A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma.

BACKGROUND We conducted a prospective randomized controlled trial comparing surgery alone (S) with concurrent chemoradiotherapy followed by surgery (CRT-S) for resectable esophageal squamous cell carcinoma (SCC) based on our previous report. PATIENTS AND METHODS One hundred and one patients with stage II/III esophageal SCC were randomized to receive either S (50 patients) or CRT-S (51 patients). The chemoradiotherapy (CRT) consisted of cisplatin 60 mg/m(2) intravenously (i.v.) on day 1, 5-fluorouracil (5-FU) 1000 mg/m(2) i.v. on days 2-5, cisplatin 60 mg/m(2) i.v. on day 22 combined with radiation therapy (45.6 Gy, 1.2 Gy b.i.d. on days 1-28). Surgery was performed 3-4 weeks after radiotherapy was completed. For patients with disease that was stable or responsive to CRT, three additional cycles of chemotherapy (cisplatin 60 mg/m(2) i.v. on day 1, 5-FU 1000 mg/m(2) on days 2-5 every 4 weeks) were given after surgical resection. RESULTS The median age was 62 years. The toxicity of CRT was acceptable and did not affect the post-operative morbidity and the duration of hospital stay. Clinical response was 86% including 21% of complete response (CR) rate. Pathological CR was achieved in 43% [95% confidence interval (CI) 27-59] of the patients who underwent surgery after CRT. At a median follow-up of 25 months, median overall survival (OS) was 27.3 months in S and 28.2 months in CRT-S (P = 0.69). Event-free survival (EFS) at 2 years was 51% in S and 49% in CRT-S (P = 0.93). This trial, which was statistically powered to detect a relatively large difference in 2-year survival rate from 30% to 50% with 80% power, was discontinued at interim analysis because of the unexpectedly high drop-out rate for esophagectomy (31%) and resultant excessive locoregional failure rate in CRT-S arm (22% versus 12%, P = 0.31), though it was not statistically significant. CONCLUSION Although preoperative CRT induced high clinical and pathological response, there was no statistically significant benefit in OS and EFS.