Neoadjuvant Chemoradiation Elicits Select Response Benefits in ESCC

Although no significant differences in survival emerged between neoadjuvant chemoradiotherapy (NCRT) and adjuvant therapy among patients with esophageal squamous cell carcinoma (ESCC), responders to NCRT may experience improved outcomes, according to findings from a prospective, randomized, open-label phase 3 trial (NCT06775652) published in JAMA Network Open.¹

After a median follow-up of 59.1 months (IQR, 54.4-65.9) among survivors, a Kaplan-Meier analysis revealed that no significant differences emerged among patients treated with NCRT (n = 118) or adjuvant therapy (n = 112) in terms of overall survival (OS; HR, 1.01; 95% CI, 0.67-1.51; P = .97) or disease-free survival (DFS; HR, 1.13; 95% CI, 0.77-1.68; P = .53).The 1-year OS rates in the respective arms were 90.7% (95% CI, 85.8%-96.1%) and 88.4% (95% CI, 82.7%-94.5%), the 3-year rates were 64.4% (95%CI, 56.3%-73.7%) and 67.0% (95% CI, 58.8%-76.3%), and the 5-year rates were 59.2% (95% CI, 51.0%-68.8%) and 59.6% (95% CI, 51.2%-69.5%). Moreover, the 1-, 3-, and 5-year DFS rates were 75.0% (95% CI, 67.5%-83.3%) vs 82.4% (95% CI, 75.5%-89.9%), 57.7% (95% CI, 49.3%-67.4%) vs 60.2% (95% CI, 51.6%-70.2%), and 53.1% (95% CI, 44.7%-63.1%) vs 56.5% (95% CI, 47.9%-66.7%), respectively.

Among patients who achieved a pathologic complete response (pCR) and patients who did not, significant differences were noted in OS (HR, 0.39; 95% CI, 0.18-0.82; P = .01) and DFS (HR, 0.50; 95% CI, 0.26-0.97; P = .04). The 1-, 3-, and 5-year OS rates were 97.1% (95% CI, 91.5%-100%) vs 88.1% (95% CI, 81.4%-95.3%), 79.4% (95% CI, 66.9%-94.2%) vs 58.3% (95% CI, 48.7%-69.9%), and 76.5% (95% CI, 63.5%-92.1%) vs 52.1% (95% CI, 42.4%-64.1%) in the pCR and non-pCR groups, respectively. The respective 1-, 3-, and 5-year DFS rates were 91.2% (95% CI, 82.1%-100%) vs 68.3% (95% CI, 58.9%-79.1%), 73.5% (95% CI, 60.1%-90.0%) vs 51.0% (95% CI, 41.3%-63.1%), and 67.6% (95% CI, 53.6%-85.3%) vs 46.8% (95% CI, 37.0%-59.2%).

“This randomized clinical trial demonstrated that NCRT followed by surgery and surgery with [adjuvant therapy] yielded comparable long-term survival outcomes in patients with locally advanced ESCC. The safety profile was comparable between the 2 groups, with no significant differences in postoperative complications or perioperative mortality,” Wenwu He, MD, PhD, of the Department of Thoracic Surgery at the Sichuan Clinical Research Center for Cancer in Chengdu, China, wrote in the publication with study coinvestigators.¹ “Whether given before or after surgery, the therapeutic goal is complete local tumor removal and effective control of micrometastatic disease. NCRT did not benefit all patients; for those unlikely to respond, surgery followed by [adjuvant therapy] remains a valid option. Therefore, universal endorsement of NCRT is not necessarily appropriate.”

The study was conducted at the Sichuan Cancer Hospital in China between January 2018 and April 2020. Patients 18 to 75 years old with histologically confirmed, resectable, locally advanced disease were randomly assigned 1:1 to receive NCRT followed by surgery or surgery followed by adjuvant therapy. All patients underwent a pretreatment workup, and for those with upper thoracic tumors, a bronchoscopy was performed with optional PET-CT.

In the investigational group, patients received paclitaxel at 135 mg/m² and carboplatin at area under the curve 2 to 5 for two 3-week cycles in addition to concurrent intensity-modulated radiotherapy (IMRT) at 40 Gy over 20 fractions for a gross tumor volume of 44 Gy. In the adjuvant group, surgery was performed after random assignment, followed by adjuvant therapy based on multidisciplinary team recommendation based on pathological staging. Adjuvant therapy was initiated 1 month after surgery and used the same regimen as NCRT.

In the NCRT and adjuvant therapy arms, 86.4% vs 86.6% of patients were male, and the median age was 62 years (IQR, 54-66) vs 63 years (IQR, 55-66). Tumors were typically located in the middle esophagus (60.2% vs 49.1%), and most patients had stage T3 disease (72.0% vs 67.0%). In the NCRT group, 85.6% of patients underwent 2 cycles of treatment, and 48.9% of patients received 2 cycles of chemotherapy in the adjuvant group.

The primary end point of the trial was OS. Secondary end points included DFS, adverse effects (AEs), R0 resection rate, and pCR rate.²

Similar AE patterns emerged between the 2 treatment arms, with non-significant differences in hematologic AEs. The incidence of any-grade leukopenia was 86.4% in the NCRT group vs 78.6% in the adjuvant therapy group (P = .17), and the incidence of any-grade neutropenia was 68.6% vs 56.3% (P = .14). Grade 3 or 4 leukopenia occurred in 35.6% vs 26.2% of each group (P = .17); grade 3 or 4 neutropenia occurred in 32.2% vs 23.3% (P = .14).

The NCRT group experienced significantly higher incidences of any-grade anorexia, at 53.4% vs 34.0% (P = .01), and vomiting, at 22.0% vs 9.7% (P = .04) vs the adjuvant therapy group. A significant difference was also observed in rates of anemia, at 3.4% vs 1.0% in the respective groups (P = .01).

References

1. He W, Li Z, Xie Q, et al. Long-term survival outcomes of NCRT with surgery vs surgery with adjuvant therapy for ESCC: a single-center prospective phase 3 randomized clinical trial. JAMA Netw Open. 2026;9(1):e2550307. doi:10.1001/jamanetworkopen.2025.50307
2. Neoadjuvant chemoradiotherapy plus surgery vs. surgery plus adjuvant therapy for ESCC (ESCC). ClinicalTrials.gov. Updated January 15, 2025. Accessed January 7, 2026. https://tinyurl.com/3m2rncu4