A pilot study of vascular endothelial growth factor inhibition with bevacizumab in patients with lymphedema following breast cancer treatment.

Abstract

Abstract Abstract #6142 Purpose: Lymphedema is a significant long-term complication of primary therapy for breast cancer but little is known regarding its etiology and persistence other than relation to the number of lymph nodes (LN) removed. We suggest the following model: Mechanical disruption of normal lymphatic drainage leads to increased back pressure on lymphatic vessels producing an increase in interstitial fluid pressure (IFP). The increased in IFP triggers local production of VEGF-C to stimulate compensatory lymphangiogenesis. As VEGF-A (and to a lesser extent –C) also increases vascular permeability, the consequent increase in interstitial fluid and edema predominate. Anecdotally, several patients (pts) with metastatic disease treated with bevacizumab monotherapy noted improvement in long-standing lymphedema. This pilot study was conducted to explore these observations prospectively.
 Methods: We used an existing biospecimen bank to conduct a case-control study to compare VEGF-A, -C, -D and VEGFR-3 serum concentrations in breast cancer pts with and without lymphedema (matched for age and LN status). In a separate pilot trial, pts with significant unilateral lymphedema receive bevacizumab, 15 mg/kg every 3 weeks. Baseline assessments include arm volume, interstitial fluid pressure (IFP), extracellular fluid volume by lymphometer (ECF), quality of life (QOL) and plasma VEGF-C, -D, and R-3. IFP is measured serially for 24 hours after the first treatment; arm volume, ECF, QOL, and plasma VEGF-C/D/R-3 are assessed at 3 and 6 weeks.
 Results: Samples were available for 16 pts with chronic lymphedema and 24 matched controls. Median VEGF-C levels were significantly increased in pts with lymphedema (6895 pg/ml vs. 5349 pg/ml, p=0.001). Median VEGF-A levels were slightly higher in pts with lymphedema (375 pg/ml vs.250 pg/ml, p=NS). Eight pts have been enrolled in the pilot trial thus far. Median duration of lymphedema was 4.4 years (2.2-16.6) Median time since surgery was 7.1 years (3.4-17.6); median time since radiation (n=7) was 4.4 years (2.3-7.9). Complete IFP data is available in 5 pts. Baseline IFP was significantly higher in the affected compared to unaffected arm (9.04 vs. -2.07 mmHg; p=0.0017). Median IFP in the affected arm decreased an average of 42.6% 24 hours after bevacizumab infusion (11.1 vs. 6.9 mmHg; p=0.09). Total arm circumference decreased by an average of 2.8 cm three weeks after initial treatment.
 Conclusions: Preliminary data supports the hypothesis that VEGF plays a central role in the development and persistence of lymphedema after local therapy for breast cancer. Inhibiting VEGF acutely decreases IFP and may be an effective treatment. Treatment and accrual to the pilot trial continues; full data will be available by December 2008. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6142.