Radioprotection from radiation-induced lymphedema without tumor protection

Lymphedema or tissue swelling from impaired lymph drainage commonly occurs after regional nodal dissection and/or radiation therapy for cancer control. Treatment options for this disabling and life-altering complication involve long-term labor-intensive commitments. Sentinel node biopsy can forestall removal of negative regional nodes, offering some protection against lymphedema, however, most preventive measures are elusive, ineffective, or unproven. Our goal was to determine whether the radioprotectant amifostine could prevent or retard the development of lymphedema in a rodent radiation therapy-dependent model yet not offer tumor protection from the therapeutic effects of radiation therapy. We pre-treated rats after unilateral radical groin dissection with the organic thiophosphate radioprotectant amifostine or placebo prior to single dose post-operative groin radiation therapy and monitored hindlimb volumes, wound scores, and tissue lymphostasis. In addition, we determined whether amifostine protected human MCF7 breast cancer cells exposed to a range of radiation therapy doses in an in vitro clonogenic assay and an in vivo MCF7 tumor xenograft model. Our findings indicate that amifostine markedly reduced the volume of limb lymphedema and dramatically improved wound healing and tissue lymphostasis in the rodent lymphedema model. The in vivo and in vitro studies further demonstrated that amifostine offered no MCF7 tumor protection from radiation therapy. These pre-clinical findings provide proof-of-principle to further delineate specific mechanisms underlying amifostine's beneficial effects, determine optimal amifostine-radiation therapy dosing regimens, and thereby expedite translation into clinical trials to reduce lymphedema incidence and severity in cancer patients at high lymphedema risk in whom radiation therapy is the recommended therapy.