Objective responses to first-line neoadjuvant carboplatin–paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial

Robert D. Morgan, Iain A. McNeish, Adrian D. Cook, Elizabeth C. James, Rosemary Lord, Graham Dark, Rosalind M. Glasspool, Jonathan Krell, Christine Parkinson, Christopher J. Poole, Marcia Hall, Dolores Gallardo-Rincón, Michelle Lockley, Sharadah Essapen, Jeff Summers, Anjana Anand, Abel Zachariah, Sarah Williams, Rachel Jones, Kate ScatchardAxel Walther, Jae Weon Kim, Sudha Sundar, Gordon C. Jayson, Jonathan A. Ledermann, Andrew R. Clamp

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Background: Platinum-based neoadjuvant chemotherapy followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced-stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase 3 trials, evaluation of response to neoadjuvant chemotherapy using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and cancer antigen 125 (CA125) has not been reported. We describe RECIST and Gynecologic Cancer InterGroup (GCIG) CA125 responses in patients receiving platinum-based neoadjuvant chemotherapy followed by DPS in the ICON8 trial. 

Methods: ICON8 was an international, multicentre, randomised, phase 3 trial done across 117 hospitals in the UK, Australia, New Zealand, Mexico, South Korea, and Ireland. The trial included women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–2, life expectancy of more than 12 weeks, and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO; 1988) stage IC–IIA high-grade serous, clear cell, or any poorly differentiated or grade 3 histological subtype, or any FIGO (1988) stage IIB–IV epithelial cancer of the ovary, fallopian tube, or primary peritoneum. Patients were randomly assigned (1:1:1) to receive intravenous carboplatin (area under the curve [AUC]5 or AUC6) and intravenous paclitaxel (175 mg/m2 by body surface area) on day 1 of every 21-day cycle (control group; group 1); intravenous carboplatin (AUC5 or AUC6) on day 1 and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 2); or intravenous dose-fractionated carboplatin (AUC2) and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 3). The maximum number of cycles of chemotherapy permitted was six. Randomisation was done with a minimisation method, and patients were stratified according to GCIG group, disease stage, and timing and outcome of cytoreductive surgery. Patients and clinicians were not masked to group allocation. The scheduling of surgery and use of neoadjuvant chemotherapy were determined by local multidisciplinary case review. In this post-hoc exploratory analysis of ICON8, progression-free survival was analysed using the landmark method and defined as the time interval between the date of pre-surgical planning radiological tumour assessment to the date of investigator-assessed clinical or radiological progression or death, whichever occurred first. This definition is different from the intention-to-treat primary progression-free survival analysis of ICON8, which defined progression-free survival as the time from randomisation to the date of first clinical or radiological progression or death, whichever occurred first. We also compared the extent of surgical cytoreduction with RECIST and GCIG CA125 responses. This post-hoc exploratory analysis includes only women recruited to ICON8 who were planned for neoadjuvant chemotherapy followed by DPS and had RECIST and/or GCIG CA125-evaluable disease. ICON8 is closed for enrolment and follow-up, and registered with ClinicalTrials.gov, NCT01654146. 

Findings: Between June 6, 2011, and Nov 28, 2014, 1566 women were enrolled in ICON8, of whom 779 (50%) were planned for neoadjuvant chemotherapy followed by DPS. Median follow-up was 29·5 months (IQR 15·6–54·3) for the neoadjuvant chemotherapy followed by DPS population. Of 564 women who had RECIST-evaluable disease at trial entry, 348 (62%) had a complete or partial response. Of 727 women who were evaluable by GCIG CA125 criteria at the time of diagnosis, 610 (84%) had a CA125 response. Median progression-free survival was 14·4 months (95% CI 9·2–28·0; 297 events) for patients with a RECIST complete or partial response and 13·3 months (8·1–20·1; 171 events) for those with RECIST stable disease. Median progression-free survival for women with a GCIG CA125 response was 13·8 months (95% CI 8·8–23·4; 544 events) and 9·7 months (5·8–14·5; 111 events) for those without a GCIG CA125 response. Complete cytoreduction (R0) was achieved in 187 (56%) of 335 women with a RECIST complete or partial response and 73 (42%) of 172 women with RECIST stable disease. Complete cytoreduction was achieved in 290 (50%) of 576 women with a GCIG CA125 response and 30 (30%) of 101 women without a GCIG CA125 response. 

Interpretation: The RECIST-defined radiological response rate was lower than that frequently quoted to patients in the clinic. RECIST and GCIG CA125 responses to neoadjuvant chemotherapy for epithelial ovarian cancer should not be used as individual predictive markers to stratify patients who are likely to benefit from DPS, but instead used in conjunction with the patient's clinical capacity to undergo cytoreductive surgery. A patient should not be denied surgery based solely on the lack of a RECIST or GCIG CA125 response. 

Funding: Cancer Research UK, UK Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.

Original languageEnglish
Pages (from-to)277-288
Number of pages12
JournalThe Lancet Oncology
Volume22
Issue number2
Early online date22 Dec 2020
DOIs
Publication statusPublished - Feb 2021

Bibliographical note

Funding Information:
RDM declares personal fees and travel expenses from AstraZeneca, outside the submitted work. IAM declares personal fees from Carrick Therapeutics, Clovis Oncology, Roche, Scancell, and Tesaro, and personal fees and grants from AstraZeneca, outside the submitted work. RJ declares personal fees from Amgen, and personal fees and travel expenses from AstraZeneca, Clovis Oncology, and Tesaro, outside the submitted work. ML declares personal fees from Roche, outside the submitted work. AW declares personal fees from AstraZeneca and Roche, and personal fees and travel expenses from Tesaro, outside the submitted work. RMG declares personal fees from AstraZeneca, Clovis, GSK/Tesaro, Immunogen, and Sotio; travel or conference registration fees from AstraZeneca and GSK; and grants from Boehringer Ingelheim and Lilly/Ignyta, outside the submitted work. RMG is also a principal investigator for trials sponsored by AstraZeneca, GSK, Pfizer, Lilly, and Immunogen, outside the submitted work. SW declares personal fees and travel expenses from AstraZeneca, Clovis Oncology, and GSK, outside the submitted work. KS declares conference fees from GSK, outside the submitted work. ARC declares personal fees for AstraZeneca, Clovis Oncology, and GSK; research funding from AstraZeneca; and travel expenses from Clovis Oncology and Tesaro, outside the submitted work. All other authors declare no competing interests.

The trial was publicly funded by Cancer Research UK (CRUK) through the CRUK Clinical Trials Awards and Advisory Committee (C1489/A12127 and CA1489/A17092) and was supported by UK Medical Research Council core funding. The trial was also funded by the Irish Health Research Board, Irish Cancer Society, and Cancer Australia. The Medical Research Council was the trial sponsor and has delegated responsibility for the overall management of the ICON8 Trials Programme to the Medical Research Council Clinical Trials Unit at University College London (UK). The trial was part of the UK National Cancer Research Network portfolio. We acknowledge Experimental Cancer Medicine Centres and National Institute for Health Research Biomedical Research Centres for support at ICON8 centres in the UK. We thank all the women who participated in ICON8 and their families.

ASJC Scopus subject areas

  • Oncology

Fingerprint

Dive into the research topics of 'Objective responses to first-line neoadjuvant carboplatin–paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial'. Together they form a unique fingerprint.

Cite this