Do medicines that restrict new blood vessel growth (angiogenesis inhibitors) help women with epithelial ovarian cancer?

What did we want to find out?

We wanted to find out if treatments that prevent new blood vessel formation (angiogenesis) improve outcomes for women with epithelial ovarian cancer (EOC). 

Ovarian cancer is the eighth most common cancer in women (and other females) worldwide, with an annual mortality rate of 4.2 per 100,000 women. EOC originates from the surface layers of ovaries or fallopian tubes and represents 90% of all ovarian cancers.

Treatment of EOC involves surgery to remove cancer deposits and platinum-based chemotherapy (medicines that kill fast-growing cells). However, despite good initial response, many with advanced disease eventually require further treatment. 

Cancers need new blood vessels to supply oxygen and nutrients for growth; inhibiting angiogenesis may slow or stop cancer growth. Angiogenesis can be blocked either by smothering the angiogenesis hormone (called VEGF) with a monoclonal antibody (an antibody that recognises a single target) or by interfering with cell responses to VEGF binding with its receptor (VEGF-R), by inhibiting enzymes (tyrosine kinases (TK)) associated with VEGF-R (tyrosine kinase inhibitor (TKI)).

What did we do?

We collected and analysed all relevant studies in women with EOC. Studies compared angiogenesis inhibitors with or without conventional chemotherapy, or different biological agents against treatment with placebo (a dummy medicine), no treatment or different biological agents. We investigated whether these medicines improved how long women with EOC lived after treatment (overall survival (OS)), if medicines delayed disease re-growth (progression-free survival (PFS)), what were the harms (adverse events), and whether they impacted on quality of life. How well EOC responds to subsequent chemotherapy depends on previous chemotherapy treatment and time from last platinum-based chemotherapy, so we analysed the results by whether people had newly-diagnosed or recurrent EOC, and by platinum-sensitivity.

What did we find?

We found 50 studies with 14,836 women.

Main results

Newly-diagnosed EOC

Monoclonal antibody treatment (called bevacizumab or Avastin) given with chemotherapy, and continued as maintenance, probably has little effect on survival following an initial diagnosis of EOC. The evidence for delaying progression is very uncertain. Treatment increases serious side effects and slightly reduces quality of life.

TKIs given with chemotherapy and continued as maintenance, probably have little effect on survival following an initial diagnosis of EOC, but may delay disease progression. Treatment causes a slight reduction in quality of life, and a slight increase in the risk of serious side effects, with a big increase in the risk of needing treatment for high blood pressure (hypertension).

Recurrent EOC (platinum-sensitive; relapse over a year after last platinum chemotherapy)

For women with platinum-sensitive recurrent EOC, bevacizumab given with chemotherapy and continued as maintenance may have little effect on survival, but may delay progression. There may be little impact on quality of life, but treatment slightly increases the risk of serious side effects. All studies found that treatment increased rates of hypertension. 

In this same group of women, TKIs given with chemotherapy and continued as maintenance probably have little effect on survival after relapse, likely delays progression, and may have little to no effect on quality of life. We were not able to estimate the effect on overall serious side effects, although serious hypertension was more common with treatment.

Recurrent EOC (platinum-resistant; relapse within six months of last platinum chemotherapy)

For women with platinum-resistant recurrent EOC, bevacizumab increased survival and probably results in a large delay in progression. However, treatment causes significant risk of hypertension and may increase the risk of bowel perforation. Other serious side effects were inconsistently reported, as were quality of life outcomes.

The addition of TKIs to chemotherapy in this group probably doesn't affect survival, but may delay progression, with little meaningful difference in quality of life. However, TKIs increase the risk of serious side effects slightly. The effect of treatment on bowel perforation rates and hypertension is very uncertain, largely due to small studies and different TKI drugs used in different studies.

What are the limitations of the evidence?

This is a rapidly moving field and evidence may change with further studies and longer follow-up of studies.

How up to date is this evidence?

This review updates our previous review of 2011 and is up to date to September 2022.

Key messages

Newly-diagnosed epithelial ovarian cancer (EOC)

The effects of bevacizumab and TKI anti-angiogenesis treatment in women with newly diagnosed EOC are uncertain. 

These treatments may have a minimal effect on how long women survive or disease re-growth (progression), with a decrease in quality of life and an increase in serious side effects.

Platinum-sensitive EOC 

Bevacizumab and TKIs probably delay progression, but may or may not improve how long women live.

Platinum-resistant EOC

Bevacizumab probably improves how long women live and probably results in a large delay in progression. 

TKIs probably delay disease progression, but may or may not improve how long women live. 

There appears to be a role for anti-angiogenesis treatment, but additional treatment burden and financial costs of maintenance treatment of anti-angiogenesis treatments should be carefully considered. 

Authors' conclusions: 

Bevacizumab likely improves both OS and PFS in platinum-resistant relapsed EOC. In platinum-sensitive relapsed disease, bevacizumab and TKIs probably improve PFS, but may or may not improve OS. The results for TKIs in platinum-resistant relapsed EOC are similar. The effects on OS or PFS in newly-diagnosed EOC are less certain, with a decrease in QoL and increase in adverse events. Overall adverse events and QoL data were more variably reported than were PFS data.

There appears to be a role for anti-angiogenesis treatment, but given the additional treatment burden and economic costs of maintenance treatments, benefits and risks of anti-angiogenesis treatments should be carefully considered. 

Read the full abstract...
Background: 

Many women, and other females, with epithelial ovarian cancer (EOC) develop resistance to conventional chemotherapy drugs. Drugs that inhibit angiogenesis (development of new blood vessels), essential for tumour growth, control cancer growth by denying blood supply to tumour nodules.

Objectives: 

To compare the effectiveness and toxicities of angiogenesis inhibitors for treatment of epithelial ovarian cancer (EOC).

Search strategy: 

We identified randomised controlled trials (RCTs) by searching CENTRAL, MEDLINE and Embase (from 1990 to 30 September 2022). We searched clinical trials registers and contacted investigators of completed and ongoing trials for further information.

Selection criteria: 

RCTs comparing angiogenesis inhibitors with standard chemotherapy, other types of anti-cancer treatment, other angiogenesis inhibitors with or without other treatments, or placebo/no treatment in a maintenance setting, in women with EOC. 

Data collection and analysis: 

We used standard methodological procedures expected by Cochrane. Our outcomes were overall survival (OS), progression-free survival (PFS), quality of life (QoL), adverse events (grade 3 and above) and hypertension (grade 2 and above).

Main results: 

We identified 50 studies (14,836 participants) for inclusion (including five studies from the previous version of this review): 13 solely in females with newly-diagnosed EOC and 37 in females with recurrent EOC (nine studies in platinum-sensitive EOC; 19 in platinum-resistant EOC; nine with studies with mixed or unclear platinum sensitivity). The main results are presented below. 

Newly-diagnosed EOC
Bevacizumab, a monoclonal antibody that binds vascular endothelial growth factor (VEGF), given with chemotherapy and continued as maintenance, likely results in little to no difference in OS compared to chemotherapy alone (hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.88 to 1.07; 2 studies, 2776 participants; moderate-certainty evidence). Evidence is very uncertain for PFS (HR 0.82, 95% CI 0.64 to 1.05; 2 studies, 2746 participants; very low-certainty evidence), although the combination results in a slight reduction in global QoL (mean difference (MD) -6.4, 95% CI -8.86 to -3.94; 1 study, 890 participants; high-certainty evidence). The combination likely increases any adverse event (grade ≥ 3) (risk ratio (RR) 1.16, 95% CI 1.07 to 1.26; 1 study, 1485 participants; moderate-certainty evidence) and may result in a large increase in hypertension (grade ≥ 2) (RR 4.27, 95% CI 3.25 to 5.60; 2 studies, 2707 participants; low-certainty evidence).

Tyrosine kinase inhibitors (TKIs) to block VEGF receptors (VEGF-R), given with chemotherapy and continued as maintenance, likely result in little to no difference in OS (HR 0.99, 95% CI 0.84 to 1.17; 2 studies, 1451 participants; moderate-certainty evidence) and likely increase PFS slightly (HR 0.88, 95% CI 0.77 to 1.00; 2 studies, 2466 participants; moderate-certainty evidence). The combination likely reduces QoL slightly (MD -1.86, 95% CI -3.46 to -0.26; 1 study, 1340 participants; moderate-certainty evidence), but it increases any adverse event (grade ≥ 3) slightly (RR 1.31, 95% CI 1.11 to 1.55; 1 study, 188 participants; moderate-certainty evidence) and may result in a large increase in hypertension (grade ≥ 3) (RR 6.49, 95% CI 2.02 to 20.87; 1 study, 1352 participants; low-certainty evidence). 

Recurrent EOC (platinum-sensitive)
Moderate-certainty evidence from three studies (with 1564 participants) indicates that bevacizumab with chemotherapy, and continued as maintenance, likely results in little to no difference in OS (HR 0.90, 95% CI 0.79 to 1.02), but likely improves PFS (HR 0.56, 95% CI 0.50 to 0.63) compared to chemotherapy alone. The combination may result in little to no difference in QoL (MD 0.8, 95% CI -2.11 to 3.71; 1 study, 486 participants; low-certainty evidence), but it increases the rate of any adverse event (grade ≥ 3) slightly (RR 1.11, 1.07 to 1.16; 3 studies, 1538 participants; high-certainty evidence). Hypertension (grade ≥ 3) was more common in arms with bevacizumab (RR 5.82, 95% CI 3.84 to 8.83; 3 studies, 1538 participants). 

TKIs with chemotherapy may result in little to no difference in OS (HR 0.86, 95% CI 0.67 to 1.11; 1 study, 282 participants; low-certainty evidence), likely increase PFS (HR 0.56, 95% CI 0.44 to 0.72; 1 study, 282 participants; moderate-certainty evidence), and may have little to no effect on QoL (MD 6.1, 95% CI -0.96 to 13.16; 1 study, 146 participants; low-certainty evidence). Hypertension (grade ≥ 3) was more common with TKIs (RR 3.32, 95% CI 1.21 to 9.10).

Recurrent EOC (platinum-resistant)
Bevacizumab with chemotherapy and continued as maintenance increases OS (HR 0.73, 95% CI 0.61 to 0.88; 5 studies, 778 participants; high-certainty evidence) and likely results in a large increase in PFS (HR 0.49, 95% CI 0.42 to 0.58; 5 studies, 778 participants; moderate-certainty evidence). The combination may result in a large increase in hypertension (grade ≥ 2) (RR 3.11, 95% CI 1.83 to 5.27; 2 studies, 436 participants; low-certainty evidence). The rate of bowel fistula/perforation (grade ≥ 2) may be slightly higher with bevacizumab (RR 6.89, 95% CI 0.86 to 55.09; 2 studies, 436 participants).

Evidence from eight studies suggest TKIs with chemotherapy likely result in little to no difference in OS (HR 0.85, 95% CI 0.68 to 1.08; 940 participants; moderate-certainty evidence), with low-certainty evidence that it may increase PFS (HR 0.70, 95% CI 0.55 to 0.89; 940 participants), and may result in little to no meaningful difference in QoL (MD ranged from -0.19 at 6 weeks to -3.40 at 4 months). The combination increases any adverse event (grade ≥ 3) slightly (RR 1.23, 95% CI 1.02 to 1.49; 3 studies, 402 participants; high-certainty evidence). The effect on bowel fistula/perforation rates is uncertain (RR 2.74, 95% CI 0.77 to 9.75; 5 studies, 557 participants; very low-certainty evidence).

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