As reported in The Lancet Oncology by Andrew R. Clamp, PhD, and colleagues, no significant differences in overall survival or updated progression-free survival were found with first-line treatment with weekly dose-dense regimens of carboplatin/paclitaxel vs every-3-week carboplatin/paclitaxel in the phase III ICON8 trial involving women with stage IC through IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma.
Andrew R. Clamp, PhD
As stated by the investigators, “Standard-of-care first-line chemotherapy for epithelial ovarian cancer is carboplatin and paclitaxel administered once every 3 weeks. The JGOG 3016 trial reported significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. However, this benefit was not observed in the previously reported progression-free survival results of ICON8. Here, we present the final co-primary outcomes of overall survival and updated progression-free survival analyses of ICON8.”
Study Details
The open-label trial included 1,566 patients from sites in the United Kingdom, Australia and New Zealand, Mexico, South Korea, and Ireland. They were randomly assigned 1:1:1 between June 2011 and November 2014 to receive six 21-day cycles of:
- Carboplatin at area under the curve (AUC) = 5 or 6 and paclitaxel at 175 mg/m² every 3 weeks (control group, n = 522)
- 3-weekly carboplatin at AUC = 5 or 6 and weekly paclitaxel at 80 mg/m² (3-weekly carboplatin/weekly paclitaxel group, n = 523)
- Weekly carboplatin at AUC = 2 and weekly paclitaxel at 80 mg/m² (weekly carboplatin/paclitaxel group, n = 521).
Patients could enter the trial after immediate primary surgery or with planned delayed primary surgery during chemotherapy or could have no planned surgery. In total, 89% of patients in each group were from the United Kingdom. Co-primary endpoints were progression-free survival and overall survival in the intention-to-treat population.
Key Findings
Median follow-up was 69 months (interquartile range [IQR] = 61–75 months) at database lock for final overall survival analysis.
Median overall survival was 47.4 months (95% confidence interval [CI] = 43.1–54.8 months) in the control group, 54.8 months (95% CI = 46.6–61.6 months) in the 3-weekly carboplatin/weekly paclitaxel group (hazard ratio [HR] = 0.87, 97.5% CI = 0.73–1.05, P = .092, vs control group), and 53.4 months (95% CI = 49.2–59.6 months) in the weekly carboplatin/paclitaxel group (HR = 0.91, 97.5% CI = 0.76–1.09, P = .24, vs control group).
In the updated progression-free survival analysis, median progression-free survival was 17.5 months (95% CI = 16.1–19.3 months), 20.1 months (95% CI = 17.9–22.0 months), and 20.1 months (95% CI = 17.8–22.1) in the three groups, respectively, with no significant differences observed between the dose-dense groups vs the control group. There was evidence of nonproportional hazards (P = .037), with subsequent restricted mean survival time analysis showing durations of 23.9 months (97.5% CI = 22.1–25.6 months), 25.3 months (97.5% CI = 23.6–27.1 months), and 24.8 months (97.5% CI = 23.0–26.5 months) in the three groups, respectively; no significant differences were observed between the dose-dense groups vs the control group.
As previously reported, grade 3 or 4 hematologic toxicity was more common among patients receiving the dose-dense regimens. Since the reporting of the primary progression-free analysis, no new serious adverse events were observed. Overall, treatment-related death occurred in one patient in the control group, four in the 3-weekly carboplatin/weekly paclitaxel group, and two in the weekly carboplatin/paclitaxel group.
The investigators concluded, “In our cohort of predominantly European women with epithelial ovarian cancer, we found that first-line weekly dose-dense chemotherapy did not improve overall or progression-free survival compared with standard 3-weekly chemotherapy and should not be used as part of standard multimodality front-line therapy in this patient group.”
Elizabeth C. James, MSc, of the MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia. For full disclosures of the study authors, visit thelancet.com.
