Pre-existing Factors, Early Detection and Early Treatment of Breast Cancer Related Lymphedema

Study Overview
=================
Brief Summary
-----------------
Breast-cancer related lymphoedema (BCRL) is a common phenomenon. Early diagnosis and treatment is very important to alter the normal progression of this disease. A threshold (>= 3% volume change) that recognizes subclinical lymphedema is promoted. When the lymphedema is diagnosed late, options for treatment are diminished as fibrous tissue is formed. Preoperative investigation with near-infrared fluorescence lymphography can show an abnormality. Even if a linear transport is visualized, velocity of the transport can be diminished or a different pathway than normal can be visualized. Such an extensive evaluation has not been performed yet. This lymphofluoroscopy gives an opportunity to detect lymphedema earlier than clinically visible (subclinical). The investigators hypothesize that the evolution of lymphedema can be altered if treatment is started in the subclinical phase.

Detailed Description
-----------------
Breast-cancer related lymphoedema (BCRL) is a common phenomenon. Estimates of incidence rates have varied over time, especially since the progression to less invasive techniques as sentinel node procedures and radiotherapy. According to a review article of DiSipio the incidence of arm lymphedema was about four times higher in women who had an axillary lymph node dissection (18 studies; 19.9%, 13.5-28.2) than in those who had sentinel lymph node biopsy (18 studies; 5.6%, 6.1-7.9). Several other risk factors are already suggested as having a negative impact on the development of lymphedema such as BMI and chemotherapy. A comprehensive overview of all treatment related risk factors and patient related risk factors, including demographics, has not been reported yet. Lymphedema is identified with upper limb volume measurements eg circumference measurements, water displacement and perometer. Bioimpedance spectroscopy can also be used to assess the extracellular fluid. A 10% limb volume change has been reported as the most accurate threshold to diagnose lymphedema. However, with this definition an underestimation of the incidence rate of lymphoedema is made. Therefore, recently a threshold of 5% limb volume change is proposed. A study by Rockson et al suggested that in almost 75 % of the cases, lymphoedema is established in the first year after breast cancer treatment. But up to two years after surgery, there still is a possibility to develop lymphoedema. Early diagnosis and treatment is very important to alter the normal progression of this disease. A threshold (>= 3% volume change) that recognizes subclinical lymphedema is promoted. When the lymphedema is diagnosed late, options for treatment are diminished as fibrous tissue is formed. During near-infrared fluorescence lymphography (lymphofluoroscopy), a fluorescent substance is injected subcutaneously in the hand and the transport of lymph is visualized from the hand up to the axilla. A normal transport is defined as a linear image and an abnormal transport as a dermal backflow image. The dermal backflow image is divided in three different classifications according to the severity. Preoperative investigation with near-infrared fluorescence lymphography can show an abnormality. Even if a linear transport is visualized, velocity of the transport can be diminished or a different pathway than normal can be visualized. Such an extensive evaluation has not been performed yet. This lymphofluoroscopy gives an opportunity to detect lymphedema earlier than clinically visible (subclinical). The investigators hypothesize that the evolution of lymphedema can be altered if treatment is started in the subclinical phase.

Official Title
-----------------
Determining the Role of Pre-existing Factors, Early Diagnostic Options and Early Treatment in the Development of Breast Cancer Related Lymphedema

Conditions
-----------------
Lymphedema of Upper Arm, Breast Cancer, Diagnoses Disease

Intervention / Treatment
-----------------
* Device: compression


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age >18y (since the investigation using ICG is not dangerous for pregnant women, women with child bearing age are included) Women/ men with breast cancer and scheduled for unilateral axillary lymph node dissection (ALND) or sentinel node biopsy (SNB) Oral and written approval of informed consent Dutch speaking Exclusion Criteria: Oedema of the upper limb from other causes Cannot participate during the entire study period Mentally or physically unable to participate in the study Contra-indication for the use of ICG: allergy to iodine, hyperthyroidism Metastatic disease

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: control group<br>Receive information: the patient receive a leaflet with information about the lymphatic system and lymphedema, clinical evaluation and conservative treatment of lymphedema Perform skin care Perform twice a day upper limb exercises at home. They are advised to use the arm as normal as possible. | |
| Active Comparator: intervention group<br>Receive information: the patient receive a leaflet with information about the lymphatic system and lymphedema, clinical evaluation and conservative treatment of lymphedema Perform skin care Perform upper limb exercises at home twice a day. They are advised to use the arm as normal as possible Wear a compression sleeve | Device: compression<br>* a compression stocking is worn, a garment compression class 2, flat knitted<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of lymphedema of arm and hand | defined as 5% volume increase compared to the contralateral side | up to 36 months | 
| Deterioration of dermal backflow | measured by lymphofluoroscopy | up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of extracellular fluid change of extracellular fluid | measured by the BIS | up to 36 months | 
| Change of quality of life | measured by Mc Gill questionnaire | up to 36 months | 
| change of pitting status | measured by the pitting test at each visit | up to 36 months | 
| Change of water content | measured with moisture meter | up to 36 months | 
| change of skinfold tickness | measured by skinfold | up to 36 months | 
| relative change of arm volume difference | relative volume difference at assessment - relative volume difference at baseline | up to 36 months | 
| severity of disturbance of lymphatic transport | scoring dermal backflow in the 13 regions | up to 36 months | 
| problems in functioning related to development of lymphedema | measured by lymph ICF questionnaire | up to 36 months |