Weekly dose-dense chemotherapy should not be recommended as a first-line treatment for epithelial ovarian cancer in women of non-Japanese ethnic origin. The ICON8 investigators reported on 29 November 2019 in The Lancet that weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer; however, it does not significantly improve progression-free survival (PFS) compared with standard 3-weekly chemotherapy in predominantly European population.
The authors wrote in the study background that carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. Weekly paclitaxel treatment is an efficacious and well tolerated approach in recurrent platinum-resistant ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in PFS and overall survival (OS) with dose-dense weekly paclitaxel and 3-weekly carboplatin. In particular, weekly treatment resulted in an 11-month prolongation of median PFS and a corresponding 38-month improvement in median OS. In ICON8, the study team aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer.
ICON8 is a phase III trial conducted in women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC–IV epithelial ovarian cancer. The patients were randomly assigned to group 1 treated with carboplatin area under the curve (AUC)5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks, group 2 treated with carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly, or group 3 treated with carboplatin AUC2 and 80 mg/m2 paclitaxel weekly.
Patients were recruited from 117 sites in the UK, Australia, New Zealand, Mexico, South Korea, and Republic of Ireland. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery.
The study coprimary outcomes were PFS and OS. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0.75 in PFS. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3).
Between June 2011 and November 2014, in total 1566 women were randomly assigned to treatment; 72% (365 patients) completed six protocol-defined treatment cycles in group 1, 60% (305 patients) in group 2, and 63% (322 patients) in group 3, although 90% (454 patients), 89% (454 patients), and 85% (437 patients) completed six platinum-based chemotherapy cycles, respectively.
Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3).
By February 2017, 65% (1018 patients) had experienced disease progression.
No significant PFS increase was observed with either weekly regimen (restricted mean survival time 24.4 months [97.5% CI 23.0–26.0] in group 1, 24.9 months [24.0–25.9] in group 2, 25.3 months [23.9–26.9] in group 3; median PFS 17.7 months [IQR 10.6–not reached] in group 1, 20.8 months [11.9–59.0] in group 2, 21.0 months [12.0–54.0] in group 3; log-rank p = 0.35 for group 2 vs group 1; group 3 vs 1 p = 0.51).
Although most patients were able to complete six chemotherapy cycles, both weekly treatments were associated with more treatment modifications and a higher incidence of grade 3 or higher toxic effects. Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups.
It is possible that ethnic pharmacogenomic differences underlie the discordant outcomes between ICON8 and JGOG3016, and that weekly dose-dense paclitaxel treatment could still be considered as a first-line treatment option for Japanese women with epithelial ovarian cancer. But the weekly dose-dense paclitaxel should not be recommended as a component of first-line epithelial ovarian cancer treatment for women of non-Japanese ethnic origin.
The International Collaboration on Ovarian Neoplasms 8 (ICON8) was conducted by the Gynecologic Cancer Intergroup.
The study was funded by the Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.
Clamp AR, James EC, McNeish IA, et al. Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial. Lancet; Published online 29 November 2019.DOI: https://doi.org/10.1016/S0140-6736(19)32259-7