Bevacizumab is the first targeted agent to show significant single agent activity in ovarian cancer. It is a humanized monoclonal antibody that targets angiogenesis by binding to VEGF-A, thereby blocking the interaction of VEGF with its receptor. There are a number of phase II studies reported using bevacizumab in patients with platinum-sensitive and platinum-resistant ovarian cancer with response rates ranging from 16% to 22% in both platinum-sensitive and -refractory patients (319). Up to 40% of patients had stabilization of disease for at least 6 months. A study of low-dose metronomic chemotherapy with 50 mg of cyclophosphamide daily and bevacizumab 10 mg/kg intravenously every 2 weeks showed significant activity in a study of 70 patients with recurrent ovarian cancer (320). The primary end point was progression-free survival at 6 months. The probability of being alive and progression free at 6 months was 56%. A partial response was achieved in 17 patients (24%). Median time to progression and survival were 7.2 and 16.9 months, respectively. This comes with toxicity. The side effects of bevacizumab are well recognized and include hypertension, fatigue, proteinuria, gastrointestinal perforation or fistula, and uncommonly, vascular thrombosis and central nervous system ischemia, pulmonary hypertension, and bleeding and wound healing complications. The most common side effects are hypertension that is grade 3 in 7% of patients and is usually treatable. The most concerning side effect is bowel perforation and the study by Cannistra et al. was stopped after recruiting 44 patients because of an 11% incidence of perforation of the bowel (321).
It was suggested that the bowel perforation complication could be avoided by carefully screening patients. Simpkins et al. limited bevacizumab treatment to patients without clinical symptoms of bowel obstruction or evidence of rectosigmoid involvement on pelvic examination or bowel involvement on CT scan (322). Their study included 25 patients with platinum-resistant ovarian cancer who were heavily pretreated, and they observed a response rate of 28% and no bowel perforations or any other grade 3 or 4 toxicities were reported. This highlights the importance of patient selection and suggests that increased experience with these agents will result in less toxicity.
VEGF Trap functions as a soluble decoy receptor soaking up ligand before it can interact with its receptor and is being evaluated in phase II trials in patients with recurrent ovarian cancer. There are other oral agents that target angiogenesis through tyrosine kinase inhibition that are in clinical trial (323).
Radiation Therapy Whole-abdominal radiation therapy given as a treatment for recurrent or persistent disease is associated with a high morbidity and is not used. The principal problem associated with this approach is the development of acute and chronic intestinal morbidity. As many as 30% of patients treated with this approach develop intestinal obstruction, which necessitated exploratory surgery with potential morbidity (324).
Intestinal Obstruction Patients with epithelial ovarian cancer often develop intestinal obstruction, either at the time of initial diagnosis or in association with recurrent disease (325–340). Obstruction may be related to a mechanical blockage or to carcinomatous ileus.
The intestinal blockage can be corrected in most patients whose obstruction appears at initial diagnosis. The decision to perform an exploratory procedure to ease intestinal obstruction in patients with recurrent disease is more difficult. For patients whose life expectancy is very short (e.g., less than 2 months), surgical relief of the obstruction is not indicated (325–330). In those patients with a longer projected lifespan, features predicting a reasonable likelihood of correcting the obstruction include young age, good nutritional status, and the absence of rapidly accumulating ascites (326).