Abstract P2-12-08: Sorafenib for treatment of breast-cancer related lymphedema
Authors: Zambetti M , Guidetti A , Carlo-Stella C , De Benedictis E , Tessari A , Balzarini A , Caraceni A , Gianni L , Gianni AM 
Published: August 2014

Abstract
BACKGROUND Lymphedema (LE) is a common complication of breast cancer (BC) treatments conditioning disability that affects quality of life. Decongestive therapy is the most popular treatment but it determines only a transient advantage, while pharmacologic therapy didn't impact on LE. On the basis of clinical observations of LE regression in patients treated with sorafenib with antitumoral intent, we hypothesized that sorafenib could have an anti-LE activity through inhibition of vascular permeability by suppressing VEGFRs.
METHODS We conducted a single-arm, monoistitutional phase II study in BC patients with treatment-acquired LE of the arm. Major or uncontrolled cardiological disease, brain metastasis, history of thromboembolism were exclusion criteria. Concomitant chemo or hormonal therapy was allowed. Pts received sorafenib 200 mg daily for a maximum of 8 weeks. The primary end-point was to evaluate the efficacy of sorafenib as reduction of LE, defined by the percentage reduction (PR) of the difference between the total arm circumference (measured as the sum of the circumference at 12 points) of the affected and the controlateral arm (Starritt, Peterk JA Cancer 2001–10): [(Initial Difference – Final Difference)/Initial Difference] × 100.
Secondary end-points were safety and duration of response (DOR). The study was designed to test the null hypothesis that the PR of edema observed with this therapy was at most 20% versus the alternative hypothesis that the PR obtained by this regimen was ≥40%.
RESULTS From May 2009 to April 2011, 36 BC pts were enrolled. All pts underwent axillary dissection and 29 pts had received adjuvant radiotherapy, but none on the axilla. Median time from primary breast surgery and from occurrence of edema to study enrollement was 65 and 49 months, respectively. All pts are evaluable for efficacy and toxicity. Most common toxicities included grade 1–2 gastralgia (17%), hypertension (17%) and rash (43%); one patient experienced grade 3 hand-foot syndrome. Twenty-five pts completed the planned 8 weeks of therapy, 11 (31%) had early treatment discontinuation after 2 (n = 6), 4 (n = 4) and 6 (n = 1) weeks of treatment due to recurrent grade 2 toxicity or to relapse of disease (n = 1). The median PR of the difference between the two arms was 34% (range, 2–100), 14 pts (39%) experienced a LE reduction ≥40%. Among 25 pts who completed therapy, 12 (48%) achieved a PR ≥40%. The median difference of total circumferences between the LE and controlateral arm was significantly reduced after treatment: 37 cm (range 8–88) vs 25 cm (range 1–62) (p = 0.006). Best response was achieved after a median of 5 weeks of therapy (range 1– 6) and the median DOR was 8 weeks (range 4–15). Reduction of LE was associated with improvement of related symptoms. After discontinuation of study drug 84% pts presented a progressive increase of total circumference of LE arm and returned to values similar to baseline after a median of 7 weeks (range 2–11).
CONCLUSIONS: Low dose of sorafenib has a good toxicity profile and exerts a significant anti-LE activity in BC patients. The early but transient effect observed in this study suggests exploring different schedule of administration. Further studies are warranted in order to obtain a durable benefit in term of reduction of LE and quality of life.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-08.