LUGANO-MADRID – European women with ovarian cancer can safely stick to the standard three-week dosing schedule for paclitaxel rather than boosting up to a weekly dose-dense regimen, according to results of the phase III ICON8 trial to be presented at the ESMO 2017 Congress in Madrid. (1)
“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, UK. “Therefore, this approach cannot be recommended as a standard-of-care treatment option for this population.”
But he added “it remains appropriate to continue to offer weekly dose-dense paclitaxel as a treatment option to Japanese women.”
The conflicting recommendations stem from the fact that findings from ICON8 contrast with those of JGOG3016, a previously reported study of Japanese ovarian cancer patients which 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. (2)
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.
In terms of toxicity, there was 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.
Noting that the study was “robust and appropriately powered”, 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. 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.”
Commenting for ESMO, Dr. Domenica Lorusso, from Fondazione IRCCS National Cancer Institute of Milan, Chair of the Gynaecological Tumours track at ESMO 2017, said: “The trial confirms that carboplatin-paclitaxel every 3 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. According to the Tokyo’s 5th Ovarian Consensus conference standard options to be discussed with the patients for first-line ovarian cancer treatment include carboplatin-paclitaxel every 3 weeks, as well as the dose-dense schedule (at least in the Japanese populations)."
The trial was funded by Cancer Research UK, and coordinated by the MRC Clinical Trials Unit at UCL.
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Notes to Editors
Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress
References
- Abstract 929O_PR ‘ICON8: A GCIG Phase III randomised trial evaluating weekly dose- dense chemotherapy integration in first-line Epithelial Ovarian/ Fallopian Tube/ Primary Peritoneal Carcinoma (EOC) treatment: Results of Primary Progression- Free Survival (PFS) analysis’ will be presented by Dr Clamp during Proffered Papers Session ‘Gynaecological cancers’ on Friday, 8 September 2017, 16:00 to 17:30 (CEST), in Cordoba Auditorium.
- Katsumata et al. Lancet 2009/ Lancet Oncol 2013.
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Abstract 929O_PR
ICON 8: A GCIG Phase III randomised trial evaluating weekly dose- dense chemotherapy integration in first-line Epithelial Ovarian/ Fallopian Tube/ Primary Peritoneal Carcinoma (EOC) treatment: Results of Primary Progression- Free Survival (PFS) analysis
A.R. Clamp1, I. McNeish2, A. Dean3, D. Gallardo4, J. Weon- Kim5, D. O'Donnell6, J. Hook7, C. Coyle8, S.P. Blagden9, J. Brenton10, R. Naik11, T. Perren12, S. Sundar13, A. Cook8, E. James14, A.M. Swart15, S. Stenning8, R. Kaplan16, J. Ledermann17
1Medical Oncology, The Christie NHS Foundation Trust and University of Manchester, Manchester/UNITED KINGDOM, 2Institute Of Cancer Sciences, University of Glasgow, Glasgow/UNITED KINGDOM, 3Oncology, St John of God Hospital, Subiaco/AUSTRALIA, 4Clinical Oncology, Instituto Nacional de Cancerologia, Mexico/MEXICO, 5Obstetrics And Gynaecology, Seoul National University Hospital, Seoul/KOREA, REPUBLIC OF, 6Department Of Medical Oncology, St James's Hospital, Dublin/IRELAND, 7Oncology, St. James's University Hospital Leeds, Leeds/UNITED KINGDOM, 8Mrc Clinical Trials Unit, Institute of Clinical Trials and Methodology-UCL, London/UNITED KINGDOM, 9Early Phase Clinical Trials Unit, Churchill Hospital University of Oxford, Oxford/UNITED KINGDOM, 10Cruk-ci, Li Ka Shing Centre, Cancer Research UK, Cambridge Research Institute Addenbrooke's Hospital, Cambridge/UNITED KINGDOM, 11Northern Gynaecology Oncology Centre, Queen Elizabeth Hospital, Gateshead/UNITED KINGDOM, 12Leeds Institute Of Cancer And Pathology, St. James's University Hospital Leeds, Leeds/UNITED KINGDOM, 13Pan- Birmingham Gynaecological Cancer Centre, University of Birmingham, Birmingham/UNITED KINGDOM, 14Statistics, Institute of Clinical Trials and Methodology-UCL, London/UNITED KINGDOM, 15Norwich Clinical Trials Unit, University of East Anglia, Norwich/UNITED KINGDOM, 16Mrc Clinical Trials Unit, University College London, London/UNITED KINGDOM, 17Cancer Research UK & UCL Cancer Trials Centre, UCL Cancer Institute, London/UNITED KINGDOM
Background: 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.
Methods: 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.
Results: 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).
Conclusions: 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
Keywords: ovarian cancer, dose-dense chemotherapy, neoadjuvant chemotherapy
Funding: Cancer Research UK; Medical Research Council
Disclosure: All authors have declared no conflicts of interest.