open access: Commentary: VEGF Trap for the treatment of malignant ascites : The Lancet Oncology

"About 10% of all cases of ascites are caused by a malignant disease. In developed countries the most common neoplasm associated with ascites is ovarian cancer. The pathophysiology of malignant ascites is multifactorial, and its molecular pathogenesis is only poorly understood. Ascites formation can result from obstruction of lymph vessels by tumour cells, resulting in incomplete absorption of intraperitoneal fluid and protein,1 especially in patients with lymphoma or breast cancer. Since malignant ascites is usually an exsudate with a high protein concentration, an increased vascular permeability has been implicated in its pathogenesis.2 In addition to mechanical obstruction and cytokines, the pathophysiology of malignant ascites includes hormonal mechanisms. Because of the accumulation of ascites caused by obstructed lymph vessels, the circulating blood volume is reduced, which results in activation of the renin-angiotensin-aldosterone system that is followed by sodium retention.

Unlike the established therapeutic options for the underlying malignancy, there is no generally accepted gold standard for the management of malignant ascites...."

"...With respect to the clinical implications of the results (Walter Gotlieb and colleagues7 in The Lancet Oncology), symptom relief has to be weighed against discomfort and potentially life-threatening adverse events (three patients had fatal gastrointestinal complications in the aflibercept group vs one in the placebo group), since the treatment is applied to patients in a highly palliative situation. Careful patient selection could reduce the incidence of gastrointestinal perforations. However, before a general recommendation of aflibercept for the treatment of malignant ascites can be made, further studies, including comparative effectiveness research,8 are needed to compare the effectiveness of the different therapeutic strategies in daily clinical practice."

abstract: Antiangiogenic Agents in Combination With Chemotherapy for the Treatment of Epithelial Ovarian Cancer

Objective: The purpose of this review was to provide an overview of angiogenesis, including the rationale for targeting angiogenesis as a treatment strategy for epithelial ovarian cancer (EOC) and to discuss available clinical trial data with antiangiogenic agents in EOC, with a focus on combinations with chemotherapy.

Methods: This was a literature review of clinical studies evaluating select antiangiogenic agents in combination with traditional cytotoxic chemotherapy for the treatment of EOC.

Results: Several therapies that target angiogenesis-specific pathways are undergoing clinical development for EOC. Although some of these agents have demonstrated single-agent activity for EOC, there is considerable interest in combining this treatment strategy with chemotherapy in an effort to potentially improve treatment benefits in this patient population. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, is the most studied antiangiogenic agent in EOC and has shown efficacy as monotherapy and combined with chemotherapy in both the relapsed/recurrent and first-line settings. However, results from recent phase 3 trials raise questions regarding patient selection and optimal dose, schedule, and duration of bevacizumab therapy. Other agents in various phases of testing include aflibercept (VEGF Trap), a fusion protein that binds all isoforms of VEGF; multitargeted antiangiogenic tyrosine kinase inhibitors (eg, BIBF 1120, cediranib, pazopanib, sorafenib); and AMG 386, a selective angiopoietin inhibitor. Toxicities associated with VEGF inhibition are also a concern with antiangiogenic therapy, including hypertension, proteinuria, thromboses, and gastrointestinal perforation.

Conclusions: Results from recently completed and ongoing clinical trials combining antiangiogenic agents with chemotherapy are awaited in hopes of expanding therapeutic options for patients with EOC.