Omission of lymphadenectomy in patients with advanced epithelial ovarian cancer treated with primary or interval cytoreductive surgery after neoadjuvant chemotherapy: The CARACO phase III randomized trial.

LBA5505 Background: Lion trial demonstrated the lack of benefit of retroperitoneal pelvic and paraaortic lymphadenectomy (RPPL) in primary surgery in advanced epithelial ovarian cancer (AEOC) with clinically negative lymph nodes. As a consequence, the question of RPPL during interval cytoreductive surgery after neoadjuvant chemotherapy remains open. Methods: CARACO was a prospective multi-institutional phase III trial including patients with newly diagnosed AEOC FIGO III-IV, with no pre- and intra-operative suspicious lymph nodes, randomized intra-operatively to RPPL versus no-RPPL, stratified by surgical strategy (primary surgery, surgery after neoadjuvant chemotherapy). The primary endpoint was progression free survival (PFS). The target sample size was 450 evaluable patients, providing 80% power at 5% alpha based on the hypothesis of a 5 years PFS of 41%. Results: Between December 2008 and March 2020, 379 patients were randomly assigned to RPPL (n=181) or no-RPPL (n=187), 11 patients were excluded. Our required sample size was not reached because of a stop of inclusion after the publication of the Lion trial. The median number of removed lymph nodes in patients randomized to RPPL was 27 [IQR=19-36]. 75% of the patients were treated with neoadjuvant chemotherapy (244 patients treated with 3 or 4 cycles before interval surgery and 41 patients treated with 6 cycles before delayed surgery) and 83 patients treated with primary surgery followed with adjuvant platinum-based chemotherapy. The rate of surgery with no residual was 86% and 88% respectively in the No RPPL and the RPPL arm. Lymph node metastases were diagnosed in 49% of the patients in the RPPL arm, with a median of 3 involved lymph nodes [IQR=2-7]. After a median follow up of 9 years, median PFS in the no-RPPL arm and in the RPPL arm was 14.8 months and 18.5 months respectively (HR 0.98, 95%CI 0.78-1.22, p=0.86). Median OS was not significantly different: 48.9 months and 58.0 months in the No RPPL and RPPL arm respectively (HR 0.96, 95%CI 0.75-1.22 p=0.72). Results considering progression free and overall survival were not different in the subgroup of patients with a complete surgery or a neoadjuvant chemotherapy. Serious post-operative complications occurred more frequently in the RPPL arm: re-laparotomies 8.3% vs 3.2% [p=0.03], transfusion rate (34% vs 25%, p=0.05). Mortality within 60 days after surgery was similar between arms (1.1 vs 0.5% [p=0.54]) respectively. Conclusions: CARACO trial is the first randomized trial showing that systematic lymphadenectomy should be omitted in AEOC with clinically negative lymph nodes also in patients undergoing neoadjuvant chemotherapy and interval complete surgery. This surgical de-escalation allows to significantly reduce serious post operative morbidity. Clinical trial information: NCT01218490 .