Trial Title:
Metastases Directed Therapy for Oligometastatic Breast Cancer
NCT ID:
NCT06144346
Condition:
Breast Cancer
Metastatic Cancer
Metastatic Breast Cancer
Conditions: Official terms:
Breast Neoplasms
Conditions: Keywords:
stereotactic radiation
oligometastatic breast cancer
Study type:
Interventional
Study phase:
N/A
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Factorial Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Radiation
Intervention name:
Stereotactic Ablative Radiation Therapy
Description:
SABR to all metastatic lesions
Arm group label:
Metastases Directed Therapy
Intervention type:
Procedure
Intervention name:
Locoregional treatment
Description:
mastectomy or BCS for the primary tumor
Arm group label:
Locoregional Treatment of the Primary
Intervention type:
Other
Intervention name:
Standard of Care
Description:
Systemic treatment and palliative treatment
Arm group label:
Standard of Care
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
site(s) in less than a year. iii) Active Connective tissue diseases (e.g 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, e.g., young patients with dense breast tissue: ACR C&D).
Metastatic workup for establishing oligometastatic status: CT chest, abdomen and pelvis
with contrast with Bone scan or PET/CT, more sophisticated imaging techniques to be done
in case of failure of modalities to establish the metastatic status (e.g., 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: (FIG.A) 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 1.1 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): 18-24Gy/S.S or 30Gy/3fx or 35Gy/5fx Liver: 45-60Gy/3fx or
40-60Gy/5fx Lung: 50-60Gy/3fx (rib tolerance must be met) or 50-60Gy/5fx Others (e.g
Adrenals and lymph nodes): according to risk organ tolerances, usually 30Gy/3Fx or
40-60Gy/5fx
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 (i.e., 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, cervical/mediastinal,
abdominal-pelvic, and spinal/paraspinal), 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
(e.g lung lesions), fusion with diagnostic imaging such as PET/CT 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 (i.e., 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 PET/CT, other specific techniques can be used when
indicated), it will follow RECIST 1.1 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; 31(5):1341-6. doi: 10.1016/0360-3016(95)00060-C.
PMID: 7713792.) Late effects will be reported as per Common Terminology Criteria for
Adverse events (CTCAE v5.0)
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_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 1:1. Based on previous studies; Glemarec G et al. (2023) &
Trovo M et al., (2018), 1 year progression free survival was 93%&75% 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 0.05 & type Ц error was
0.2. Sample size was calculated using Med calc statistical package version (18.2.1)
(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 Student's t-test while for non-normally distributed
numeric variables, comparisons will be done by Mann-Whitney test. Chi square or
Fisher's 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 < 0.05 will be considered significant.
10-Time plan (when to start/when expected to finish/when 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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Female patients aged 18 to 70 years.
- Pathological evidence of breast cancer, any grade, any T stage.
- Radiological (at least) evidence of metastatic activity with maximum number of 5
extracranial lesions.
- Performance status ≤ 2
- No pre-existing conditions that may prohibit radiotherapy.
Exclusion Criteria:
•.Pregnant and lactating women.
- Prior radiotherapy to affected site(s) in less than a year.
- Active Connective tissue diseases (e.g Rheumatoid Arthritis).
- Progression to widespread metastatic disease
- Cases with brain metastasis
Gender:
Female
Gender based:
Yes
Gender description:
Biological identity
Minimum age:
18 Years
Maximum age:
70 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
National Cancer Institute
Address:
City:
Cairo
Zip:
11796
Country:
Egypt
Status:
Recruiting
Contact:
Last name:
Rimoun R Boutrus, M.D., Ph.D.
Phone:
00201061056900
Email:
rimoun.boutrus@nci.cu.edu.eg
Contact backup:
Last name:
Medhat El Sebaie, M.D., Ph.D
Phone:
00201221900822
Email:
melsebaie@gmail.com
Start date:
September 20, 2023
Completion date:
September 20, 2028
Lead sponsor:
Agency:
National Cancer Institute, Egypt
Agency class:
Other
Source:
National Cancer Institute, Egypt
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06144346
