Personalization of Breast Radiotherapy According to Loco-regional Recurrence Risk and Toxicity Probability

Breast Cancer Clinical Trial

— PROBA  

Official title:

Personalization of Breast Radiotherapy According to Loco-regional Recurrence Risk and Toxicity Probability

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06382818
• Other study ID #: PROICM 2023-10 PRO
• Status: Not yet recruiting
• Phase: N/A
• Start date: April 26, 2024
• Est. completion date: April 26, 2036

Study information

• Verified date: April 2024
• Source: Institut du Cancer de Montpellier - Val d'Aurelle
• Contact: MOUSSION AURORE
• Phone: 0467613102
• Email: aurore.moussion[@]icm.unicancer.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Our objective is based on a personalized approach of adjuvant breast radiotherapy by selecting patients according to tumor recurrence and toxicity risk.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 854
• Est. completion date: April 26, 2036
• Est. primary completion date: April 26, 2027
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Cancer
• Recurrence

Intervention

Radiation:
• COHORT A
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
• COHORT B
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.
• COHORT C
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).
• COHORT D
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.

Locations

Country	Name	City	State
France	Institut Du Cancer de Montpellier	Montpellier

Sponsors (1)

Lead Sponsor	Collaborator
Institut du Cancer de Montpellier - Val d'Aurelle

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of patients without any grade 2 or more fibrosis, nor radio-induced sarcoma	Toxicity free survival is defined as the interval between date of inclusion and the occurrence of fibrosis grade 2 or more or radio-induced sarcoma. Patients without event at the analysis will be censored at the date of last follow-up.	at 10 years
Secondary	Acute toxicity	according to NCI-CTCAE v5 is defined as side effects observed	from the start of RT to 12 weeks post RT
Secondary	Late toxicity	according to NCI-CTCAE v5 is defined as side effects observed	from 12 weeks post RT to 3, 5 and 10 years post RT
Secondary	Local recurrence rate (LRR)	LRR will be deducted from the local recurrence survival defined as the interval between date of inclusion and the occurrence of local relapse. Patients without local relapse at the analysis will be censored at the date of last follow-up	at 3, 5, 10 years
Secondary	Relapse-free survival (RFS) rate	RFS is defined as the interval between date of inclusion and the occurrence of relapse. Patients without relapse at the analysis will be censored at the date of last follow-up	at 3, 5, 10 years
Secondary	Overall survival (OS) rate	OS is defined as the interval between date of inclusion and the occurrence of death, due to any cause. Patients alive at the analysis will be censored at the date of last follow-up.	at 3, 5, 10 years:
Secondary	Radiation-induced Breast Sarcoma prevalence	Prevalence of Radio-induced Breast Sarcoma at 10 years will be estimated using the Kaplan-Meier method, and then described using rate at 10 years with its associated 95% confidence interval.	at 10 years