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Trial registered on ANZCTR


Registration number
ACTRN12621000817842
Ethics application status
Approved
Date submitted
9/05/2021
Date registered
28/06/2021
Date last updated
5/11/2023
Date data sharing statement initially provided
28/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Relationship between indocyanine green axillary reverse mapping related factors and lymphoedema in breast cancer
Scientific title
Relationship between patient characteristics and nodal information gathered using indocyanine green axillary reverse mapping and postoperative lymphoedema in patients undergoing axillary lymph node dissection for clinically node negative breast cancer and a positive sentinel lymph node biopsy
Secondary ID [1] 304144 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer Related Lymphoedema 321841 0
Condition category
Condition code
Surgery 319566 319566 0 0
Surgical techniques
Cancer 320062 320062 0 0
Breast
Cardiovascular 320063 320063 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All interventions will be performed on patients with early stage clinically node negative breast cancer with a positive sentinel lymph node biopsy who are undergoing axillary lymph node dissection.

Sentinel Lymph Node Biopsy:
SLN biopsy technique will proceed as standard-of-care. This involves peri-areolar or peri-tumour subdermal injection of technetium 99m (Tc99m) and lymphoscintigraphy which is performed prior to the day of surgery. Through either a mastectomy incision or axillary incision, a handheld gamma-detecting probe will be used to identify areas of increased radioactivity within the axilla. All hot nodes will be excised. Hot SLNs are defined as any nodes with a 10:1 gamma-detecting probe ratio of SLN to non-SLNs. Excision of these nodes will occur during the appropriate mastectomy procedure (wide local excision, simple mastectomy, skin-sparing mastectomy or nipple-sparing mastectomy). This element of the procedure has a duration of approximately one hour or less.

Axillary Lymph Node Dissection (ALND) & Axillary Reverse Mapping (ARM):
This procedure will involve using ICG technology to observe the relationship of ARM nodes and lymphatics in addition to standard-of-care axillary lymph node dissection. Before incision, 1 mL of Infracyanine® 25mg/mL (SERB, Paris, France) will be injected subdermally into the internal bicipital sulcus of the ipsilateral arm. The injection site will be massaged until fluorescent ARM lymphatics are observed in the upper inner arm. During SLNB, a NIR fluorescence imaging system (SPY-PHI, Novadaq Technologies Inc., Mississauga, Canada) will be used to identify the ARM nodes and lymphatics. The locations of all identified ARM nodes and lymphatics will be documented in relation to axillary surgical landmarks, which include the axillary vein, thoracodorsal neurovascular bundle and second intercostobrachial nerve. The superior, medial and lateral limits of the ALND field will be the axillary vein, chest wall, and anterior edge of latissimus dorsi muscle, respectively. Nodes that fluoresce with the NIR camera will be labelled as ARM nodes. The ARM nodes within the ALND field will be removed and separately sent for histopathology. Lymph nodes outside of the ALND field will be preserved. ARM will be performed prior to ALND. ALND and ARM will both be performed during the appropriate mastectomy procedure (wide local excision, simple mastectomy, skin-sparing mastectomy or nipple-sparing mastectomy). This element of the procedure has a duration of approximately one to two hours.

Mastectomy:
Wide local excision, simple mastectomy, skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM) with or without immediate breast reconstruction will be performed, depending on the extent of breast cancer and the patient’s preference. This will be performed as part of standard of care. This element of the procedure has a duration of approximately one to two hours.

All procedures will be performed by breast surgeons at a hospital (Chris O'Brien Lifehouse).
Intervention code [1] 320507 0
Treatment: Surgery
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 327454 0
Location of identified ARM nodes as determined from operative reports.
Timepoint [1] 327454 0
At time of mastectomy/ALND.
Primary outcome [2] 327939 0
Rate of ARM node positivity as determined by histopathological analysis of excised nodes.
Timepoint [2] 327939 0
At time of mastectomy/ALND.
Primary outcome [3] 327940 0
Number of excised ARM nodes as determined from operative reports.
Timepoint [3] 327940 0
At time of mastectomy/ALND.
Secondary outcome [1] 395163 0
Occurrence of of Superficial, Deep or Organ space surgical site infection as defined by the Centres for Disease Control and Prevention (CDC). Patients treated with oral or IV antibiotics will be documented, including patients who have loss of implant due to infection. Infection status, requirement for IV antibiotics and implant loss due to infection will be determined from from hospital records or by patient report at follow up. This is a composite secondary outcome.
Timepoint [1] 395163 0
30 days post mastectomy/ALND.
Secondary outcome [2] 395164 0
Occurrence of seroma/haematoma. Any evidence of seroma/ haematoma will be documented based on requirement of a surgical intervention or non-surgical management. Occurrence of seroma/haematoma and requirement for either medical or surgical management will be collected from hospital records or by patient report at follow up.
Timepoint [2] 395164 0
30 days post mastectomy/ALND..
Secondary outcome [3] 395165 0
Occurrence of readmission and other complications as determined from hospital records or patient reported complications at follow up visits. This is a composite secondary outcome.
Timepoint [3] 395165 0
30 days post mastectomy/ALND.
Secondary outcome [4] 397059 0
Rate of partially or totally preserved ARM nodes or lymphatic ducts as determined from operative reports. This is a primary outcome.
Timepoint [4] 397059 0
At time of mastectomy/ALND
Secondary outcome [5] 397060 0
Rate of lymphoedema defined as a difference in volume between arms of 10% or >2cm increase in arm circumference. This will be determined by volumetric measurement at follow up. This is a primary outcome.
Timepoint [5] 397060 0
30 days post mastectomy/ALND

Eligibility
Key inclusion criteria
- Participant has clinically node-negative early breast cancer with a positive sentinel lymph node biopsy undergoing axillary lymph node dissection
- Participant has clinically node-positive early breast cancer undergoing axillary lymph node dissection
- Female, age 18 years or older
- Participant understands the study procedures and can provide informed consent to participate in the study
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
- Participant does not have clinically node-negative early breast cancer with a positive sentinel lymph node biopsy
- Participant does not have clinically node-positive early breast cancer
- Participant has known contraindication to ICG injection, i.e., previous reaction to ICG
- Participant has Iodine allergy
- Participant has chronic kidney disease stage 3, 4, or 5
- Participant is pregnant
- Refusal to consent to participation in the study

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Chi-squared or Mann-Whitney U test to estimate differences in clinicopathological and ARM associated data of patients with and without lymphedema (LE). Two-sided p values 0.05 will be considered statistically significant. Odds ratio for LE incidence with respect to the multivariate clinical and ARM-associated data will be calculated using logistic multivariate regression model. Statistical analysis will be performed with RStudio, version 1.4.1106.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
4/07/2022
Actual
1/05/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
72
Accrual to date
10
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 19366 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment postcode(s) [1] 33945 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 308520 0
Hospital
Name [1] 308520 0
Chris O'Brien Lifehouse
Country [1] 308520 0
Australia
Primary sponsor type
Individual
Name
Dr Sanjay Warrier
Address
Chris O'Brien Lifeshouse, 119-143 Missenden Rd, Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 309374 0
None
Name [1] 309374 0
Address [1] 309374 0
Country [1] 309374 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308476 0
Sydney Local Health District Ethics Review Committee
Ethics committee address [1] 308476 0
Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 308476 0
Australia
Date submitted for ethics approval [1] 308476 0
26/04/2021
Approval date [1] 308476 0
02/07/2021
Ethics approval number [1] 308476 0

Summary
Brief summary
Breast cancer-related lymphoedema (BCRL) is a common complication after breast cancer surgery which involves the accumulation of fluid in the arm. It affects breast cancer survivors causing discomfort, reduced function and quality of life. It occurs due to the unnecessary sacrifice of the lymphatics of the arm during sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) procedures. A SLNB is a procedure in which the sentinel lymph node (SLN) is identified, removed, and examined to determine whether cancer cells are present. A SLN is defined as the first lymph node to which cancer cells are likely spread into. An ALND is a procedure to remove lymph nodes from the axilla.

Axillary reverse mapping (ARM) is a technique used to distinguish lymphatic drainage of the arm from that of the breast in the axilla by allowing surgeons to visualise lymphatic channels and nodes which drain the arm using a fluorescent tracer. The axilla and breast have mostly separate drainage pathways. ARM may allow for minimal disruption of the arm lymphatics in order to reduce the risk of BCRL during SLNB and ALND. This study aims to perform ARM using a tracer called indocyanine green (ICG) with near-infrared fluorescence imaging on patients with a positive SLNB who are undergoing ALND.

Who is it for?
You may be eligible for this study if you are an adult who has been diagnosed with early breast cancer and is undergoing axillary lymph node dissection.

Study details:
All participants in this study will complete axillary reverse mapping using ICG during the axillary lymph node dissection. This procedure will take approximately one to two hours and will be completed by a breast surgeon.

Participants will then undergo removal of the tumour as standard of care, with the surgeon using an approach which has been discussed with the patient prior to surgery. This may involve removal of the tumour alone or additionally removal of the affected breast depending on the extent of the breast cancer and the patient's preferences.

It is hoped that this research will aid in the understanding the anatomical relationship of ARM nodes and lymphatics, which could help predict patients at risk of lymphoedema.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 110826 0
A/Prof Sanjay Warrier
Address 110826 0
Chris O'Brien Lifehouse, 119-143 Missenden Rd, Camperdown NSW 2050
Country 110826 0
Australia
Phone 110826 0
+61 2 8514 0793
Fax 110826 0
Email 110826 0
[email protected]
Contact person for public queries
Name 110827 0
Dr Chu Nguyen
Address 110827 0
Chris O'Brien Lifehouse, 119-143 Missenden Rd, Camperdown NSW 2050
Country 110827 0
Australia
Phone 110827 0
+61 401608581
Fax 110827 0
Email 110827 0
[email protected]
Contact person for scientific queries
Name 110828 0
Dr Chu Nguyen
Address 110828 0
Chris O'Brien Lifehouse, 119-143 Missenden Rd, Camperdown NSW 2050
Country 110828 0
Australia
Phone 110828 0
+61 401608581
Fax 110828 0
Email 110828 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11621Study protocol    381942-(Uploaded-09-05-2021-19-14-07)-Study-related document.docx



Results publications and other study-related documents

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