Ignite Creation Date:
2024-05-06 @ 8:26 PM
Last Modification Date:
2024-10-26 @ 3:27 PM
Study NCT ID:
NCT06382818
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-04-24
First Post:
2024-04-19
Brief Title:
Personalization of Breast Radiotherapy According to Loco-regional Recurrence Risk and Toxicity Probability
Sponsor:
Institut du Cancer de Montpellier - Val dAurelle
Organization:
Institut du Cancer de Montpellier - Val dAurelle
Study Overview
Official Title:
Personalization of Breast Radiotherapy According to Loco-regional Recurrence Risk and Toxicity Probability
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PROBA
Brief 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 individuals 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 1614
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 ie an adjustment in the radiotherapy protocol change in fractionation or total dose the addition or elimination of a concomitant treatment eg 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 NTCP1516 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 425 Gy in 16 fractions or 40 Gy in 15 fractions can be offered according to the Canadian or UK regimen respectively1718 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 daide à la pratique e-cancerfr 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 control2324
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
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 individuals 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 1614
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 ie an adjustment in the radiotherapy protocol change in fractionation or total dose the addition or elimination of a concomitant treatment eg 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 NTCP1516 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 425 Gy in 16 fractions or 40 Gy in 15 fractions can be offered according to the Canadian or UK regimen respectively1718 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 daide à la pratique e-cancerfr 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 control2324
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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None