The phase III JCOG1109, NExT trial, aimed to confirm the superiority of docetaxel, cisplatin and 5-fluorouracil (DCF) or cisplatin plus 5-fluorouracil with chemoradiotherapy (CF+RT) over cisplatin plus 5-fluorouracil alone (CF) as preoperative therapy for squamous cell carcinoma of oesophagus. Results from the primary analysis demonstrated that neoadjuvant DCF, but not neoadjuvant CF+RT significantly improved overall survival over neoadjuvant CF, with a manageable toxicity.
Most patients with oesophageal cancer (EC) are diagnosed at an advanced stage. For patients with locally advanced EC, preoperative therapy followed by surgery is recommended, but the prognosis of these patients remains poor. According to the results of JCOG9907, neoadjuvant chemotherapy with cisplatin plus 5-fluorouracil (CF) is the current standard for locally advanced EC in Japan. JCOG1109, the NExT trial, is a three-arm phase III trial to confirm the superiority of docetaxel plus CF (DCF) and radiotherapy with CF (CF-RT) in overall survival over CF as neoadjuvant therapy. At ASCO GI 2022, the first results of the primary analysis were presented.
Eligible patients with oesophageal squamous cell cancer of clinical stage IB, II, III (excluding T4) (UICC 7th) from 44 institutions were randomised (1:1:1) to neoadjuvant CF (cisplatin 80 mg/m2 on day 1 plus 5-FU 800 mg/m2 on days 1-5 Q3W x 2 courses), DCF (docetaxel 70 mg/m2 on day 1, cisplatin 70 mg/m2 on day 1, plus 5-FU 750 mg/m2 on days 1-5 Q3W x 3 courses), or CF-RT (cisplatin 75 mg/m2 on day 1 plus 5-FU 1000 mg/m2 on days 1-4 Q4W x 2 courses, radiation 41.4 Gy/23 fr). All patients underwent transthoracic oesophagectomy with regional lymphadenectomy. Both minimal the invasive and open thoracic approach were acceptable. Primary endpoint was overall survival.
Of the 601 enrolled patients, 199 were randomised to CF, 202 to DCF and 200 to CF-RT. Of them, 88.2% of patients were male, median age was 65 years and 62.6% of patients were clinical stage III (nonT4). At data cut-off (July 20, 2021), the minimum follow-up was 36 months and approximately 85% of patients completed the scheduled protocol treatment in all three treatment arms. The neoadjuvant DCF arm showed superior OS as compared to neoadjuvant CF (HR[95% CI]: 0.68[0.50–0.92], stratified log-rank test: p= 0.006). Median OS in CF, DCF, and CF-RT arm were 5.6 years, not reached, and 7.0 years, and the corresponding 3-year OS rates were 62.6%, 72.1%, and 68.3%, respectively. As such, neoadjuvant CF+RT did not demonstrate superiority over neoadjuvant CF alone in terms of OS (HR[95% CI]: 0.84[0.63–1.12], stratified log-rank test: p= 0.12). The OS benefit of DCF over CF was however generally consistent across all evaluated subgroups. Median PFS was 2.7 years for CF and not reached for DCF (HR[95%CI]: 0.67[0.51-0.88]) with 3-year PFS rates of 47.7% and 61.8%, respectively. For CF+RT, the median PFS was 5.3 years with a 3-years PFS rate of 58.5% (HR[95%CI] as compared to CF: 0.77[0.59-1.01]).
During neoadjuvant therapy, febrile neutropenia in CF, DCF, and CF-RT arms was reported in 1.0%, 16.3% and 4.7% of patients, and oesophagitis (grade>3) in 1.0%, 1.0% and 8.9% of patients, respectively. R0 resection was achieved in respectively 168 (90.3%), 173 (94.5%), and 175 (98.9%) patients who underwent surgery. Furthermore, 2.2% of patients receiving CF, 18.6% of those receiving DCF and 36.7% of those treated with CF+RT who underwent surgery achieved a pathologic complete response. Importantly, intensive neoadjuvant chemotherapy did not increase the rate of post-operative complications or mortality. Treatment-related death was reported in 3.2%, 5.5% and 2.3% of all eligible patients in CF, DCF, and CF-RT arms, respectively. However, there were more deaths due to other diseases in the CF+RT arm (26.4%), as compared to the CF (11.6%) and DCF arm (8.2%).
Neoadjuvant DCF, but not neoadjuvant CF+RT significantly improved overall survival over neoadjuvant CF for locally advanced ESCC, with a manageable toxicity. Neoadjuvant DCF represents a new standard treatment for ESCC.
Kato K, Ito Y, Daiko H, et al. A randomized controlled phase III trial comparing two chemotherapy regimen and chemoradiotherapy regimen as neoadjuvant treatment for locally advanced esophageal cancer, JCOG1109 NExT study. Presented at ASCO GI 2022; Abstract 238.