{"title":"Neoadjuvant Chemoradiation (CROSS) vs. Perioperative Chemotherapy (FLOT) in Esophageal Adenocarcinoma (EAC): ESOPEC – a Randomised Controlled Prospective Multicentre Phase III Trial","authors":"","doi":"10.1016/j.ijrobp.2024.08.020","DOIUrl":null,"url":null,"abstract":"<div><h3>Purpose/Objective(s)</h3><div>When designing the ESOPEC trial, the CROSS (C) regimen provided the highest level of evidence of neoadjuvant therapy for both, squamous cell (ESCC) and EAC. During recruitment into ESOPEC, the FLOT(F)-4 trial identified perioperative 5-fluorouracil, leucovorin (L), oxaliplatin (O) and docetaxel (T) as best evidence of chemotherapy. The ESOPEC trial aimed to compare the two protocols exclusively in EAC and hypothesized F to be superior to C.</div></div><div><h3>Materials/Methods</h3><div>Included were patients with cM0 EAC staged cT1 N+ or cT2-4a, cN0/+. C was the control arm with 41.4 Gy in 23 fractions and 5 weekly simultaneous doses of carboplatin (2 mg/ml/min AUC) and paclitaxel [(50 mg/m²); CP]. GTV and PTV were defined as described by Matzinger et al. (doi: 10.1016/j.radonc.2009.03.018). F was the experimental arm with 5-fluorouracil 2600 mg/m² (24 hours), d1 L 200 mg/m², d1 O 85 mg/m², d1 T 50mg/m2, d1 every two weeks (q2w); 4 neoadjuvant cycles (8 weeks) prior to surgery and 4 adjuvant cycles (8 weeks) postoperatively. Esophagectomy was done 4-6 weeks after neoadjuvant therapies. Primary endpoint was overall survival (OS), secondary endpoints were progression free survival (PFS), ypTNM stage, tumor regression grading, recurrence free survival (RFS) in patients with R0/R1 resection, site of tumor recurrence, postoperative complications, adverse events, and quality of life. Sample size calculation was based on 1-sided significance level of 2.5% and 90% power assuming a hazard ratio (HR) of 0.645 with respect to OS, and required 218 death events (438 patients). Prospectively documented chemoradiotherapy specific variables consisted in administered percentage of planned chemo- and radiotherapy, adherence to target volume definitions, doses to organs at risk, specifically heart and lungs.</div></div><div><h3>Results</h3><div>From 2/16 to 4/20, 438 patients were randomized to C (217) and F (221), intention-to-treat population (ITT). Characteristics were well balanced with mean age of 63 years, 89.3% males, 73.9% cT3, 6.7% cT4, 79.7% cN+. Neoadjuvant treatment was started in 90.3% (196) vs 93.7% (207) in C vs F (per-protocol-population (PP)). In PP, full RT dose was given in 98.0% (192); 75.0% (147), 18.9% (37) and 6.1% (12) had 5, 4 or <4 cycles of CP. In ITT, surgery rates were C 82.9% (180) vs F 86.4% (191). In 371 patients with surgery, local pCR rates were 13.3% (C) vs 18.3% (F), and near CR rates 39.4% (C) vs 25.1% (F). In 368 patients with R0/R1 resection, 3-year RFS after surgery was 36.5% (C) and 52.8% (F), median RFS was 17 (C) vs 43 (F) months (HR 0.68 [0.51 – 0.90]; p = 0.0076). Postoperative morbidity was comparable. In ITT, 3-year-OS was 50.7% (C) and 57.4% (F), and median OS was 37 (C) vs 66 (F) months (HR 0.70 [0.53 – 0.92]; p = 0.012).</div></div><div><h3>Conclusion</h3><div>Both C and F were well tolerated. OS was superior after F vs C, and F should be preferred over C. Posthoc limitations of C were: baseline FDG-PET/CT not mandatory and absence of additive immunotherapy.</div></div>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":null,"pages":null},"PeriodicalIF":6.4000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Radiation Oncology Biology Physics","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0360301624032450","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose/Objective(s)
When designing the ESOPEC trial, the CROSS (C) regimen provided the highest level of evidence of neoadjuvant therapy for both, squamous cell (ESCC) and EAC. During recruitment into ESOPEC, the FLOT(F)-4 trial identified perioperative 5-fluorouracil, leucovorin (L), oxaliplatin (O) and docetaxel (T) as best evidence of chemotherapy. The ESOPEC trial aimed to compare the two protocols exclusively in EAC and hypothesized F to be superior to C.
Materials/Methods
Included were patients with cM0 EAC staged cT1 N+ or cT2-4a, cN0/+. C was the control arm with 41.4 Gy in 23 fractions and 5 weekly simultaneous doses of carboplatin (2 mg/ml/min AUC) and paclitaxel [(50 mg/m²); CP]. GTV and PTV were defined as described by Matzinger et al. (doi: 10.1016/j.radonc.2009.03.018). F was the experimental arm with 5-fluorouracil 2600 mg/m² (24 hours), d1 L 200 mg/m², d1 O 85 mg/m², d1 T 50mg/m2, d1 every two weeks (q2w); 4 neoadjuvant cycles (8 weeks) prior to surgery and 4 adjuvant cycles (8 weeks) postoperatively. Esophagectomy was done 4-6 weeks after neoadjuvant therapies. Primary endpoint was overall survival (OS), secondary endpoints were progression free survival (PFS), ypTNM stage, tumor regression grading, recurrence free survival (RFS) in patients with R0/R1 resection, site of tumor recurrence, postoperative complications, adverse events, and quality of life. Sample size calculation was based on 1-sided significance level of 2.5% and 90% power assuming a hazard ratio (HR) of 0.645 with respect to OS, and required 218 death events (438 patients). Prospectively documented chemoradiotherapy specific variables consisted in administered percentage of planned chemo- and radiotherapy, adherence to target volume definitions, doses to organs at risk, specifically heart and lungs.
Results
From 2/16 to 4/20, 438 patients were randomized to C (217) and F (221), intention-to-treat population (ITT). Characteristics were well balanced with mean age of 63 years, 89.3% males, 73.9% cT3, 6.7% cT4, 79.7% cN+. Neoadjuvant treatment was started in 90.3% (196) vs 93.7% (207) in C vs F (per-protocol-population (PP)). In PP, full RT dose was given in 98.0% (192); 75.0% (147), 18.9% (37) and 6.1% (12) had 5, 4 or <4 cycles of CP. In ITT, surgery rates were C 82.9% (180) vs F 86.4% (191). In 371 patients with surgery, local pCR rates were 13.3% (C) vs 18.3% (F), and near CR rates 39.4% (C) vs 25.1% (F). In 368 patients with R0/R1 resection, 3-year RFS after surgery was 36.5% (C) and 52.8% (F), median RFS was 17 (C) vs 43 (F) months (HR 0.68 [0.51 – 0.90]; p = 0.0076). Postoperative morbidity was comparable. In ITT, 3-year-OS was 50.7% (C) and 57.4% (F), and median OS was 37 (C) vs 66 (F) months (HR 0.70 [0.53 – 0.92]; p = 0.012).
Conclusion
Both C and F were well tolerated. OS was superior after F vs C, and F should be preferred over C. Posthoc limitations of C were: baseline FDG-PET/CT not mandatory and absence of additive immunotherapy.
期刊介绍:
International Journal of Radiation Oncology • Biology • Physics (IJROBP), known in the field as the Red Journal, publishes original laboratory and clinical investigations related to radiation oncology, radiation biology, medical physics, and both education and health policy as it relates to the field.
This journal has a particular interest in original contributions of the following types: prospective clinical trials, outcomes research, and large database interrogation. In addition, it seeks reports of high-impact innovations in single or combined modality treatment, tumor sensitization, normal tissue protection (including both precision avoidance and pharmacologic means), brachytherapy, particle irradiation, and cancer imaging. Technical advances related to dosimetry and conformal radiation treatment planning are of interest, as are basic science studies investigating tumor physiology and the molecular biology underlying cancer and normal tissue radiation response.