Angiogenesis inhibitors for the treatment of ovarian cancer
Abstract
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 methods
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.
PICOs
Plain language summary
Are substances that inhibit the growth of new blood vessels (angiogenesis inhibitors), alone or in combination with conventional chemotherapy, likely to improve outcomes for women with ovarian cancer?
Ovarian cancer is the seventh most common cancer in women worldwide, with an annual incidence of about 6.3 cases per 100,000 women, and an annual mortality rate of 3.8 per 100,000 women. Standard treatment of advanced ovarian cancer usually involves surgery, to remove as much of the cancer as possible ('debulking'), and platinum‐based chemotherapy, with or without the addition of a taxane. However, despite good initial responses to platinum agents and taxanes, most women have disease relapse, require further treatment with chemotherapy, and eventually develop resistance to conventional chemotherapy drugs.
Many researchers are trying to find new drugs, which target different pathways, in order to treat ovarian cancer that has become resistant to standard chemotherapy. One target is the pathway for angiogenesis: the growth of new blood vessels. Although new blood vessels can form as part of the body's normal processes, cancers are especially reliant on angiogenesis, as they need a blood supply in order to grow. It is hoped that drugs that act to inhibit the growth of new blood vessels will slow or stop the progression of the cancer.
In this review we found evidence from five studies, comparing drugs which inhibit angiogenesis against either standard chemotherapy (carboplatin + paclitaxel) or placebo.
Two trials looked at the effect of adding bevacizumab to conventional chemotherapy in women who had just been diagnosed with ovarian cancer and had debulking surgery. Bevacizumab was given both alongside the chemotherapy, and then continued afterwards (called maintenance therapy). Taking the results of these two trials together, there was no significant benefit from adding bevacizumab to standard chemotherapy in terms of survival time, but there was fairly strong evidence that it might slow the growth of the cancer (increased progression‐free survival (PFS)). However, the trials also showed that there were worse side effects in women who received bevacizumab in addition to chemotherapy (particularly high blood pressure, serious bowel problems and bleeding). One of these two trials also looked at the effect of giving bevacizumab concurrently with chemotherapy (not continuing afterwards), and found no significant improvement in either survival time or slowing cancer growth, but did find a significant increase in moderate and severe high blood pressure (hypertension).
A third trial looked at adding a different agent, AMG 386, to paclitaxel chemotherapy in women with recurrent ovarian cancer. The trial compared the addition of either a higher or lower dose of AMG 386 to placebo. It found no improvement in survival with either the higher or lower dose of AMG 386, but there were suggestions that it might slow cancer growth. It did not seem to increase side effects.
We identified two other trials; one comparing placebo to BIBF 1120, and the other comparing placebo to VEGF (vascular endothelial growth factor)‐Trap. Neither study found evidence of slowing cancer growth/prolonging survival, or worsening side effects. However, these were both relatively small studies, which made them less likely to detect an effect that may or may not have been present.
All of the included trials that we identified reported only preliminary results, which had been presented at conferences, but not yet published in full. It is thus difficult to be sure of the specific details of how these trials were performed, and therefore to assess their risk of bias. We found 12 other on‐going studies that fulfilled our inclusion criteria, and some of these are expected to release preliminary results soon.
