CHRONO: A randomized phase II trial of the chronology of surgery after neoadjuvant chemotherapy for ovarian cancer.

Abstract

5505 Background: In patients treated for advanced ovarian cancer not suitable for complete primary surgery, interval surgery after three courses of neoadjuvant chemotherapy (NAC) has been considered standard management since the EORTC randomized trial published in 2010 (NCT00003636, DOI: 10.1056/NEJMoa090880). Delaying surgery after six courses of NAC in highly chemosensitive patients amenable to complete surgery after 3 cycles remains controversial. CHRONO is a multicenter, randomized phase II trial addressing this question (NCT03579394). Methods: Patients treated for a stage IIIB-IVA high grade epithelial ovarian cancer by NAC and amenable to complete surgery after 3 cycles were randomized (1:1) to either complete surgery followed by 5 cycles of chemotherapy (control arm: C) or an additional 3 cycles of NAC followed by complete surgery then 2 cycles of chemotherapy (experimental arm: E). Maintenance treatment was administered according to standard of care. Primary endpoint was disease free survival (DFS) defined as the time from randomization until the date of disease progression or second cancer or death from any cause. The study was designed to detect an improvement in median (m) DFS from 10 months to 17 months (HR=0.59) with a 85% power and 2-sided α=0.05. Main secondary endpoints were Pathological complete response (CC0) rate, post operative morbidity and mortality, quality of life (QOL) and overall survival (OS). Results: Between 18/10/2018 and 23/04/2024, 209 patients (median age: 69 years) were randomized to arm C (n=103) or E (n=106). Median total number of cycles of NAC was 7 (5-9) and 8 (3-9) in arm C and E .CC0 rate was 83.2% vs 90%. After a median follow up of 40.4 months, mDFS was 20.2 months (95%CI: 18.2-23.6) in arm C vs 23.4 (19.0-30.4) in arm E (Log-rank test p=0.48, HR: 0.88 (95%CI: 0.63-1.24). The longitudinal analysis of QoL found no significant differences between the two arms, however, social functioning, insomnia, and sexuality showed a trend toward further improvement (≥5 points) in arm E. Major postoperative complication rates within 30 days were 5% and 11% in arm C and E, (p=0.11) , with no death within 30 days after surgery. Conclusions: CHRONO is the first randomized trial addressing the clinical impact of delayed surgery after 6 courses of NAC in first line treatment of advanced ovarian cancer. No statistically significant difference was shown between the two arms of the study considering DFS, severe morbidity, mortality or QoL. New trials are needed for a better understanding of this alternative to interval surgery in highly chemosensitive advanced ovarian cancer patients. Clinical trial information: NCT03579394 .