Ketogenic Diet: a Novel Metabolic Strategy to Treat Lymphedema Patients? (KETOLYMPH)

Lymphedema is a debilitating disorder that severely impairs the quality of life of the patients and requires life-long attention. Treatment for lymphatic dysfunction remains largely symptomatic, without real cure. According to the International Society of Lymphology, lymphedema has to be treated with Decongestive Lymphatic Therapy. Research in the lab of Angiogenesis and Vascular Metabolism (PCA lab) reported in mice that metabolism of endothelial cells controls vessel sprouting. Experiments showed that a ketogenic diet (KD) reduced the edema of the mice tail and enhanced the lymphatic transport. Based on these proof-of-concept data, the investigators plan to test this innovative concept to ameliorate lymph vessel dysfunction in lymphedema patients. Randomisation will be performed between a ketogenic diet and a isocaloric diet.

Lymphedema is a debilitating disorder that severely impairs the quality of life of the patients and requires life-long attention. It can be classified as primary or secondary, based on the etiology. Primary lymphedema is a rare, congenital disorder caused by inherited genetic mutation on a number of genes that are essential for lymphatic vessel development and function. Acquired (or secondary) lymphedema is a consequence of lymphatic trauma, predominantly due to surgery or radiotherapy for various types of cancers, with axillary and/or inguinal lymph node dissection being the most common cause. At the cellular level, perturbed or dysfunctional lymphatic drainage triggers accumulation of interstitial fluid, negatively affects cellular behavior, and induces infiltration of fibroblasts, adipocytes and keratinocytes, eventually leading to possible fibrosis and ulceration. Upper extremity lymphedema most commonly affects breast cancer patients, while lower extremity lymphedema is typically associated with gynecological cancers, prostate cancer, lymphoma and melanoma. Besides the functional impairments, lymphedema severely reduces the quality of life, causing psychosocial problems such as depression, sexual dysfunctions, social avoidance and a decrease in self-confidence. While the prevalence of lymphedema is relatively high (1.33-1.44 pro mille), its true prevalence is likely underestimated and 1 in 6 patients undergoing treatment for a solid tumor ultimately develops lymphedema. Nevertheless, treatment for lymphatic dysfunction remains largely symptomatic, without real cure. According to the International Society of Lymphology, lymphedema has to be treated with Decongestive Lymphatic Therapy, a two-stage treatment program. During the first or intensive phase, lymphedema has to be maximally reduced: this phase consists of skin care, manual lymph drainage (MLD), multi-layer bandaging and exercise therapy. The second or maintenance phase aims to conserve and optimize the result obtained in the first phase, and consists of skin care, compression by a low-stretch elastic sleeve, exercises and MLD. Skin care, multi-layer bandaging, elastic sleeve and exercises are treatment modalities that can be performed by the patients themselves, after careful instruction from the physician. On the contrary, MLD has to be applied by a physical therapist and hence entails a big financial cost for the patient and the Health Care. In addition, reductive techniques, such as direct excision and liposuction, can be applied in patients with more advanced stages of lymphedema with a predominant fibrofatty component10. Encouraging initial results, i.e. symptomatic improvement and reduction in excess volume, have been obtained with lymphovenous bypass, the microsurgical anastomosis of collecting lymphatic vessels to adjacent venules, and vascularized lymph node transplantation, where lymph nodes are harvested from an unaffected region and transferred to the lymphedematous area. However, all the treatments available so far can offer only stabilisation of lymphedema and prevent further evolution, but they do not offer a definitive cure. There is thus a large unmet need to develop new effective therapies for lymphedema and, more general, lymph vessel dysfunction. In contrast to various strategies inhibiting lymphatic vessel growth, stimulating lymphatic vessel growth has been more challenging; there is currently no approved clinical strategy for ameliorating lymphatic dysfunctions. In this trial we will evaluate an entirely novel pro-lymphangiogenic strategy, not based on the delivery of lymphangiogenic growth factors, but rather based on modulating lymphatic endothelial cell metabolism. The lab of Angiogenesis and Vascular Metabolism (PCA lab), Catholic University Leuven, led by Prof. Peter Carmeliet recently reported that metabolism (glycolysis, fatty acid β-oxidation, glutamine metabolism) of endothelial cells, the cells lining blood vessels, controls vessel sprouting. Initial experiments from this PCA lab indicate that the Ketogenic Diet (KD) , which is effective in increasing the levels of ßOHB both in the plasma and lymph, ameliorates the disease outcome in the mouse (tail) model of lymphedema, by reducing edema formation over time. Strikingly, lymphangiography with Evans blue dye revealed that KD improves lymph vessel function, increasing dye uptake after subcutaneous injection in the lymphedematous tissue and its drainage into lymph, plasma and lymph nodes. Based on these proof-of-concept data, the investigators plan to test this innovative concept to ameliorate lymph vessel dysfunction in lymphedema patients. Randomisation will be performed between a ketogenic diet and a isocaloric diet. After randomization and baseline measurements (determination of energy requirements and intake), the intervention will consist of 3 phases: a one week run-in period, 24 weeks strict KD and 24 weeks Modified Atkins Diet. In the first phase, the one week run-in period, is establishment of the individual ketosis level (on average after five days ketosis is introduced). During this run-in period, the exact ratio of lipids over proteins and carbohydrates will be determined per patient based on an isocaloric diet; this ratio will vary per patient and over time. Every day, 40 g of KetoCal, a nutritionally complete ready-to-drink liquid, is foreseen to ensure adequate amounts of vitamins and minerals and to ensure ketosis during the night (some patients drink some sips of the shake during the night). During this run-in period, patients will become familiar with their diet and, in particular, they will learn which foods are allowed and which are not. To assist the patients, the ketobel program (a computer program developed by the metabolic dieticians of the Clinical Nutrition Unit, University Hospital Leuven) will allow the calculation of the exact amount of foods/lipids each patient can/needs to consume. The instructions given by the program will allow patients to create a menu according to their personal preferences, with the final aim of increasing the adherence to the KD. A dietician will assist every participant intensively in this run-in period (10 h/week). To ensure ketotic state, ketosis will be measured twice a day (morning and evening) using urinary sticks. If there is a change in the ketotic state, the lipid/non-lipid fraction ratio will be adjusted in collaboration with the dietician. In the second phase, 24 weeks of strict KD , the patients will receive 40 g of KetoCal daily and the dietician will assist the patient during this phase 2 hours/week. This support is necessary as the lipid/non-lipid ratio to obtain ketosis varies over time as well. In the second phase, the dietician will assess on a weekly basis general health status, body parameters (weight, waist circumference), physical activity, weight loss and compliance to diet. The plasma metabolite profile (different types of cholesterol, triglycerides, fasting glucose, hsCRP, ketone bodies) will be performed every 3 weeks. To stimulate adherence to the diet, chat sessions will be organized between patients and a dietician, as moderator; these sessions will take place once a week and allow patients to exchange ideas/recipes about the diet and to motivate each other. These chat sessions have been organized previously by the members of the Clinical and Experimental Endocrinology group in other projects and were considered by the patients as an added value and a stimulation to continue with the intervention. In the third phase, the patients' diet will be less strict and adapted to a Modified Atkins Diet. This shift is necessary to enhance adherence on the one hand and to allow follow-up for a longer period. During the run-in period, the energy requirements and intake of the control group will be assessed as well. During this run-in period, the dietician will discuss the diet and maintenance of an isocaloric diet with the patients. As such, the diet of the control group will not change from their normal dietary pattern, unless a patient is following an Atkins-like diet. In the latter case, the patient will be asked to change the diet to a normal Belgian diet. During the first 24 weeks of intervention period, the patients will be contacted every 3 weeks to stimulate the participants and to follow up on some basic anthropometric markers, such as weight and waist circumference. The dietician will also adapt, if needed, the isocaloric diet of the control group during the intervention period to match possible unwanted weight loss of patients in the KD group. In the third phase of the study, patients will not be contacted outside the standard of care and the data will only be collected after 48 weeks.

After baseline assessment, patients will be randomized in one of the treatment groups. Randomization is performed according to 'www.randomization.com'. This free generator randomizes each subject to a single treatment by using the method of randomly permuted blocks. Assessments are performed by a person blinded to the treatment allocation groups. Randomization will be stratified for baseline lymphedema volume (3-9.9%, 10.0-19.9% and ≥20%), affected limb (arm or leg) and gender (females or males). The staff members who perform the measurements are blinded for the allocation.

the intervention will consist of 3 phases: a one week run-in period, 24 weeks strict KD and 24 weeks Modified Atkins Diet. Every day, 40 g of KetoCal, a nutritionally complete ready-to-drink liquid, is foreseen to ensure adequate amounts of vitamins and minerals and to ensure ketosis during the night (some patients drink some sips of the shake during the night). During this run-in period, patients will become familiar with their diet and, in particular, they will learn which foods are allowed and which are not.

During the run-in period, the dietician will discuss the diet and maintenance of an isocaloric diet with the patients. As such, the diet of the control group will not change from their normal dietary pattern, unless a patient is following an Atkins-like diet. In the latter case, the patient will be asked to change the diet to a normal Belgian diet.

Ketocal, a nutritionally complete ready-to-drink liquid, is foreseen to ensure adequate amounts of vitamins and minerals will be used. After 24 weeks a Modified Atkins diet will be started.

measured with QOL questionnaire, a scale from 0-10 on 16 items, how higher the score, how higher the QOL

measured with Lymph ICF (international classification of functioning, disability and Health), a scale from 0-10 on 29 items, total score ranged from 0-100, 0-4: indicate no problem; 5-24 a small problem; 26-49: moderate problem; 50-95: severe problem; 96-100: very severe problem

Inclusion Criteria: >18 years; unilateral lymphedema of the arm or leg after lymph node dissection lymphedema onset less than a year before the therapy starts lymphedema defined as >3% volume difference between both arms/legs lymphedema stage 1 or 2 absence of pregnancy at the time of enrollment and willingness to use adequate contraceptive measures until the end of the study; oral and written approval of the informed consent presented at the time of the consultation by the physicians; understanding Dutch Exclusion Criteria: <18 years; edema of the limb with different etiology or later stage/onset as specified in the inclusion criteria; presence of active cancer pregnancy or active breastfeeding; impossibility to participate for the entire study period; mentally or physically unable to participate to the study; presence of gastrointestinal intolerance or other serious illness (e.g. renal failure, hepatic dysfunction, heart failure, neurological impairment); presence of diabetes or other metabolic disease; contra-indication for the use of indocyanine green (ICG): allergy to ICG or iodine, hyperthyroidism.