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
Menée à partir de données portant sur 1 566 femmes atteintes d'un carcinome de l'ovaire, des trompes de Fallope ou du péritoine et incluses dans un essai international de phase III, cette étude évalue l'efficacité, du point de vue du taux de réponse objective, d'un traitement comportant une chimiothérapie néoadjuvante à base de carboplatine et de paclitaxel et une intervention chirurgicale différée (durée médiane de suivi : 29,5 mois)
Background : Platinum-based neoadjuvant chemotherapy followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced-stage epithelialovarian cancer. Although this therapeutic approach has been validated in randomised,phase 3 trials, evaluation of response to neoadjuvant chemotherapy using ResponseEvaluation 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 Groupperformance 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-gradeserous, 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, orprimary peritoneum. Patients were randomly assigned (1:1:1) to receive intravenouscarboplatin (area under the curve [AUC]5 or AUC6) and intravenous paclitaxel (175mg/m 2 by body surface area) on day 1 of every 21-day cycle (control group; group 1); intravenouscarboplatin (AUC5 or AUC6) on day 1 and intravenous dose-fractionated paclitaxel (80mg/m 2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 2); or intravenousdose-fractionated carboplatin (AUC2) and intravenous dose-fractionated paclitaxel(80 mg/m 2 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 aminimisation method, and patients were stratified according to GCIG group, diseasestage, and timing and outcome of cytoreductive surgery. Patients and clinicians werenot masked to group allocation. The scheduling of surgery and use of neoadjuvant chemotherapy were determined by local multidisciplinary case review. In this post-hoc exploratoryanalysis of ICON8, progression-free survival was analysed using the landmark methodand defined as the time interval between the date of pre-surgical planning radiologicaltumour 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 whom779 (50%) were planned for neoadjuvant chemotherapy followed by DPS. Median follow-upwas 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 completeor partial response. Of 727 women who were evaluable by GCIG CA125 criteria at thetime of diagnosis, 610 (84%) had a CA125 response. Median progression-free survivalwas 14·4 months (95% CI 9·2–28·0; 297 events) for patients with a RECIST completeor partial response and 13·3 months (8·1–20·1; 171 events) for those with RECIST stabledisease. Median progression-free survival for women with a GCIG CA125 response was13·8 months (95% CI 8·8–23·4; 544 events) and 9·7 months (5·8–14·5; 111 events) forthose 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 172women 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 CA125response. 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 markersto stratify patients who are likely to benefit from DPS, but instead used in conjunctionwith 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.
The Lancet Oncology 2020