the <Serious Adverse Event Notification Form= (Appendix 8). This form should be 
completed following the completion instructions (Appendix 9) and be send to the ICM 
Clinical Research Pharmacovigilance Unit: 
E-mail: Notification-EIG-DRCI@icm.unicancer.fr 
 
Every SAE occurring beyond the 2 year-period after the withdrawal of the investigational 
radiotherapy/, judged by the investigator to be related to the device or device deficiency 
leading to SAE / investigational radiotherapy, or to the research should also be notified to the 
sponsor in the same conditions as every other SAE. 
 
The <Serious Adverse Event Notification Form= should be completed in English and only one 
diagnosis or one symptom (except for linked symptoms) should be reported to enable the 
MedDRA coding. If several symptoms are documented in the source documents, only the 
main symptom will be reported as verbatim on the notification form. 
 
After the initial notification, a follow-up report should be completed and sent every time 
complementary information on the SAE becomes available. Finally, when the case is closed, 
a final report with the complete information should be completed and sent to the 
Pharmacovigilance Unit (Notification-EIG-DRCI@icm.unicancer.fr) 
 
Complementary information or clarification may be requested by the Sponsor using Data 
Clarification Forms (DCFs). The Sponsor could also ask the site to send the anonymized 
medical records or laboratory findings corresponding to the SAE. The ICM, as the Sponsor of 
the trial, receives all SAE Notification Forms and evaluates the imputability and the 
expectedness of the SAEs. 
 
For other safety information:  
E-mail: Pharmacovigilance-icm105@icm.unicancer.fr 
 
Mme Nadia BENSMAIL 
Clinical Research Pharmacovigilance Unit 
Institut régional du Cancer Montpellier, Bât. A 
208, rue des Apothicaires, 34298 Montpellier 
Tel: +33 4 67 61 45 68 
 Fax: +33 4 67 61 31 04 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 37 / 42 
 
 
 
 
 
 
The risk-benefit balance of the study is evaluated continuously by the ICM Clinical Research 
Pharmacovigilance Unit and this risk-benefit balance will be discussed in the periodic safety 
reports. These reports will contain all required regulatory aspects and will be submitted to 
the competent authorities. 
 
 
13. 
Quality assurance 
 
 
13.1. MANAGEMENT OF THE STUDY 
 
In order to guarantee the authenticity and the credibility of the data according to GCPs, the 
Sponsor sets up a system of quality assurance, this comprises: 
- Management of the study according to the procedures of the Clinical Research Unit, 
- Quality control of data of the investigational site by the monitor whose role is to verify the 
similarity and coherence of CRF data compared to the source documents. Monitors will 
contact investigational sites prior to the start of the study to review with the site staff the 
protocol, study requirements, and their responsibility to satisfy ethical and regulatory 
requirements. 
 
The investigator should maintain a list of appropriately qualified persons to whom he/she as 
delegated trial duties. Study staff involved in conducting this study will be qualified by 
education, training, and experience to perform their respective task(s). 
 
 
13.2. CONFIDENTIALITY 
 
The coordinators commit themselves all the persons necessary for the performance of the 
trial, to guarantee the confidentiality of all information related to the project until the 
publication of the study results. The obligation of confidentiality will not be applied to the 
information that the investigator has to communicate to the patients in the context of their 
participation in the trial or to information already published. The investigator commits 
himself not to publish, disclose or use, in any way, directly or indirectly, the scientific or 
technical information related to the study. 
 
 
13.3. ARCHIVING 
 
Regarding patient clinical source documents, subject notes must be kept for the maximum 
time period permitted by the hospital, institution or private practice. Essential documents 
(copies of patients CRF and the Investigator9s Trial File) will be securely archived by the 
Sponsor for 15 year duration in accordance with the applicable regulatory requirement of the 
European Good Clinical Practices. Subject files may be reviewed under the investigator9s 
responsibility, and will be readily available upon authorities9 request. 
 
 
14. 
Ethical and Regulatory considerations 
 
The study will be conducted in accordance with the protocol, Good Clinical Practices (GCPs) 
guidelines as defined by the International Conference on Harmonization (ICH), the French 
regulations in force, namely the French Public Health Law No 2004-806 of 9 August 2004 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 38 / 42 
 
 
 
 
(Loi no 2004- 806 du 9 août 2004 relative à la politique de santé publique), the Bioethical 
Laws, the ethical principles that have their origin in the Declaration of Helsinki (appendix 14) 
and the the Informatics and Freedom Law and the European Regulation 2016/679 concerning 
the protection of the physical persons towards the personal data processing and concerning 
the free circulation of these data says <RGPD= (Règlement Général sur la Protection des 
Données)  
This study is registered at the ClinicalTrials.gov website (http://clinicaltrials.gov/): Identifier 
                NCT03254420 
 
 
14.1. ETHICS COMMITTEE 
 
This study has received the approval from the local Ethics Committee (CPP Sud Méditerranée 
III, Ref.2015.12.05). 
 
 
14.2. SUBJECT INFORMATION AND CONSENT 
 
The patient9s written informed consent must be obtained by the investigator or a person 
designated by the investigator before collecting any personal data. The written informed 
consent form should be signed and personally dated by the subject or by the subject9s legally 
acceptable representative, and by the person who conducted the informed consent 
discussion. The patient will be encouraged to ask the study investigator or delegate any 
question concerning the study and to discuss the study with any individual or other medical 
personnel. In addition, the patient will be offered the option to take home the consent forms 
and review them at her/his convenience and to discuss the study with other individuals to 
determine whether to participate in the study. 
 
 
15. 
Study insurance 
 
As study Sponsor, the Montpellier Cancer Institute (ICM) has subscribed to an insurance 
against civil liability in accordance with the applicable regulatory requirements of the Article 
L1121-10 of the French Public Health Code: SHAM – 18 rue Edouard Rochet - 69372 Lyon 
Cedex 08 (contract n° 140.474). 
 
 
16. 
Publication Policy 
 
The authors of the publications will be the persons who i) draft the article or revise it 
critically for intellectual content, ii) substantially contribute to conception, design, data 
collection, analysis and interpretation of data, iii) approve the final version to be published. 
No information can be used for publication or oral presentation without the written agreement 
of the study coordinator. 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 39 / 42 
 
 
 
 
 
17. 
References 
 
1. ©La situation du cancer en France en 2012. Collection état des lieux et des connaissances, ouvrage 
collectif édité par l’INCa, Boulogne-Billancourt, décembre 2012. . 
 
2. Jereczek-Fossa BA, Orecchia R: Evidence-based radiation oncology: definitive, adjuvant and salvage 
radiotherapy for non-metastatic prostate cancer. Radiother Oncol 2007, 84:197–215. 
 
3. Zaorsky NG, Harrison AS, Trabulsi EJ, Gomella LG, Showalter TN, Hurwitz MD, Dicker AP, Den RB: 
Evolution of advanced technologies in prostate cancer radiotherapy. Nat Rev Urol 2013, 10:565–579. 
 
4. Budäus L, Bolla M, Bossi A, Cozzarini C, Crook J, Widmark A, Wiegel T: Functional outcomes and 
complications following radiation therapy for prostate cancer: a critical analysis of the literature. Eur 
Urol 2012, 61:112–127. 
 
5. Ohri N, Dicker AP, Showalter TN: Late toxicity rates following definitive radiotherapy for prostate 
cancer. Can J Urol 2012, 19:6373–6380. 
 
6. Pardo Y, Guedea F, Aguiló F, Fernández P, Macías V, Mariño A, Hervás A, Herruzo I, Ortiz MJ, Ponce 
de León J, Craven-Bratle J, Suárez JF, Boladeras A, Pont À, Ayala A, Sancho G, Martínez E, Alonso J, 
Ferrer M: Quality-of-life impact of primary treatments for localized prostate cancer in patients without 
hormonal treatment. J Clin Oncol 2010, 28:4687–4696. 
 
7. de Crevoisier R, Fiorino C, Dubray B: [Dosimetric factors predictive of late toxicity in prostate 
cancer radiotherapy]. Cancer Radiother 2010, 14:460–468. 
 
8. Valdagni R, Rancati T, Fiorino C: Predictive models of toxicity with external radiotherapy for 
prostate cancer: clinical issues. Cancer 2009, 115(13 Suppl):3141–3149. 
 
9. Yu JB. Hypofractionated Radiotherapy for Prostate Cancer: Further Evidence to Tip the Scales. J Clin 
Oncol. 2017;35:1867–9.  
10. Dearnaley D, Syndikus I, Mossop H, Khoo V, Birtle A, Bloomfield D, et al. Conventional versus 
hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes 
of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17:1047–60.  
11. Lee WR, Dignam JJ, Amin MB, Bruner DW, Low D, Swanson GP, et al. Randomized Phase III 
Noninferiority Study Comparing Two Radiotherapy Fractionation Schedules in Patients With Low-Risk 
Prostate Cancer. J Clin Oncol. 2016;34:2325–32.  
12. Incrocci L, Wortel RC, Alemayehu WG, Aluwini S, Schimmel E, Krol S, et al. Hypofractionated versus 
conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final 
efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17:1061–
9.  
13. Arcangeli G, Saracino B, Arcangeli S, Gomellini S, Petrongari MG, Sanguineti G, et al. Moderate 
Hypofractionation in High-Risk, Organ-Confined Prostate Cancer: Final Results of a Phase III 
Randomized Trial. J Clin Oncol. 2017;35:1891–7.  
14. Catton CN, Lukka H, Gu C-S, Martin JM, Supiot S, Chung PWM, et al. Randomized Trial of a 
Hypofractionated Radiation Regimen for the Treatment of Localized Prostate Cancer. J Clin Oncol. 
2017;35:1884–90.  
15. Mottet N, van den Bergh RCN, Briers E, Van den Broeck T, Cumberbatch MG, De Santis M, et al. 
EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer-2020 Update. Part 1: Screening, 
Diagnosis, and Local Treatment with Curative Intent. Eur Urol. 2021;79:243–62.  

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 40 / 42 
 
 
 
 
16. Rodin D, Tawk B, Mohamad O, Grover S, Moraes FY, Yap ML, et al. Hypofractionated radiotherapy 
in the real-world setting: An international ESTRO-GIRO survey. Radiother Oncol J Eur Soc Ther Radiol 
Oncol. 2021;157:32–9.  
17. Chapet O, Decullier E, Bin S, Faix A, Ruffion A, Jalade P, et al. Prostate Hypofractionated Radiation 
Therapy With Injection of Hyaluronic Acid: Acute Toxicities in a Phase 2 Study. Int J Radiat Oncol. 
2015;91:730–6.  
18. Palombarini M, Mengoli S, Fantazzini P, Cadioli C, Degli Esposti C, Frezza GP: Analysis of inter- 
fraction setup errors and organ motion by daily kilovoltage cone beam computed tomography in 
intensity modulated radiotherapy of prostate cancer. Radiat Oncol 2012, 
 
19. Tanyi JA, He T, Summers PA, Mburu RG, Kato CM, Rhodes SM, Hung AY, Fuss M: Assessment of 
planning target volume margins for intensity-modulated radiotherapy of the prostate gland: role of 
daily inter- and intrafraction motion. Int J Radiat Oncol Biol Phys 2010, 78:1579–1585. 
 
20. Nguyen NP, Davis R, Bose SR, Dutta S, Vinh-Hung V, Chi A, Godinez J, Desai A, Woods W, Altdorfer 
G, D’Andrea M, Karlsson U, Vo RA, Sroka T, International Geriatric Radiotherapy Group: Potential 
applications of image-guided radiotherapy for radiation dose escalation in patients with early stage 
high-risk prostate cancer. Front Oncol 2015, 5:18. 
 
21. Zaorsky NG, Harrison AS, Trabulsi EJ, Gomella LG, Showalter TN, Hurwitz MD, Dicker AP, Den RB: 
Evolution of advanced technologies in prostate cancer radiotherapy. Nat Rev Urol 2013, 10:565–579. 
 
22. Créhange G, Martin E, Supiot S, Chapet O, Mazoyer F, Naudy S, Maingon P: [Image-guided 
radiotherapy in prostate cancer: concepts and implications]. Cancer Radiother 2012, 16:430–438. 
 
23. Bernchou U, Agergaard SN, Brink C: Radiopaque marker motion during pre-treatment CBCT as a 
predictor of intra-fractional prostate movement. Acta Oncol 2013, 52:1168–1174. 
 
24. Badakhshi H, Wust P, Budach V, Graf R: Image-guided radiotherapy with implanted markers and 
kilovoltage imaging and 6-dimensional position corrections for intrafractional motion of the prostate. 
Anticancer Res 2013, 33:4117–4121. 
 
25. Tong X, Chen X, Li J, Xu Q, Lin M-H, Chen L, Price RA, Ma C-M: Intrafractional prostate motion 
during external beam radiotherapy monitored by a real-time target localization system. J Appl Clin 
Med Phys 2015, 16:5013. 
 
26. Das S, Liu T, Jani AB, Rossi P, Shelton J, Shi Z, Khan MK: Comparison of image-guided radiotherapy 
technologies for prostate cancer. Am J Clin Oncol 2014, 37:616–623. 
 
27. Foster RD, Pistenmaa DA, Solberg TD: A comparison of radiographic techniques and 
electromagnetic transponders for localization of the prostate. Radiat Oncol 2012, 7:101. 
 
28. Korreman S, Rasch C, McNair H, Verellen D, Oelfke U, Maingon P, Mijnheer B, Khoo V: The 
European Society of Therapeutic Radiology and Oncology-European Institute of Radiotherapy 
(ESTRO-EIR) report on 3D CT-based in-room image guidance systems: a practical and technical review 
and guide. Radiother Oncol 2010, 94:129–144. 
 
29. Santanam L, Malinowski K, Hubenshmidt J, Dimmer S, Mayse ML, Bradley J, Chaudhari A, Lechleiter 
K, Goddu SKM, Esthappan J, Mutic S, Low DA, Parikh P: Fiducial-Based Translational Localization 
Accuracy of Electromagnetic Tracking System and On-Board Kilovoltage Imaging System. International 
Journal of Radiation Oncology*Biology*Physics 2008, 70:892–899. 
 
30. Langen KM, Willoughby TR, Meeks SL, Santhanam A, Cunningham A, Levine L, Kupelian PA: 
Observations on Real-Time Prostate Gland Motion Using Electromagnetic Tracking. International 
Journal of Radiation Oncology*Biology*Physics 2008, 71:1084–1090. 
 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 41 / 42 
 
 
 
 
31. Willoughby TR, Kupelian PA, Pouliot J, Shinohara K, Aubin M, Roach M, Skrumeda LL, Balter JM, 
Litzenberg DW, Hadley SW, Wei JT, Sandler HM: Target localization and real-time tracking using the 
Calypso 4D localization system in patients with localized prostate cancer. International Journal of 
Radiation Oncology*Biology*Physics 2006, 65:528–534. 
 
32. Mayyas E, Chetty IJ, Chetvertkov M, Wen N, Neicu T, Nurushev T, Ren L, Lu M, Stricker H, Pradhan 
D, Movsas B, Elshaikh MA: Evaluation of multiple image-based modalities for image-guided radiation 
therapy (IGRT) of prostate carcinoma: a prospective study. Med Phys 2013, 40:041707. 
 
33. Noel C, Parikh PJ, Roy M, Kupelian P, Mahadevan A, Weinstein G, Enke C, Flores N, Beyer D, 
Levine L: Prediction of Intrafraction Prostate Motion: Accuracy of Pre- and Post-Treatment Imaging 
and Intermittent Imaging. International Journal of Radiation Oncology*Biology*Physics 2009, 
73:692–698. 
 
34. Zhu M, Bharat S, Michalski JM, Gay HA, Hou W-H, Parikh PJ: Adaptive radiation therapy for 
postprostatectomy patients using real-time electromagnetic target motion tracking during external 
beam radiation therapy. Int J Radiat Oncol Biol Phys 2013, 85:1038–1044. 
 
35. Su Z, Zhang L, Murphy M, Williamson J: Analysis of Prostate Patient Setup and Tracking Data: 
Potential Intervention Strategies. International Journal of Radiation Oncology*Biology*Physics 2011, 
81:880–887. 
 
36. Kupelian P, Willoughby T, Mahadevan A, Djemil T, Weinstein G, Jani S, Enke C, Solberg T, Flores N, 
Liu D, Beyer D, Levine L: Multi-institutional clinical experience with the Calypso System in localization 
and continuous, real-time monitoring of the prostate gland during external radiotherapy. International 
Journal of Radiation Oncology*Biology*Physics 2007, 67:1088–1098. 
 
37. Klayton T, Price R, Buyyounouski MK, Sobczak M, Greenberg R, Li J, Keller L, Sopka D, Kutikov A, 
Horwitz EM: Prostate Bed Motion During Intensity-Modulated Radiotherapy Treatment. International 
Journal of Radiation Oncology*Biology*Physics 2012, 84:130–136. 
 
38. Mantz C: A Phase II Trial of Stereotactic Ablative Body Radiotherapy for Low-Risk Prostate Cancer 
Using a Non-Robotic Linear Accelerator and Real-Time Target Tracking: Report of Toxicity, Quality of 
Life, and Disease Control Outcomes with 5-Year Minimum Follow-Up. Front Oncol 2014, 4:279. 
 
39. Sandler HM, Liu P-Y, Dunn RL, Khan DC, Tropper SE, Sanda MG, Mantz CA: Reduction in Patient- 
reported Acute Morbidity in Prostate Cancer Patients Treated With 81-Gy Intensity-modulated 
Radiotherapy Using Reduced Planning Target Volume Margins and Electromagnetic Tracking: 
Assessing the Impact of Margin Reduction Study. Urology 2010, 75:1004–1008. 
 
40. Ozsahin M, Crompton NEA, Gourgou S, Kramar A, Li L, Shi Y, Sozzi WJ, Zouhair A, Mirimanoff RO, 
Azria D: CD4 and CD8 T-lymphocyte apoptosis can predict radiation-induced late toxicity: a 
prospective study in 399 patients. Clin Cancer Res 2005, 11:7426–7433. 
 
41. Azria D, Betz M, Bourgier C, Sozzi WJ, Ozsahin M: Identifying patients at risk for late radiation- 
induced toxicity. Crit Rev Oncol Hematol 2010. 
 
42. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, 
Fleishman SB, de Haes JC: The European Organization for Research and Treatment of Cancer QLQ- 
C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 
1993, 85:365–376. 
 
43. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A: The international index of 
erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 
1997, 49:822–830. 
 
44. Victoria Nyawira Nyaga & Marc Arbyn & Marc Aerts, 2014. "METAPROP: Stata module to 
perform fixed and random effects meta-analysis of proportions," Statistical Software Components 

RCMIGI trial – Protocol n° 6.0 15/10/2021 RCB n°2015-A00817-42 
 
 
Page 42 / 42 
 
 
 
 
S457781, Boston College Department of Economics, revised 15 Apr 2020. 
 
45. Nyaga, V.N., Arbyn, M. & Aerts, M. Metaprop: a Stata command to perform meta-analysis of 
binomial data. Arch Public Health 72, 39 (2014)).