Ignite Creation Date:
2024-05-06 @ 7:49 PM
Last Modification Date:
2024-10-26 @ 3:14 PM
Study NCT ID:
NCT06144346
Status:
RECRUITING
Last Update Posted:
2023-11-22
First Post:
2023-11-04
Brief Title:
Metastases Directed Therapy for Oligometastatic Breast Cancer
Sponsor:
National Cancer Institute Egypt
Organization:
National Cancer Institute Egypt
Study Overview
Official Title:
Role of Metastases Directed Radiotherapy in Addition to Standard of Care Systemic Treatment in the Management of Extracranial Oligometastatic Breast Cancer
Status:
RECRUITING
Status Verified Date:
2023-11
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:
None
Brief Summary:
This is a phase III randomized study evaluating the benefit from adding metastases directed therapy and locoregional treatment of the primary in breast cancer patients diagnosed with de novo oligometastatic disease patients will be randomized to receive the standard of care SOC treatment vs systemic treatment Stereotactic Ablative Radiation Therapy Responders will be randomized to either undergo loco-regional management of the primary tumor or not
Detailed Description:
Objectives
Primary objectives
Assessment of the outcome progression free survival of patients with extracranial oligometastatic breast cancer receiving standard of care systemic treatment compared to patients receiving ablative radiotherapy in addition to systemic treatment
Secondary objectives
Improving quality of life of patients with oligometastatic breast cancer OMBC
Ensuring a safe toxicity profile among the patients receiving SBRT to the metastatic sites in addition to SOC treatment vs patients who receive SOC treatment alone
Study Methodology
1 Study Design Randomized Controlled Trial
2 Study population disease Condition Adult female patients with pathologically and radiologically proven Oligometastatic breast cancer presenting to National Cancer Institute Cairo University
3 Background and Demographic characteristics
Adult 18 years old Egyptian female patients who present for treatment in the National Cancer Institute Cairo University A detailed informed consent will be signed proper contraception is a must during systemic and radiotherapy treatment
4 Inclusion criteria
i Female patients aged 18 to 70 years ii Pathological evidence of breast cancer any grade any T stage iii Radiological at least evidence of metastatic activity with maximum number of 5 extracranial lesions
iv Performance status 2 v No pre-existing conditions that may prohibit radiotherapy e Exclusion criteria i Pregnant and lactating women ii Prior radiotherapy to affected sites in less than a year iii Active Connective tissue diseases eg Rheumatoid Arthritis iv Progression to widespread metastatic disease v Cases with brain metastasis
f Interventions in details
Pre-treatment evaluation
Laboratory studies
CBC Liver and Kidney functions and Tumor markers CA15-3 CEA and CA-125
Imaging Studies
Initial Sono-mammography for assessment of local disease MRI breast to be done whenever indicated eg young patients with dense breast tissue ACR CD
Metastatic workup for establishing oligometastatic status CT chest abdomen and pelvis with contrast with Bone scan or PETCT more sophisticated imaging techniques to be done in case of failure of modalities to establish the metastatic status eg Dynamic MRI of liver in cases which conventional imaging fails to confirm the nature of a suspected hepatic focal lesion
Pathological diagnosis Tru-Cut core-cut or excisional biopsy from suspicious primary breast mass also core biopsy from suspected metastatic site whenever indicated
Treatment plan
Patients will be randomized into 2 arms FIGA i Arm A interventional ii Arm B control
The interventional arm will receive Metastasis Directed Therapy MDT using Stereotactic body radiotherapy SBRT to oligometastatic lesions initially along with standard of care systemic treatment SOC according to discretion of multi-disciplinary team decision
The control arm will receive SOC alone
Locoregional control to the primary will be done in cases with regressive disease or complete response according to RECIST 11 criteria
The radiation schedule in Arm A will be as follows
SBRT is recommended to be completed within no more than 3 weeks since the start of the first session Not all metastases need to receive radiotherapy in the same day IGRT assisted treatment is a must PTV expansion will be decided separately for each site treated
Patients will receive single fraction 3 fractions or 5 fractions of SBRT according to treated site as follows Data from NRG BR-002 protocol and ASTRO 2022 conference
Bone Peripheral and spine 18-24GySS or 30Gy3fx or 35Gy5fx Liver 45-60Gy3fx or 40-60Gy5fx Lung 50-60Gy3fx rib tolerance must be met or 50-60Gy5fx Others eg Adrenals and lymph nodes according to risk organ tolerances usually 30Gy3Fx or 40-60Gy5fx
Treatment Setup and simulation
All patients will undergo CT-based treatment planning in with proper immobilization and comfortable setup position High resolution CT scans should be obtained with uniform slice thickness of 3mm When treating multiple metastases such as a lung and extremities varying the treatment position may be necessary ie simulation with arms up and arms to the side The use of IV contrast will be required for liver and nodal metastases For other metastases central peripheral lung cervicalmediastinal abdominal-pelvic and spinalparaspinal the use of IV contrast is encouraged but will be left to the discretion of the treating physician As an SBRT protocol this study requires the use of IGRT cone-beam CT CBCT using a specially mounted kV imaging will be the routine verification method
Delineation of target volume and organs at risk OARs
It will be done using the RTOG contouring guidelines a maximum intensity projection MIP volume will be created in lesion situated in organs with remarkable internal motion eg lung lesions fusion with diagnostic imaging such as PETCT will be done when delineation of gross lesions is infeasible
Treatment planning
General guidelines include the following
Multiple coplanar or non-coplanar beam arrangements are acceptable
A minimum field dimension of 3 cm should be observed while treating small metastases
Doses higher than the prescription isodose ie hotspots should be manipulated to occur within the target
Planning SBRT Near Prior Radiotherapy Volumes with toxicity of delivering SBRT to multiple metastases in close proximity to previously irradiated volumes is a bit challenging A multicenter analysis by German Society of Radiation Oncology DEGRO was done in 2021 included patients with primary and secondary pulmonary tumors that has been subject to reirradiation using SBRT to same or near target volumes It showed feasibility of reirradiation and safe toxicity profile close adherence to dose constraints made by AAPM TG-101 report will be ensured Re-irradiated volumes will be delineated with the best possible simulation setup and reproducibility plans of previous treatment will be fused with overlapping volumes to be minimized as much as possible
Contouring of Normal Tissue Structures In order to verify each of these limits
The organs must be contoured such that appropriate volume histograms can be generated
Dose Tolerance to OARs will be followed as the SABR consortium guidelines published in 2019
Data Collection
Demographic data Age family history comorbidity grade stage
Pretreatment Evaluation
Laboratory Radiological and pathological data as previously mentioned
Response Evaluation by physical examination and standard imaging CT Chest abdomen and pelvis with contrast and Bone scan or PETCT other specific techniques can be used when indicated it will follow RECIST 11 criteria
Fig Consort Diagram showing roadmap of treatment and randomization g Possible Risk Acute radiation therapy adverse events will be scored according to the RTOG acute radiation morbidity criteria which is the most commonly used in routine practice
Cox JD Stetz J Pajak TF Toxicity criteria of the Radiation Therapy Oncology Group RTOG and the European Organization for Research and Treatment of Cancer EORTC Int J Radiat Oncol Biol Phys 1995 Mar 30 3151341-6 doi 1010160360-30169500060-C PMID 7713792 Late effects will be reported as per Common Terminology Criteria for Adverse events CTCAE v50 httpsctepcancergovprotocoldevelopmentelectronic_applicationsctchtmctc_50 Adverse events related to SBRT for the treatment of metastases are dependent on the location of the metastases treated as well as from exposure of surrounding normal tissues For all treated metastases fatigue is likely to occur and should be transient lasting 8 weeks Other adverse events are likely to be related to the specific metastatic location receiving SBRT such as esophagitis and pneumonitis during treatment of lung lesions erythema and alopecia in treatment of bony sites and gastrointestinal upset in volumes related to digestive tract
Complications of systemic treatment they shall be discussed in the Multidisciplinary team meeting prior to enrollment in the treatment protocol patients are also required to be informed about them the informed consent form for inclusion in this study will have a special section to state the possible side effects of the given systemic treatment as well as radiotherapy
h Primary outcome parameters
Progression Free Survival PFS and Overall Response Rate ORR i Secondary outcome parameters
Overall survival OS
Quality of life measurements QoL among patients of both arms during the follow up period using Breast Cancer Treatment Outcome Scale BCTOS verified questionnaire
Occurrence and degrees of treatment related toxicities among patients of both arms during the follow up period
j Sample size This study aiming to assess progression free survival of patients with extracranial oligometastatic breast cancer receiving either standard of care systemic treatment or ablative radiotherapy in addition to standard of care systemic treatment with ratio 11 Based on previous studies Glemarec G et al 2023 Trovo M et al 2018 1 year progression free survival was 9375 for systemic treatment alone group1 and local ablative treatment group 2 respectively so we need to study 70 patients per group This number will be compensated by 5 for suspected losses so the final sample size will be 75 patients per group total 150 breast cancer patients to be able to reject the null hypothesis The Type I error probability associated with test of this null hypothesis is 005 type Ц error was 02 Sample size was calculated using Med calc statistical package version 1821 34 35
k Statistical analysis Data management and analysis will be performed using Statistical Package for Social Sciences SPSS vs 28 Numerical data will be summarized using means and standard deviations or medians and ranges as appropriate Categorical data will be summarized as numbers and percentages Numerical data will be explored for normality using Kolmogrov-Smirnov test and Shapiro-Wilk test Comparisons between two groups for normally distributed numeric variables will be done using the Students t-test while for non-normally distributed numeric variables comparisons will be done by Mann-Whitney test Chi square or Fishers tests will be used to compare between the groups with respect to categorical data as appropriate
Kaplan-meire method will be used to estimate the overall survival and progression free survival Overall survival will be calculated from date of diagnosis to date of death or last follow up While progression free survival will be calculated from the date of intiation of treatment to date of progression Differences between the survival curves will be assessed for statistical significance with the log-rank test Cox regression analysis will be done to evaluate independent prognostic variables affecting survival time All tests will be two-sided P-values 005 will be considered significant
10-Time plan when to startwhen expected to finishwhen to publish Start from April 2023 Expected time to finish March 2025 Expected date for publishing October 2025 11-Ethical committee approval
This study will be started after approval of Institutional Review Board and Ethical Research Committee
The study protocol will be presented to the Scientific Ethics Committee of the radiotherapy Department at the National Cancer Institute - Cairo University
Patients data will be presented anonymously with protection of privacy and confidentiality
The aim and nature of the study will be explained to each patient before their inclusion in the study An informed written consent will be obtained from each patient or a first degree relative before enrolment
Primary objectives
Assessment of the outcome progression free survival of patients with extracranial oligometastatic breast cancer receiving standard of care systemic treatment compared to patients receiving ablative radiotherapy in addition to systemic treatment
Secondary objectives
Improving quality of life of patients with oligometastatic breast cancer OMBC
Ensuring a safe toxicity profile among the patients receiving SBRT to the metastatic sites in addition to SOC treatment vs patients who receive SOC treatment alone
Study Methodology
1 Study Design Randomized Controlled Trial
2 Study population disease Condition Adult female patients with pathologically and radiologically proven Oligometastatic breast cancer presenting to National Cancer Institute Cairo University
3 Background and Demographic characteristics
Adult 18 years old Egyptian female patients who present for treatment in the National Cancer Institute Cairo University A detailed informed consent will be signed proper contraception is a must during systemic and radiotherapy treatment
4 Inclusion criteria
i Female patients aged 18 to 70 years ii Pathological evidence of breast cancer any grade any T stage iii Radiological at least evidence of metastatic activity with maximum number of 5 extracranial lesions
iv Performance status 2 v No pre-existing conditions that may prohibit radiotherapy e Exclusion criteria i Pregnant and lactating women ii Prior radiotherapy to affected sites in less than a year iii Active Connective tissue diseases eg Rheumatoid Arthritis iv Progression to widespread metastatic disease v Cases with brain metastasis
f Interventions in details
Pre-treatment evaluation
Laboratory studies
CBC Liver and Kidney functions and Tumor markers CA15-3 CEA and CA-125
Imaging Studies
Initial Sono-mammography for assessment of local disease MRI breast to be done whenever indicated eg young patients with dense breast tissue ACR CD
Metastatic workup for establishing oligometastatic status CT chest abdomen and pelvis with contrast with Bone scan or PETCT more sophisticated imaging techniques to be done in case of failure of modalities to establish the metastatic status eg Dynamic MRI of liver in cases which conventional imaging fails to confirm the nature of a suspected hepatic focal lesion
Pathological diagnosis Tru-Cut core-cut or excisional biopsy from suspicious primary breast mass also core biopsy from suspected metastatic site whenever indicated
Treatment plan
Patients will be randomized into 2 arms FIGA i Arm A interventional ii Arm B control
The interventional arm will receive Metastasis Directed Therapy MDT using Stereotactic body radiotherapy SBRT to oligometastatic lesions initially along with standard of care systemic treatment SOC according to discretion of multi-disciplinary team decision
The control arm will receive SOC alone
Locoregional control to the primary will be done in cases with regressive disease or complete response according to RECIST 11 criteria
The radiation schedule in Arm A will be as follows
SBRT is recommended to be completed within no more than 3 weeks since the start of the first session Not all metastases need to receive radiotherapy in the same day IGRT assisted treatment is a must PTV expansion will be decided separately for each site treated
Patients will receive single fraction 3 fractions or 5 fractions of SBRT according to treated site as follows Data from NRG BR-002 protocol and ASTRO 2022 conference
Bone Peripheral and spine 18-24GySS or 30Gy3fx or 35Gy5fx Liver 45-60Gy3fx or 40-60Gy5fx Lung 50-60Gy3fx rib tolerance must be met or 50-60Gy5fx Others eg Adrenals and lymph nodes according to risk organ tolerances usually 30Gy3Fx or 40-60Gy5fx
Treatment Setup and simulation
All patients will undergo CT-based treatment planning in with proper immobilization and comfortable setup position High resolution CT scans should be obtained with uniform slice thickness of 3mm When treating multiple metastases such as a lung and extremities varying the treatment position may be necessary ie simulation with arms up and arms to the side The use of IV contrast will be required for liver and nodal metastases For other metastases central peripheral lung cervicalmediastinal abdominal-pelvic and spinalparaspinal the use of IV contrast is encouraged but will be left to the discretion of the treating physician As an SBRT protocol this study requires the use of IGRT cone-beam CT CBCT using a specially mounted kV imaging will be the routine verification method
Delineation of target volume and organs at risk OARs
It will be done using the RTOG contouring guidelines a maximum intensity projection MIP volume will be created in lesion situated in organs with remarkable internal motion eg lung lesions fusion with diagnostic imaging such as PETCT will be done when delineation of gross lesions is infeasible
Treatment planning
General guidelines include the following
Multiple coplanar or non-coplanar beam arrangements are acceptable
A minimum field dimension of 3 cm should be observed while treating small metastases
Doses higher than the prescription isodose ie hotspots should be manipulated to occur within the target
Planning SBRT Near Prior Radiotherapy Volumes with toxicity of delivering SBRT to multiple metastases in close proximity to previously irradiated volumes is a bit challenging A multicenter analysis by German Society of Radiation Oncology DEGRO was done in 2021 included patients with primary and secondary pulmonary tumors that has been subject to reirradiation using SBRT to same or near target volumes It showed feasibility of reirradiation and safe toxicity profile close adherence to dose constraints made by AAPM TG-101 report will be ensured Re-irradiated volumes will be delineated with the best possible simulation setup and reproducibility plans of previous treatment will be fused with overlapping volumes to be minimized as much as possible
Contouring of Normal Tissue Structures In order to verify each of these limits
The organs must be contoured such that appropriate volume histograms can be generated
Dose Tolerance to OARs will be followed as the SABR consortium guidelines published in 2019
Data Collection
Demographic data Age family history comorbidity grade stage
Pretreatment Evaluation
Laboratory Radiological and pathological data as previously mentioned
Response Evaluation by physical examination and standard imaging CT Chest abdomen and pelvis with contrast and Bone scan or PETCT other specific techniques can be used when indicated it will follow RECIST 11 criteria
Fig Consort Diagram showing roadmap of treatment and randomization g Possible Risk Acute radiation therapy adverse events will be scored according to the RTOG acute radiation morbidity criteria which is the most commonly used in routine practice
Cox JD Stetz J Pajak TF Toxicity criteria of the Radiation Therapy Oncology Group RTOG and the European Organization for Research and Treatment of Cancer EORTC Int J Radiat Oncol Biol Phys 1995 Mar 30 3151341-6 doi 1010160360-30169500060-C PMID 7713792 Late effects will be reported as per Common Terminology Criteria for Adverse events CTCAE v50 httpsctepcancergovprotocoldevelopmentelectronic_applicationsctchtmctc_50 Adverse events related to SBRT for the treatment of metastases are dependent on the location of the metastases treated as well as from exposure of surrounding normal tissues For all treated metastases fatigue is likely to occur and should be transient lasting 8 weeks Other adverse events are likely to be related to the specific metastatic location receiving SBRT such as esophagitis and pneumonitis during treatment of lung lesions erythema and alopecia in treatment of bony sites and gastrointestinal upset in volumes related to digestive tract
Complications of systemic treatment they shall be discussed in the Multidisciplinary team meeting prior to enrollment in the treatment protocol patients are also required to be informed about them the informed consent form for inclusion in this study will have a special section to state the possible side effects of the given systemic treatment as well as radiotherapy
h Primary outcome parameters
Progression Free Survival PFS and Overall Response Rate ORR i Secondary outcome parameters
Overall survival OS
Quality of life measurements QoL among patients of both arms during the follow up period using Breast Cancer Treatment Outcome Scale BCTOS verified questionnaire
Occurrence and degrees of treatment related toxicities among patients of both arms during the follow up period
j Sample size This study aiming to assess progression free survival of patients with extracranial oligometastatic breast cancer receiving either standard of care systemic treatment or ablative radiotherapy in addition to standard of care systemic treatment with ratio 11 Based on previous studies Glemarec G et al 2023 Trovo M et al 2018 1 year progression free survival was 9375 for systemic treatment alone group1 and local ablative treatment group 2 respectively so we need to study 70 patients per group This number will be compensated by 5 for suspected losses so the final sample size will be 75 patients per group total 150 breast cancer patients to be able to reject the null hypothesis The Type I error probability associated with test of this null hypothesis is 005 type Ц error was 02 Sample size was calculated using Med calc statistical package version 1821 34 35
k Statistical analysis Data management and analysis will be performed using Statistical Package for Social Sciences SPSS vs 28 Numerical data will be summarized using means and standard deviations or medians and ranges as appropriate Categorical data will be summarized as numbers and percentages Numerical data will be explored for normality using Kolmogrov-Smirnov test and Shapiro-Wilk test Comparisons between two groups for normally distributed numeric variables will be done using the Students t-test while for non-normally distributed numeric variables comparisons will be done by Mann-Whitney test Chi square or Fishers tests will be used to compare between the groups with respect to categorical data as appropriate
Kaplan-meire method will be used to estimate the overall survival and progression free survival Overall survival will be calculated from date of diagnosis to date of death or last follow up While progression free survival will be calculated from the date of intiation of treatment to date of progression Differences between the survival curves will be assessed for statistical significance with the log-rank test Cox regression analysis will be done to evaluate independent prognostic variables affecting survival time All tests will be two-sided P-values 005 will be considered significant
10-Time plan when to startwhen expected to finishwhen to publish Start from April 2023 Expected time to finish March 2025 Expected date for publishing October 2025 11-Ethical committee approval
This study will be started after approval of Institutional Review Board and Ethical Research Committee
The study protocol will be presented to the Scientific Ethics Committee of the radiotherapy Department at the National Cancer Institute - Cairo University
Patients data will be presented anonymously with protection of privacy and confidentiality
The aim and nature of the study will be explained to each patient before their inclusion in the study An informed written consent will be obtained from each patient or a first degree relative before enrolment
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