Pilot Study of Intraperitoneal Bevacizumab for the Palliation of Malignant Ascites

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Malignant ascites is a frequent complication of advanced cancer. It is most commonly associated with adenocarcinoma of the ovary, breast, colon, stomach and pancreas. Ascites has a significant impact on quality of life. Increasing abdominal pressure causes distressing symptoms such as abdominal discomfort, early satiety, nausea and vomiting, dyspnoea, impaired mobility and lethargy. In severe cases vomiting and bowel obstruction may occur. Approximately half of patients with malignant ascites present with ascites at the time of cancer diagnosis. For the other 50% of patients, ascites is a sign of progressive disease or treatment failure. Median survival for all tumour types after the diagnosis of malignant ascites is 20-25 weeks. If ascites is present at diagnosis systemic cancer therapy can provide early palliation, particularly for those with chemotherapy-sensitive tumours. However in end stage disease tumours are often refractory to cytotoxic chemotherapy and other management options must be considered. Current guidelines advocate repeat paracentesis, indwelling catheter placement or peritoneovenous shunting for symptom control in malignant ascites. However all of these treatments have significant limitations. Repeat paracentesis is most commonly performed, however this provides only short-term relief, necessitating repeat trips to hospital for further intervention. The average time to repeat paracentesis for patients with malignant ascites is 10-13 days. There is no evidence to support how long the drain should remain in place, whether the drain should be clamped to regulate output, whether intravenous fluids should be administered or whether vital signs should be regularly recorded. The alternatives to repeat paracentesis are less than ideal. In-dwelling catheters risk infection and dislodgement. Peritoneovenous shunting is an invasive procedure and is associated with potentially fatal complications. Vascular endothelial growth factor (VEGF) is a glycoprotein secreted by tumour cells. VEGF stimulates tumour angiogenesis and increases vascular permeability via interaction with tyrosine kinase receptors on the endothelium of both normal and tumour-induced blood vessels. Malignant pleural and ascitic fluid demonstrates markedly elevated VEGF concentrations, up to 60 fold higher than in matched serum. The role of VEGF on vascular permeability is thought to be central to the pathogenesis of malignant ascites. Preclinical studies have demonstrated the efficacy and safety of intraperitoneal inhibition of VEGF as therapy to prevent accumulation of ascites. Bevacizumab is a recombinant humanised monoclonal antibody that binds and inhibits the biological activity of VEGF. Intraperitoneal administration of bevacizumab may be the route of choice when the goal of treatment is to palliate malignant ascites. These patients are routinely managed with repeat paracentesis and intraperitoneal bevacizumab administration can be performed during this procedure. Intraperitoneal administration also has the benefit of directing therapy in to the peritoneal cavity where high VEGF concentrations promote fluid secretion. One pilot study and two case studies have reported the safety and efficacy of intraperitoneal administration of bevacizumab for the treatment of malignant ascites. Systemic administration of bevacizumab is usually well tolerated but has been associated with an increased risk increased risk of bowel perforation. This rare but serious complication occurs in 1-2% of patients. Risk factors have not been well defined but may include bowel implants, large tumour burden, prior radiotherapy, recent surgery and bowel obstruction. The mechanism of bevacizumab-associated bowel perforation is likely to be related to the anti-VEGF effects on bowel perfusion and/or tumour regression. Gastrointestinal perforation has not been described following intraperitoneal administration of bevacizumab. Other side effects of systemic treatment with bevacizumab include hypertension (3-14.8% Grade III/IV), venous and arterial thromboembolic events (0-3%), bleeding, proteinuria, delay in wound healing, and fistula formation. Our pilot study will evaluate the safety and efficacy of intraperitoneal administration of bevacizumab to prevent the recurrence of malignant ascites. Given the significant cost of bevacizumab, the aim of the study is to find lowest effective dose. As the published data suggests an average time to repeat paracentesis in malignant ascites is 10-13 days, our treatment would be considered potentially efficacious if the median time to repeat paracentesis is greater than 14 days.

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