SORAFENIB OF NO BENEFIT IN OVARIAN CANCER

In a study of women with stage III/IV epithelial ovarian cancer, the addition of sorafenib (Nexavar) to traditional paclitaxel/carboplatin therapy resulted in no greater efficacy and increased toxicity, according to a report by Hainsworth et al in Cancer Medicine. The investigators suggested that sorafenib is not the angiogenesis inhibitor of choice in the treatment of patients with advanced ovarian cancer.

In patients with advanced ovarian cancer, the combination of paclitaxel and carboplatin remains the most widely used chemotherapy regimen, and is associated with a mean survival rate of approximately 36 months. Other cytotoxic agents have been added to the paclitaxel/carboplatin regimen, with limited positive results.

One such cytotoxic agent, sorafenib, has been shown to have some benefit in extending survival in limited studies but has been associated with significant toxicity. To address the risk/benefit associated with the addition of sorafenib, the investigators compared the efficacy and toxicity of standard first-line treatment with paclitaxel/carboplatin with those of paclitaxel/carboplatin plus sorafenib in patients with advanced ovarian carcinoma.

Study Details

Included in the study were women with histologically confirmed stage III or IV epithelial ovarian carcinoma. They had not been previously treated with chemotherapy or radiation therapy. In total, 85 women were selected among eligible patients from 14 sites in the Sarah Cannon Oncology Research Consortium.

Patients were randomly assigned to receive paclitaxel/carboplatin plus sorafenib or paclitaxel/carboplatin alone. The doses of paclitaxel and carboplatin were identical in both groups: paclitaxel, 175 mg/m2 for 1 to 3 hour intravenous infusion on day 1, and carboplatin, area under the curve of 6.0 for 20-minute intravenous infusion on day 1. Those receiving the additional oral sorafenib were dosed at 400 mg twice daily.

Patients received standard premedications prior to each dose of paclitaxel, including diphenhydramine at 50 mg, cimetidine at 300 mg (or equivalent), and dexamethasone at 20 mg, all administered intravenously. After completing two cycles of therapy, patients were reevaluated with repeat computed tomography (CT) scans, CA-125 levels, and tumor measurements.   

For patients who developed grade 3 or 4 nonhematologic toxicity related to paclitaxel and/or carboplatin, dosing was delayed until the toxicity had decreased to grade 1 or less, and then 75% dosing was continued. Dose reductions of sorafenib were specified for expected toxicities, including skin rash, hand-foot skin reaction, and hypertension. Sorafenib was reintroduced at a one dose level reduction when the toxicities had improved to grade 1 or less.

The primary endpoint was the proportion of patients with progression-free survival at 2 years. Progression-free survival was defined as the interval from the date of study entry to the date of tumor progression or death.

No Difference in Efficacy but More Toxicity

In regard to the efficacy of the treatment regimens, the investigators found no difference between the two therapies in terms of progression-free survival (16.3 months for the paclitaxel/carboplatin cohort vs 15.4 months for the paclitaxel/carboplatin/sorafenib cohort). After 2 years, the median overall survival rate was 81% for the paclitaxel/carboplatin cohort and 76% for the paclitaxel/carboplatin/sorafenib cohort.

As for toxicity, patients receiving paclitaxel/carboplatin/sorafenib had substantially more grade 3/4 nonhematologic toxicity, primarily skin toxicity, hand-foot syndrome, mucositis, and hypertension. Grade 3/4 neutropenia occurred in 26% of patients receiving paclitaxel/carboplatin therapy and 31% of patients receiving paclitaxel/carboplatin/sorafenib therapy.

Closing Thoughts

According to the investigators, the addition of sorafenib to standard paclitaxel/carboplatin therapy did not improve efficacy and substantially increased toxicity in the first-line treatment of advanced epithelial ovarian cancer.

“As more evidence accumulates, it is evident that sorafenib is not the angiogenesis inhibitor of choice in the treatment of patients with advanced ovarian cancer,” they remarked. “Future clinical trials should focus on agents with new targets.”    

John Hainsworth, MD, Chief Scientific Officer of the Sarah Cannon Research Institute, Nashville, Tennessee, is the corresponding author of this article in Cancer Medicine.