2.3.1 Main drugs involved
The pathophysiological mechanism of drug-induced lymphedema results from impaired lymphatic drainage that overcomes transcapillary filtration. Few drugs are involved such as tamoxifen (Das et al., 2015), taxanes (e.g., paclitaxel (Zamora et al., 2019) and docetaxel (Park et al., 2014)), mTOR (mammalian target of rapamycin) inhibitors (e.g., everolimus, sirolimus (Gharbi, Gueutin, & Izzedine, 2014)) and PI3K/AKT inhibitors (Daniell et al., 2019) (e.g., alpelisib, idelalisib). Peripheral edema is a common adverse reaction to tamoxifen that is associated with a substantial risk of drug withdrawal (Cluze et al., 2012). Several studies have found, after adjusting for age, stage, breast cancer treatment, and axillary lymph node dissection, a trend towards a positive association of tamoxifen use and lymphedema (Das et al., 2015). These observations are supported by experimental data where Morfoisse et al. (Morfoisse et al., 2018) found that tamoxifen, by blocking estrogen receptor-α, interferes with lymphatic vasculature stability, predisposing to lymphedema aggravation. Apart from tamoxifen, all these drugs interfere with the vascular endothelial growth factors (VEGF) involved in lymphangiogenesis, namely VEGF-C which selectively activates VEGFR-3 through the PI3K/AKT pathway (Huber et al., 2007; Wang, Xu, Wen, Wang, & Yuan, 2019; Zamora et al., 2019). Diagnosis is made difficult by the fact that these drugs are also responsible for peripheral edema due to increased capillary permeability (e.g., taxanes (Sibaud et al., 2016), sirolimus (Zaza et al., 2013)) and that early-stage lymphedema mimics other causes of extremity swelling (Grada & Phillips, 2017). As in other causes of lymphedema (Grada & Phillips, 2017), transient nontender pitting edema occurs in newly developed drug-induced lymphedema. Over time, the skin becomes indurated with a leathery texture because of skin thickening and fibrosis.