What is the aim of this review?
The aim of this Cochrane Review is to find out whether vascular endothelial growth factor (VEGF) targeting drugs, which inhibit the formation of new blood vessels, can improve survival in women with cervical cancer that has spread to distant sites (metastasised) or has not responded to or come back (recurred) after initial treatment. These drugs include bevacizumab, cediranib, apatinib, pazopanib, anlotinib, and nintedanib.
Key messages
Bevacizumab plus chemotherapy may improve survival and probably increases specific and serious adverse events, including gastrointestinal perforations through the gut wall, blood clot formation (thromboembolic events) in blood vessels, hypertension (increased blood pressure), and bleeding (haemorrhage).
Cediranib or apatinib plus chemotherapy, or pazopanib alone, may make little to no difference in survival. Pazopanib plus lapatinib may reduce survival.
What are the main results of the review?
We found four randomised controlled trials (RCTs) that met our inclusion criteria and enrolled 808 women.
We found one study, which included 452 women, that assessed the use of bevacizumab plus chemotherapy versus chemotherapy alone. The inclusion of bevacizumab may improve overall survival and probably increases the incidences of specific and serious adverse events.
A second study analysed 69 women treated with cediranib plus chemotherapy versus chemotherapy alone. Cediranib may make little to no difference in survival, and it is uncertain whether it increases the incidences of specific or serious adverse events.
Another study with 59 women reported data on the use of apatinib plus chemotherapy or chemoradiotherapy (concurrent chemotherapy and radiotherapy) versus chemotherapy or chemoradiotherapy alone. Apatinib may make little to no difference in survival, but it exhibited promising efficacy for progression-free survival.
We found one study with 228 women that compared pazopanib plus lapatinib versus only lapatinib, or pazopanib versus lapatinib: pazopanib plus lapatinib may reduce survival and probably increases the incidence of hypertension; pazopanib alone may make little to no difference in survival and probably increases the incidence of hypertension.
Overall the quality (certainty) of the evidence was low, as each comparison included only one study and most studies were small.
We found low-certainty evidence in favour of the use of bevacizumab plus chemotherapy. However, bevacizumab probably increases specific adverse events (gastrointestinal perforations or fistulae, thromboembolic events, hypertension) and serious adverse events. We found low-certainty evidence that does not support the use of cediranib plus chemotherapy, apatinib plus chemotherapy, apatinib plus chemotherapy/brachytherapy, or pazopanib monotherapy. We found low-certainty evidence suggesting that pazopanib plus lapatinib worsens outcomes. The VEGF inhibitors apatinib and pazopanib may increase the probability of hypertension events.
Cervical cancer ranks as the fourth leading cause of death from cancer in women. Historically, women with metastatic or recurrent cervical cancer have had limited treatment options. New anti-angiogenesis therapies, such as vascular endothelial growth factor (VEGF) targeting agents, offer an alternative strategy to conventional chemotherapy; they act by inhibiting the growth of new blood vessels, thereby restricting tumour growth by blocking the blood supply.
To assess the benefits and harms of VEGF targeting agents in the management of persistent, recurrent, or metastatic cervical cancer.
We performed searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, online registers of clinical trials, and abstracts of scientific meetings up until 27 May 2020.
We examined randomised controlled trials (RCTs) that evaluated the use of VEGF targeting agents alone or in combination with conventional chemotherapy or other VEGF targeting agents.
Three review authors independently screened the results of search strategies, extracted data, assessed risk of bias, and analysed data according to the standard methods expected by Cochrane. The certainty of evidence was assessed via the GRADE approach.
A total of 1634 records were identified. From these, we identified four studies with a total of 808 participants for inclusion. We also identified two studies that were awaiting classification and nine ongoing studies.
Bevacizumab plus chemotherapy versus chemotherapy
Treatment with bevacizumab plus chemotherapy may result in lower risk of death compared to chemotherapy alone (hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.62 to 0.95; 1 study, 452 participants; low-certainty evidence). However, there are probably more specific adverse events when compared to chemotherapy alone, including gastrointestinal perforations or fistulae (risk ratio (RR) 18.00, 95% CI 2.42 to 133.67; 1 study, 440 participants; moderate-certainty evidence); serious thromboembolic events (RR 4.5, 95% CI 1.55 to 13.08; 1 study, 440 participants; moderate-certainty evidence); and hypertension (RR 13.75, 95% CI 5.07 to 37.29; 1 study, 440 participants; moderate-certainty evidence). There may also be a higher incidence of serious haemorrhage (RR 5.00, 95% CI 1.11 to 22.56; 1 study, 440 participants; low-certainty evidence). In addition, the incidence of serious adverse events is probably higher (RR 1.44, 95% CI 1.16 to 1.79; 1 study, 439 participants; moderate-certainty evidence). The incremental cost-effectiveness ratio was USD 295,164 per quality-adjusted life-year (1 study, 452 participants; low-certainty evidence).
Cediranib plus chemotherapy versus chemotherapy
Treatment with cediranib plus chemotherapy may or may not result in similar risk of death when compared to chemotherapy alone (HR 0.94, 95% CI 0.53 to 1.65; 1 study, 69 participants; low-certainty evidence). We found very uncertain results for the incidences of specific adverse events, including gastrointestinal perforations or fistulae (RR 3.27, 95% CI 0.14 to 77.57; 1 study, 67 participants; very low-certainty evidence); serious haemorrhage (RR 5.45, 95% CI 0.27 to 109.49; 1 study, 67 participants; very low-certainty evidence); serious thromboembolic events (RR 3.41, 95% CI 0.14 to 80.59; 1 study, 60 participants; very low-certainty evidence); and serious hypertension (RR 0.36, 95% CI 0.02 to 8.62; 1 study, 67 participants; very low-certainty evidence). In addition, there may or may not be a similar incidence of serious adverse events compared to chemotherapy alone (RR 1.15, 95% CI 0.75 to 1.78; 1 study, 67 participants; low-certainty evidence).
Apatinib plus chemotherapy or chemotherapy/brachytherapy versus chemotherapy or chemotherapy/brachytherapy
Treatment with apatinib plus chemotherapy or chemotherapy/brachytherapy may or may not result in similar risk of death compared to chemotherapy alone or chemotherapy/brachytherapy alone (HR 0.90, 95% CI 0.51 to 1.60; 1 study, 52 participants; low-certainty evidence). However, hypertension events may occur at a higher incidence as compared to chemotherapy alone or chemotherapy/brachytherapy alone (RR 5.14, 95% CI 1.28 to 20.73; 1 study, 52 participants; low-certainty evidence).
Pazopanib plus lapatinib versus lapatinib
Treatment with pazopanib plus lapatinib may result in higher risk of death compared to lapatinib alone (HR 2.71, 95% CI 1.16 to 6.31; 1 study, 117 participants; low-certainty evidence). We found very uncertain results for the incidences of specific adverse events, including gastrointestinal perforations or fistulae (RR 2.00, 95% CI 0.19 to 21.59; 1 study, 152 participants; very low-certainty evidence); haemorrhage (RR 2.00, 95% CI 0.72 to 5.58; 1 study, 152 participants; very low-certainty evidence); and thromboembolic events (RR 3.00, 95% CI 0.12 to 72.50; 1 study, 152 participants; very low-certainty evidence). In addition, the incidence of hypertension events is probably higher (RR 12.00, 95% CI 2.94 to 49.01; 1 study, 152 participants; moderate-certainty evidence). There may or may not be a similar incidence of serious adverse events as compared to lapatinib alone (RR 1.45, 95% CI 0.94 to 2.26; 1 study, 152 participants; low-certainty evidence).
Pazopanib versus lapatinib
Treatment with pazopanib may or may not result in similar risk of death as compared to lapatinib (HR 0.96, 95% CI 0.67 to 1.38; 1 study, 152 participants; low-certainty evidence). We found very uncertain results for the incidences of specific adverse events, including gastrointestinal perforations or fistulae (RR 1.03, 95% CI 0.07 to 16.12; 1 study, 150 participants; very low-certainty evidence); haemorrhage (RR 1.03, 95% CI 0.31 to 3.40; 1 study, 150 participants; very low-certainty evidence); and thromboembolic events (RR 3.08, 95% CI 0.13 to 74.42; 1 study, 150 participants; very low-certainty evidence). In addition, the incidence of hypertension events is probably higher (RR 11.81, 95% CI 2.89 to 48.33; 1 study, 150 participants; moderate-certainty evidence). The risk of serious adverse events may or may not be similar as compared to lapatinib (RR 1.31, 95% CI 0.83 to 2.07; 1 study, 150 participants; low-certainty evidence).