For several decades, standard first-line chemotherapy for EOC has been carboplatin (C) and paclitaxel (T), administered 3-weekly (q3w). The JGOG3016 trial reported clinically significant lengthening of PFS and overall survival in Japanese women using dose-dense weekly (q1w) T but with increased toxicity. ICON8 is a 3-arm trial, comparing standard q3w CT with dose-dense q1w regimens in a predominantly European patient group.
Eligible women with FIGO stage IcG3- IV EOC were randomised 1:1:1 to Arm 1 (standard) - q3w C AUC5/6 + q3w T 175mg/m2; Arm 2 - q3w C AUC5/6 + q1w T 80mg/m2; Arm 3 - q1w C AUC2 + q1w T 80 mg/m2. Patients entered ICON8 after immediate primary surgery (IPS), or received neo-adjuvant chemotherapy with planned delayed primary surgery (DPS). Primary intention to treat analysis compared arm 2v1 and arm 3v1 using methods for data with non-proportional hazards.
1566 women were randomised Jun 2011-Nov 2014. Median age- 62 years, 72% serous histology, 93% ECOG performance status 0/1. 48% had IPS, 50% planned DPS, 2% inoperable. 72%, 60%, 63% completed 6 cycles protocol-defined treatment in arms 1, 2, 3. Completion rate for 6 cycles platinum was 88% (90%; 89%; 85%). Paclitaxel dose-intensification was achieved (median total dose T (mg/m2)-1011; 1234; 1274). Grade (G) 3/4 toxicity (predominantly uncomplicated low neutrophils) was seen in 42%; 63%; 53% patients. Incidence of G3/4 febrile neutropenia (4%; 6%; 3%) and ≥G2 sensory neuropathy (28%; 25%; 23%) were similar across arms. At Feb 2017, 64% patients had experienced disease progression. No significant increase in PFS was observed with either weekly treatment (log-rank arm 2v1 p = 0.45; arm 3v1 p = 0.56, non-proportionality p = 0.02, restricted mean survival time=24.4; 24.9; 25.3 months in arms 1, 2, 3, median PFS- 17.9; 20.6; 21.1months, HR = 0.92 arm 2v1, HR = 0.94 arm 3v1).
Although weekly dose-dense chemotherapy can be delivered successfully as first-line EOC treatment without substantial toxicity increase, it does not significantly improve PFS compared to standard 3-weekly CT.
Clinical trial identification
ISRCTN: ISRCTN10356387 EUDRACT: 2010-022209-16 CTA: 2010-022209-16 ENGOT: OV-13 MREC: 11/LO/0043
Legal entity responsible for the study
Medical Research Council Clinical Trials Unit at University College London
Cancer Research UK; Medical Research Council
All authors have declared no conflicts of interest.