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prospective cohort study to evaluate the effect of regional nodal irradiation omission on the regional recurrence rate after neoadjuvant chemotherapy followed by breast conserving surgery and sentinal lymph node biopsy in clinical T1-3 with lymph node metastasis in axillary level I and ypN0 breast cancer patient

Status Approved

  • First Submitted Date

    2019/12/12

  • Registered Date

    2019/12/19

  • Last Updated Date

    2024/03/15

CRIS Required

WHO ICTRP (International Clinical Trial Registry Platform) Required

  • 1. Background

    Background - CRIS Registration Number, Unique Protocol ID, Public/Brief Title, Scientific Title, Acronym, MFDS Regulated Study, IND/IDE Protocol, Registered at Other Registry, Name of Registry/Registration Number
    CRIS
    Registration Number
    KCT0004567
    Unique Protocol ID NCC 2019-0279
    Public/Brief Title study to evaluate the effect of regional nodal irradiation omission in ypN0 breast cancer patient
    Scientific Title prospective cohort study to evaluate the effect of regional nodal irradiation omission on the regional recurrence rate after neoadjuvant chemotherapy followed by breast conserving surgery and sentinal lymph node biopsy in clinical T1-3 with lymph node metastasis in axillary level I and ypN0 breast cancer patient
    Acronym
    MFDS Regulated Study No
    IND/IDE Protocol No
    Registered at Other Registry No
    Healthcare Benefit Approval Status Not applicable
  • 2. Institutional Review Board / Ethics Committee

    Institutional Review Board Information
    Board Approval Status Submitted approval
    Board Approval Number NCC 2019-0279
    Approval Date 2019-11-12
    Institutional Review Board Name National Cancer Center Institutional Review Board
    Institutional Review Board Address 323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do
    Institutional Review Board Telephone 031-920-0425
    Data Monitoring Committee No
  • 3. Contact Details

    Contact Details Information - Contact Person for Principal Investigator / Scientific Queries, Contact Person for Public Queries, Contact Person for Updating Information의 Name, Title, Email, Telephone, Cellular Phone, Affiliation, Address
    Contact Person for Principal Investigator / Scientific Queries
    Name Yeon Joo Kim
    Title Ph.D
    Telephone +82-31-920-1785
    Affiliation National Cancer Center
    Address 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do
    Contact Person for Public Queries
    Name SUNG YI KIM
    Title researcher
    Telephone +82-31-920-0143
    Affiliation National Cancer Center
    Address 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do
    Contact Person for Updating Information
    Name SUNG YI KIM
    Title researcher
    Telephone +82-31-920-0143
    Affiliation National Cancer Center
    Address 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do
  • 4. Status

    Status Information - Study Site, Overall Recruitment Status, Date of First Enrollment, Status of First Enrollment, Target Number of Participant, Primary Completion Date, Recruitment Status by Participating Study Site, Name of Study Site, Recruitment Status, Date of First Enrollment, Status of First Enrollemnt
    Study Site Multi-center Number of center : 7
    Overall Recruitment Status Recruiting
    Date of First Enrollment 2019-12-10 Actual
    Target Number of Participant 844
    Primary Completion Date 2029-12-01 , Anticipated
    Study Completion Date 2029-12-31 , Anticipated
    Recruitment Status by Participating Study Site 1
    Name of Study National Cancer Center
    Recruitment Status Recruiting
    Date of First Enrollment 2019-12-10 ,
    Recruitment Status by Participating Study Site 2
    Name of Study Samsung Medical Center
    Recruitment Status Recruiting
    Date of First Enrollment 2020-03-02 ,
    Recruitment Status by Participating Study Site 3
    Name of Study Keimyung University Dongsan Hospital
    Recruitment Status Recruiting
    Date of First Enrollment 2020-01-16 ,
    Recruitment Status by Participating Study Site 4
    Name of Study Kyungpook National University Medical Center
    Recruitment Status Recruiting
    Date of First Enrollment 2020-04-28 ,
    Recruitment Status by Participating Study Site 5
    Name of Study The Catholic University of Korea, St. Vincent's Hospital
    Recruitment Status Recruiting
    Date of First Enrollment 2021-12-30 ,
    Recruitment Status by Participating Study Site 6
    Name of Study Chonnam National University Hospital Hwasun Hospital
    Recruitment Status Recruiting
    Date of First Enrollment 2020-04-16 ,
    Recruitment Status by Participating Study Site 7
    Name of Study Gachon University Gil Medical Center
    Recruitment Status Recruiting
    Date of First Enrollment 2021-03-17 ,
  • 5. Source of Monetary / Material Support

    Source of Monetary / Material Support Information - Organization Name, Organization Type, Project ID
    1. Source of Monetary/Material Support
    Organization Name National Cancer Center
    Organization Type Medical Institute
    Project ID 1911900-1
  • 6. Sponsor Organization

    Sponsor Organization Information - Organization Name, Organization Type
    1. Sponsor Organization
    Organization Name National Cancer Center
    Organization Type Medical Institute
    2. Sponsor Organization
    Organization Name Samsung Medical Center
    Organization Type Medical Institute
  • 7. Study Summary

    Study Summary Information
    Lay Summary
    1) Purpose and background: According to the results of NSABP B-18 and B-27, published in the Journal of Clinical Oncology in 2012, the 10-year cumulative lymph node (LN) recurrence rate was extremely low at 0%–2.4% in 230 patients with ypN0 disease who had undergone breast conservation surgery after neo-adjuvant chemotherapy for clinical stage T1–3N1 breast cancer without RNI (Regional nodal irradiation). This was similar to the LN recurrent rate in patients with clinical N0 (0.5%–2.3%). According to a retrospective study published in the British Journal of Cancer (KROG 12-05) in 2014, regional recurrence was found in 3 (2.4%) of 124 patients with confirmed ypN0 disease after neo-adjuvant chemotherapy for cT1–4cN+ without RNI and 2 (1.4%) of 136 patients who had undergone RNI. According to another retrospective study (KROG 16-16) published in the Clinical Breast Cancer in 2018, of 159 patients with confirmed ypN0 disease after neo-adjuvant chemotherapy for cT1–4N+ disease without RNI, none showed regional recurrence, whereas 3 (2.9%) of 102 patients who had undergone RNI showed regional recurrence.
    
    However, as reported in a review article published in Strahlentherapie und Onkologie in 2018, there are no definitive data that support the omission of RNI in patients with ypN0 disease who have undergone breast conservation surgery after neo-adjuvant chemotherapy for cN1 disease. The 2019 NCCN guideline also recommends radiotherapy according to the worst clinical stage. 
    
    According to ACOSOG Z1071 published in JAMA in 2013 and the SENTINA study published in Lancet Oncology in the same year, the false-negative rate (FNR) was 4.9–9.1% in patients who had undergone SLNB with ≥3 dissected LNs. In the case of dual-tracer use, the FNR was 8.6–10.8%. According to a 2015 study in the Journal of Clinical Oncology, the FNR decreased to 4.9% in patients who had undergone SLNB with ≥2 dissected LNs. Recently, several institutions in Korea have been conducting SLNB instead of axillary LN dissection (ALND) to decrease surgery-related morbidity, even in patients who have undergone neo-adjuvant chemotherapy. A multicenter retrospective study published in Breast Cancer Research and Treatment in 2017 and a 2018 study in Journal of Breast Cancer showed no difference in axillary recurrence-free survival between patients with ypN0 who had undergone SLNB alone and those who had undergone ALND. Many institutions are conducting SLNB in patients who have undergone neo-adjuvant chemotherapy for cN+ disease, and axillary LN sampling or dissection is performed only when necessary. 
    
    KROG 12-05 and KROG 16-16 study included 236 patients (90.7%) and 213 patients (81.6%) who had undergone ALND. Therefore, a prospective study is needed to assess the safety of omitting RNI in patients who have undergone SLNB alone. 
    
    Patients who have undergone RNI have a higher risk of lymphedema, shoulder stiffness, and radiation pneumonitis than do those who have not undergone RNI. According to the study published in Breast Cancer Research in 2016, patients who had undergone RNI showed a more than twofold increase in the incidence of lymphedema. 
    
    With the rapid advancements in chemotherapy and target therapy recently, DFS has improved. Therefore, a prospective study is needed to assess whether RNI can be omitted in patients with confirmed ypN0 disease on SLNB who have received cutting-edge chemotherapy or targeted therapy.
    
    2) study hypothesis: This is a prospective cohort study to evaluate the effects of regional nodal irradiation omission on regional recurrence rate after neo-adjuvant chemotherapy followed by breast conserving surgery and sentinel lymph node biopsy. The primary outcome is non-inferiority of 5-year regional recurrence rate, which is defined as a recurrence rate of not more than 6% for the whole breast irradiation group compared with an expected 3% in the whole breast and regional nodal irradiation group.
  • 8. Study Design

    Study Design Information - Study Type, Observational Study Model, Time Perspective, Target Number of Participant, Cohort/Group Number, Cohort/Group, Cohort/Group Label, Cohort/Group Description, Biospecimen Collection & Archiving, Biospecimen Description
    Study Type Observational Study
    Observational Study Model Cohort
    Time Perspective Prospective  
    Target Number of Participant 844
    Cohort/Group Number 2
    Cohort/
    Group 1

    Cohort/Group Label

    breast and lymph node

    Cohort/Group Description

    treat all of whole breast and regional node with radiation.
    researchers observe variables through confirmed clinical data, assessed toxicity and quality-of-life
    Cohort/
    Group 2

    Cohort/Group Label

    breast alone

    Cohort/Group Description

    treat all of whole breast with radiation.
    researchers observe variables through confirmed clinical data, assessed toxicity and quality-of-life
    Biospecimen
    Collection & Archiving
    Not collect nor Archive
    Biospecimen Description
  • 9. Subject Eligibility

    Subject Eligibility Information
    Study Population Description
    neoadjuvant chemotherapy followed by breast conserving surgery and sentinel lymph node biopsy in clinical T1-3 with lymph node metastasis in axillary level I and ypN0 breast cancer patient.
    Sampling Method
    Estimated enrollment:  844 participants
    The 5-year recurrence rate is estimated to be 3% in the breast and LN treatment arm (LN radiotherapy arm). In the breast-only treatment arm (no LN radiotherapy arm), the 5-year recurrence-free survival rate is expected to be similar to that in the LN radiotherapy group. An increase of <3% (DFS rate ≤6%) is deemed non-inferior. Assuming enrollment of 400 patients in each arm has a 1:1 ratio, the power to show non-inferiority with 5% alpha-level according to the 5-year cumulative incidence is 80%. Considering a 5% dropout rate, 422 patients will be recruited to each arm, with a total of 844 patients. 
    If patients are enrolled to the two arms at a 7:3 or 3:7 ratio, 954 patients must be enrolled to obtain 80% power, and considering a 5% dropout rate, 1005 patients need to be recruited. 
    Once 50% of the target sample size (422 patients) is recruited, the safety of this study and adequacy of the sample size will be monitored. The study will be terminated earlier if the LN recurrence rate exceeds 6% in the no LN radiotherapy group. If the ratio between the two arms is not 1:1, the sample size to achieve 80% power will be recalculated, and the sample size will be adjusted. 
    The ratio between the LN radiotherapy group and the no LN radiotherapy group will be confirmed before stopping enrollments to adjust the sample size if 80% power is not reached.
    Condition(s)/Problem(s) * (C00-D48)Neoplasms 
       (C50.99)Malignant neoplasm of breast unspecified, unspecified side 

    clinical T1-3 with lymphnode metastasis in axillary level I and ypN0 breast cancer
    Rare Disease No
    Inclusion Criteria

    Gender

    Female

    Age

    20Year~70Year

    Description

    1. Ages eligible for study: between 20-70 years old
    2. Patient must have had pathologic confirmation of invasive breast cancer
    3. The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of
    0 or 1
    4. Patient must have clinically T1-3 (before neo-adjuvant therapy)
    5. Patient must have axillary level I nodal involvement at presentation (before neo-adjuvant therapy) based on either a positive fine needle aspirate (FNA) or positive in positron emission tomography (PET) scan
    6. Patients with metastatic lymph node at axilla level I only
    7. Patient who have undergone breast conserving surgery
    8. Patient who have undergone either sentinel lymph node biopsy or axillary lymph node sampling
    9. Patients with pathologic staging of ypN0, ypN0(i+) or ypN0(mol+) are eligible (Note: postneo-adjuvant therapy is designated with a "yp" prefix.)
    10. Patients must have had estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67 index testing performed on the primary breast tumor before neo-adjuvant therapy
    Exclusion Criteria
    1. T4 tumors including inflammatory breast cancer
    2. Definitive clinical or radiologic evidence of metastatic disease 
    3. Patients with metastatic lymph node at axilla level II-III, internal mammary and supraclavicular area by imaging 
    4. Patient must have not completed a minimum of 50% of standard neo-adjuvant chemotherapy
    5. Patients who showed progression during neo-adjuvant chemotherapy
    6. Patient who have undergone mastectomy
    7. Patient who have undergone axillary lymph node dissection
    8. Bilateral breast cancer patients
    9. Male breast cancer patients
    10. Prior breast or thoracic radiation therapy (RT) for any condition
    11. History of non-breast malignancies (except for in situ cervical cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to radiotherapy
    12. Pregnancy or lactation at the time of study entry
    Healthy Volunteers No
  • 10. Outcome Measure(s)

    Outcome Measure(s) Information - Type of Primary Outcome, Primary Outcome, Outcome, Timepoint, Secondary Outcome, Outcome, Timepoint
    Type of Primary Outcome clinical-equivalence
    Primary Outcome(s) 1
    Outcome
    regional recurrence rate
    Timepoint
    from radiation treatment last day to 5 years
    Secondary Outcome(s) 1
    Outcome
    cumulative toxicity rate (lymphedema, brachial plexopathy, shoulder joint range of motion decreased, radiation pneumonitis, myocardial infartion)
    Timepoint
    from radiation treatment last day to 5 years
    Secondary Outcome(s) 2
    Outcome
    local recur-free survival, diease-free survival, cancer-specific survival, overall survival
    Timepoint
    from radiation treatment last day to 5 years
    Secondary Outcome(s) 3
    Outcome
    Quality of life
    Timepoint
    from radiation treatment last day to 5 years
    Secondary Outcome(s) 4
    Outcome
    molecular subtype layering analysis and subgroup analysis
    Timepoint
    from radiation treatment last day to 5 years
  • 11. Study Results and Publication

    Study Results and Publication Information - Result Registered, Final Enrollment Number, Number of Publication, Publications, Results Upload, Date of Posting Results, Protocol URL or File Upload, Brief Summary
    Result Registered No
  • 12. Sharing of Study Data(Deidentified Individual-Patient Data, IPD)

    Sharing of Study Data Information - Sharing Statement, Time of Sharing, Way of Sharing
    Sharing Statement No
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