Pharmacological Management of Lymphedema

Current clinically available pharmacotherapy of lymphedema is limited to symptomatic management and conventional nonspecific use of benzopyrones or venotonics. Diuretic use with purpose of reduction of fluid stasis has limited role and potential adverse effect. Prophylactic antibiotics can be used for the patients with recurrent cellulitis and skin preparation agents can be applied to reduce keratinization of hardened skin. Stimulating phagocytosis and lymphatic vessels drainage are the proposed effects of benzopyrone but their clinical effectiveness is inconclusive and coumarin is withdrawn due to hepatotoxicity. Flavonoids originally developed as phlebotonics and selenium are widely used but their benefits are unclear. Hyaluronidase directly administered to the affected tissue facilitates breaking down hyaluronan in the interstitium and lymphangiogenesis. With small benefits of current pharmacotherapy options, growing interest in searching for targeted therapy has led to significant numbers of studies on lymphatic regeneration in molecular biology level. Vascular endothelial growth factor-C (VEGF-C) through vascular endothelial growth factor receptor-3 (VEGFR3) is main target in promoting lymphangiogenesis, and the application of VEGF-C proven to be effective in lymphedema management in animal model. Combination therapy of VEGF-C with stem cells, lymph node transfer or ESWT has shown potential benefits. Lymphangiogenesis is possibly promoted by other agents like hepatocyte growth factor (HGF), interleukin 8 (IL-8), G-protein-coupled receptors, cilostazol and matrix metalloproteinase (MMP)-9.