Nutritional Ketosis: a Novel Metabolic Strategy to Treat Lymphedema Patients?

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 to patients with more advanced stages of lymphedema with a predominant fibrofatty component. 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 3 arms: a ketogenic diet and a isocaloric diet without or including ketone monoester supplementation (KE).