Tacrolimus as Treatment of Breast Cancer-Related Lymphedema

Study Overview
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Brief Summary
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BACKGROUND Breast cancer-related lymphedema is a severe and life-long side-effect to breast cancer treatment. The condition increases the risk of infections and decreases health-related quality of life (HR-QOL) in patients. No prophylactic or curative treatment is currently available for this condition. CD4+-cells plays a critical role in the development of lymphedema. The cells facilitate inflammation and fibrosis formation in the subcutaneous tissue which inhibits lymphatic regeneration. Tacrolimus is an immunosuppressive and anti-inflammatory macrolide that targets the CD4+-cells. Tacrolimus as treatment of lymphedema has already shown promising results in animal studies. Tacrolimus has the potential to cure an otherwise uncurable and life-long side-effect of BC and will therefore benefit a large number of patients who suffers from BCRL. AIM To assess the effect of Tacrolimus treatment on breast cancer-related lymphedema METHOD Study design A pilot study with a planned inclusion of 20 patients with a 12 month follow-up period. The purpose of this study is to assess the effect of tacrolimus treatment on lymphedema and HR-QOL. Results are attained from objective measures and questionnaires. The patients will be seen at a consultation prior to the treatment start and then 3 times hereafter (at 3, 6 and 12 months) as follow up consultations where effect of treatment is evaluated. Primary endpoint: - Arm volume measured with water displacement test. Secondary endpoints: Arm volume measured with measuring tape and calculated with volume of a cone formula Patient-reported outcome measured through the Danish versions of , LYMPH-ICF, DASH and SF-36 questionnaires Bioimpedance Lymphangiography Primary- and secondary endpoint data will be collected at each of the 3 consultations (prior to treatment and 3 and 6 months after the treatment start). CLINICAL IMPACT This will be the first clinical pharmacological study on regarding treatment of lymphedema with Tacrolimus. This study will test the feasibility and efficacy of Tacrolimus ointment in a population of breast cancer patients who have developed lymphedema. The study may lead to a routine clinical implementation of tacrolimus ointment to patients diagnosed with Lymphedema. Regardless of the outcome, the study will benefit the patients and future research in the field of lymphedema.

Official Title
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Tacrolimus as Treatment of Breast Cancer-Related Lymphedema

Conditions
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Breast Cancer Lymphedema

Intervention / Treatment
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* Drug: Protopic 0.1 % Topical Ointment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 30-65 years Female Lymphedema diagnosis as a result of breast cancer treatment Active Lymphedema (excessive fluid) Significant lymphedema Grade I-II lymphedema Postmenopausal (Absence/lack of menstruation in at least 12 consecutive months) or continuously usage of contraceptive drugs (Spiral, birth-control pills, implant, transdermal patches, vaginal ring or depot injection). Contraceptive drugs must be used throughout the project and at least three weeks subsequent to the ending of the project (last application of the ointment). Clinically good general condition No lymphedema in the opposite arm (normal arm) Understands the purpose og the study and gives written consent to participate Can read and understand the danish language Exclusion Criteria: Pregnant, breast-feeding or with wish of pregnancy within the next year Bilateral breast cancer Grade 0, III or IV lymphedema Known allergies for Tacrolimus or and other macrolide Removal of lymph nodes in the opposite armpit Suffers from psychiatric disorders that may affect the participation in the project Reduced kidney or liver function Defect skin-barrier Diagnosed immunodeficiency

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Women with stage 1-2 lymphedema due to breast cancer treatment | Drug: Protopic 0.1 % Topical Ointment<br>* Applied in a thin layer covering all of the arm including the armpit and hand once a day for six months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Arm volume from Baseline | measured with water displacement test. The patient lowers her arm in a basin of water (Bravometer, Novuqare BV, PJ Horst, NL) and arm volume is hereafter read in mL prior to and after the lowering of the arm. This method is established at the department we use for this project. Arm volume of both arms are measured at each consultation. | Baseline + change in arm volume at 3, 6 and 12 months from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bioimpedance | Bioimpedance measuring is a tool in estimating the excess liquid in the body. The test is non-invasive and is done by placing electrodes on the skin of the hands and feet similarly to the procedure of an ECG. Signals run through the electrodes connected to a machine that sends electric impulses trough the body and estimates the excess liquid in the extremities. The test is done at every consultation and has a duration of a couple of minutes. There is no side-effects or discomfort associated to the test. | Baseline + at 3, 6 and 12 month follow-up | 
| Lymphangiography | An imaging-tool to quantify the lymph-flow and -vessels. ICG is a fluorescent that is absorbed in the lymphatic system and metabolized in the liver with a half-life at 3-4 minutes. The florescent ICG is detectable by cameras at specific wavelengths and is thereby possible to visualize. The outcome of this test is classified into groups: linear pattern and dermal backflow patterns. Dermal backflow patterns can then be subdivided into splash, stardust and diffuse patterns via pattern-recognition. The procedure is done by injecting 0.02 mL ICG subcutaneously in the web space between each finger. Fluorescent imaging of the lymph-vessels and -flow is then obtained by using an infrared camera. There is no exposition of radiation associated with this test. The ICG lymphangiography is done on both arms. Outcome is measured as the pattern of the lymph-flow. | Baseline + at 6 and 12 month follow-up | 
| Questionnaire: Lymphedema Functioning, Disability and Health questionnaire (Lymph-ICF) LYMPH-ICF | A Danish validated questionnaire developed specifically for lymphedema-patients. The questionnaire contains 5 domains: lymphedema symptoms, mental function, household activities, mobility activities movement and life and social activities. 29 questions regarding the 5 domains are answered on a scale ranging from 0-10. Raw scores will be transformed into scores ranging from 0 (Worst) to 100 (best) using the original scoring key | Baseline + at 3, 6 and 12 month follow-up | 
| Questionnaire: The disabilities of the arm, shoulder and hand (DASH) questionnaire | A Danish validated questionnaire developed for patients with disabilities of the arms, shoulders and hands. It includes 38 questions about the patient's ability to perform different actions/movements. The questions are answered on a 5-step scale from not difficult to impossible. Raw scores will be transformed into scores ranging from 0 (Worst) to 100 (best) using the original scoring key | Baseline + at 3, 6 and 12 month follow-up | 
| Questionnaire: 36-Item Short-Form Health Survey questionnaire (SF-36) | A Danish validated generic quality of life-questionnaire. The questionnaire includes 36 questions regarding the patient's the general quality of life. The questions are answered on a 3-, 5- and 6-step scale and binary (Yes/No) depending on the question. Raw scores will be transformed into scores ranging from 0 (Worst) to 100 (best) using the original scoring key | Baseline + at 3, 6 and 12 month follow-up | 
| Arm volume measured with measuring tape | Manual measuring with measuring tape and then calculated with through volume of a cone formula | Baseline + at 3, 6 and 12 month follow-up |