Trial Title:
Personalization of Breast Radiotherapy According to Loco-regional Recurrence Risk and Toxicity Probability
NCT ID:
NCT06382818
Condition:
Breast Cancer
Conditions: Official terms:
Recurrence
Conditions: Keywords:
Radiotherapy breast cancer
Study type:
Interventional
Study phase:
N/A
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Intervention model description:
- COHORT A = Low risk of recurrence / Low risk of breast toxicity
- COHORT B = Low risk of recurrence / High risk of breast toxicity
- COHORT C = High risk of recurrence / Low risk of breast toxicity
- COHORT D = High risk of recurrence / High risk of breast toxicity
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Radiation
Intervention name:
COHORT A
Description:
IMRT radiotherapy on whole breast according to the investigator's decision among:
- Moderate whole breast hypofractionated RT according to the START B schema with Fixed
Field IMRT Technique: 40.05 Gy in 15 daily fractions over 3 weeks and a Sequential
boost (+ 16 Gy/8 fr) or (+13.5/5 fr) if applicable.
- Extreme whole breast hypofractionated RT according to :
- The FAST schema: Once-a-week ultra-HypoRT with Fixed Field IMRT Technique, 28.5
Gy in 5 fractions in 5 weeks
- The FAST-Forward schema: Very accelerated course of HypoRT with Fixed Field
IMRT Technique, 26 Gy in 5 fractions in 5 consecutive days
Arm group label:
COHORT A
Intervention type:
Radiation
Intervention name:
COHORT B
Description:
Breast radiotherapy according to the investigator's decision among:
- External partial VMAT: 40 Gy in 15 fractions to the partial breast only (tumorectomy
bed).
- Exclusive Brachytherapy: 30.1 Gy in 7 fractions or 32.0 Gy in 8 fractions of
high-dose-rate brachytherapy in 5 days or as 50 Gy of pulsed-dose-rate brachytherapy
over 5 treatment days.
- Whole Breast Normo fractionated IMRT with Fixed Field IMRT Technique: 50 Gy in 25
daily fractions over 5 weeks +/- Sequential (+ 16 Gy/8fr) or SIB (60 Gy/25 fr)
treatment for boost if applicable.
Arm group label:
COHORT B
Intervention type:
Radiation
Intervention name:
COHORT C
Description:
Whole breast and nodes Hypofractionated VMAT and a localized simultaneous boost according
to the HypoG01 schema protocol:
VMAT Technique, 42.3 Gy in 18 fractions on all target volume on 3.5 weeks +/- SIB boost
if need (52.2Gy in 18 fractions).
Arm group label:
COHORT C
Intervention type:
Radiation
Intervention name:
COHORT D
Description:
Breast radiotherapy based on available clinical trials:
- Whole Breast and Nodes Hypofractionated VMAT with adaptive treatment (margin
reduction): HypoG01 Schema with VMAT Technique, 42.3 Gy in 18 fractions on all
target volume over 3.5 weeks +/- SIB boost if need (52.2Gy in 18 fr) In case of
patient refusal or technique unavailable, a standard treatment available in the
center for this indication will be delivered.
Arm group label:
COHORT D
Summary:
Our objective is based on a personalized approach of adjuvant breast radiotherapy by
selecting patients according to tumor recurrence and toxicity risk.
Detailed description:
Breast cancer is the most common cancer in women in the world and remains a major public
health burden with 25% of all cancer cases and 15% of all cancer deaths among females1.
The Incidence has increased with the introduction of mammography screening and continues
to rise, mainly due to population aging; meanwhile, breast cancer survival has
significantly improved over the past decades.
Adjuvant radiotherapy (RT) is an essential component of the treatment. After breast
surgery for invasive carcinoma, RT is commonly used and delivered without considering the
different tumor subtypes, unless the node involvement risk, because it decreases the rate
of local recurrence and by this way, specific mortality. The " one size fits all "
approach is widely applied, with two main options: breast or chest wall only radiotherapy
or breast or chest wall plus nodes radiotherapy. Rare are the centers that discuss IMRT
use, external partial breast irradiation, adaptive breast necessity, etc....
1. Breast cancer and loco-regional recurrence risk Ten-year cancer specific survival
exceeds 70%, with 89% survival for local and 62% for regional disease1. The risk of
recurrence is high during the first two years after the initial diagnosis for
patients with hormonal receptor (HR)-negative breast cancer, but rapidly decreases
below the recurrence risk of HR-positive tumors2.
Loco-regional recurrence (LRR) occurs in 5-15% of cases treated with breast
conservative surgery (BCS) plus adjuvant radiotherapy (RT) or mastectomy3-5 and is
considered an independent poor prognostic factor6. The management of LRR requires a
multidisciplinary approach7. Total mastectomy is the standard of care for isolated
LRR after BCS. However, secondary BCS ± RT is an alternative approach that could be
discussed case by case7.
Parameters to predict the risk of recurrence are those included in the NHS UK
updated PREDICT score such as age, node status, tumor grade, proliferation index,
Her2 and hormone receptor expression8.
2. Adjuvant breast radiotherapy and subcutaneous toxicity probability Severe but also
moderate toxicities after curative-intent radiotherapy (RT), such as fibrosis,
retraction or telangiectasia with poor cosmetic outcome can have a negative impact
on quality of life following breast cancer and a marked effect on subsequent
psychological outcome. Multiple factors are known to increase the risk of radiation
toxicity including individual radiosensitivity9. While the toxicity risks for
patients are well-established, determining an individual's normal tissue
radiosensitivity is rarely possible before treatment.
Nevertheless, current practice standards often prescribe radiation dose and volume
without regard to individual radiosensitivity.
In that context, a normal tissue radiosensitivity test that includes a rapid (72h)
radiosensitivity assay10 based on flow cytometric assessment of radiation-induced
CD8 T-lymphocyte apoptosis (RILA) was developed by Ozsahin et al. A prospective
study was conducted to determine whether the RILA assay could help identifying
patients at high risk of severe toxicities11. The RILA assay was performed in 399
patients with different cancer types before RT. Findings confirmed that patients who
developed severe toxicities displayed a compromised apoptotic response.
More recently, the RILA assay was validated in a prospective multicenter trial with
more than 500 patients with breast cancer12. The negative predictive value for grade
≥2 breast fibrosis was 91% for RILA scores ≥20% and the positive predictive value
was 22% for RILA scores <12% (the overall prevalence of grade ≥2 breast fibrosis was
estimated at 14%). For the first time, RILA as a continuous variable was
significantly associated with toxicities. Recently, the French results have been
validated by a prospective European trial with similar predictive values of the
RILA13.
In the CO-HO-RT trial, the RILA assay was used as the main stratification factor and
no late toxicity occurred in patients with a RILA score >16%14.
In 2022, the RILA assay was included in the French recommendation (RECORAD) as the
only validated predictive test for post-radiotherapy toxicity in a large,
multi-center, prospective study15.
Based on these data, the NovaGray RILA Breast® test has been developed and combine
both a biological analysis (radio-induced lymphocyte apoptosis) and an algorithmic
analysis.
The NovaGray RILA Breast is an vitro diagnostic medical device (IVMD) pertaining
CE-mark. This prognostic test that assesses the risk of developing grade 2+ breast
fibrosis at 36 months following radiotherapy. The test is performed on a blood draw
and results are provided within a week, which does not delay the beginning of the
radiotherapy.
3. Matrix approach according to tumor recurrence and toxicity risk When using a
predictive radiosensitivity test in clinical practice, an alternative treatment must
be available to the patient in case of an unfavourable result, i.e. an adjustment in
the radiotherapy protocol (change in fractionation or total dose), the addition or
elimination of a concomitant treatment (e.g. chemotherapy) or the absolute
contraindication to radiotherapy in highly radiosensitive patients for whom the
treatment-related risk may be greater than the expected benefit.
Based on tumor control probability (TCP) and normal tissue complication probability
(NTCP)15,16, we can group the patients into four situations described below.
1. Clinical situation #1 : High TCP / Low NTCP : COHORT A This circumstance is the
optimum situation: a high local control probability and a low risk of developing
toxicity. In this situation, the total dose of radiotherapy could be limited to the
strict necessity since the probability of tumor control is already high. However,
alternative fractionations such as moderate hypofractionation can be proposed to
shorten the duration of treatment. In breast cancer, a regimen delivering 42.5 Gy in
16 fractions or 40 Gy in 15 fractions can be offered according to the Canadian or UK
regimen, respectively17,18. Recently, hypofractionation regimen are becoming more
extreme with shorten fractionation regimen over 5 weeks (FAST protocol19) or over 1
week (FAST-forward protocol20). From a radiobiological and economic standpoint,
these short regimens can provide a benefit in terms of quality of life with a lower
cost of treatment.
All of them are now included in the recommendations of the French National Society
of Radiation Oncology21 and the French National Cancer Institute (INCa, Cancers du
sein - Recommandations et outils d'aide à la pratique (e-cancer.fr)). All are
considered as an option in daily clinical practice.
2. Clinical situation #2 : High TCP / High NTCP : COHORT B In this situation, the
patient is at risk of developing toxicity, but the probability of tumor control is
high16). In those cases, possible alternatives to radiotherapy may be discussed such
as surgical treatment alone. In breast cancer, this can mean offering total
mastectomy for a small tumor (possibly with immediate breast reconstruction) to
postpone the indication of adjuvant radiotherapy. For a tumor with a very favorable
prognosis, namely after 65 years old, avoiding radiotherapy after breast surgery may
also be an option22. In that case, treatment with partial irradiation of the breast
(using external technique or brachytherapy) can also be proposed, to improve the
long-term cosmetic results, while ensuring good local control23,24.
All of them are now included in the recommendations of the French National Society
of Radiation Oncology21. All are considered as an option in daily clinical practice.
3. Clinical situation #3 : Low TCP / Low NTCP : COHORT C In that situation, the patient
is at low risk of developing toxicity but the probability of tumor control is low16.
One of the possibilities is to increase the total dose of radiotherapy, namely with
a localized boost within the tumor bed in invasive disease 5 and nodes irradiation
according to the HypoG trial (ESTRO - Session Item).
This treatment is also included in the recommendations of the French National
Society of Radiation Oncology21.
4. Clinical situation #4 : Low TCP / High NTCP : COHORT D This is the most unfavourable
situation, with a radiation-resistant tumor and a patient with a high risk of
developing toxicity. Dose de-escalation cannot be proposed to decrease toxicity in
such cases, as the risk of tumor recurrence may be too high. Alternative
fractionations, such as hyperfractionation (moderate or high depending on the organs
at risk) could however be useful by decreasing the risk of toxicity while retaining
a satisfactory level of tumor control. These regimens have not been validated and
discussions should be carried out on a case-by-case basis. However, the impact on
the decrease of toxicity, especially late-onset toxicity, has yet to be
demonstrated. If adjusted radiotherapy regimens are not feasible and standard
oncological treatment administered, the radioprotection of normal tissue should be
discussed using adaptive techniques as it could decrease the risk of toxicity while
maintaining good tumor control.
In this specific COHORT, inclusion in a new clinical trial evaluating adaptive treatment
will be proposed to the patient. In case of patient refusal or technique unavailable, a
standard treatment available in the center for this indication will be delivered.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
General criteria (for all cohorts):
1. Women ≥ 18 years old.
2. Invasive breast cancer treated by conservative or radical surgery.
3. Conservative breast cancer surgery or radical mastectomy.
4. Indication of breast irradiation.
5. Extension evaluation of disease will be proven negative (M0).
6. Negative pregnancy test (blood or urine at the choice of investigator), to be
carried out within 7 days of registration, for women of childbearing age only.
7. Effective contraception for women of childbearing age
8. Must be geographically accessible for follow-up.
9. Written and dated informed consent.
10. Affiliated to the French national social security system.
Cohort A and B:
- Low risk of recurrence (all of the criteria) adapted form the UK PREDICT
• pT1-T2
- SBR grade ≤ 2 (low grade)
- ER+ and / or PR+ (hormone-receptor positive)
- cN0/pN-
- HER 2 -
- Ki67 ≤10%
pN- with T3-4 and grade 3 and internal tumor will be considered at high risk of
recurrence and will be proposed node irradiation (and will be switched to COHORT C
or D).
Cohort C and D:
- High risk of recurrence (pN+ and at least one of all) adapted from the UK
PREDICT
• ER- and PR-
• HER2 amplified
• pT3-4
• SBR grade ≥ 3
- KI67 > 10%
Cohort A and C:
- Low risk of breast toxicities identified by the NovaGray RILA Breast® test
Cohort B and D:
- High risk of breast toxicities identified by the NovaGray RILA Breast® test
Exclusion Criteria:
-
1. Patients with distant metastases.
2. Patients with breast DCIS 3. Concomitant bilateral breast cancer 4. Previous breast
radiotherapy 5. Patients with previous or concomitant other (not breast cancer)
malignancy within the past 5 years EXCEPT adequately treated basal or squamous cell
carcinoma of the skin or in situ carcinoma of the cervix. Patients who have had a
previous other malignancy must have been disease free for at least five years.
6. Patients with other non-malignant systemic diseases (cardiovascular, renal, hepatic,
lung embolism, etc.) which would prevent prolonged follow-up.
7. Patients known to be HIV positive (no specific tests are required to determine the
eligibility).
8. Patients known as hypersensitive to radiation (ATM Homozygote, p53-/-,...) 9.
Patients treated with systemic investigational drugs during the present study
(Observational cohorts are accepted if the collection of data does not interfere
with the current trial) 10. Pregnant or breast-feeding women 11. Patient unable to
comply with study obligations for geographic, social, or physical reasons, or who is
unable to understand the purpose and procedures of the study 12. Person deprived of
their liberty or under protective custody or guardianship
Gender:
Female
Gender based:
Yes
Gender description:
Breast cancer
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Institut Du Cancer de Montpellier
Address:
City:
Montpellier
Country:
France
Contact:
Last name:
MOUSSION AURORE
Phone:
0467613102
Email:
aurore.moussion@icm.unicancer.fr
Investigator:
Last name:
AZRIA DAVID
Email:
Principal Investigator
Investigator:
Last name:
MEGE ALICE
Email:
Principal Investigator
Investigator:
Last name:
BRETON-CALLU CHRISTEL
Email:
Principal Investigator
Start date:
April 26, 2024
Completion date:
April 26, 2036
Lead sponsor:
Agency:
Institut du Cancer de Montpellier - Val d'Aurelle
Agency class:
Other
Source:
Institut du Cancer de Montpellier - Val d'Aurelle
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06382818
