NEW YORK (Reuters Health) - Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), increases progression-free survival in patients with metastatic clear cell renal carcinoma, according to results of a study discontinued early because of treatment-related benefit. The study is reported in the New England Journal of Medicine for July 31.

Clear-cell renal cancers are usually caused by mutations in the von Hippel-Lindau tumor suppressor gene, leading to VEGF overproduction, Dr. James C. Yang and colleague at the National Cancer Institute in Bethesda, Maryland, point out. They believe that bevacizumab inhibits tumor angiogenesis.

Dr. Yang's group enrolled 116 patients in a double-blind, placebo-controlled study. Thirty-nine patients were randomly assigned to high-dose bevacizumab (10 mg/kg every 2 weeks), 37 to low-dose bevacizumab (3 mg/kg), and 40 to vehicle only.

Median progression-free survival was 4.8 months in the high-dose group compared with 2.5 months in the placebo group (p < 0.001). The median time to progression was 3.0 months in the low dose group (p = 0.041 compared with placebo).

However, there was no significant difference in overall survival between treatment groups.

The criteria for declaring progression and removing a patient from the trial were quite stringent, the authors point out, which probably resulted in lower estimates of efficacy and a lack of survival benefit associated with active treatment. "It would be worthwhile to determine survival in patients allowed to continue to receive bevacizumab despite tumor progression," they suggest.

There were no life-threatening toxicities or deaths related to bevacizumab. There was an increased incidence of hypertension and asymptomatic proteinuria.

Dr. Yang and his associates theorize that combining bevacizumab with inhibitors of fibroblast growth factor could lead to even greater benefit in patients with this disease.

Only four patients in the high-dose group had objective responses. According to Drs. Daniel J. George and William G. Kaelin, writing in an accompanying editorial, this means that "VEGF inhibition alone is unlikely to cause regression of established, mature blood vessels."

They propose that dual inhibitors of endothelial cells and pericytes may lead to tumor regression. Furthermore, knowledge of the function of the von Hippel-Lindau gene product "would support combining antiangiogenic agents with agents that interrupt specific tumor-cell autocrine loops (such as that created by TGF-alpha and its receptor, epidermal growth factor receptor)."

N Engl J Med 2003;419-421,427,434.

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