Caucasian ovarian cancer patients should stick to standard dosing, study finds

European women with ovarian cancer should stick to the standard three-week dosing schedule for paclitaxel rather than boosting up to a weekly dose-dense regimen, according to the results of the phase III ICON8 trial. The results are being presented at the ESMO 2017 Congress in Madrid.

ICON8 is a randomised three-arm, three-stage Gynaecologic Cancer InterGroup (GCIG) phase III trial designed to evaluate the safety and efficacy of dose-dense, dose-fractionated carboplatin-paclitaxel chemotherapy in the treatment of patients with ovarian cancer. Coordinated by the MRC Clinical Trials Unit at University College London (UCL), it comes four years after JGOG3016, a study of Japanese ovarian cancer patients, showed significantly increased median progression-free survival (PFS) and overall survival (OS) in those treated with dose-dense weekly paclitaxel compared to the standard three-weekly schedule.

“Dose-dense treatment offers better survival than conventional treatment and is a potential new standard of care for first-line chemotherapy for patients with advanced epithelial ovarian cancer,” the authors of that study wrote, publishing their results in the journal Lancet Oncology.

To evaluate for a similar effect from weekly paclitaxel, ICON8 randomised 1566 predominantly European patients to receive six cycles of either the standard three-week dosing regimen (carboplatin AUC 5/6-paclitaxel 175 mg/mq; Arm 1), compared to two different regimens that included once-weekly dose-dense paclitaxel (carboplatin AUC 5/6+paclitaxel 80 mg/mq weekly, Arm 2; and carboplatin AUC2+paclitaxel 80 mg/mq weekly, Arm 3). All patients entered ICON8 after immediate primary surgery or received neo-adjuvant chemotherapy with planned delayed primary surgery.

The study found no benefit to either of the once-weekly regimens. PFS was 24.4 months with standard dosing, compared to 24.9 and 25.3 months in Arms 2 and 3 respectively. There was also a slight increase in grade 3–4 toxicity in Arms 2 and 3 compared to Arm 1 (63% vs 53% vs 42% respectively), although this increase was predominantly due to uncomplicated haematological toxicity.

“The results clearly demonstrate that, although well tolerated, using weekly scheduling to achieve dose-intensification of paclitaxel as part of the first-line treatment of epithelial ovarian cancer does not extend progression-free survival in this population,” said study investigator Dr Andrew Clamp, from The Christie NHS Foundation Trust and The University of Manchester. “Therefore, this approach cannot be recommended as a standard-of-care treatment option for this population.”

Noting that the study was “robust and appropriately powered”, Dr Clamp said it is “not entirely clear” why ICON8 and JGOG3016 showed contrasting results.

“Both were well-conducted trials and achieved the goal of increasing paclitaxel dose-intensity,” he said. “We know the histological profile of ovarian cancer is slightly different between Japanese and Caucasian women, but I think it is unlikely that this accounts for the difference. It is more likely that there are pharmacogenomic differences between these two ethnic groups that account for the different results seen.

Dr Domenica Lorusso, chair of the Gynaecological Tumours track at ESMO 2017, said: “The trial confirms that carboplatin-paclitaxel every three weeks is the standard first-line treatment in ovarian cancer — a standard which has remained unmodified in the last 20 years, at least in the Caucasian population.” She agreed that success with weekly dosing in the Japanese population “is possibly due to genetic differences”.

Dr Clamp said it “remains appropriate” to continue to offer weekly dose-dense paclitaxel as a treatment option to Japanese women.