Perioperative chemotherapy improves survival in esophageal cancer

1. Among patients with resectable esophageal cancer, perioperative chemotherapy with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) resulted in improved survival compared to preoperative chemoradiotherapy.

2. Perioperative FLOT chemotherapy was also associated with higher incidence of adverse events than preoperative chemoradiotherapy.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Esophageal carcinoma is among the most common cancers with significant mortality risk and its incidence is increasing. Radical esophagectomy is the first-line treatment for nonmetastatic disease. However, the risks of post-resection recurrence and mortality are high with surgery alone. Both preoperative chemoradiotherapy and perioperative FLOT chemotherapy have become standard of care to improve survival outcomes. Nevertheless, whether one regimen is superior remains unclear. This trial compared perioperative FLOT chemotherapy against preoperative chemoradiotherapy (carboplatin and paclitaxel plus radiation) in addition to surgery in patients with resectable esophageal adenocarcinoma. By 3 years, perioperative chemotherapy was superior to preoperative chemoradiotherapy in overall survival and progression-free survival. The incidence of adverse events, including serious adverse events, occurred more frequently with perioperative chemotherapy. Mortality at 90 days after surgery was higher in the preoperative-chemoradiotherapy group. These results established perioperative FLOT chemotherapy as the superior regimen in treating esophageal carcinoma in addition to surgery. Further escalation of therapy with immunotherapy is being investigated. Whether preoperative chemoradiotherapy should be preferred in patients for whom FLOT is contraindicated remains unelucidated.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: This was a phase three, multi-center, unblinded, randomized trial comparing perioperative FLOT chemotherapy and preoperative chemoradiotherapy in addition to surgery in the treatment of resectable esophageal adenocarcinoma. Patients 18 years of age or older, who had confirmed esophageal adenocarcinoma with clinical stage of cT1 cN+, cT2-4a cN+, or cT2-4a cN0 without evidence of metastasis on imaging, were eligible for inclusion. In total, 438 patients were randomized 1:1 to receive either perioperative FLOT chemotherapy, consisting of four cycles of chemotherapy before surgery and four cycles after surgery, or preoperative chemoradiotherapy, consisting of 41.4 Gy radiotherapy and carboplatin plus paclitaxel chemotherapy. The primary outcome was overall survival by trial closure at 3 years.  The median follow-up was 55 months. Overall survival at three years was 57.4% in the perioperative-chemotherapy group (95% confidence interval [CI] 50.1-64.0) and 50.7% for the preoperative-chemoradiotherapy group (95% CI 43.5-57.5). Progression-free survival by 3 years was 51.6% (95% 44.3-58.4) in the perioperative-chemotherapy group and 35.0% (95% CI 28.4-41.7) in the preoperative-chemoradiotherapy group. Pathological complete response after surgery (defined as the absence of cancer in resected primary tumor and lymph nodes) was observed in 16.7% of patients in the perioperative-chemotherapy group and 10.1% in the preoperative-chemoradiotherapy group. Grade 3 or higher adverse events occurred in 58.0% of patients in the perioperative-chemotherapy group and 50.0% in the preoperative-chemoradiotherapy group; while serious adverse events occurred in 47.3% and 41.8%, respectively. The postoperative mortality rate was 3.1% in the perioperative-chemotherapy group and 5.6% in the preoperative-chemoradiotherapy group. Overall, these results provided robust evidence that perioperative FLOT chemotherapy was the superior regimen compared to preoperative chemoradiotherapy in addition to surgery in the treatment of resectable esophageal adenocarcinoma.

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