Cediranib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Patients treated with standard chemotherapy for metastatic or relapsed cervical cancer respond poorly to conventional chemotherapy (response achieved in 20-30% of patients) with an overall survival of less than 1 year. High tumour angiogenesis and high concentrations of intratumoural VEGF are adverse prognostic features. Cediranib is a potent tyrosine kinase inhibitor of VEGFR1, 2, and 3. In this trial, we aimed to assess the effect of the addition of cediranib to carboplatin and paclitaxel chemotherapy in patients with metastatic or recurrent cervical cancer. METHODS: In this randomised, double-blind, placebo-controlled phase 2 trial, which was done in 17 UK cancer treatment centres, patients aged 18 years or older initially diagnosed with metastatic carcinoma or who subsequently developed metastatic disease or local pelvic recurrence after radical treatment that was not amenable to exenterative surgery were recruited. Eligible patients received carboplatin AUC of 5 plus paclitaxel 175 mg/m(2) by infusion every 3 weeks for a maximum of six cycles and were randomised centrally (1:1) through a minimisation approach to receive cediranib 20 mg or placebo orally once daily until disease progression. The stratification factors were disease site, disease-free survival after primary therapy or primary stage IVb disease, number of lines of previous treatment, Eastern Cooperative Oncology Group performance status, and investigational site. All patients, investigators, and trial personnel were masked to study drug allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat, and the safety analysis included all patients who received at least one dose of study drug. This trial is registered with the ISCRTN registry, number ISRCTN23516549, and has been completed. FINDINGS: Between Aug 19, 2010, and July 27, 2012, 69 patients were enrolled and randomly assigned to cediranib (n=34) or placebo (n=35). After a median follow-up of 24·2 months (IQR 21·9-29·5), progression-free survival was longer in the cediranib group (median 8·1 months [80% CI 7·4-8·8]) than in the placebo group (6·7 months [6·2-7·2]), with a hazard ratio (HR) of 0·58 (80% CI 0·40-0·85; one-sided p=0·032). Grade 3 or worse adverse events that occurred in the concurrent chemotherapy and trial drug period in more than 10% of patients were diarrhoea (five [16%] of 32 patients in the cediranib group vs one [3%] of 35 patients in the placebo group), fatigue (four [13%] vs two [6%]), leucopenia (five [16%] vs three [9%]), neutropenia (10 [31%] vs four [11%]), and febrile neutropenia (five [16%] vs none). The incidence of grade 2-3 hypertension was higher in the cediranib group than in the control group (11 [34%] vs four [11%]). Serious adverse events occurred in 18 patients in the placebo group and 19 patients in the cediranib group. INTERPRETATION: Cediranib has significant efficacy when added to carboplatin and paclitaxel in the treatment of metastatic or recurrent cervical cancer. This finding was accompanied by an increase in toxic effects (mainly diarrhoea, hypertension, and febrile neutropenia). FUNDING: Cancer Research UK and AstraZeneca.

Chemotherapy for metastatic and recurrent cervical cancer.

BACKGROUND: Cervical cancer is the second most common cancer among women up to 65 years of age and is the most frequent cause of death from gynaecological cancers worldwide. A woman's risk of developing cervical cancer by 65 years of age ranges from 0.69% in developed countries to 1.38% in developing countries. Although screening by Pap smear should mean early detection at a curable stage for most women, many still present with advanced or metastatic disease with a worse prognosis. The addition of platinum-based chemotherapy to radiotherapy has improved outcome compared to radiotherapy alone; however, 30% to 50% fail to respond to treatment or develop recurrent disease. There are no standard treatment options for these patients, although platinum-based chemotherapy is frequently used and trials are on-going. OBJECTIVES: To compare different types and combinations of cytotoxic chemotherapy for the treatment of metastatic/recurrent cervical cancer. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2012), MEDLINE (1950 to January 2012) and EMBASE (1980 to January 2012). The reference lists from these and those of review articles were also checked. SELECTION CRITERIA: All randomised controlled trials (RCTs) involving chemotherapy for metastatic/recurrent cervical cancer. Trials involving radiotherapy, chemoradiotherapy, intra-arterial chemotherapy, biological agents or immunomodulators were excluded. DATA COLLECTION AND ANALYSIS: Three review authors independently reviewed trials for inclusion and data extraction and assessed risk of bias. MAIN RESULTS: There were no data comparing best supportive care with chemotherapy. Cisplatin-based regimens are the most widely used and therefore we have concentrated on these trials. In terms of response rates some non-platinum regimens are equivalent but toxicity is higher. The most common cisplatin regimen was 50 mg/m(2) day 1 q21days. Higher doses had similar survivals. There was no direct comparison between single-agent cisplatin and carboplatin. Overall survival (OS) and progression-free survival (PFS) were not adequately reported and quality of life (QoL) outcomes were incompletely documented. Combination regimens were more toxic than single agents, but in the limited reported data this did not appear to adversely affect QoL.No significant difference in response rate by site of recurrence was found, although there was a trend towards improved response when the main site of disease was beyond the previously irradiated pelvis. AUTHORS' CONCLUSIONS: Combination cisplatin-based chemotherapy could be a viable option for patients of good performance status with recurrent/metastatic cervical cancer, but further trials that report adequate survival and QoL data are sought. Response rates and improvements in survival are low. Cisplatin-based combinations have significant toxicity. Outcomes are poor and novel cytotoxic/biological agents and optimal scheduling need further investigation. Future trials need to stratify for and perform planned subgroup analysis with respect to previous treatment and site of recurrence.