Perioperative chemotherapy is superior to neoadjuvant chemoradiotherapy in patients with resectable, locally advanced oesophageal cancer

Results of the phase III ESOPEC study, presented as a late breaking abstract during the plenary session of ASCO 2024, demonstrate that perioperative chemotherapy with docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil (FLOT protocol) leads to a significantly longer overall survival (OS) than neoadjuvant chemoradiation (CROSS protocol) in patients with resectable, locally advanced oesophageal cancer. While the FLOT regimen resulted in a median OS of 66 months, this was only 37 months with the CROSS schedule.

Background

The optimal treatment strategy for patients with resectable, locally advanced oesophageal cancer remains to be subject for debate. Available options include neoadjuvant chemoradiotherapy followed by surgery and perioperative chemotherapy in combination with surgery. The objective of the randomised, phase III ESOPEC study was to compare the impact of these two strategies on the overall survival of patients with resectable, locally advanced oesophageal cancer.

Study design

ESOPEC is a prospective multicentre study that enrolled 438 patients with oesophageal adenocarcinoma across 25 sites in Germany. Eligible patients were ≥18 years old, did not receive prior abdominal or thoracic radiotherapy, had an ECOG performance status of ≤2 and had an adequate organ function. Patients were also required to have pretreatment stage cT1N+, M0 or cT2-4a, N0/+, M0 disease. Patients in the study were randomly assigned (1:1) to be treated with the so-called FLOT or CROSS protocol. Patients in the FLOT arm received repeated doses of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel every 2 weeks over 4 neoadjuvant cycles 4-6 weeks prior to surgery, followed by an additional 4 cycles of adjuvant chemotherapy 4-6 weeks after discharge. In the CROSS arm, patients were treated with neoadjuvant radiation therapy (41.4 Gy) and concurrent chemotherapy with carboplatin and paclitaxel 4-6 weeks prior to surgery. The primary endpoint of ESOPEC was OS, with progression-free survival (PFS), postoperative pathological stage, postoperative complications, recurrence-free survival (RFS), and postsurgical quality of life as secondary study objectives.

Results

The baseline patient and disease characteristics were well-balanced between the two treatment arms. The median age of patients in the study was 63 years, 89% was male and about 80% had a clinical cT3-4 disease stage. About 4 out of 5 patients had nodal involvement. In the intent-to-treat (ITT) population, the FLOT regimen proved to be associated with a significantly better OS than CROSS, with a median of 66 and 37 months, respectively (HR[95%CI]: 0.70[0.53-0.92]; p= 0.012). At the 5-year landmark, this translated into an OS rate of 51.8% and 40.5% for FLOT and CROSS, respectively. The OS benefit obtained with FLOT was observed irrespective of sex, age, ECOG performance status, and clinical T or N stage.

The FLOT protocol also proved to be superior to CROSS in terms of PFS, with a median PFS of 38 and 16 months, respectively (HR[95%CI]: 0.66[0.51-0.85]; p= 0.001). At 5 years, 44.4% of patients who were treated with the FLOT protocol were alive and free of progression, while this was only the case for 30.9% with CROSS.

The rate of R0 resections was similar in both treatment arms at 94.2% with FLOT and 95.0% with CROSS. A pathological complete remission (ypT0ypN0) following surgery was obtained by 16.8% of patients in the FLOT group as compared to 10% in the CROSS group. The post-operative morbidity was similar in both treatment arms, while the 90-day post-operative mortality was slightly higher with CROSS (5.6%) than with FLOT (3.2%).

Conclusions

Perioperative chemotherapy (FLOT) plus surgery leads to a better OS than neoadjuvant chemoradiation (CROSS) plus surgery in patients with cT1cN+ and cT2-4a,cN-/+ M0 oesophageal adenocarcinoma. Of note, since the conception of ESOPEC, adjuvant immunotherapy following neoadjuvant chemoradiation has been introduced in the treatment of patients without a pathological complete response following neoadjuvant chemoradiation. In addition, organ preservation and active surveillance is gaining momentum in patients with a clinical complete response following chemoradiation. Further studies will be necessary to see whether these novel approaches also have an impact on the ESOPEC conclusions.

Reference

Hoeppner J, et al. Prospective randomized multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (ESOPEC trial). Presented at ASCO 2024, Abstract LBA1.