Prolonged and Intensified Neoadjuvant Therapy for Esophageal Adenocarcinoma


Key Points

  • In patients with esophageal adenocarcinoma, four cycles of neoadjuvant ECX did not significantly improve overall survival vs two cycles of CF.
  • Median overall survival was 26.1 vs 23.4 months, respectively.

A UK phase III trial (UK MRC OE05) has shown no significant survival benefit of extended and intensified neoadjuvant chemotherapy with epirubicin, cisplatin, and capecitabine vs standard cisplatin/fluorouracil followed by resection in patients with esophageal adenocarcinoma. The findings were reported in The Lancet Oncology by Alderson et al.

Study Details

In the open-label trial, 897 patients with stage cT1N1, cT2N1, cT3N0/N1, or cT4N0/N1 disease from 72 UK sites were randomized between January 2005 and October 2011 to receive 2 cycles of cisplatin and fluorouracil (CF; two 3-weekly cycles of cisplatin at 80 mg/m² on day 1 and fluorouracil at 1 g/m² per day on days 1–4; n = 451) or 4 cycles of epirubicin, cisplatin, and capecitabine (ECX; four 3-weekly cycles of epirubicin at 50 mg/m² and cisplatin at 60 mg/m² on day 1 and capecitabine at 1,250 mg/m² daily throughout the 4 cycles; n = 446) before surgery. Randomization was stratified by center and clinical disease stage. Two-phase esophagectomy with two-field (abdomen and thorax) lymphadenectomy was performed within 4 to 6 weeks of completion of adjuvant chemotherapy. The primary endpoint was overall survival in the intention-to-treat population.

Overall Survival

Median follow-up for surviving patients was 6.4 years. Median overall survival was 23.4 months in the CF group vs 26.1 months in the ECX group (hazard ratio [HR] = 0.90, P = .19). Overall survival at 3 years was 39% vs 42%. Median disease-free survival using a 6-month landmark analysis was 11.6 months vs 14.4 months (HR = 0.86, P = .051).

Adverse Events

No unexpected chemotherapy toxicity was observed. The most common grade 3 or 4 adverse event was neutropenia, observed in 17% of the CF group vs 23% of the ECX group (P = .023). Other grade 3 or 4 adverse events included diarrhea (1% vs 8%, P < .0001) and stomatitis (6% vs 2%, P = .0018). Serious adverse events occurred in 16% vs 24% (P = .003). Among patients with available data, postoperative complications occurred in 56% vs 62% (P = .089). One patient in the ECX group died of suspected treatment-related neutropenic sepsis. No statistically or clinically significant differences between the groups were observed in health-related quality of life in any prespecified domains of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 or the disease-specific esophageal module EORTC QLQ-OES18.

The investigators concluded: “Four cycles of neoadjuvant ECX compared with two cycles of CF did not increase survival and cannot be considered standard of care. Our study involved a large number of centres and detailed protocol with comprehensive prospective assessment of health-related quality of life in a patient population confined to people with adenocarcinomas of the oesophagus and gastro-oesophageal junction (Siewert types 1 and 2). Alternative chemotherapy regimens and neoadjuvant chemoradiation are being investigated to improve outcomes for patients with oesophageal carcinoma.”

The study was funded by Cancer Research UK and the Medical Research Council Clinical Trials Unit at the University College London.

David Cunningham, MD, of The Royal Marsden NHS Foundation Trust, is the corresponding author of The Lancet Oncology article. 

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