Observational Study of Intra-operative Partial Irradiation of Invasive Ductal Breast Carcinomas With a Good Prognosis
Conditions: Invasive Breast Cancer, Breast-conserving Surgery
Sponsor: Institut du Cancer de Montpellier - Val d'Aurelle

PROTOCOLE INTRA OBS 
PROT ID : 2009/OBS-01 
NCT : NCT04414202 
Date : 15 Dec 2019 
 
 
TITLE 
INTRA-OBS: Observational study of intra-operative 
partial 
irradiation 
of 
invasive 
ductal 
breast 
carcinomas with a good prognosis 
Protocol ID: 2009/OBS-01 
N° NCT : NCT04414202 
 
 
SPONSOR 
CRLC [Regional Anti-Cancer Center] Val d’Aurelle  
208, rue des Apothicaires 
34298 Montpellier cedex 5, France 
 
 
COORDINATOR 
Dr C. LEMANSKI  
CRLC [Regional Anti-Cancer Center] Val d’Aurelle  
34298 Montpellier Cedex 5, France 
Tel: +33 (0)467613134  
 
INDICATION 
Invasive breast cancer with a good prognosis that is accessible 
to breast-conserving surgery. 
 
METHODOLOGY 
Monocentric observational study 
 
 
RATIONALE 
 
Due to screening, T1N0 early-stage breast cancer now 
accounts for more than 50% of the tumors diagnosed in 
France. The prognosis of these tumors is good, even excellent 
in women ≥ 65 years of age, with specific survival of 98% at 5 
years.  
The treatment of these tumors most often combines breast-
conserving surgery and external whole breast irradiation for 6.5 
weeks. 
 
A true de-escalation of treatment is taking place with these 
tumors, both surgically and medically. Surgery therefore now 
prefers breast-conserving methods in combination with 
exeresis of the sentinel lymph node only. In the same way, in 
many international studies, radiotherapy has been evaluating 
the possibility of reducing both: 
- 
the irradiation volume at the excision site (partial 
irradiation) 
- 
the 
duration 
of 
this 
irradiation 
(accelerated 
radiotherapy)  
 
Between 2004 and 2007, the CRLC [Regional Anti-Cancer 
Center] thus evaluated the feasibility and the oncological 
results of intra-operative partial irradiation via a phase II study 
in women 65 years of age and older with T1N0M0 hormone-
sensitive tumors with a good prognosis. 
From 2010 to 2013, the ICM carried out an observational study 
of these tumors with an excellent prognosis. 
 
In July 2009, the American Society for Radiation Oncology 
(ASTRO) published a consensus statement with specific 
recommendations and indications for accelerated partial breast 
irradiation (APBI). 
 
This APBI technique has been developing in France over the 
past 5 years within the framework of clinical studies and in 
compliance with the 2012 recommendations of the French 
National Cancer Institute. This APBI can be given by 3D 
external radiotherapy or, as in this study, by intra-operative 
radiotherapy (IORT) in order to obtain optimal precision and 
spare as much of the surrounding healthy tissue as possible.  

PROTOCOLE INTRA OBS 
PROT ID : 2009/OBS-01 
NCT : NCT04414202 
Date : 15 Dec 2019 
We therefore propose a cohort study to prospectively analyze 
the results of this technique applied to the indications strictly 
defined by the ASTRO.  
 OBJECTIVES 
Primary: 
      Local intra-mammary relapse rate 
 
Secondary: 
- 
Cosmetic results 
- 
Survival without metastatic relapse 
- 
Satisfaction of the patient with regard to her treatment 
- 
Impact of the accelerated treatment on the maintenance 
of autonomy in elderly patients 
 PATIENT SELECTION 
INCLUSION CRITERIA:  
-. Women 60 years of age or older,  
-  Histologically proven invasive ductal breast cancer or of a 
histologically favorable sub-type (mucinous, tubular or 
colloid), 
-. Unifocal tumor, 
-  T1 (diameter ≤ 20 mm), 
-  N0 (pN0 or pNi+),   
-  M0, 
-  Gland exeresis margins ≥ 2 mm,  
-  Estrogen receptor positive,  
-  Information and non-opposition of the patient.  
 
EXCLUSION CRITERIA: 
-. Inflammatory breast cancer, 
-  Associated peri-tumoral lymphatic 
-  Associated extensive intra-ductal component 
-  Invasive lobular carcinoma  
-  Pure ductal carcinoma in situ, 
-  Sarcoma or lymphoma-type non-epithelial tumor 
-  Synchronous bilateral breast cancer, 
-  Any prior neo-adjuvant treatment: radiotherapy, 
chemotherapy, hormone therapy  
 TREATMENT 
The treatment combines extended tumorectomy with axillary 
dissection (sentinel lymph node) in addition to 20 Gy of per-
operative partial irradiation at the tumor site. 
 NUMBER OF PATIENTS 
The number of patients is based on a recruitment potential of 
50 patients per year for 3 years, i.e. 150 patients.  
 STATISTICAL ANALYSIS 
We seek to demonstrate that the intra-mammary relapse rate 
is not increased, i.e. a local relapse rate for patients over 60 
years of age of between 4 and 7.3% at 10 years. 
 STUDY PERIOD 
3 years of inclusion. 
10 years of follow-up.    
 
 
 
 
 
 
 
 
 

PROTOCOLE INTRA OBS 
PROT ID : 2009/OBS-01 
NCT : NCT04414202 
Date : 15 Dec 2019 
 
 
 
 
2- STUDY RATIONALE 
 
Breast carcinoma remains the most common cancer in women in France, where it is currently a major 
public health issue, accounting for 37% of new cases of cancer (1). 
Its incidence increases considerably and regularly between 30 and 60 years of age, reaching a 
maximum plateau (at 320 cases in 100 000) in women 60 to 80 years of age (2). 
 
At the same time, breast cancer mortality has been decreasing since 1980 thanks to the improvement 
in treatments along with earlier diagnosis (1). 
Therefore, the early pT1N0 stages (diameter ≤ 2 cm without lymph node involvement), which currently 
account for 50 to 60% of diagnosed tumors (1), have a specific survival of 88% at 5 years. This 
percentage rises to 96% in patients 65 years of age and older (4). 
 
From a therapeutic standpoint, over the past 30 years, many international studies (5-7) have 
demonstrated that the combination of breast-conserving surgery and external radiotherapy administered 
over the entire breast was equivalent to mastectomy in terms of survival. It has now also been shown 
that the addition of this adjuvant radiotherapy to breast-conserving surgery increases overall survival (8-
9). Today, this surgery consists of a tumorectomy and axillary sentinel lymph node dissection.  
This radio-surgical combination is therefore the most common strategy. 
 
More recently, studies have shown that the addition of supplementary irradiation at the excision site 
further reduced the risk of local relapse (10), bringing it down to 6% with no differentiation based on age 
after 10 years of follow-up. 
Based on this, considering the most often very localized nature of this relapse, over the past years, 
many radiotherapy teams have developed the concept of Partial Breast Irradiation (PBI), proposing a 
reduction in irradiation volume (reduction in the irradiated volume of the breast, but also of the adjacent 
healthy organs such as the underlying heart and lungs).  
 
This partial irradiation therefore allows for an interesting de-escalation of treatment. 
Today, it is therefore being evaluated in many international studies using various irradiation techniques 
(interstitial curietherapy, MammoSite, intra-operative irradiation or 3D conformal radiation therapy). 
 
At the Montpellier CRLC [Regional Anti-Cancer Center], which has a great deal of experience in intra-
operative irradiation using electron therapy in breast cancer (11-12), we thus conducted a phase II study 

PROTOCOLE INTRA OBS 
PROT ID : 2009/OBS-01 
NCT : NCT04414202 
Date : 15 Dec 2019 
(13) between 2004 and 2007 evaluating the feasibility and reliability of this technique within the 
framework of single-dose intra-operative partial irradiation for tumors with an excellent prognosis 
(hormone sensitive T1N0M0 invasive ductal carcinoma in patients 65 years of age and older).       
 
 
With regard to the primary objective, the dosimetric results proved the reliability and reproducibility of 
the technique. With regard to the secondary objectives, the oncological results turned out to be good (2 
intra-mammary relapses out of 42 patients and 100% of patients alive and disease-free at 30 months). 
The cosmetic results were also considered to be good to excellent in 90% of patients. 
The immense clinical advantage of this intra-operative technique over the other partial irradiation 
techniques is its accelerated mono-fractionated character.  
Radiotherapy is thus administered during surgery and relieves the patient of 6 and a half weeks of 
demanding, costly, out-patient radiotherapy that elderly patients often have a hard time accepting.  
This APBI technique must however only be used in well-defined indications for tumors with an excellent 
prognosis for which the risk of occult microscopic disease in the rest of the non-irradiated breast is the 
lowest. 
It was with this objective that in July 2009 the American Society for Radiation Oncology (ASTRO) 
reviewed all of the 4 randomized studies and the 38 published studies conducted between 1993 and 
2008 regarding ABPI. This learned society then published a consensus statement (Smith, etc.) that very 
precisely defined the characteristics of a group of patients that could routinely benefit from this partial 
irradiation outside of a clinical study context. 
 
These criteria correspond to all the points that we have retained for our phase II study conducted at the 
Montpellier CRLC, thus validating the routine practice today of partial irradiation for: 
 
 
patients ≥ 60 years of age 
 
without known BRCA1/2 genetic mutation 
 
with an invasive cancer (exclusion of pure ductal carcinoma in situ) histologically proven by 
biopsy 
 
invasive ductal type or histologically favorable type (mucinous, tubular, colloid) 
 
T1: tumor diameter ≤ 20 mm (radiologically on the pre-operative MRI or ultrasound and 
extemporaneous measurement) 
 
Clinical N0 (and extemporaneously)  
 
Of any SBR grade 
 
Without vascular or lymphatic emboli (on the pre-operative biopsy)  
 
With estrogen receptors (ER+)  
 
Having received no neo-adjuvant treatment 
 

PROTOCOLE INTRA OBS 
PROT ID : 2009/OBS-01 
NCT : NCT04414202 
Date : 15 Dec 2019 
In conclusion, we are thus proposing a monocentric cohort study (this intra-operative technique is only 
used in France in this Center) to prospectively analyze the course of all the patients treated with intra-
operative partial irradiation at the Montpellier CRLC. 
 
 
3-OBJECTIVES OF THE STUDY 
3.1 Primary objective 
To evaluate the local relapse rate after local treatment combining extended tumorectomy with axillary 
(sentinel lymph node) dissection and per-operative partial irradiation of the tumor bed. 
3.2 Secondary objectives 
To study: 
- 
Cosmetic results 
- 
Survival without metastatic relapse 
- 
Satisfaction of the patient with regard to her treatment. 
- 
Impact of accelerated treatment on the maintenance of autonomy in elderly patients 
4-METHODOLOGY 
4.1 Study type 
This is a monocentric observational study. 
4.2 Patient registration 
The patients will be seen before surgery at a pre-operative consultation. Information will be given orally 
and in writing (annex 2). 
After checking the inclusion and exclusion criteria, eligible patients will be registered. 
 
Registration will be carried out by fax (+33 (0)4 67 61 37 18) at the biostatistics coordination center of 
the CRLC Val d’Aurelle during the stay in the surgical unit once the results of the extemporaneous 
analysis have been obtained. 
4.3 Inclusion evaluation 
Patients who are eligible for the study must have an initial evaluation during the 10 weeks prior to 
registration. 
 
This evaluation will include: 
Physical examination 

PROTOCOLE INTRA OBS 
PROT ID : 2009/OBS-01 
NCT : NCT04414202 
Date : 15 Dec 2019 
- WHO index, weight, height 
- Bra size (band and cup size) 
- 2D tumor size 
- ADL and IADL indexes (annexes 4 and 5) evaluated by the investigator or CRA 
- Listing of co-morbidities and concomitant treatments 
 
Para-clinical examinations 
- Bilateral mammography 
- Bilateral breast ultrasound with 2D measurement of tumor size 
- Breast MRI may be recommended, but remains optional 
- Chest X-ray  
- Liver ultrasound or abdominal CT scan 
- Bone scintigraphy 
- Photograph of both breasts straight on and the profile of the breast to be treated 
4.4 Follow-up evaluation during the study 
 
The follow-up of patients treated in the study is conventional monitoring in compliance with the current 
recommendations. 
It will be based on a physical examination every semester for the first 5 years. This clinical follow-up will 
then be carried out annually from the 6th to the 10th year. 
The para-clinical examinations will be limited to annual mammography and breast ultrasound. Breast 
MRI remains optional. In case of suspected local relapse (clinical and/or radiological), histological 
confirmation will be obtained. 
 
The evaluation of autonomy (ADL and IADL) (annex 3) as well as the patient satisfaction index (annex 
4) will be evaluated at 3 weeks, 6 months and 12 months of treatment to assess its impact. 
4.5 End of study evaluation and long-term follow-up 
At the end of the 10 years of observation of the study, in compliance with current recommendations, 
the patients will have annual clinical and radiological monitoring, as usual. 
 
If the patient withdraws or stops the study, the examination will be carried out at the planned date on 
the follow-up calendar (except for withdrawal from the study for an exceptional reason with conduct of 
the end of study examination within the 3 days following the withdrawal). 
5-PATIENT SELECTION  
5.1 Inclusion criteria 
1. Women 60 years of age or older,  
2. Histologically proven invasive ductal breast cancer or of a histologically favorable sub-type (mucinous, 
tubular or colloid), 

PROTOCOLE INTRA OBS 
PROT ID : 2009/OBS-01 
NCT : NCT04414202 
Date : 15 Dec 2019 
3. Unifocal tumor, 
4. T1 (diameter ≤ 20 mm), as per the pre-operative MRI and/or ultrasound dimensions and after per-
operative confirmation (extemporaneous examination), 
5. N0 (pN0 or pNi+),   
6. M0, 
 
7. Gland exeresis margins ≥ 2 mm,  
8. Estrogen receptor positive,  
9. Information and non-opposition of the patient 
5.2 Exclusion criteria 
1. Inflammatory breast cancer, 
2.  Associated peri-tumoral lymphatic 
3.  Associated extensive intra-ductal component 
4.  Invasive lobular carcinoma  
5.  Pure ductal carcinoma in situ, 
3. Sarcoma or lymphoma-type non-epithelial tumor 
7. Synchronous bilateral breast cancer, 
8.  Any prior neo-adjuvant treatment: radiotherapy, chemotherapy, hormone therapy 
6-TREATMENT ADMINISTERED IN THE STUDY 
6.1 Surgery  
6.1.1 Breast-conserving surgery 
 
 Skin incision 
The skin incision must be suited to the size and the location of the tumor to allow for exeresis in one 
piece. It must also allow for the insertion of the localizer necessary for irradiation. 
 Tumorectomy: 
The gland exeresis aims to obtain complete resection of the tumor, centered by pre-operative 
localization, with safety margins. 
 Orientation of the specimen and any other resections  
The surgeon must give the pathologist the oriented operative specimen and with stained margins as per 
the current recommendations. An extemporaneous measurement of the gland exeresis margins will 
always be carried out per-operatively. The tumor must be resected with a minimum gland margin of 
2 mm. 
 Axillary node dissection must preferably be of the sentinel lymph node type. 
 

PROTOCOLE INTRA OBS 
PROT ID : 2009/OBS-01 
NCT : NCT04414202 
Date : 15 Dec 2019 
6.2 INTRA-OPERATIVE RADIOTHERAPY  
6.2.1 Technique 
 
Per-operative irradiation must be localized precisely on the tumor bed. The gland resection areas of the 
tumorectomy site are mobilized for this, brought closer together and sutured by the surgeon. A circular 
localizer is then placed opposite the excision site and fixed to the table using a jointed metal device in 
order to avoid any mobilization. Its diameter (between 4 and 6 cm) is chosen based on the tumor 
diameter.  
 
The patient is then transferred under the dedicated linear accelerator located inside the surgical block. 
This localizer is then positioned in perfect alignment with the targeting device of the accelerator. 
Anesthesia monitoring of the patient is ensured during the transfer and during irradiation using several 
fixed and mobile monitors. The interval between surgery and per-operative radiotherapy is 30 to 35 
minutes.  
6.2.2 Per-operative irradiation 
The choice of electron beam energy is decided by the radiotherapist based on the tumor diameter and 
the thickness of the area to be treated, assessed jointly with the surgeon. An energy of 6 to 13 MeV is 
usually used. 
The dose delivered to the tumor bed is 21 Gy, which is calculated based on the isodose of 90%. 
6.2.3 
Remodeling and clips 
After the intra-operative radiotherapy, clips will always be left in place in the tumor bed in order to 
facilitate later follow-up of the surgical area. 
The surgeon will carry out breast remodeling in order to optimize the later final cosmetic result. 
6.3 Anatomical pathology analysis 
The operative and sentinel lymph node specimens are analyzed as per the conventional recommended 
procedures. 
The limits are considered negative if there is a safety margin of at least 2mm between the tumour and 
the resection margin marked with ink (Fisher 1994).6.3 Additional local treatments   
6.4 Conduct of the study 
During the consultation with the surgeon, intra-operative partial irradiation is offered to patients who 
meet the recommended criteria. The patient is invited to participate in the observational study. 
6.5 Systemic treatments  
Chemotherapy, if necessary, will be started at least 3 weeks after surgery with per-operative irradiation. 
Hormone therapy will be initiated after surgery and per-operative irradiation. 
7-EVALUATION OF EFFICACY 
The summary table of investigations is given in annex 1. 

PROTOCOLE INTRA OBS 
PROT ID : 2009/OBS-01 
NCT : NCT04414202 
Date : 15 Dec 2019 
7.1 Primary endpoint 
The primary endpoint of this study is the local relapse rate, defined as the number of intra-mammary 
relapses in the treated breast (regardless of the quadrant and including the skin) and homolateral lymph 
node, assessed at 10 years. 
7.2 Secondary endpoints 
 
- Study of survival without metastatic relapse, overall survival and specific survival. 
- Evaluation of the cosmetic result (annex 4) 
- Assessment of the impact of this accelerated treatment on the maintenance of subject’s autonomy 
using the geriatric scale (ADL, IADL) (annex 3). 
-Satisfaction of the patient (annex 4) 
 
8-STATISTIC ANALYSIS  
 
The number of patients is not limited.  
However, based on a potential recruitment of 50 patients per year, this study can be analyzed after a 
recruitment period of 3 years, or about 150 patients.  
The primary assessment will be the rate of intra-mammary relapse, which should remain the same as 
after traditional irradiation of the entire breast.  This rate of recurrence is estimated in the age series 
reported by EORTC (10) between 4 and 7.3% at 10 years for patients over 60 years of age ( 2 to 3.7% 
at 5 years for exponential distribution , with a unilateral confidence interval of 10%). The finding of a 
number of relapses 10 / 150 cases at 5 years – during the intermediate analysis - would lead to 
questioning this technique. 
9- REGULATORY AND ETHICAL ASPECTS 
9.1 General considerations 
This study does not involve changes in the management of patients related to the performance of any 
additional examination, does not result in the performance of any additional examination and does not 
change the doctor-patient relationship. It does not fall within the scope of the amended law on biomedical 
research, known as the Huriet-Sérusclat law of 9 August 2004. 
A statement of the study will be made to the National Commission for Information Technology and 
Freedoms (CNIL). 
The Committee on the Protection of Persons of XXXXXXX issued an opinion on XXXXXX. 
9.2 Patient information 
Prior to the completion of this study, the patient will be informed about the purpose of the research, the 
course and duration of the study, the benefits, potential risks and constraints of the study as well as the 
nature of the product under investigation and the advice given by the CPC (art. L.1122-1). 
All information will be summarized in a patient information leaflet that will be given to each patient. 

PROTOCOLE INTRA OBS 
PROT ID : 2009/OBS-01 
NCT : NCT04414202 
Date : 15 Dec 2019 
 
 
 

PROTOCOLE INTRA OBS 
PROT ID : 2009/OBS-01 
NCT : NCT04414202 
Date : 15 Dec 2019 
 
10- BIBLIOGRAPHIC REFERENCES 
(1) Source : Institut de Veille Sanitaire- Institut National du Cancer 
(2) Trétarre B, Guizard AV, Fontaine D, Réseau Francim, CédiDc-Inserm : Cancer du sein chez la femme : incidence 
et mortalité, France 2000 –  INVS, BEH 44/2004 26 octobre 2004 
(3) Grosclaude P, Colonna M, Hedelin G, Tretarre B, Sauvage-Machelard M : Survival of women with breast cancer 
in France : variation with age, stage and treatment.  Breast Cancer Res Treat. 2001 Nov, 70(2): 137-43 
(4) Fisher B, Anderson S, Bryant J et al: Twenty- year follow-up of a randomised trial comparing total mastectomy, 
lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002; 347: 
12 
(4) Vlastos G., Mirza NQ., Meric F, Buchholtz TA, Hortobagyi GN, Singletary SE: Breast conservation therapy as a 
treatment option for the elderly. The MD Anderson experience. Cancer 2001; 92(5): 1092-100 
(5) Fisher B, Anderson S, Bryant J et al: Twenty- year follow-up of a randomised trial comparing total mastectomy, 
lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002; 347: 
1233-1241 
(6) Van Dongen JA, VoogdAC, Fentiman IS, et al: Long-term results of a randomized trial comparing breast-
conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J 
Natl Cancer Inst 2000; 92: 1143-1150  
(7) Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-
conserving surgery with radical mastectomy for early breast cancer. . N Engl J Med 2002; 347: 1227-1232 
(8) Clarke M, Collins R, Darby S, et al. Effetcs of radiotherapy and differences in the extent of surgery for early 
breast cancer on local recurrence and 15-year survival: AN overview of the randomised trials.  Lancet 2005; 366: 
2087-2106  
(9) Vinh-Hung V, Verschraegen C.  Breast-conserving wit hor without radiotherapy: Pooled-analysis for risks of 
ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 2004; 96: 115-121 
(10) Bartelink H, Horriot JC, Poortmans PM, et al. Inmpact of a higher radiation dose on local control and survival 
in breast conserving therapy of early-breast cancer: 10-year results of the randomized boost versus no boost 
EORTC 22881-10882 trial. JClin Oncol  2007; 25: 3259-3265 
(11) Dubois JB, Hay M, Gely S, et al. IORT in breast carcinomas. Front Radiat Ther Oncol 1997; 31: 131-37 
(12) Lemanski C, Azria D, Dubois JB et al : Intraoperative radiotherapy given as a boost for early breast cancer: 
long term clinical ans  cosmetic results. Int J Radiat Oncol Biol Phys 2006; 64: 1410-1415 
(13) Lemanski C, Azria D, Dubois JB et al : Intraoperative radiotherapy in early breast cancer: results of the 
Montpellier Phase II trial. Int J Radiat Oncol Biol Phys 2009; May 23 
(14) Smith BD, Douglas AW, Buchholz TA ,et al : Accelerated Partial Breast Irradiation Consensus Statement From 
the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys 2009; 74: 987-1001