New phase II data of the CIRCCa trial indicate that adding the experimental drug cediranib - a tyrosine kinase inhibitor of VEGF receptors 1,2 and 3 - to standard chemotherapy improves tumour shrinkage and adds a modest improvement in the progression-free survival (PFS) of patients with recurrent or metastatic cervical cancer. As such, CIRCCa is the second recent trial to show the benefit of adding an antiangiogenic drug to chemotherapy in cervical cancer, after the excellent results obtained with bevacizumab in this setting.
In Europe, about 70% of patients with cervical cancer are cured by either surgery or chemo-radiotherapy. The patients with recurrent or secondary cancer have a very poor prognosis. Only about 20-30% of these patients have tumour shrinkage after conventional chemotherapy and their survival is usually less than one year. High tumor angiogenesis along with high levels of intratumoral vascular endothelial growth factor (VEGF) are adverse prognostic features making anti-angiogenic therapy an interesting option in this setting.
In the phase II CIRCCa trial, researchers compared two groups of patients with relapsed or metastatic cervical cancer given conventional chemotherapy (carboplatin AUC5 + paclitaxel 175 mg/m2 3 weekly for a maximum of 6 cycles) plus either cediranib (20 mg/day; N= 34) or placebo (N= 35) until progression occurred. The primary endpoint of the trial was progression-free survival (PFS), while secondary endpoints included changes in sVEGFR-2 from baseline to day 28, overall survival (OS), response rate, toxicity and quality of life.
In the study, patients who received cediranib in addition to chemotherapy had greater tumour shrinkage than those treated by chemotherapy plus placebo (66% vs. 42%; p= 0.030). There was also a modest but statistically significant increase in the median progression-free survival in favor of the cediranib arm (35 weeks vs. 30 weeks; HR[80%CI]: 0.61[0.41, 0.89]; p = 0.046). There was no statistically significant difference in median overall survival between both regimens (63 weeks with placebo versus 59 weeks with cediranib; HR[80%CI]: 0.93[0.64, 1.36]; p = 0.401). A complete or partial response was seen in 66% of patients in the cediranib arm compared with 42% of patients in the placebo arm (p = 0.030). After one month of treatment, the VEGF receptor 2 levels in the blood were more likely to be reduced in the cediranib group (median change in log10 VEGFR-2 from baseline 0.036 vs. 0.067; p< 0.001).
Patients in the cediranib arm experienced more grade 2/3/4 diarrhoea (50% vs. 18%, p= 0.005) and hypertension (34% vs. 12%, p= 0.038) as compared to patients receiving placebo. Nevertheless, these side effects were in general easily manageable with standard medication.
In summary, targeting the tumour blood supply seems to be a promising way to increase the effectiveness of chemotherapy in cervical cancer. Adding cediranib led to an improvement in PFS, inhibition of VEGFR-2 levels and an improved respons. The researchers are now conducting an individual patient analysis to correlate response to chemotherapy with the fall in VEGF receptor levels in the blood and are also looking at other tumour biomarkers that may have been reduced by cediranib. Recurrent or metastatic cervical cancer is really difficult to treat with a low response rate and poor survival. The FDA recently approved the use of bevacizumab in this setting which will completely change the clinical practice. Phase III trial results confirming the favorable predictions of this treatment with cediranib are eagerly awaited.
Symonds P, Gourley C, Davidson S, et al. CIRCCa: A randomised double blind phase II trial of carboplatin-paclitaxel plus cediranib versus carboplatin-paclitaxel plus placebo in metastatic/recurrent cervical cancer. (CRUK Grant Ref: C1256/A11416). Presented at ESMO 2014; Abstract 25LBA.