Gastrointestinal ulceration as a possible side effect of bevacizumab which may herald perforation

Colorectal cancer is the second most common cause of cancer deaths worldwide with 492,000 related deaths in 2000 [ 1 ]. Approximately 50% of patients will eventually develop distant metastases, for which usually palliative systemic treatment is administered. Over the past decades the treatment options for patients with advanced colorectal cancer (ACC) have changed considerably. Currently available cytotoxic drugs, the fluoropyrimidines (5FU, UFT and capecitabine), oxaliplatin and irinotecan have improved the median overall survival from 8 months with supportive care alone to approximately 17–19 months [ 2 ]. Recently, a new class of agents has been developed that inhibits signal transduction pathways, and which are usually referred to as targeted therapy. In ACC two drugs of this class are currently being used in the clinic: inhibitors of the epidermal growth factor receptor (EGFR) and of the vascular endothelial growth factor (VEGF) [ 3 ]. VEGF is a potent angiogenic factor that exerts its effect by binding to one or more of the VEGF receptors (VEGFR), leading to activation of several intracellular signal transduction pathways. In addition to the stimulation of neoangiogenesis, VEGF shows significant mitogenic activity for arterial, venous and lymphatic endothelial cells and plays a role in endothelial cell proliferation, vascular permeability and the inhibition of apoptosis [ 4 ]. Bevacizumab (Avastin®) is a humanized monoclonal antibody to VEGF. The addition of bevacizumab to fluoropyrimidine-containing chemotherapy significantly prolongs the median overall survival (OS) in previously untreated patients with ACC [ 5 , 6 ] and is currently considered as the standard first-line treatment. In 2nd line, bevacizumab also shows a significant increase in OS when added to chemotherapy [ 7 ]. Bevacizumab is generally well tolerated. The most common toxicities are hypertension and proteinuria. Arterial thromboembolic events, bleeding diathesis (mainly gastrointestinal bleeding) and gastrointestinal perforations have consistently been reported but at a low frequency. The focus of bleeding has been located along the entire digestive tract. In patients with ACC with their primary tumour in situ and who were treated with chemotherapy plus bevacizumab, the primary tumour was the focus of bleeding in 50% (8/16) of the patients [ 8 ]. The overall incidence of GI perforation in large series of ACC patients is approximately 1–2% [ 6 , 8 , 9 ]. In phase II studies with bevacizumab and chemotherapy the incidence of GI perforations was 6% in 47 patients with advanced gastric or gastroesophageal junction carcinoma [ 10 ], and 8% in 52 patients with advanced pancreatic cancer [ 11 ]. In the latter study, one patient developed ulceration at the site of the gastrojejunostomy anastomosis with secondary perforation at this site. In advanced ovarian cancer, a large variation in the incidence of GI perforations after treatment with bevacizumab either as monotherapy or combined with chemotherapy has been reported, ranging from 0% to 15.4% [ 12 ]. The intra-abdominal spread of ovarian cancer metastases compared to other cancer types may play a role in the higher incidence of perforations in this disease. The etiology of GI perforations occurring upon treatment with bevacizumab is unknown. Perforations may develop at the site of the primary tumour or elsewhere in the digestive tract, amongst others in the stomach or duodenum [ 9 ]. In patients without previous resection of the primary tumour, the site of perforation is related to the primary tumour site in 50% of the patients [ 9 ]. Predisposing factors for GI perforation are acute diverticulitis, GI obstruction, primary tumour in situ, abdominal carcinomatosis and prior abdominal or pelvic radiotherapy [ 13 ].