Axillary Reverse Mapping (ARM) in Breast Cancer Surgery to Prevent Lymphedema. (ARMtrial)

Study Overview
=================
Brief Summary
-----------------
Breast cancer related lymphedema (BCRL) is a debilitating and distressing condition affecting approximately one out of five breast cancer survivors. BCRL is a chronic swelling of the upper arm following axillary lymph nodes dissection, and it is associated to a significant functional, psychological and social morbidity, with an heavy impact on life quality. Several studies reported BCRL incidence between 6.7% and 62.5% for different population cohorts. Randomized clinical trials (RCTs) reported that sentinel lymph node biopsy (SLNB) when compared with axillary lymph node dissection (ALND) leads to a significant reduction in postoperative complications. However, the advent of SLNB does not solve the problem of BCRL with a concrete chance to develop a lymphedema after single SLNB around 7%. Health care cost of BCRL rehabilitative treatment is not available in literature yet. Few studies considered incidence, risk factors and treatment costs of BCRL among working-age women after breast cancer treatment, reporting that BCRL population had significantly higher rehabilitative medical costs ($14,877 to $23,167) with twice as much risk to develop BCRL complications, such as lymphangitis or cellulitis when compared to BCRL free population (OR = 2.02, P = .009). Axillary reverse mapping (ARM) procedure claims to map and preserve arm lymphatic drainage during ALND and/or during SLNB, reducing BCRL development. ARM is developed as result of assumption that arm's lymphatic pathway is not involved by metastatic tumor cells of the primary breast cancer. However, when the arm lymph node correspond to the SLN it should be removed for correct tumor staging, thus a lymphatic drainage disruption onset will be expected with BCRL risk increase. During the ARM procedure, a fluorescence imaging technique (photodynamic procedure) is useful for detecting lymphatic drainage of the upper limb and it allows in differentiating the fluorescent ARM node from the SLN identified by the radioguided technique (99mTC-Nanocoll).

Detailed Description
-----------------
The investigators will conduct a randomized clinical trial (RCT) at the S. Anna University Hospital of Ferrara (Italy) on consecutive patients undergoing SLNB for breast cancer and subsequent ALND in case of SLN metastases. Eligible patients for radioguided sentinel lymph node biopsy (rSLNB) will be randomly divided in two groups: 1) experimental group in which patients undergoing rSLNB and ARM photodynamic procedure; and, in case of SLN metastases, subsequent ALND with ARM node preservation; 2) control group in which patients undergoing rSLNB and ARM photodynamic procedure; and, in case of SLN metastases, subsequent ALND with ARM node removal. Consent procedure Patients will be visited in the outpatient clinic by one of the treating surgeon, who will approach the subject and explain the study. If the patient is interested in participating, further details will be provided and consent will be obtained. Experimental design Step 1 Patients enrolled in both groups will be subjected to rSLNB associated to ARM photodynamic procedure. Radioguided SLNB technique: The day before surgery, four peri-areolar subcutaneous injections of Tc-99m Nanocoll® will be performed for an overall volume of 0.4 ml (standard activity of 74 MBq). Pre-operative imaging of SLN consists of an anterior and lateral static acquisition, generally performed between 1 and 5 hours post-injection (max. 18 hours), by means of a double head gammacamera (Siemens, ECAM). The gamma camera energy selection peak is centered on the 140 KeV of 99mTc (with a window of ± 10%), and the use of high-resolution collimators and of a 256x256 acquisition matrix. Acquisition time varies between 2 and 8 minutes. Cutaneous projection of SLN will be marked with a skin-marking pen. The day of surgery, after intraoperative routine prep and drape, a handheld gamma probe (EuroProbe III, EURORAD, Chennevières-sur-Marne, France) will be used to localize radioactivity before skin incision and during axillary dissection to identify SLN, that is defined by counts >10% of background. ARM photodynamic procedure: The day of surgery, 15 minutes before surgical incision, patients will be subjected to injection of 1 ml of ICG (5mg/ml) in the upper forearm and during SLNB we will perform an evaluation of lymphatic arm pathways with fluorescence (IC-Flow Diagnostic Green, SEDA S.p.a., Milano, Italy). If a crossover between SLN of the breast and the arm's lymph node will be find, the ARM lymph node identified by the photodynamic technique will be excised for pathological evaluation. Step 2 Patients with tumor positive SLN, eligible for ALND, will undergo to preoperative arm lymphoscintigraphy in order to asses possible changes in lymphatic drainage pathways of the arm after rSLNB. The day before ALND, an injection of a volume of 0.4 ml of Tc-99m Nanocoll® in each hand will be performed, fractioned in all interdigital space. The subsequent scintigraphic planar acquisition is performed using a double head gamma-camera (Siemens, Ecam) according the following protocol: 5 minutes post injection: imaging acquisition on hands and forearms positioned over collimator with a marker near right arm; 10 minutes post injection :anterior acquisition with gamma camera head 1 on elbows and shoulders; 15 minutes post injection : anterior acquisition on both axilla and thorax using cobalt wires markers drawing cranium profile; 20 minutes post injection :marking with skin-marking pen of skin projection of most radioactive axillary nodes; 120/180 minutes post injection : acquisition in the same position for checking of possible number and/or site changes of nodes marked before. Step 3 Experimental group: In case of SLN metastases, during radical ALND (I, II,III levels of Berg), the ARM lymph node identified with both radioguided and photodynamic methods will be isolated from the other axillary lymph nodes and preserved. Photodynamic method will also allow us to visualize the lymphatic drainage of the arm that will be preserved. Control group: In case of SLN metastases, during radical ALND (I, II,III levels of Berg), the ARM lymph node identified with both radioguided and photodynamic method will be isolated from the other axillary lymph nodes and removed. Step 4 The post-operative follow up will be conducted in inpatient setting and after discharge in outpatient setting (surveillance for early and delayed surgical complications). All patients will be clinically evaluated at 10, 30, 60, and 180 days after surgery and undergoing bilateral arms lymphoscintigraphy at 60 days after surgery to determine possible lymphoscintigraphic changes underlying a subclinical BCRL. Clinically follow-up will include the clinical presentation (pain, integumentary abnormalities, paresthesia, hypoesthesia, neuro-vascular deficits), measurement of 7 records [diameters of the upper limb (hand, wrist, 15 cm and 10 cm distally to olecranon, elbow (olecranon), 10 cm and 15 cm proximally to olecranon)] and final conversion into volumes. In case of BCRL diagnosis patients will be addressed to rehabilitative center for therapy. Statistical analysis A prospective analysis will be obtained from database in which patients data will be collected, with details of the patients and tumors characteristics, lymphatic drainage of the upper extremity, intra- and post-operative outcome, and follow up. The power analysis, based on preliminary results, reports that 150 women in each group are required to achieve a power of 0.9 and to detect a significant difference (p<0.05). Data will be expressed as mean ± standard deviation or median (interquartile range - IQR 25-75) according to the distribution. The Shapiro-Wilk test will be used to assess the assumption of normality. Categorical data will be presented as number (%). Data will be analyzed using the Chi-square test to compare percentages, t-Student test will be used to compare the means and Mann-Whitney test to compare non parametric data. Logistic regression analysis will be employed to construct a model predicting BCRL using factors regarding the patient [age, gender, BMI, American Society of Anesthesiology (ASA) classification], the tumor (size, stage, bio-molecular characteristics ), crossover, type of intervention (preservation of ARM lymph node vs. dissection), and post-operative treatment (chemotherapy, radiotherapy). Significance will be considered for values of p<0.05. Statistical analysis will be performed with IBM SPSS Statistics for Windows, Version 24.0 (IBM Corp. Armonk, NY: IBM Corp.).

Official Title
-----------------
Axillary Reverse Mapping (ARM). Identification of the Arm Lymphatic Pathways in Breast Cancer Surgery to Prevent Breast Cancer Related Lymphedema (BCRL): a Randomized Clinical Trial.

Conditions
-----------------
Breast Cancer Lymphedema

Intervention / Treatment
-----------------
* Procedure: Axillary Reverse Mapping (ARM)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: T1-T2 stage breast cancer Exclusion Criteria: axillary lymph node metastasis; previous surgery on the ipsilateral axilla; neoadjuvant chemo-radiotherapy; presence of primitive lymphedema of the arm; allergy to Iodine, thyroid disease, renal and hepatic impairment (for issues related to Indocyanine Green) pregnancy; patients refusing to participate in the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible patients for radioguided sentinel lymph node biopsy (rSLNB) will be randomly divided in two groups: experimental group in which all patients will be sent to both rSLNB and photodynamic Axillary Reverse Mapping (ARM) to evaluate the crossover between SLN and ARM lymph node. In case of SLN metastases, an ALND with ARM lymph node preservation will be performed. control group in which all patients will be sent to both rSLNB and photodynamic Axillary Reverse Mapping (ARM) to evaluate the crossover between SLN and ARM lymph node. In case of SLN metastases, an ALND with ARM lymph node removal will be performed.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARM lymph node preservation<br>All patients will be sent to both rSLNB and photodynamic Axillary Reverse Mapping (ARM) to evaluate the crossover between SLN and ARM lymph node. In case of SLN metastases, an ALND with ARM lymph node preservation will be performed. | Procedure: Axillary Reverse Mapping (ARM)<br>* ARM lymph node preservation versus removal<br>|
| Active Comparator: ARM lymph node removal<br>All patients will be sent to both rSLNB and photodynamic Axillary Reverse Mapping (ARM) to evaluate the crossover between SLN and ARM lymph node. In case of SLN metastases, an ALND with ARM lymph node removal will be performed. | Procedure: Axillary Reverse Mapping (ARM)<br>* ARM lymph node preservation versus removal<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Breast Cancer Related Lymphedema (BCRL) after Axillary Lymph Node Dissection (ALND) | Incidence of BCRL in patients in whom the ARM lymph node is preserved compared to those in which it is removed. Clinically follow-up will include the clinical presentation (pain, integumentary abnormalities, paresthesia, hypoesthesia, neuro-vascular deficits), standardized measurement of 7 records [diameters of the upper limb (hand, wrist, 15 cm and 10 cm distally to olecranon, elbow (olecranon), 10 cm and 15 cm proximally to olecranon)] and final conversion into volumes. | From the day of surgery to 12 months after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Breast Cancer Related Lymphedema (BCRL) after Sentinel Lymph Node Biopsy (SLNB) alone | Clinically follow-up will include the clinical presentation (pain, integumentary abnormalities, paresthesia, hypoesthesia, neuro-vascular deficits), standardized measurement of 7 records [diameters of the upper limb (hand, wrist, 15 cm and 10 cm distally to olecranon, elbow (olecranon), 10 cm and 15 cm proximally to olecranon)] and final conversion into volumes. | From the day of surgery to 12 months after surgery | 
| Crossover between Sentinel Lymph Node (SLN) of the Breast and the ARM lymph node | Intraoperatively, the radioguided technique (Tc-99m Nanocoll) will be used to identify the SLN of the breast; at the same time, the Axillary Reverse Mapping (ARM) of the upper limb will be carried out by Indocyanine Green, and the ARM lymph node will be identified and preserved. If a crossover between SLN of the breast and the arm's lymph node will be find, the ARM lymph node identified by the photodynamic technique will be excised for pathological evaluation. | Intraoperatively | 
| Lymphoscintigraphic sub-clinical modifications of arm lymphatic drainage after ALND | Bilateral arms lymphoscintigraphy | The day before ALND and at 60 days after ALND | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Breast Neoplasms, Sentinel Lymph Node Biopsy, Lymph Node Excision, Technetium Tc 99m, Indocyanine Green, Lymphatic System, Secondary Prevention