Neoplasms

Symptoms and General Pathology

All Conditions

Skin and Connective Tissue Diseases

Blood and Lymph Conditions

Neoplasm Metastasis

Breast Neoplasms

Lymphedema

Breast Diseases

Skin Diseases

Lymphatic Diseases

Conservative treatment with physiotherapy and compression

Surgery

Treatment with compression stockings and manual drainage (massage therapy)

Compression and drainage therapy

Lars Johan Sandberg, MD

A randomised prospective investigation of volume and quality of life results with lymphovenous anastomosis in patients with unilateral arm lymphedema after breast cancer using Indocyanine Green lymphangiography and MD Anderson Staging.

This is a randomized study comparing lymphovenous anastomosis versus conservative (compression) treatment for lymphoedema after breast cancer surgery - 50 patients to be included in each study arm. The primary endpoint is volume change measured by submersion and changes in arm circumference at defined levels from the wrist. Secondary endpoint is health related quality of life measured by questionnaire Short Form 36 (SF-36), Hospital Anxiety Depression Score (HADS), Fatigue Questionnaire (FQ) and a disease-specific questionnaire, Upper Limb Lymphedema score (ULL27).

Supermicrosurgery for Breast Cancer Survivors With Lymphedema.

Supermicrosurgery for Breast Cancer Survivors With Lymphedema. -Prospective Randomized Clinical and Patient-reported Outcomes.

There is no plan to share IPD with other researchers

Volume of arm as described by submersion and circumference measures

To be measured by questionnaire "Upper Limb Lymphedema score 27" (ULL27) by Professor Robert Launois at REES France. The scale measures health related quality of life in patients with upper limb lymphedema.

Construction: 27 questions rated from 1 (lowest quality of life) to 5 highest quality of life.

Dimensions: There are 3 dimensions assessing symptoms, self value, everyday social life. Total score 27-135 Symptom score: 18-90 Self value: 5-25 Social life: 4-20 Question 20 and 22 are part of the self value dimension and are control questions with reverse scores, i.e 1 represents highest quality of life and 5 represents lowest quality of life. The scores for question 20 and 22 are later reversed when adding the total score.

University of Oslo

Ohio State University

Sykehuset Telemark

Injection of ICG as a fluorophore for Near Infrared fluorescence Imaging (NIRF)

Indocyanine Green (ICG)

Mathias Alstrup, stud.med

Shayant Mohanakumar, cand.med.

Vibeke Hjortdal, Professor

Vibeke Hjortdal, professor

Protocol resume

Swelling of tissue due to excess fluid, called lymphedema, is a common side effect of breast cancer treatment that requires lifelong treatment but in what way the treatment of breast cancer affects the lymphatic vasculature is not yet fully understood.

The overall aim of this study is to examine the baseline lymphatic function and anatomy in women who have undergone and completed treatment for breast cancer.

Comparison will be made between:

* The treated arm and the untreated arm in the participant.
* The treated arm in patients who did not develop lymphedema and the treated arm in patients who did.

By using an emerging technique, Near Infrared fluorescence imaging (NIRF), and non-contrast MRI it is now possible to examine the link between breast cancer treatment and the development of lymphedema. This project will describe the impact of breast cancer treatment on contractile function and morphological changes of the lymphatic vasculature in the upper extremity in patients treated for breast cancer.

The study population will consist of 28 patients treated for breast cancer who simultaneously are enrolled in the Skagen 1 trial. The NIRF imaging and MRI will be performed after completion of breast cancer treatment and no later than half a year after completion treatment. All examinations will be made under similar conditions, on the same segment of lymphatic vasculature, in the same room and bed and with patients in the supine position. The estimated duration of each examination is approximately 3,5 hours.

Upon arrival participants will receive three injections of ICG distally on each arm, two on the dorsal side and one on the palmar side. Ten minutes after injection, the primary sequence of the lymphatic vessels will be recorded, allowing for calculation of frequency and velocity. Following, the pumping pressure of the lymphatic vessels will be estimated. After completion of the NIRF examination, an MRI scan of the upper body and extremities will be made, allowing for morphological evaluation of the lymphatic system in the region.

By studying the lymphatic vessels in these patients, data may elucidate the characteristics of the changes taking place and thus provide new insight for future studies and possibly future treatments and ways to prevent or reduce the development of edema.

Aim:

The overall aim of this study is to examine the baseline lymphatic function and anatomy in women who have undergone and completed treatment for breast cancer.

Comparison will be made between:

* The treated arm and the untreated arm in the patient.
* The treated arm in patients who did not develop lymphedema and the treated arm in patients who did.

Introduction:

The lymphatic vasculature is distributed around the entire body where it pumps excess protein-rich fluid from the interstitial space back to the circulatory system. It does so partly by intrinsic contraction of lymphatic smooth muscle cells in the lymphatic vessel wall and partly by the forces applied to the lymphatic vessels by surrounding contracting muscles. Lymphatic valves in the vessels prevent backflow of the fluid. Lymphedema occurs when the lymphatic vasculature is unable to transport the lymphatic fluid out of an affected region. (1) There are two types of lymphedema. The first is idiopathic lymphedema and consist of lymphedema caused by genetic dysfunction or inherent anatomical abnormalities of the lymphatic vasculature. The second type is called acquired lymphedema and is due to external factors such as physical disruption, compression of lymphatic vessels, surgery or radiotherapy. (2) The commonest reason for lymphedema in the western world is cancer treatment. It is seen after treatment of several different cancer types such as gynecologic cancer, melanoma, genitourinary cancer, head and neck cancers and particularly breast cancer being the most frequent cancer type in women in Denmark. (3-7) More than one in five patients surviving breast cancer experience lymphedema, however, estimates range from 13-65%.(8, 9) Radiation therapy to the breast or to the axilla appears to increase the risk of lymphedema significantly. (10-12) These patients experience a large number of severe consequences, both physical and psychological, following development of lymphedema. These include decrease of physical strength, range-of-motion and sense in the upper extremities. An increased feeling of pain and heaviness is also experienced. Psychologically, these women experience anxiety, depression, sexual dysfunction, reduced body confidence and a lowering of general quality of life. (13-18) The current treatment of lymphedema consists primarily of complete decongestive treatment (CDT), which combines different treatment approaches such as bandaging, compression garments, manual lymphatic drainage, and exercise. Although the current treatment options can help patients with lymphedema significantly, the patients still have to undergo a lifelong treatment and cope with some of the complications previously mentioned. (19) In order to secure a foundation for the development of curative or preventive treatments of lymphedema developed due to breast cancer treatment, the impact of this oncological treatment on the function and anatomy of the lymphatic vessels has to be understood.

Design:

Study population:

The study population will consist of 28 patients treated for breast cancer who simultaneously are enrolled in the Skagen 1 trial. The NIRF imaging and MRI will be performed after completion of breast cancer treatment and no later than half a year after completed treatment.

Information to the patient:

All women being candidates for the Skagen 1 Trial will be invited to participate in this study by their oncologist. If the patient is interested contact information will be passed along to the principal investigator. He and the participant will make an agreement of place and time for the meeting to happen and the participant will be informed that she is requested to participate in a health scientific research project. The participant is encouraged to bring along an assessor to the information. The meeting takes place in a quiet and undisturbed room affiliated with the Department of Cardiothoracic and Vascular Surgery. Oral as well as written information of the study are given to the participant and the procedures, the risks and the gains of the study are carefully explained. If the patient is interested in participating she will be asked to give her written consent. The patient will be told that she should consider it before deciding and that her consent is not binding and can be withdrawn at any time should she wish to do so. The study will be performed no earlier than two weeks after the information is given. Therefore, they will have two weeks to consider whether to participate or not.

After the meeting the participant will be informed:

* If new information regarding risks, side effects or complications emerges.
* If any changes to the research design is made that affects the participant.
* If new information regarding the health status of the participant emerges unless she has asked to not be informed.
* Of the results obtained and their consequences regarding the participant in she wishes.
* If the project is cancelled and the reason why.

Study procedures:

By using a novel lymphatic imaging technique, the Near Infrared Fluorescence imaging (NIRF), and non-contrast MRI scans the function and the anatomy of the lymphatic vasculature can be visualized and analyzed. These two imaging techniques have been shown to be superior to other techniques in lymphedema imaging. (20) All examinations will be made under similar conditions, on the same segment of lymphatic vasculature, in the same room and bed and with patients in the supine position. The estimated duration of each examination is approximately 3,5 hours.

NIRF setup: This study will be using a custom-built setup previously used by the Department of Cardiothoracic and Vascular Surgery at Aarhus University Hospital (21, 22): A EM-CCD camera (C9100-13 Hamatsu, Japan), with a Navitar lens (25mm f 0.95) and 835±15nm band-pass filters on each side of the lens. The light source is a custom designed 785 nm 450 mW laser (PowerTechnology, Arkansas, US). A 780±28nm band-pass filter is placed in front of the laser to minimize light leakage. Indocyanine Green (ICG) will be used as a fluorophore, and a 0,1 mL injection of 0.025% ICG dissolved in saline, equivalent to a 25μg dose per injection, will be given prior to commensal of the study.

Research design:

Near Infrared Fluorescence Imaging: In this study, different tests will be made to measure lymphatic activity.

Frequency and velocity: Contraction frequency and package velocity will be examined and calculated using LabView. Contraction frequency will be defined as lymphatic contractions generated per minute, and contraction package velocity as the velocity by which the lymph is propelled forward following each contraction.

Pumping pressure: A highly accurate (±1mmHg) cuff system (Hokanson E20 rapid cuff inflator, Hokanson AG101 air source) will be positioned around the proximal antebrachium, after having manually emptied the lymph vessels proximally to the cuff. The cuff will then be inflated to 80 mmHg, and after every 5 minutes, the pressure will be lowered by 5 mmHg. Over time the pressure of the lymphatic vessels will exceed that of the cuff, and lymph will pass through, giving an estimate of the pressure within the lymphatic vessel. The cuff will be placed identically during both examinations.

Magnetic Resonance Imaging: MRI will be used to visualize the anatomy and the morphology of the lymphatic system.

MRI: The lymphatic anatomy of the neck, entire chest, abdomen, and arms will be imaged and investigated with a 3 T MRI system (Siemens Skyra; Siemens Medical, Germany). MRI will included a respiratory-gated (navigator) 3D fast spin-echo sequence with the following parameters: matrix = 448 × 448, voxel size = 0.9 × 0.9 × 0.8 mm3 FOV = 100 - 400 cm2, repletion time = 2830 ms, echo time = 649 ms, flip angle = 125˚. This sequence will be repeated sequentially for whole-body coverage using multiple phased-array coils, with each coil covering a different body region, without coil repositioning

Protocol:

Upon arrival participants will receive three injections of ICG distally on each arm, two on the dorsal side and one on the palmar side. Ten minutes after injection, the primary sequence of the lymphatic vessels will be recorded, allowing for calculation of frequency and velocity. Following, the pumping pressure of the lymphatic vessels will be estimated as described above. All NIRF sequences will be recorded of the same region of lymphatic vessels and on both arms. After completion of the NIRF examination, an MRI scan of the upper body and extremities will be made, allowing for morphological evaluation of the lymphatic system in the region.

Study drug:

Drugs used as a tool:

ICG (0.5mg/ml solution) will be injected intradermally distally on each arm, two on the dorsal side and one on the palmar side for a total dose of 180μg. The Danish Health and Medicines Authority have approved the use of ICG to visualize lymphatic vessels using near infrared fluorescence in this study (reference number: LMST-2012025009). ICG green was FDA approved in the 1950's and has safely been used in different clinical procedures (ophthalmology, neurosurgery, hepatology and cardiology) ever since. In comparison to doses used in these procedures, up to 2mg/kg, the dose administered in the investigator's study (180μg) is considered small. ICG associates with albumin and as soon as it reaches the blood stream it is taken up by the liver and secreted into the bile, resulting in a biological half-life of 2-4 minutes in the blood. The only "side-effect" seen is a 4-5 mm green discolouration of the skin at the injections sites, which will disappear in a couple of days.

Side-effects:

The possible side effects of ICG (ICG-pulsion, Nomeco A/S, Denmark) are severe allergic reaction, which occurs very rarely (affects fewer than one in every 10,000 patients) and local irritation of the skin.

Together with the symptoms of the allergic reaction, an increase of special white blood cells associated with allergic reactions can occur (hypereosinophilia).

The possibility of an allergic reaction is greater in patients with extremely serious kidney failure.

Study duration:

The study will start September 1st, 2018 and terminate August 31st, 2019.

Ethical concerns Aside from the ICG injections and the discomfort of being inside an MRI machine, no inconvenience will be applied to the participants. The participants will not benefit from this study themselves other than knowing that they could contribute with knowledge that might enable a possible future treatment. The gain of knowledge this study provides outweighs the discomfort the participants may experience.

The participants participate on a voluntary basis with informed consent that can be withdrawn at any time. The participant's integrity and privacy will be respected. The study is conducted in accordance with the Helsinki declaration and Danish law.

Compensation to volunteers There will be no compensation to the participants.

Publication Positive, negative and inconclusive results will be published in an international scientific journal.

Clinical Perspectives:

The physiology behind the development of edema in breast cancer patients undergoing treatment is still not clear, however, a possible part of the explanation could be a change in function and/or anatomy of the lymphatic vessels after breast cancer treatment.

So far, the treatment of lymphedema is unsatisfactory. It is often life long treatment and invalidating for the quality of the patients life. If a change can be shown further studies can clarify what part or parts of the treatments are responsible for the change. This could be done by including patients before the start of treatment and then examine the patients after surgery/chemotherapy and after radiotherapy subsequently.

By studying the lymphatic vessels in these patients, data may elucidate the characteristics of the changes taking place and thus provide new insight for future treatments and ways to prevent or reduce the development of edema.

Case-control. Patients function as their own control since the treated arm will be compared with the non-treated arm.

Lymphatic Function in Patients Who Have Undergone Breast Cancer Treatment

The pumping pressure in the lymphatic vessels.

the frequency of contraction of the lymphatic vessels

Novo Nordisk A/S

University of Aarhus

Neoplastic Processes

Lymfactin® will be administered as a single dose via perinodal injection in a volume of 2 mL.

Placebo will be administered as a single dose via perinodal injection in a volume of 2 mL.

Lymfactin® (1x10E11 vp)

Placebo

Anne Saarikko, MD, PhD

Maria Mani, MD, PhD

This study evaluates the efficacy of Lymfactin® in patients with secondary lymphedema associated with the treatment of breast cancer by comparing the effects of active study treatment Lymfactin® to placebo. The study product will be administered in combination with a surgical lymph node transfer operation. In addition, the safety and tolerability of the Lymfactin® treatment will be evaluated.

This is a Phase II, double-blind, placebo-controlled, multi-centre clinical study, in which 40 patients with breast cancer associated secondary lymphedema will be randomized 1:1 either to Lymfactin® (1 x 10E11 viral particles, vp) or placebo (0.9% physiological saline) group.

The study product (Lymfactin® or placebo solution) will be administered as a single dose in a volume of two (2) mL, by ex vivo perinodal injection into the fat pad of a flap of tissue containing lymph nodes from the patient's own abdominal wall or the groin area. This flap of tissue will then be surgically implanted into the axillary region of the affected arm. This treatment with the study product is performed in combination with a surgical lymph node transfer, in conjunction with or without breast reconstruction surgery.

Patients will be followed-up for efficacy and safety according to a specified schedule up to 5 years post-treatment.

Double-blind, placebo-controlled, randomized

Clinical Study With Lymfactin® in the Treatment of Patients With Secondary Lymphedema (AdeLE)

Phase 2, Double-Blind, Placebo-Controlled, Randomized Efficacy, Safety and Tolerability Study of Lymfactin in Combination With Surgical Lymph Node Transfer To Patients With Secondary Lymphedema Associated With the Treatment of Breast Cancer

Changes in anatomy and functionality of lymphatic vessels by newly developed MRI lymphangiography and comparison of the correlation of the method to the already established lymphoscintigraphy in the assessment of lymphedema.

Changes in PWC measurement of water content and edema in affected arm and comparison to the unaffected arm.

Changes in the volume of the affected arm and comparison to the unaffected arm.

Assessment of the changes in the lymphatic flow.

Assessment of changes in the quality of life using Lymphedema Quality of Life Inventory (LQOLI) in which the patients assess how their lymphedema is affecting the activities of daily living. LQOLI consists of three dimensions: Physical, psychosocial and practical, which are reported separately as the mean score of that part. Each part of the LQOLI is scored from 0 to 3, where score 0 means "no impact", 1 means "a little bit impact", 2 means "somewhat impact" and score 3 means "significant impact" on the quality of life of the patient, the smaller score thus being the better.

Adverse Events as assessed by CTCAE v4.0 to evaluate the safety profile after administration of Lymfactin.

Changes in CT scans of chest and abdomen in order to detect malignancies.

Changes in Lymfactin genome copy number in blood.

Changes in Lymfactin genome copy number in wound secretion.

Changes in anti-Lymfactin antibody titer in blood.

Changes in the VEGF-C concentration in blood.

Herantis Pharma Plc.

Lymfactin® \[1 x 10E10 vp\] will be administered as a single dose via perinodal injection in a volume of 2 mL.

Lymfactin® \[1 x 10E11 vp\] will be administered as a single dose via perinodal injection in a volume of 2 mL.

Lymfactin® [1 x 10E10 vp]

Lymfactin® [1 x 10E11 vp]

Indicated for the Treatment of Secondary Lymphedema Associated with the Treatment of Breast Cancer.

Primary objective is to evaluate the safety and tolerability of a single dose of Lymfactin® in patients with secondary lymphedema associated with the treatment of breast cancer.

This is an open label, multi-center, uncontrolled first in human trial that uses a standard 3 + 3 dose escalation scheme. Lymfactin® will be administered as a single dose by ex vivo perinodal injection into the fat pad of a flap of tissue containing lymph nodes from the abdominal wall. This flap of tissue will then be surgically implanted into the axillary region of the affected arm. This treatment with Lymfactin® may be performed in conjunction with or without breast reconstruction surgery.

Up to two dose cohorts are planned to be included. Each dose of Lymfactin® will be administered as a single dose via perinodal injection in a volume of 2 mL:

* Cohort 1: Lymfactin® \[1 x 10E10 vp\]
* Cohort 2: Lymfactin® \[1 x 10E11 vp\]

Should the dose escalation go up to Cohort 2 with initiation of a subsequent Extension Cohort a total of 15 - 21 patients may be treated in this study.

A Phase I Study With Lymfactin® in the Treatment of Patients With Secondary Lymphedema

A Phase I Open-Label Study to Assess the Safety, Tolerability and Preliminary Efficacy of Lymfactin® (AdAptVEGF-C Adenoviral Vector) in Combination With a Surgical Lymph Node Transfer for the Treatment of Patients With Secondary Lymphedema

Adverse events and serious adverse events assessed by CTCAE v4.0 to evaluate the safety profile after administration of Lymfactin

Changes in the CT scan of chest and abdomen in order to detect malignancies

Changes in Lymfactin genome copy number in blood

Changes in the anti-Lymfactin antibody titer in blood

Changes in the volume of the affected arm and comparison to the unaffected arm

Assessment of the changes in the lymphatic flow

Assessment of changes in the quality of life using Lymphedema Quality of Life Inventory (LQOLI) in which patients assess how their lymphedema is affecting the activities of daily living. LQOLI consists of three dimensions: Physical, psychosocial and practical, which are reported separately as the mean score of each dimension. Each dimension of the LQOLI is scored from 0 to 3, where score 0 means "no impact", 1 means "a little bit impact", 2 means "somewhat impact", and 3 means "significant impact" on the quality of life of the patient, the smaller score thus being the better.

Facies

Head and Neck Neoplasms

A combination of manual lymph drainage , compression bandaging, physical exercise and a skin care regimen

Complete Decongestive Therapy

Standard of care is currently observation

Observation

Ashley Mays, MD

This will be a prospective, randomized controlled study of \~60 adult patients who have undergone a laryngectomy, neck dissection, maxillectomy or mandibulectomy surgical procedure for the treatment of head and neck cancer at Our Lady of the Lake Hospital and have been referred by their physician for evaluation of head and neck lymphedema while serving as an inpatient. Consenting patients will be evaluated by certified speech and language pathologists trained to ascertain lymphedema severity using a series of visual and tangible measurements immediately following surgery and randomized into two cohorts, one receiving the complete decongestive therapy regimen and the other not receiving this specific combination treatment for their edema. Facial and neck measurements will be taken at baseline following surgery and at several points prior to and at discharge as well as at the 2 week follow up visit to the clinic. Measurements and overall change/reduction in edema will be compared between the cohorts.

BACKGROUND:

Head and neck lymphedema (HNL) is a common and sometimes debilitating complication of head and neck cancer (HNC) treatment. It occurs when the lymphatic system is either overloaded or damaged and cannot clear the high protein lymphatic fluid within the interstitial tissues. This in turn causes inflammation, connective tissue proliferation and overall functional impairment of the lymph system and bodily extremities. The long-term effects that edema can have in the cranio-facial region are not simply a cosmetic nuisance, but can lead to severe functional and psycho-social issues when affecting the lips, tongue, throat, eyes, mouth and neck. The ability to communicate, swallow, breath and see can be greatly impeded by the lymphatic swelling, which clearly affects the quality of life for many patients. Additional deficits may include dysfunction of the arms and shoulders with reduced cervical range of motion. Although lymphedema is well recognized in patients within the fields of urinary, breast and gynecologic cancer, it has only recently been addressed in the area of head and neck cancer.

The therapeutic management of HNL in HNC patients is a growing topic of research, as this condition pushes to the forefront and crosses over multi-disciplinary departments from otolaryngology to cancer therapy to speech and language therapy and rehabilitation. Historically, the technique of manual lymph drainage (MLD), a series of gentle circular massage strokes applied to the skin to increase lymphatic flow has been used. Decades later, the MLD technique was combined with compression bandaging, physical exercises and a skin care regiment to create a complete decongestive therapy (CDT) in the outpatient setting and is now considered to be best practice for outpatient lymphedema treatment at some institutions. The HNL program at M.D. Anderson Cancer Center has also created a series of formal evaluation and treatment techniques which include patient interviews/survey, visual assessment of the cranio-facial, neck and shoulder areas, functional assessments of communication and swallowing, photography, tape measurements and staging scales of edema to characterize the appearance and severity of the swelling.

Herein, investigators propose to examine the effects of complete decongestive therapy on head and neck cancer patients at Our Lady of the Lake Regional Medical Center who experience post-surgical head and neck lymphedema after total laryngectomy, neck dissection, maxillectomy or mandibulectomy compared to a control cohort. Investigators aim to assess the improvement of patient outcomes through the use of this technique to reduce cranio-facial edema and compare to those who do not receive CDT in an in-patient setting. Our study is novel in that there is minimal data on the effect of CDT in the acute care setting and in the areas of the head and neck, hence contributing to the growing body of knowledge about this therapy in this acute patient population.

OBJECTIVES:

The objective of of this research study is to assess physical improvements in visual, measureable and functional outcomes in head and neck cancer patients with head and neck lymphedema who have undergone Complete Decongestive Therapy (CDT) as a part of in-patient care at Our Lady of the Lake Hospital and compare this to patients in a control group who do not receive CDT.

STUDY DESIGN:

This will be a prospective, randomized controlled study of \~60 adult patients who have undergone a laryngectomy, neck dissection, maxillectomy or mandibulectomy surgical procedure for the treatment of head and neck cancer and have been referred by their physician for evaluation of head and neck lymphedema while admitted to inpatient care at Our Lady of the Lake Regional Medical Center following surgery. Patients will be evaluated by certified speech and language pathologists trained to ascertain lymphedema severity using a series of visual and tangible measurements immediately following surgery. Specific therapies for speech and language performance are provided beginning 24-72 hours post op per standard of care. At the time of speech therapy, patients will be informed and consented at the hospital bedside about this study. Those that agree to participate will be randomized into a CDT treatment arm or a control arm. The CDT therapy arm will be a combination of manual lymph drainage (MLD), tissue compression or kinesio tape bandaging, remedial exercises and a skin care regiment. This therapy will be administered every time the patient is seen by the speech pathologist, which is typically on a daily basis until discharge. Patients who are randomized into the control arm will not receive the specific CDT, but will still receive any speech or language therapy or other medical treatment services that are standard for their care management plan. Cranio-facial measurements will be taken of both cohorts by a blinded measurer prior to therapy and prior to hospital discharge, after several rounds of CDT have been administered to the patient. Those in the non-CDT cohort will be measured at the day of inpatient consult and again on day of discharge. Changes in the measurements will determine if the CDT has a positive effect on the edema symptoms.

One speech pathologist on the study team will perform the CDT or control therapy and will only be aware of the participant's cohort arm at the time of random assignment. A second speech pathologist will be blinded to the cohort arm and will be responsible for taking the cranio facial measurements for all participants.

Patients will be randomized into one of two groups. Group A will receive the CDT during their inpatient stay. Group B will not receive the CDT. The randomization of the patients into these 2 cohorts will be predetermined by pulling 15 permuted blocks of 4 (Ex. AABB, ABAB, BABB, ABBA, etc) pre-drawn by an individual not involved in the therapy. The permuted blocks will be lined up sequentially (Ex. AABBABABBABBABBA.....) and each letter placed in one of 60 envelopes. The speech pathologist assigned to the patient will pull the next envelope in order to determine if the patient will be in Group A (CDT) or Group B (no CDT) post-surgery. The principal investigator and the individual who will perform the measurements will be completely blinded to the patient's cohort assignment and in this way, minimize investigator bias.

A medical chart review will also be conducted to gather additional variables such as age, gender, race and any prior head and neck cancer medical history.

Double Blind randomization of patients and investigator outcome assessor. Patients that agree to participate will be randomized into a CDT treatment arm or a control arm that does not receive CDT. One speech pathologist on the study team will perform the CDT and will only be aware of the participant's cohort arm at the time of random assignment. The second speech pathologist will be blinded to the cohort arm and will be responsible for taking the cranio facial measurements for all participants to minimize investigator bias.

Complete Decongestive Therapy on Head and Neck Lymphedema

The Effects of Complete Decongestive Therapy on Head and Neck Lymphedema in Post-surgical Head and Neck Cancer Patients (Randomized Control Trial)

Data will be de-identified upon collection

2 % percent change of composite facial measurement

Our Lady of the Lake Hospital

Academic Research Director

Syndrome

Postoperative Complications

Breast Cancer Lymphedema

Lymphovenous anastomosis surgery with pre-operative planning using ICG lymphography and ultra high frequency ultrasound.

Pre-operative planning prior to lymphovenous anastomosis using ICG lymphography and ultra high frequency ultrasound for mapping of applicable vessels.

During surgery, mapped vessels are freely dissected and anastomosed.

Lymphovenous anastomosis

Caroline Lilja, MD

Jens Ahm Sørensen, MD, Prof, PhD

Jørn Bo Thomsen, MD, Prof, PhD

The primary aim of this study is to investigate and test whether the use of combined indocyanine green (ICG) lymphography and ultra high frequency ultrasonography can correctly identify lymphatic vessels and venoles in close proximity to each other, for identification prior to lymphovenous anastomosis (LVA) surgery.

BACKGROUND

Breast-cancer related lymphedema is a life-disabling side-effect of breast cancer treatment, affecting more than 1 in every 5 patients. With breast-cancer being the most common cancer diagnosis in women, affecting up to 2.3 million new cases globally, and with a generally high survival rate of 80% or higher in developed countries, the number of breast-cancer survivors with long-term sequela is significant. Compression garments have been considered the standard treatment and rehabilitation for lymphedema. Some of the disadvantages with these treatments include variability in patient compliance, clinical effect and lack of statistical significant results. Therefore, the rehabilitation and treatment options for lymphedema are in high demand, affecting patients physical and mental health.

Lymphovenous anastomosis (LVA) surgery is an attempt to re-establish the lymphatic flow, utilizing the patient's own lymphatic- and venous vessels. Surgical treatment seems effective in selective patient groups, but systematic studies for this are lacking. It is based on this lack of knowledge of patient characteristics and preoperative planning that the project's hypothesis and idea was formed.

Indocyanine green (ICG) lymphography is commonly used for identification of lymphatic vessels pre-operatively, and is considered superior to other modalities. However, until recently, the identification of adjacent venoles has remained a challenge. Ultra high frequency ultrasound may have solved the challenge of identifying the small venoles prior to surgery. The combined use of ICG lymphography and ultra high frequency ultrasound may be the key to optimise patient selection and pre-operative planning of lymphovenous anastomosis surgery.

METHOD

This study is designed as a pilot study with a planned inclusion of 10 patients with a 3 months follow-up period.

The inclusion of patients, the surgical procedure and 3 months follow-up evaluation will take place at the Department of Plastic Surgery Odense University Hospital (OUH), Denmark.

The ICG lymphography is performed by injecting ICG subcutaneously, and used for visualization of the superficial lymphatics for preoperative planning. During real-time visualization, lymphatic vessels are drawn up on the patients arm using a permanent marker.

Ultra high frequency ultrasound (\>30MHz) has the ability to visualize small, superficial anatomical layers. Using this ultra high frequency ultrasound (70MHz), following the mapped lymphatic vessels, venous vessels are found nearby and likewise mapped for anastomosis.

The number of LVA anastomosis sites is set to a minimum of two sites per extremity. The number of mapped lymphatics vessels and venoles are compared to the number identified during surgery and recorded.

Prior to and 3 months after surgery, patients are seen for objective measures of upper extremity volume, body composition, L-Dex score of the affected arm and health-related quality-of-life, in addition to ICG lymphography.

Lymphaticovenous Anastomosis as Treatment for Lymphedema

Lymphaticovenous Anastomosis as a Surgical Treatment for Breast Cancer-Related Lymphedema

The number of mapped lymphatics vessels and venoles.

The number of vessels found during surgery. This number will be compared to the number of vessels planned for surgery.

The change of arm volume difference at baseline and at three months follow-up after surgery.

Volume calculation Manual circumferential measurements are taken from both arms for volume calculation, based on the formula for multiple blunt cones.

Water displacement for volume assessment The water displacement test estimates the volume of the arm, based on lowering the extremity in a basin of water, and calculating the water volume difference in mL. Both extremities are measured.

The change in extracellular fluid (liters), relative to total body water (liters), measured by a stand-on bioimpedance at baseline and 3 months follow-up. The stand-on device measure the body composition through small electric impulses between two electrodes.

Extracellular fluid and total body water measures will be aggregated to one reported value (extracellular fluid (liters) / total body water (liters)).

The change in intracellular fluid (liters), relative to body water (liters), measured by a stand-on bioimpedance at baseline and 3 months follow-up. The stand-on device measure the body composition through small electric impulses between two electrodes.

Intracellular fluid and total body water measures will be aggregated to one reported value (intracellular fluid (liters) / total body water (liters)).

The change in total body water (liters), relative to body weight (kg), measured by a stand-on bioimpedance at baseline and 3 months follow-up. The stand-on device measure the body composition through small electric impulses between two electrodes.

Total body water and weight measures will be aggregated to one reported value (total body water (liters) / weight (kg)).

The change in proteins and minerals (kg), relative to body weight (kg), measured by a stand-on bioimpedance at baseline and 3 months follow-up. The stand-on device measure the body composition through small electric impulses between two electrodes.

Proteins and minerals and weight measures will be aggregated to one reported value (proteins and minerals (kg) / weight (kg)).

The change in fat mass (kg), relative to body weight (kg), measured by a stand-on bioimpedance at baseline and 3 months follow-up. The stand-on device measure the body composition through small electric impulses between two electrodes.

Fat mass and weight measures will be aggregated to one reported value (fat mass (kg) / weight (kg)).

The change in active tissue mass (kg), relative to body weight (kg), measured by a stand-on bioimpedance at baseline and 3 months follow-up. The stand-on device measure the body composition through small electric impulses between two electrodes.

Active tissue mass and weight measures will be aggregated to one reported value (active tissue mass (kg) / weight (kg)).

The change in skeletal muscle mass (kg), relative to body weight (kg), measured by a stand-on bioimpedance at baseline and 3 months follow-up. The stand-on device measure the body composition through small electric impulses between two electrodes.

Skeletal muscle mass and weight measures will be aggregated to one reported value (skeletal muscle mass (kg) / weight (kg)).

L-Dex score is a measurement of extracellular fluid of the arm. A stand-on bioimpedance device, estimates the extracellular fluid trough electric impulses between its electrodes. Based upon the impedance ratio of the affected and unaffected arm, the bioimpedance calculates a Lymphedema index, called L-Dex ratio score. A number between -10 and 10 is considered normal, and diagnostic for lymphedema if above 10. Its sensitivity and specificity are 0.66 and 0.99, respectively, at a receiver operating characteristic curve (ROC) value of 10. The score correlates with the limb volume and lymphatic function.

The LYMPH-Q Upper extremity module questionnaire is a validated patient-reported outcome tool for women with breast cancer related lymphedema. The module contains seven individual scales, measuring: symptoms, function, appearance, psychological function, and satisfaction with information on lymphedema and satisfaction with arm sleeve. Each scale gives an independent score reaching from 0 (worst) to 100 (best), which can be used for comparison of change over time. A higher score indicates a better outcome.

Patients will complete the questionnaire at baseline and 3 months follow-up.

Video recordings of ICG lymphographies are stored for later classification of the lymphedema. Staging will be done using the MD Anderson scale; a classification system based upon pattern recognition of the dermal backflow from the ICG lymphography, see table 1.

MD Anderson stage ICG lymphography findings Stage 0 No dermal backflow Stage 1 Many patent lymphatics and minimal dermal backflow Stage 2 Moderate number of patent lymphatics and segmental dermal backflow Stage 3 Few patent lymphatics with extensive dermal backflow Stage 4 Dermal backflow involving the hand Stage 5 ICG does not move proximally to injection site Table 1: MD Anderson classification based upon ICG lymphography findings.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Supermicrosurgery for Breast Cancer Survivors With Lymphedema.	NCT03578380	Secondary Lymph... Breast Cancer	Surgery Compression and...	-	Sykehuset Telemark
Lymphatic Function in Patients Who Have Undergone Breast Cancer Treatment	NCT03572998	Secondary Lymph...	Indocyanine Gre...	18 Years -	University of Aarhus
Clinical Study With Lymfactin® in the Treatment of Patients With Secondary Lymphedema (AdeLE)	NCT03658967	Secondary Lymph...	Lymfactin® (1x1... Placebo	18 Years - 70 Years	Herantis Pharma Plc.
A Phase I Study With Lymfactin® in the Treatment of Patients With Secondary Lymphedema	NCT02994771	Secondary Lymph...	Lymfactin® [1 x... Lymfactin® [1 x...	18 Years - 70 Years	Herantis Pharma Plc.
Complete Decongestive Therapy on Head and Neck Lymphedema	NCT04045860	Lymphedema of F... Secondary Lymph...	Complete Decong... Observation	18 Years -	Our Lady of the Lake Hospital
Lymphaticovenous Anastomosis as Treatment for Lymphedema	NCT05441943	Breast Cancer L... Secondary Lymph... Iatrogenic Lymp... Lymphedema Lymphedema of U... Lymphedema Arm Lymphedema, Bre... Breast Neoplasm Neoplasms Breast Cancer Breast Diseases Lymphatic Disea... Skin Diseases Postoperative C... Pathologic Proc... Anastomose Surgery Surgical; Lymph... Postmastectomy ... Postmastectomy ... Postmastectomy ... Postmastectomy ...	Lymphovenous an...	18 Years -	Odense University Hospital
Lymphaticovenous Anastomosis as Treatment for Lymphedema	NCT05441943	Breast Cancer L... Secondary Lymph... Iatrogenic Lymp... Lymphedema Lymphedema of U... Lymphedema Arm Lymphedema, Bre... Breast Neoplasm Neoplasms Breast Cancer Breast Diseases Lymphatic Disea... Skin Diseases Postoperative C... Pathologic Proc... Anastomose Surgery Surgical; Lymph... Postmastectomy ... Postmastectomy ... Postmastectomy ... Postmastectomy ...	Lymphovenous an...	18 Years -	Odense University Hospital
Clinical Study With Lymfactin® in the Treatment of Patients With Secondary Lymphedema (AdeLE)	NCT03658967	Secondary Lymph...	Lymfactin® (1x1... Placebo	18 Years - 70 Years	Herantis Pharma Plc.
Supermicrosurgery for Breast Cancer Survivors With Lymphedema.	NCT03578380	Secondary Lymph... Breast Cancer	Surgery Compression and...	-	Sykehuset Telemark

Spots Global Cancer Trial Database for secondary lymphedema