RADIOPROTECTION FROM RADIATION-INDUCED LYMPHEDEMA WITHOUT TUMOR PROTECTION

Abstract

Lymphedema or tissue swelling fromimpaired lymph drainage commonly occursafter regional nodal dissection and/or radiationtherapy for cancer control. Treatmentoptions for this disabling and life-alteringcomplication involve long-term labor-intensivecommitments. Sentinel node biopsy canforestall removal of negative regional nodes,offering some protection against lymphedema,however, most preventive measures areelusive, ineffective, or unproven. Our goal wasto determine whether the radioprotectantamifostine could prevent or retard thedevelopment of lymphedema in a rodentradiation therapy-dependent model yet notoffer tumor protection from the therapeuticeffects of radiation therapy. We pre-treatedrats after unilateral radical groin dissectionwith the organic thiophosphate radioprotectantamifostine or placebo prior to singledose post-operative groin radiation therapyand monitored hindlimb volumes, woundscores, and tissue lymphostasis. In addition,we determined whether amifostine protectedhuman MCF7 breast cancer cells exposed to arange of radiation therapy doses in an in vitroclonogenic assay and an in vivo MCF7 tumorxenograft model. Our findings indicate thatamifostine markedly reduced the volume oflimb lymphedema and dramatically improvedwound healing and tissue lymphostasis in therodent lymphedema model. The in vivo andin vitro studies further demonstrated thatamifostine offered no MCF7 tumor protectionfrom radiation therapy. These pre-clinicalfindings provide proof-of-principle to furtherdelineate specific mechanisms underlyingamifostine’s beneficial effects, determineoptimal amifostine-radiation therapy dosingregimens, and thereby expedite translationinto clinical trials to reduce lymphedemaincidence and severity in cancer patients athigh lymphedema risk in whom radiationtherapy is the recommended therapy.