Angiogenesis inhibitors for the treatment of ovarian cancer.
Gaitskell K., Martinek I., Bryant A., Kehoe S., Nicum S., Morrison J.
BACKGROUND: Many women with ovarian cancer eventually develop resistance to conventional chemotherapy drugs, and so novel agents are being developed to target specific molecular pathways. One such class of drugs inhibits angiogenesis (the development of new blood vessels), which is essential for tumour growth. It is important to establish whether the addition of these new drugs to conventional chemotherapy regimens improves survival, and what the side-effects may be. OBJECTIVES: To compare the effectiveness and toxicities of angiogenesis inhibitors in the treatment of ovarian cancer. SEARCH STRATEGY: We sought to identify completed randomised controlled trials (RCTs) by searching The Cochrane Gynaecological Cancer Review Group's Trial Register, The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 10), MEDLINE and EMBASE (1990 to October 2010). We also searched registers of clinical trials, and contacted investigators of completed and ongoing trials for further information. SELECTION CRITERIA: Randomised controlled studies comparing angiogenesis inhibitors with either standard chemotherapy or no treatment, in women with ovarian cancer. DATA COLLECTION AND ANALYSIS: Two independent authors carried out data collection and extraction. We used a random-effects model for pooling data. MAIN RESULTS: We did not find any fully-published, completed RCTs of angiogenesis inhibitors that met our inclusion criteria. We identified five abstracts of completed RCTs of four different angiogenesis-inhibiting agents, with a total of 3701 participants.Meta-analysis of two trials found no statistically significant difference in overall survival (OS) between women with newly-diagnosed advanced ovarian cancer who received concurrent and maintenance bevacizumab compared to those who received chemotherapy (carboplatin and paclitaxel) alone. However, women who received concurrent and maintenance bevacizumab had their risk of disease progression reduced by a quarter (hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.68 to 0.83; P < 0.001); they also had a significantly increased risk of severe gastrointestinal adverse events, moderate or severe hypertension and severe bleeding.One trial also compared chemotherapy to concurrent (but not maintenance bevacizumab), and found no statistically significant difference in OS or progression-free survival (PFS). However, the women who received bevacizumab had a significantly higher risk of moderate or severe hypertension.A three-armed RCT, of paclitaxel alone or with low- or high-dose AMG 386, in women with recurrent ovarian cancer, found no statistically significant difference in OS. However, women who received low-dose AMG 386 had a third less risk of disease progression than those who received placebo (HR 0.57, 95% CI 0.36 to 0.91; P = 0.02). The trial found no evidence of increased adverse events in the intervention arms.Two relatively small RCTs (one of VEGF-Trap, the other of BIBF 1120) found no evidence of either significant survival benefit or increased severe adverse events, compared to placebo, but they both lacked statistical power. All five trials had unclear risk of bias, largely because they have only been published in abstract form, and thus many methodological details are unclear. We identified twelve suitable ongoing trials. AUTHORS' CONCLUSIONS: There is, as yet, no fully-published RCT evidence for the efficacy or safety of angiogenesis inhibitors for the treatment of ovarian cancer, but some preliminary results are available from five trials. There is some evidence from a meta-analysis of two trials that the addition of concurrent and maintenance bevacizumab to standard chemotherapy may reduce the risk of disease progression, in women with newly-diagnosed advanced ovarian cancer. There is also some evidence from a single trial that low-dose AMG 386 may reduce the risk of disease progression in women with recurrent ovarian cancer. However, there is currently no evidence that angiogenesis inhibitors improve OS, nor is there enough evidence to justify the routine use of angiogenesis inhibitors in treating women with ovarian cancer. We eagerly await both the more detailed results of these five completed trials, and the preliminary results of the several ongoing trials.