Dose-Dense Chemotherapy Fails to Improve PFS in Ovarian Cancer

Weekly dose-dense chemotherapy can be delivered successfully and with lower toxicity than standard 3-weekly regimens, but it does not improve progression-free survival (PFS) among patients with epithelial ovarian cancer, according to a large new study (abstract 929O_PR) presented at the European Society for Medical Oncology (ESMO) 2017 Congress in Madrid.

The results of a previous study, the JGOG3016 trial in Japan, found that a dose-dense paclitaxel and carboplatin regimen was more effective than the standard regimen. Based on those results, investigators conducted the ICON8 trial in the United Kingdom, including 1,566 women with epithelial ovarian/fallopian tube/primary peritoneal cancer. Andrew Clamp, MRCP, PhD, of the Christie NHS Foundation Trust in Manchester.

“There is a strong rationale for the evaluation of weekly dose-dense paclitaxel scheduling,” Clamp said. This includes preclinical evidence for improved drug delivery, as well as improvements seen in survival in women with breast cancer with the dose-dense approach.

The study used a 1:1:1 randomization approach. One group received the standard 3-weekly regimen (Arm 1, 522 patients); another received carboplatin 3-weekly and the dose-dense weekly paclitaxel regimen (Arm 2, 522 patients); and the third received both agents in the dose-dense approach (Arm 3, 521 patients).

Clamp said that the goal of dose intensification was achieved. The median total dose of paclitaxel was 1,011 mg/m², 1,234 mg/m², and 1,274 mg/m² in the three groups, respectively.

In spite of that, no improvement in PFS was seen. Arm 1 had a median PFS of 17.9 months, compared with 20.6 months in Arm 2 and 21.1 months in Arm 3. The hazard ratio (HR) for progression compared with Arm 1 was 0.92 in Arm 2 (95% CI, 0.77–1.09; P = .45). In Arm 3 vs Arm 1, the HR was 0.94 (95% CI, 0.79–1.12; P = .56). There were no differences between the regimens in subsets of patients who had immediate and delayed primary surgery.

The overall survival data was not yet mature, with only 58% of events required, but Clamp said that no overall survival signal appeared to be emerging.

The dose-dense approach did not appear to significantly impact toxicity, Clamp said. In total, 42% of Arm 1 patients experienced any grade 3/4 toxicity, compared with 63% and 53% in Arms 2 and 3. Most of that difference was due to uncomplicated neutropenia.

Though the approach does appear to allow delivery of a higher paclitaxel dose intensity without increasing toxicity, Clamp said that these results suggest that the standard regimen should remain the standard of care in this malignancy.

Sandro Pignata, MD, PhD, of the National Cancer Institute in Naples, Italy, was the discussant for the session, and he noted that the Japanese study on this topic was the only one to-date that showed a benefit for this approach. He suggested that this is likely due to the difference in pharmacokinetics and pharmacodynamics in Asian patients. “We need more translational research to identify Western patients that may benefit,” he said.