The lost evidence: A phase III, multicenter randomized controlled trial of neoadjuvant chemotherapy paclitaxel plus cisplatin versus surgery alone for stage IIA–IIIB esophageal squamous cell carcinoma.

4074 Background: The efficacy of neoadjuvant chemotherapy (NAC) vs primary surgery alone for treatment of locally advanced esophageal squamous cell carcinoma (ESCC) remain controversial between Western and Eastern countries. The daily NAC practice in China was without the high level evidence. The Esophageal Cancer Committee of the China Anti-Cancer Association tried to connect the the lost chain of evidence. To compare safety and long-term survival of NAC followed by surgery with that of surgery alone. Methods: A prospective, multicenter, open-label, randomized phase III clinical trial that compared safety and efficacy of NAC vs primary surgery for ESCC. From July 18, 2015, to March 29, 2018, we enrolled 605 clinical stage IB-III thoracic ESCC (excluding stage T4b, N3, 7th UICC-TNM staging, 2009). They were randomized to NAC plus surgery (group NAC; n=304) or primary surgery alone (group S; n=301). In group NAC, paclitaxel 175 mg/m2 intravenously (IV) and cisplatin 75 mg/m2 every 3 weeks for two cycles. All patients underwent McKeown, Ivor Lewis or minimally invasive esophagectomy and extended 2-field lymph node dissection. The primary outcome was 5-year overall survival (OS). Secondary outcomes included disease free survival (DFS), R0 resection rate, pathologic complete response rate and toxicities. The intention-to-treat principle was followed for analysis. The SPSS, version 23.0 (IBM Corp). The statistically significant was assumed as a 2-sided P< 0.05. The Kaplan-Meier method was used to calculate OS and DFS with the log-rank test. The last follow-up data was April 12, 2024. The 5-year OS of primary surgery was 30%. A 5-year survival with a 12% increase for the NAC group was assumed. The sample size was calculated with a two-sided alpha level of 5%, a power of 80%, an expectation of 2 years accruement and a 5-year followup period. The total sample size was set at 528 patients with 10% of patients lost to follow-up. Results: Among 605 patients (432 men [71.4%]; mean [SD] age, 61.7 [7.9] years; most frequent clinical stages IIIA 170 [30.2%]), Leukopenia (28%) and neutropenia (49.8%) were the most common grade 3 or 4 adverse events during NAC. Complications was similar between the 2 groups based on Clavien-Dindo classification. The 90-day perioperative mortality rate was 1.6% for the NAC group (4 of 244) and 2.2% for the Surgery alone group (6 of 268) ( P = 0.754). The pathologic complete response rate was 6.58% (20 of 304) in NAC group. NAC group had a higher R0 resection rate (98.8% v 98.5%; P > 0.999), a better 5 years OS rate (61.1% vs 51.6%; hazard ratio, 0.79; 95% CI, 0.63 to 1.0; P = 0.0469), and a prolonged DFS (58.5% vs 46.2% months; hazard ratio, 0.71; 95% CI, 0.56 to 0.91; P=0.0067). 0.71 (0.56,0.91). The max follow up period of NAC group was 110 months, S group 105 months. The median follow up period of NAC group was 79.4, whereas 55.2 in surgery group. Conclusions: This trial showed that NAC plus surgery improves survival over surgery alone among patients with locally advanced ESCC, with acceptable and manageable adverse events. Clinical trial information: NCT02395705 .