Optimization of diagnostic and treatment modalities to influence the natural history of breast cancer-related lymphedema

Lymphedema is a chronic, progressive and debilitating disease. It decreases patients quality of life not only because of the enlargement of the diseased limb but also because of the decreased mobility and recurrent infections. Lymphedema can be divided into primary and secondary lymphedema. In primary lymphedema there is an anomaly in the development of the lymphatic system. Secondary lymphedema, which is the majority, results from damage or malfunction of the lymphatic transport. It can be the result of an obstruction of the lymphatic transport (previous surgery, infection, malignancies,…) or an overload of interstitial fluid (e.a. advanced venous insufficiency).  The incidence of upper extremity lymphedema after breast cancer treatment (with axillary lymph node dissection) for example ranges between 9 to 41%.

Edema is the presence of an excess of interstitial fluid. It can progress from a soft pitting edema to a hard, fibrotic, non-pitting edema. This is because lymph stasis will not only cause extravasation of fluid in the interstitium but will also promote lipogenesis, fibrosis, inflammation, lymphangiogenesis, and immunosuppression. Different clinical stage systems are being used (stage 1 to 3), recently a subclinical stage 0 has been added. This staging system is not complete because it does not take into account why some patients develop a soft, fatty lymphedema and others a hard fibrotic one.

Lymphoscintigraphy is now the gold standard for examination of the extremity lymphedema. A radionuclide (99mTc-labeled tracer) is injected and followed with sequential gamma imaging. Near-infrared fluorescence is an alternative by which indocyanine green (ICG) is injected in the first web space. With a small amount of ICG, visualization of the superficial lymphatic architecture is possible. An infrared camera system obtains the fluorescence images and velocity and acceleration can be measured at certain points, but only with early stage lymphedema. The images themselves can be classified according to the severity of lymphedema. However, standardization of the technique and further validation is needed before this technique can be used as a reproducible tool to characterize lymphedema patients. Furthermore quantification methods of the near infrared fluorescence in all stages of lymphedema has not been developed yet. Exploring if there are pre-existing factors for the development of secondary lymphedema. A randomized controlled trial will be performed to examine if lymphovenous anastomosis is more effective than Decongestive Lymphatic Therapy (DLT) for progressive lymphedema using near-infrared fluorescence imaging pre- and post-surgery.