Recurrence patterns in the prospective, randomized, controlled, multicenter phase III ESOPEC trial comparing perioperative chemotherapy with preoperative chemoradiotherapy in patients with esophageal adenocarcinoma.

4014 Background: The ESOPEC trial (NCT02509286) showed that perioperative chemotherapy improved overall and progression free survival in pts with esophageal adenocarcinoma (EAC) compared with preoperative chemoradiotherapy. Understanding of the pattern of recurrence is important for the development of more effective future treatment strategies. Methods: Pts with cT1 cN+ cM0 or cT2-4a cNany cM0 EAC undergoing preoperative chemotherapy with FLOT (5-FU/leucovorin/oxaliplatin/docetaxel) or preoperative chemoradiotherapy with CROSS (41.4Gy/carboplatin/paclitaxel) plus tumor resection from the ESOPEC trial were eligible. Recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and patterns of local, regional and distant recurrence were analyzed. Treatment groups were compared with respect to sites of recurrence by calculating 3-year cumulative incidences considering competing events, and by Cox regression models for event-specific hazards stratified by trial center and including treatment assignment (FLOT vs CROSS), cN stage (cN0 vs cN+), and age as covariates. Event-specific hazard ratios (HR) with two-sided 95% confidence intervals (CI) and p-values are presented. Results: Of the 438 pts enrolled in ESOPEC, 192 of 221 (86.9%) in the FLOT group and 179 of 217 (82.5%) in the CROSS group underwent tumor resection and represent the population for this analysis. R0 resection was achieved in 354 pts (182 (94.8%) FLOT; 172 (96.1%) CROSS). 142 (74.0%) pts in FLOT received postoperative chemotherapy. After a median follow-up of 56 months 178 pts had disease recurrence (81 FLOT; 97 CROSS), and 28 pts died without recurrence (12 FLOT; 16 CROSS). The 3-year RFS rate was 54.5% in FLOT vs 39.0% in CROSS (HR for recurrence or death 0.67; 95% CI, 0.51 - 0.89, p = 0.005). The 3-year DMFS rate was 57.6% in FLOT vs 41.0% in CROSS (HR for distant recurrence or death 0.64; 95% CI, 0.48 – 0.85, p = 0.002). Conclusions: Perioperative chemotherapy with FLOT improves RFS and DMFS compared to preoperative chemoradiotherapy with CROSS in EAC. The prognosis of pts is determined by distant recurrence, which is less common after FLOT than CROSS. Clinical trial information: NCT02509286 . Treatment group comparisons regarding site of recurrence. Site of recurrence FLOTN=192 CROSSN=179 FLOT vs CROSS N (%)* N (%)* HR(for recurrence) 95% CI P-value Locoregional 39 (20.2) 32 (17.4) 1.00 0.62 – 1.61 0.99 Local 19 (9.5) 15 (8.1) 1.03 0.51 – 2.06 0.94 Regional 29 (15.1) 27 (14.5) 0.89 0.52 – 1.52 0.68 Distant 64 (31.5) 89 (47.2) 0.59 0.43 – 0.82 0.002 Distant lymphatic 21 (9.3) 31 (15.6) 0.60 0.34 – 1.05 0.074 Hematogenous 33 (17.2) 48 (26.1) 0.59 0.37 – 0.92 0.021 Pleural/Peritoneal 24 (12.0) 31 (16.4) 0.63 0.36 – 1.09 0.10 *% calculated as 3-year cumulative incidence.