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.